The Oncologist

Phase I study of bevacizumab and temsirolimus combination therapy in advanced malignancies: safety, efficacy, and ovarian cancer expansion

Abstract Background Bevacizumab and temsirolimus target angiogenic and mTOR pathways in cancer progression. Methods This phase I study enrolled 48 heavily pretreated patients with advanced solid tumors, including an ovarian cancer expansion cohort. Patients received bevacizumab biweekly plus temsirolimus weekly in a 3 + 3 design to assess safety, maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Exploratory analyses included tumor genomic profiling and dynamic contrast-enhanced MRI (DCE-MRI). Results Patients had a median age of 59 and median four prior therapies. Common tumor types were ovarian (27%) and head and neck (15%). Treatment-related adverse events occurred in 93.8%, with 31.3% ≥grade 3. Five patients experienced DLTs, including grade 3 enteritis, fatigue, bowel obstruction/abdominal ileus/pulmonary embolism, bowel perforation and grade 3/4 elevated liver enzymes. MTD was bevacizumab 10 mg/kg biweekly plus temsirolimus 20 mg weekly. Overall, objective response rate (ORR) was 7.3% and 19.5% achieved stable disease ≥6 months (clinical benefit rate [CBR] 26.8%). In ovarian cohort, ORR was 16.7% and CBR 33.3%. Patients with tumor regression on DCE-MRI had lower ΔKtrans values. Conclusion Combination therapy showed acceptable safety and modest activity. Molecular and imaging findings were exploratory and limited. These preliminary observations could inform future biomarker studies. (ClinicalTrials.gov Identifier: NCT01552434)

Treatment response after chemoradiation with an external beam radiation therapy boost in cervical cancer patients in Rwanda

Abstract Background Cervical cancer remains a significant public health burden in Rwanda, where brachytherapy is not widely available. This study assessed treatment response in cervical cancer patients post-chemoradiation using magnetic resonance imaging (MRI)-based Response Evaluation Criteria in Solid Tumors (RECIST), focusing on the effectiveness of external beam boost as an alternative. Patients and Methods This retrospective study was conducted at the Rwanda Cancer Centre, including patients treated with chemoradiation followed by an external beam boost from January 2020 to June 2022. MRI scans performed before treatment and 3-6 months post-treatment were analyzed using RECIST criteria to classify treatment response as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Agreement between clinical and MRI staging pre- and post-treatment was assessed using kappa coefficients. Results Eighty-eight patients were included (mean age: 57.7 ± 10.6 years). CR, PR, SD, and PD were observed in 67%, 17%, 9%, and 7% of patients, respectively. MRI findings demonstrated substantial agreement with clinical staging before pre-treatment (78%, K = 0.63) and after post-treatment (71%, K = 0.71). CR rates were highest in early-stage disease (FIGO stage I: 90%), whereas PD was more frequent in advanced stages (FIGO stage II: 9%; FIGO stage III: 13%). Conclusion The MRI-based RECIST criteria effectively assess the cervical cancer treatment response after post-chemoradiation. The high CR rate (67%) suggests that an external beam boost may serve as a viable alternative for brachytherapy. However, PD in advanced-stage disease highlights the need for further research to optimize treatment strategies. Future studies should evaluate long-term outcomes and explore advanced MRI techniques to enhance the response assessment.

Tumor Evolution in a Patient with Recurrent Endometrial Cancer and Synchronous Neuroendocrine Cancer and Response to Checkpoint Inhibitor Treatment

Abstract Both metachronous and synchronous tumors pose a diagnostic and clinical challenge, more so when one of the specimens demonstrates the rare neuroendocrine histology. We describe a patient with sarcoidosis who was treated for endometrial and ovarian neoplasm, recurred with two separate histologies (adenocarcinoma and high grade neuroendocrine), both associated with microsatellite instability (MSI)-high status. Targeted next-generation sequencing of tumor with synonymous somatic alterations pointed to a common ancestry of all three tumors and patient was successfully treated with a tailored immunotherapy regimen. Her sarcoidosis worsened only slightly, and immunotherapy did not need to be discontinued. This case highlights the importance of molecular testing for the optimal therapy of complex synchronous tumors and the need for communication between surgical and medical oncologists in patients with MSI-high cancer. Key Points The case of a patient with a recurrent gynecological cancer presenting as microsatellite instability (MSI)-high endometrial adenocarcinoma and MSI-high neuroendocrine tumor is reported. This case demonstrated a common genetic lineage with good response to checkpoint inhibition without clinical worsening of autoimmune disease. This article adds to the literature, suggesting tumor evolution with neuroendocrine differentiation in some cancers, and argues that a molecular-based approach to treatment might achieve better understanding and possibly superior treatment outcomes.

Contributing effects of sarcopenia on cancer occurrence: novel evidence based on NHANES 1999–2020 and two-sample mendelian randomization study

Abstract Background Sarcopenia is associated with worse prognosis in patients with cancer, and patients with cancer usually have poor muscle condition. However, it is still not clear whether sarcopenia contributes to cancer occurrence. Methods This study utilized data from the National Health and Nutrition Examination Survey (NHANES) 1999–2020 to assess the relationship between sarcopenia and cancer. Key sarcopenia indicators, including lean mass measurements and sarcopenia diagnosed by European Working Group on Sarcopenia in Older People (EWGSOP) or Foundation for the National Institutes of Health (FNIH) criteria, were analyzed using quantile logistic regression models. A two-sample Mendelian Randomization (MR) approach was employed to explore the causal link between sarcopenia and cancer, leveraging genetic variants as instrumental variables. Results We found that after adjusting covariates, left arm lean mass, left leg lean mass and appendicular lean mass (ALM) were found to have significant negative influences on the occurrence of overall-cancer types, particularly in individuals over 40 years old. Sarcopenia (FNIH) significantly increased the risk of overall-cancer types, especially colon, ovarian, and uterine cancers. Smooth curve fitting showed that cancer incidence decreased with increasing muscle mass. MR analysis confirmed that ALM and whole body lean mass (WBLM) had causally negative effects on cancer, while grip strength and sarcopenia (by EWGSOP/FNIH criteria) demonstrated significant causal effects on specific cancer types, including lymphoid hematopoietic cancer, lymphoid leukemia, and breast cancer. Conclusion Sarcopenia significantly impacts the incidence of various cancers and may causally contribute to cancer development. Managing sarcopenia could potentially benefit cancer prevention and treatment strategies.

Fertility preservation practices and gastrointestinal oncologist in Europe: a pan-European study

Abstract Introduction The rising incidence of early-onset gastrointestinal (GI) cancer has made the impact of treatments on fertility of high significance. While there is abundant evidence on oncofertility outcomes in breast cancer and hematological malignancies, data regarding these perspectives in GI cancers is lacking. We sought to evaluate current practices of fertility preservation (FP) among GI oncologists across Europe. Methods A cross-sectional survey was distributed through the Gastrointestinal Tract Cancer Group (GITCG) of the EORTC network and affiliated cooperative groups and cancer centers using a 10-item electronic survey regarding oncofertility practices. The target population was oncologists who routinely treat GI cancers. A statistical analysis was performed based on country, patient volume, and tumor type. Results Two hundred and twenty-six GI oncologists from 27 countries completed the survey, the majority from high volume cancer centers. Fifty seven percent of the participating oncologists routinely discuss the impact of treatment on fertility in any patient <40 years, while 36% discuss this only in the curative setting. Fifty-nine percent refer female patients to standard FP options (embryo/oocyte preservation), while 24% chose to refer to ovarian cryopreservation. Of note, 17% indicated they would not refer a curative patient for FP at all due to time or resource issues. Sixty five percent routinely refer male patients to sperm preservation. Use of Gonadotropin Releasing Hormone analogues (GnRHa) in CRC patients is recommended by 34% of oncologists. In the setting of pelvic radiation, 65% refer a female patient for ovarian transposition before pelvic irradiation; 32% would consider uterine transposition. Sixty one percent would consider a nonradiation protocol as perioperative chemotherapy as a valid option for young female patients. We observed heterogeneity upon country but not upon physician gender. Conclusion Our study indicates a substantial diversity in current practices in Europe with regard to FP in young cancer patients with GI malignancies, which is not always aligned with current guidelines. There is a need to disseminate and educate GI oncologists on oncofertility perspectives and contemporary data. Additionally, there is a need to establish evidence on the utility of fertility preservation options for patients with GI cancers.

Germline BRCA pathogenic variants and hematologic adverse events in patients with ovarian carcinoma receiving PARP inhibitors: a retrospective cohort study

Abstract Background Patients with a germline BRCA pathogenic variant (gBRCA-PV) and advanced high grade ovarian carcinoma (aHGOC) experience higher hematologic adverse events (HAEs) when receiving platinum salts and ionizing radiations, compared to non-carriers, due to a possible higher susceptibility of the hemopoietic stem cells to DNA targeting agents. However, the incidence of PARP inhibitor (PARPi)-related HAEs according to the gBRCA-PV status is currently unknown. Patients and Methods We conducted a single-center retrospective cohort study to describe the occurrence of HAEs in patients with aHGOC receiving ≥8 weeks of maintenance PARPi in any line of therapy, comparing gBRCA-PVs carriers to non-carriers. HAEs were manually identified by searching the patients’ electronic medical records and classified by CTCAE v5.0. The main endpoint was the incidence rate of any HAE (ie, anaemia, neutropenia, or thrombocytopenia) of grade 2 or more (G ≥ 2). Results One hundred and sixty-six patients were included; 95 (57%) had a gBRCA-PV. In total, 162 incident cases of G ≥ 2 HAEs were reported over 255.3 person-years. The incidence rates of G ≥ 2 HAEs were 1003/1000 person-years in gBRCA-PV carriers and 993/1000 person-years in non-carriers. No difference in the incidence rate of G ≥ 2 HAEs emerged comparing gBRCA-PV carriers to non-carriers (crude-incidence rate ratio [IRR]: 1.01; 95% CI: 0.72, 1.43; P = .96), even after adjusting for the type of PARPi (Mantel-Haenszel IRR: 0.99; 95% CI: 0.67, 1.46). Conclusion Patients with aHGOC and a gBRCA-PV do not experience higher PARPi-related HAEs compared to non-gBRCA-PV carriers, unlike platinum salt-related HAEs.

A prospective study of serum folate levels in patients with solid tumors treated with olaparib

Abstract Background Olaparib is a polyadenosine 5’-disphosphoribose polymerase inhibitor approved to treat advanced ovarian cancers with germline mutations. The link between olaparib-induced anemia and folate deficiency was described in a retrospective case series in which 87.5% of patients developed concomitant folate deficiency and anemia. We sought to prospectively evaluate this association. Patients and Methods This is an open-label prospective trial of patients with solid tumors treated with olaparib to determine the frequency and timing of folate deficiency anemia. Patients who developed grade 1 anemia (Hgb < 12.0 g/dL) concomitantly with folate deficiency (serum folate < 7.0 ng/mL) were randomized to receive placebo or folic acid. Secondary endpoints included the impact of folic acid supplementation on serum folate and hemoglobin, transfusion needs, and need for olaparib treatment interruption, dose reduction, or drug discontinuation. Results Nine subjects were enrolled, with ovarian or breast cancer. Two patients were randomized to forgo folate supplementation, two were randomized to receive folate, and the rest were not randomized per protocol. Three withdrew due to disease progression. All patients demonstrated decreased folate levels after initiation of olaparib, eight occurring within 3 months. Seven patients developed a concomitant grade 1 anemia. Folate deficiency did not correlate with clinically significant anemia. Conclusions This trial demonstrated folate deficiency in nearly all patients starting olaparib within weeks but, deficiencies did not result in a clinically significant anemia. Folate levels normalized with supplementation and improved with olaparib discontinuation. This data warrant checking serum folate in patients receiving olaparib who develop anemia and replacing folate if deficiency is found.

Phase 3 clinical trials evaluating poly(ADP-ribose) polymerase inhibition plus immunotherapy for first-line treatment of advanced ovarian cancer

Abstract Background Ovarian cancer is the second deadliest gynecologic malignancy globally. The current standard of care first-line therapy for newly diagnosed advanced epithelial ovarian cancer is surgery and platinum-based chemotherapy (±bevacizumab), followed by maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor, bevacizumab, or a combination of the two. Although anti-programmed cell death (PD) protein 1 and anti–PD ligand 1 antibodies (PD-[L]1 inhibitors) have shown benefit in several solid tumors, their effect in ovarian cancer remains uncertain. Several trials are evaluating PD-(L)1 inhibitors in combination with first-line platinum-based chemotherapy and PARP inhibitor maintenance treatment. Here, we review trial designs to understand key similarities and differences for future assessments of the results. Materials and Methods The clinical trials registry “ClinicalTrials.gov” was searched using keywords, including ovarian cancer and niraparib, olaparib, or rucaparib. Search results were then filtered for phase 3 and manually reviewed to identify trials evaluating combinations of PARP inhibitors and PD-(L)1 inhibitors in the first-line setting. Results Four trials, ENGOT-OV44/FIRST (NCT03602859), ENGOT-OV46/AGO-OVAR 23/GOG-3025/DUO-O (NCT03737643), ENGOT-OV43/GOG-3036/KEYLYNK-001 (NCT03740165), and ENGOT-OV45/GOG-3020/ATHENA (NCT03522246), were identified. Of these, FIRST, DUO-O, and KEYLYNK-001 are evaluating both first-line use in combination with chemotherapy and maintenance, whereas ATHENA focuses on maintenance after a response to chemotherapy; however, DUO-O and KEYLYNK-001 do not include a PARP inhibitor in the comparator arm, limiting the ability to compare the added benefit of immunotherapy over the current standard of care. Conclusions Results of these trials will determine whether PARP inhibitor and PD-(L)1 inhibitor combination with or without bevacizumab can improve patient outcomes.

Retrospective study of elderly patients with advanced ovarian cancer who did not undergo surgery

Abstract Objective To evaluate the clinical outcomes of elderly patients with advanced ovarian cancer who did not undergo surgery and received chemotherapy with or without maintenance therapy. Methods We retrospectively analyzed the clinical data of 15 patients with advanced high-grade serous ovarian cancer who were treated at our hospital between 2018 and 2023. These patients either had multiple comorbidities or refused surgery. Data collected included patient demographics, treatment regimens, chemotherapy cycles, clinical response, progression-free survival (PFS), and overall survival (OS). Results The median age of the patients was 73 years (range, 50-86 years). Fourteen patients received platinum-based chemotherapy combined with paclitaxel or liposomal doxorubicin, with or without bevacizumab, for 3 to 6 cycles. Twelve patients who achieved disease control received PARP inhibitor maintenance therapy. The overall response rate (ORR) was 80.0%, or 12/15 patients achieved partial response (PR); nobody achieved complete response. The disease control rate (DCR) was 100%. The median PFS1 was 19.0 months (95% CI, 11.85-26.15), and the median PFS2 was 10 months. The 3-year OS rate was 65.2%, with a median OS of 57.0 months (95% CI, 13.00-100.99). Conclusions Chemotherapy with or without bevacizumab, followed by PARP inhibitor maintenance therapy, is a viable alternative for elderly or surgically ineligible patients with advanced ovarian cancer. The findings of this study should be considered exploratory and require validation through large-scale studies.

Survivorship in advanced ovarian cancer: a prognostic model for overall survival and risk of recurrence

Abstract Objective Advanced epithelial ovarian cancer (EOC) poses a significant clinical challenge due to its typically late diagnosis and poor prognosis. However, a subset of patients exhibit remarkably prolonged survival. Identifying prognostic factors and developing tools for estimating outcomes may provide tailored strategies for treatment escalation or de-escalation. This study aimed to identify prognostic factors associated with patient survival and develop a prognostic model estimating EOC patients’ overall survival and risk of recurrence (ROR). Methods We conducted a retrospective analysis of 1049 women diagnosed with EOC from January 2002 until June 2024. Clinical, pathological, and molecular data, including germline BRCA pathogenic variants (PVs), and homologous recombination repair analysis were performed. Long-term survivors (LTS), defined as those surviving over 7 or 10 years, and short-term survivors (STS), defined as those surviving less than 2 years were compared. A prognostic model was developed using multivariable logistic regression to estimate survival probabilities and recurrence risk. Results Among the study cohort with advanced disease (FIGO stage III-IV), 20.3% survived beyond 7 years and 9.8% beyond 10 years. Factors significantly associated with LTS included younger age, lower disease stage, complete tumor resection, BRCA PV, and treatment with poly (ADP-ribose) polymerase inhibitors. The prognostic model, integrating age, stage, BRCA status, and tumor resection, provided survival estimates and ROR for 2, 5, 7, and 10 years from diagnosis. This tool is based on retrospective logistic regression analysis of long-term and STS across all stages (I-IV). Conclusions This study reaffirms established prognostic factors of LTS with advanced EOC and introduces a novel prognostic calculator integrating clinical variables. The tool may assist in personalizing treatment plans and guiding clinical decisions. Validation in multi-institutional cohorts is necessary to confirm its universal utility and applicability.

Improving genetics equity: identifying women eligible for genetic care services using mammography clinics in underserved areas as screening hubs

Abstract Purpose Fewer than 20% of underserved individuals undergo guideline-concordant hereditary breast and ovarian cancer (HBOC) genetic testing (GT). Our study aimed to determine the proportion of women eligible for HBOC GT using a cancer genetics risk assessment (CGRA) tool at breast cancer (BC) screening clinics in underserved communities and to describe the program’s impact. Methods Participants were women who presented for BC screening at The Rose clinics, serving low-income underserved communities in southeast Texas, and completed the CGRA. High-risk individuals received bilingual educational materials and a saliva-based GT kit. Those with a pathogenic variant (PV) or a variant of uncertain significance (VUS) received telegenetic counseling and risk reduction resources. Results A total of 501 women completed the CGRA, with 30.1% uninsured. 150 women were identified as eligible for GT, but only 14 (9.9%) completed GT (11 negative, 2 VUS, 1 PV in NF1). GT completion was significantly associated with being White, Native American/Alaskan Native, and Ashkenazi Jewish (P < .05). Hispanic, low-income, and uninsured individuals, or those with fewer relatives with cancer, were as likely to complete GT as others. Conclusions We successfully identified underserved women at high risk of HBOC using CGRA, but the GT completion rate was low. However, the completion rate did not differ by Hispanic ethnicity, income, or insurance status, suggesting that financial navigation by our study coordinator, support from Spanish-language staff at The Rose clinics, and the use of Spanish-language educational materials and translation may have helped overcome some barriers.

The prognostic and predictive value of homologous recombination deficiency in gastrointestinal cancer

Abstract The homologous recombination (HR) system repairs DNA double-strand breaks produced by the DNA damage response, which is a complex signaling pathway consisting of the key proteins BRCA1/2 and other DNA repair proteins, such as the ATM, PALB2, BARD1, RAD51, and Fanconi anemia proteins. Mutations and epigenetic alterations in HR-related genes may lead to homologous recombination deficiency (HRD), resulting in genomic instability and contributing to the development of certain solid tumors. The biological significance and molecular mechanism of BRCA1/2 mutation-related HRD are well understood, but the relationships of other HR-related genes and their variant forms with HRD have not been sufficiently studied. These genes exhibit multiple forms of variation, including one or more HR genes, germline or somatic mutations, monoallelic or biallelic variants, and not all variants present HRD. Therefore, HRD is usually defined as HR-related gene variation, but recent studies have shown that defining it as the combined score of loss of heterozygosity, LST and TAI, known as the HRD score, can more accurately assess genomic instability. In patients with HRD, platinum-based therapy and poly ADP-ribose polymerase enzyme inhibitor (PARPi) have been shown to perform well in ovarian, breast, and prostate cancers. For gastrointestinal cancer (GI cancer), HRD has been relatively well studied in pancreatic cancer, but its role in other cancers has rarely been reported. Herein, we review the pathogenesis and predictive value of HRD, including the use of platinum drugs, PARPi, and immunotherapy, in digestive system tumors.

First-in-human phase I/II, open-label study of mRNA-2416 alone or combined with durvalumab in patients with advanced solid tumors and ovarian cancer

Abstract Background mRNA-2416 is a novel lipid nanoparticle-encapsulated messenger RNA (mRNA) encoding human OX40 ligand (OX40L) for intratumoral (Itu) injection. OX40L plus immune checkpoint inhibitor (ICI) increased preclinical antitumor activity, thus mRNA-2416 plus ICI may potentiate antitumor activity. Methods This first-in-human, phase I/II, open-label, multicenter study examined the safety, tolerability, and efficacy of mRNA-2416 alone (arm A) or with durvalumab (arm B) in patients with advanced solid tumors or lymphoma (NCT03323398). Phase I primary objectives included assessment of safety/tolerability and maximum tolerated dose (MTD)/recommended dose for expansion; phase II arm B dose expansion assessed objective response rate in ovarian cancers. Secondary objectives included pharmacokinetics, disease control rate, duration of response, and progression-free survival (PFS). Assessments of immunologic response to treatment were exploratory. Results From August 2017 to August 2021, 79 patients were enrolled; 61 received treatment (arm A: 39, arm B: 22), including 16 in the expansion cohort. MTD was not reached. Treatment-related emergent adverse events were primarily grade 1/2, with 8 grade 3 and no grade 4/5 events. On-treatment tumor biopsies demonstrated increased OX40L protein expression, elevated PD-L1, and proinflammatory responses. Tumor shrinkage occurred in injected and surrounding non-injected tumors. Median (95% CI) PFS was 60.0 (50.0 to 108.0) and 50.0 (38.0 to 55.0) days for arms A and B, respectively. Conclusions mRNA-2416 alone or with durvalumab was well tolerated. Pharmacodynamic analyses support Itu mRNA proof-of-concept. Predefined primary efficacy endpoints were not met in an exploratory cohort of ovarian cancer. Additional research is warranted to further inform this therapeutic approach.

PARP inhibitors as maintenance therapy in ovarian cancer after platinum-sensitive recurrence: real-world experience from the Unicancer network

Abstract Background Based on results of randomized clinical trials, polyADP-ribose polymerase inhibitors (PARPi) have become the standard of care in patients with platinum-sensitive recurrent ovarian cancer (OvC) in patients responding to platinum chemotherapy. However, little is known about their impact on survival in a real-world setting. Patients and methods This retrospective French multicenter observational study included women with platinum-sensitive recurrent OvC (not limited to the first platinum-sensitive relapse) receiving PARPi as maintenance after response to platinum-based chemotherapy. They were compared to patients with similar characteristics undergoing observation after chemotherapy completion. Data were collected in the Ovarian Cancer Epidemiological Strategy and Medical Economics (ESME-OC) database between 2011 and 2021. We explored progression-free survival (PFS) and overall survival (OS) benefits with PARPi maintenance. Results One hundred and twenty-three patients matching the selection criteria were included in the PARPi group and 397 patients in the control group. Median PFS was 19.9 months (95CI [15.0-21.9]) in the PARPi group vs 13.4 months (95CI [11.8-15.0]) in the control group, with a HR = 0.71 (95CI [0.55-0.93]), P = .01). Median OS was 82.0 months (95CI [48.6-Not Estimable]) in the PARPi group vs 44.7 months (95CI [38.8-53.7]) in the control group (HR = 0.47, 95CI [0.30-0.74], P < .001). Multivariate analyses including performance status, histological subtype, achievement of cytoreductive surgery at relapse, and platinum-free interval, confirmed the independent prognostic impact of PARPi treatment. Conclusion This first national study focusing on the efficacy of PARPi in a real-world population shows similar benefits than in randomized clinical trials, supporting their use in clinical routine practice. Database registration clinicaltrials.gov Identifier NCT03275298.

Therapeutic targeting of the protein tyrosine kinase-7 in cancer: an overview

ABSTRACT The protein tyrosine kinase-7 (PTK7) is an evolutionarily conserved transmembrane receptor that has emerged as a potential therapeutic target for human tumors. PTK7 is a pseudokinase that is involved in the modulation of the Wnt signaling pathway through interactions with other receptors. These interactions result in targeted gene activation that regulates cell polarity, migration, and proliferation during embryogenesis. Aside of this role during development, PTK7 has been shown as overexpressed in numerous cancers including colon carcinoma, leukemia, neuroblastoma, hepatoma, and ovarian cancer. The activity of PTK7 and the direct correlation with poor prognosis have fostered preclinical investigations and phase I clinical trials, aiming at inhibiting PTK7 and inducing antitumoral effects. In this review, we provide an exhaustive overview of the diverse approaches that use PTK7 as a new molecular target for cancer therapy in different tumor types. We discuss current therapies and future strategies including chimeric antigen receptor-T cells, antibody-drug conjugates, aptamers, based on up-to-date literature and ongoing research progress.

Ovarian clear cell carcinoma: open questions on the management and treatment algorithm

Abstract Ovarian clear cell carcinoma (OCCC) accounts for ~10% of all epithelial ovarian cancers and is considered a different entity from the more common high-grade serous ovarian carcinoma (HGSC), with distinct clinical presentations, different risk, and prognostic factors, and specific molecular features. Most OCCCs are diagnosed at an early stage and show favorable outcomes, in contrast to those diagnosed at advanced stages, which exhibit intrinsic resistance to platinum-based chemotherapy regimens and a very poor prognosis. The standard treatment of advanced OCCC is currently based on primary debulking surgery followed by platinum-based chemotherapy according to recent international guidelines. However, these recommendations are extrapolated from several trials mainly featuring a large cohort of HGSC, with only a small minority of OCCC. Because of its rarity, many questions remain unanswered regarding the surgical and medical treatment. Lymph node staging, fertility-sparing treatment, the use of targeted therapies and radiotherapy as well as the adjuvant treatment for early-stage disease and second or further lines of chemotherapy are still under debate. This review aims to address these unresolved issues, by providing a comprehensive overview of the current data on this disease, and to suggest possible directions for future research.

High expression of phosphoglycerate dehydrogenase predicts poor outcome in patients with high-grade serous ovarian cancer

Abstract Introduction High-grade serous ovarian cancer (HGSOC) is characterized by high mortality and prevalent recurrences. This study investigates the prognostic value of phosphoglycerate dehydrogenase (PHGDH) in HGSOC which has been linked to metabolic reprogramming and recurrences in other cancers. Methods Data from 306 patients with advanced-stage HGSOC treated between 2008 and 2015 were analyzed. PHGDH expression levels were determined using immunohistochemistry and categorized as “low” or “high.” Results PHGDH-high was associated with higher FIGO stage and increased use of neoadjuvant chemotherapy. Patients with PHGDH-high tumors had significantly worse survival than PHDH-low, even after adjusting for confounding factors.

Endocrine therapy in advanced high-grade ovarian cancer: real-life data from a multicenter study and a review of the literature

Abstract Background In women, ovarian cancer is the eighth most frequent cancer in incidence and mortality. It is often diagnosed at advanced stages; relapses are frequent, with a poor prognosis. When platinum resistant, subsequent lines of chemotherapy are of limited effect and often poorly tolerated, leading to quality of life deterioration. Various studies suggest a hormonal role in ovarian carcinogenesis, with a rationale for endocrine therapy in these cancers. Patients and Methods This multicenter, retrospective study assessed the use of endocrine treatment for high-grade ovarian epithelial carcinomas treated between 2010 and 2020. Results Eighty-one patients with ovarian cancers were included. The median duration of platinum sensitivity was 29 months. We observed a 35% disease control rate with endocrine therapy, and 10% reported symptom improvement. For 19 patients (23.5%), the disease was stabilized for more than 6 months. Median overall survival from diagnosis was 62.6 months. Regarding endocrine therapy predictive factors of response, in a multivariate analysis, 3 factors were statistically significant in favoring progression-free survival: platinum sensitivity (P = .021), an R0 surgical resection (P = .020), and the indication for hormone therapy being maintenance therapy (P = .002) Conclusion This study shows real-life data on endocrine therapy in ovarian cancer. As it is a low-cost treatment with many advantages such as its oral administration and its safety, it may be an option to consider. A perspective lies in the search for cofactors to aim as future therapeutic targets to improve the effectiveness of hormone treatment by means of combination therapy.

Development of an Electronic Decision Aid Tool to Facilitate Mainstream Genetic Testing in Ovarian Cancer Patients

Abstract Background Multigene panel testing is an important component of cancer treatment plans and risk assessment, but there are many different panel options and choosing the most appropriate panel can be challenging for health care providers and patients. Electronic tools have been proposed to help patients make informed decisions about which gene panel to choose by considering their preferences and priorities. Materials and Methods An electronic decision aid (DA) tool was developed in line with the International Patient Decision Aids Standards collaboration. The multidisciplinary project team collaborated with an external health care communications agency and the MGH Cancer Center Patient and Family Advisory Council (PFAC) to develop the DA. Surveys of genetic counselors and patients were used to scope the content, and alpha testing was used to refine the design and content. Results Surveys of genetic counselors (n = 12) and patients (n = 228) identified common themes in discussing panel size and strategies for helping patients decide between panels and in identifying confusing terms for patients and distribution of patients’ choices. The DA, organized into 2 major sections, provides educational text, graphics, and videos to guide patients through the decision-making process. Alpha testing feedback from the PFAC (n = 4), genetic counselors (n = 3) and a group of lay people (n = 8) identified areas to improve navigation, simplify wording, and improve layout. Conclusion The DA developed in this study has the potential to facilitate informed decision-making by patients regarding cancer genetic testing. The distinctive feature of this DA is that it addresses the specific question of which multigene panel may be most suitable for the patient. Its acceptability and effectiveness will be evaluated in future studies.

A Novel Germline Mutation of BRCA1 and Integrated Analysis With Somatic Mutation in a Chinese Multi-Cancer Family

Abstract The presence of mutations in the BRCA1 gene (MIM: 113705) is widely recognized as a significant genetic predisposition for ovarian cancer. This study investigated the genomic mutations in a Chinese family with a history of ovarian, breast, and rectal adenocarcinoma. A novel germline mutation (Phe1695Val) in BRCA1 was identified through whole-exome sequencing. Subsequently, we performed whole-genome sequencing to identify somatic mutations and analyze mutational signatures in individuals carrying the novel germline mutation. Our findings revealed a correlation between somatic mutational signatures and the BRCA1 germline mutation in the proband with ovarian cancer, while no such association was observed in the tumor tissue from the patient with breast cancer. Furthermore, distinct somatic driver mutations were identified, a truncated mutation in the TP53 gene in the ovarian tumor tissue, and a hotspot mutation in the PIK3CA gene in the breast cancer. According to our findings, the BRCA1 F1695V mutation is linked to ovarian cancer susceptibility in the family and causes specific somatic mutational profiles.

Prognostic and histologic significances of the expression profile of membrane tissue factor for aggressive endometrial carcinomas

Abstract Background Tissue factor (TF) is involved in tumor-induced coagulation cascade, which plays crucial roles in the tumor microenvironment, and is being clinically explored as a therapeutic target. However, the prognostic role of TF and the related proteins in endometrial cancer is yet to be clarified and was systematically investigated in this study. Materials and Methods The expression profiles of membrane/cytoplasmic TF, nuclear/cytoplasmic phospho-TF (p-TF), PAR-1, PAR-2, VEGF as well as CD8, a marker for cytotoxic T cells, in tumors from 229 patients with endometrial carcinoma were immunohistochemically evaluated and correlated with clinicopathologic parameters and patient survival. Bioinformatics analyses were further conducted to strengthen the observations. Results High membrane TF (mTF) expression correlated with worse overall survival (OS), and was found to be an independent prognostic factor for unfavorable OS by the univariate and multivariate analyses (P = .028 and .0087). High mTF expression correlated with aggressive histology, and remained independent for unfavorable OS even in the aggressive histological subset (P = .037 and .0064). Moreover, mTF expression inversely correlated with CD8+ tumor-infiltrating immune cell count, and TF expression positively correlated with the infiltration of Treg cells, known to suppress CD8+ T cells, by the The Cancer Genome Atlas (TCGA) data analysis (P = .037 and .0015), suggesting that the detrimental prognostic role of mTF involves immune evasion. Conclusions Taken together, mTF serves as a potential biomarker for patient prognosis and therapeutic target for the aggressive histological type of tumor, providing significant rationales for incorporating TF-directed drugs into the novel strategy for refractory endometrial carcinomas.

Weekly Carboplatin and Paclitaxel for Ovarian Cancer: The “Finer Points”

First-line ovarian cancer platinum doublet is paclitaxel-carboplatin. Superiority of weekly paclitaxel schedules has not been confirmed; however, a novel schedule with both drugs given weekly (days 1, 8, 15) followed by a 2-week break may be advantageous to some.

Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Cancer Receiving Lenvatinib Plus Pembrolizumab

Abstract Background Lenvatinib plus pembrolizumab significantly improved efficacy compared with chemotherapy in patients with advanced endometrial cancer (aEC) regardless of microsatellite instability status or histologic subtype, who had disease progression following prior platinum-based therapy, in Study-309/KEYNOTE-775. The safety profile of the combination was generally consistent with that of each monotherapy drug and of the combination in patients with endometrial cancer and other solid tumors. Given the medical complexity of patients with aEC, this paper aims to characterize key adverse reactions (ARs) of the combination treatment and review management strategies, providing a guide for AR management to maximize anticancer benefits and minimize treatment discontinuation. Materials and Methods In Study-309/KEYNOTE-775, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks) or chemotherapy (doxorubicin or paclitaxel). The incidence and median time to the first onset of ARs, dose modifications, and concomitant medications are described. Key ARs characterized include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight decreased, proteinuria, and palmar-plantar erythrodysesthesia syndrome. Results As expected, the most common any-grade key ARs included: hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders. Grades 3-4 key ARs with incidence ≥10% included: hypertension, fatigue, and weight decreased. Key ARs first occurred within approximately 3 months of treatment initiation. AR management strategies consistent with the prescribing information and the study protocol are discussed. Conclusion Successful AR management strategies for lenvatinib plus pembrolizumab include education of the patient and entire treatment team, preventative measures and close monitoring, and judicious use of dose modifications and concomitant medications. Clinicaltrials.gov ID NCT03517449

FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer

Abstract On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)–positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. Implications for Practice These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient–positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

Successful Treatment of Patients with Refractory High-Grade Serous Ovarian Cancer withGOPC-ROS1Fusion Using Crizotinib: A Case Report

AbstractBackgroundRecently, multiple poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated excellent efficacy among patients with ovarian cancer with or without BRCA mutations. However, alternative therapeutic options are urgently required for patients who cannot benefit from conventional chemotherapy or PARP inhibitors.Case PresentationA patient with high-grade serous ovarian carcinoma presented to our clinic after developing resistance to chemotherapy. Paired tumor-normal next-generation sequencing (NGS) was performed using peripheral blood to identify potential actionable mutations. NGS revealed the patient harboring a GOPC-ROS1 fusion, which was subsequently verified using a reverse transcription polymerase chain reaction assay. No germline or somatic mutation in BRCA1/2 or mismatch repair genes was detected. Therefore, the patient received crizotinib treatment. A rapid, favorable clinical response (partial response at 1 month) was observed, with further pathological response monitored and evaluated in follow-up interrogation.ConclusionThis study suggested that crizotinib was an off-the-shelf, practical, and ostensibly effective treatment option for patients with ovarian cancer with ROS1 rearrangement. NGS-based genetic testing may guide to plan therapeutic paradigms, and render precision medicine promising in ovarian cancer treatment.Implications for PracticeDespite the previous report of ROS1 fusion in patients with ovarian cancer, it remains unknown whether patients can benefit from targeted therapeutic drugs. This study reports a GOPC-ROS1 fusion identified by next-generation sequencing in a patient with chemotherapy-resistant ovarian cancer. The patient was administered crizotinib and showed rapid, remarkable response. This study suggests that comprehensive sequencing should be offered for patients with ovarian cancer without effective therapeutic strategies, and crizotinib can be used to treat ROS1-rearranged ovarian carcinomas.

Dual Fulvestrant-Trametinib Therapy in Recurrent Low-Grade Serous Ovarian Cancer

Abstract Low-grade serous ovarian carcinoma (LGSOC) is known to exhibit chemoresistance. Effective treatment options for recurrent disease are few and often limited to hormone antagonism. Combination of endocrine therapies with MEK-inhibitors displays synergism in preclinical ovarian cancer models, however. This brief communication presents the use of combination anti-estrogenic and MEK-inhibitor therapies, fulvestrant and trametinib, as treatment in a heavily pretreated patient with estrogen receptor-positive, recurrent LGSOC. The dual-therapy regimen was well tolerated and appeared to confer 9 months of progression-free survival. Further investigation is warranted to explore this effect.

Metastatic Thymoma Harboring a Deleterious BRCA2 Mutation Derives Durable Clinical Benefit from Olaparib

Abstract Thymomas comprise a group of rare epithelial neoplasms of the anterior mediastinum. Whereas localized disease carries a favorable prognosis, the majority of patients with metastatic thymomas experience progression or recurrence over a 10-year period. Although targeted therapies have become standard of care in many malignancies, no clinically actionable mutations have consistently been identified in metastatic thymomas. Here, we describe a patient with an aggressive thymoma complicated by extensive pleural metastases. Over a 16-year period, she progressed on multiple treatment regimens. To identify additional treatment options, tissue from a pleural metastasis was sent for next-generation sequencing, revealing mutations in BRCA2, tyrosine kinase 2, and SET domain containing 2. Based on supporting evidence for poly (ADP-ribose) polymerase (PARP) inhibition in other BRCA-mutated tumors, the patient was started on the PARP inhibitor olaparib. She derived significant clinical benefit from treatment, with imaging showing overall stabilization of her disease. Here, we review the genotyping results of her tumor and discuss the functional and clinical significance of the mutations in her cancer as well as implications for managing patients with advanced BRCA-mutant thymomas. Key Points Targeted therapy has yet to enter the standard clinical management of metastatic thymomas. Patients with BRCA2-mutant thymomas may benefit from poly (ADP-ribose) polymerase inhibition.

A Long-Term Extension Study of Bevacizumab in Patients With Solid Tumors

Abstract Background Bevacizumab has been studied in numerous clinical trials in multiple types of cancer; however, patients may receive bevacizumab over an extended period of time. This study assessed the long-term safety and tolerability of bevacizumab among patients with solid tumors. Materials and Methods Patients enrolled in a Roche/Genentech-sponsored trial who had derived benefit from bevacizumab therapy as monotherapy or in combination with anticancer drugs were eligible for continuation of bevacizumab in this long-term extension (LTE) study. The primary endpoints were the incidence of adverse events (AEs) of Common Terminology Criteria for AEs (CTCAE) grade ≥3 related to bevacizumab treatment, serious AEs (SAEs), and deaths. Results Ninety-five patients with the following cancer types were enrolled in the LTE: ovarian cancer or peritoneal carcinoma (n = 41), non-small cell lung cancer (n = 16), glioblastoma multiforme (n = 14), breast cancer (n = 11), colorectal cancer (n = 7), or renal cell carcinoma (n = 6). The median (range) duration of bevacizumab treatment was 15.6 (0.0–81.0) months during the LTE and 57.5 (16.4–134.9) months overall (parent trial + LTE), with three patients receiving bevacizumab for >10 years. Overall, 17 patients (17.9%) experienced SAEs, and 21 (22.1%) had a bevacizumab-related AE of CTCAE grade ≥3 (proteinuria and hypertension were the most common). Four patients died: three from disease progression and one from an AE considered unrelated to bevacizumab. Conclusion The safety outcomes observed support the tolerability of long-term bevacizumab in patients with various solid tumors, with a median extended treatment duration of almost 5 years overall and >10 years in some individual patients. ClinicalTrials.gov identifier: NCT01588184. Implications for Practice In this long-term extension study of patients with solid tumors, the median duration of bevacizumab treatment (including parent trials) was just under 5 years, with a long-term exposure in some patients of 7 to >10 years. Grade ≥3 adverse events related to bevacizumab were consistent with the established safety profile, with proteinuria and hypertension being the most common. Patients received bevacizumab over an extended period of time (beyond the length of most clinical trials), and the overall safety outcomes observed support the tolerability of long-term bevacizumab treatment in patients with solid tumors, with clinical benefit achieved over an extended period.

Treatment of Pediatric Glioblastoma with Combination Olaparib and Temozolomide Demonstrates 2-Year Durable Response

Abstract For pediatric patients with high-grade gliomas, standard-of-care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high-grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3-year-old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal-parietal-temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard-of-care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high-grade gliomas. Key Points Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome. Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome. Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP-ribose) polymerase (PARP) inhibitors. Combining PARP inhibitors with temozolomide (standard-of-care treatment) revealed no adverse events or toxicities over the course of 18 months.

Phase I Pharmacokinetic Study of Niraparib in Chinese Patients with Epithelial Ovarian Cancer

Abstract Lessons Learned Pharmacokinetics characteristics of niraparib in Chinese patients were similar to those in white patients. Niraparib could be well tolerated by Chinese patients, and adverse events were manageable in this study. Population pharmacokinetics analysis indicated that baseline body weight had a modest impact on pharmacokinetics parameters of niraparib; however, it was not considered clinically important. Background This randomized, open-label, single-arm, phase I study was designed to investigate the pharmacokinetics (PK) and safety of niraparib in Chinese patients with epithelial ovarian cancer. Methods Eligible patients were randomized in a 1:1:1 ratio to receive 100, 200, or 300 mg of niraparib once daily. PK parameters were analyzed after single and multiple dose administrations. Results Thirty-six Chinese patients were enrolled in total. Niraparib was rapidly absorbed after administration, and median time-to-peak (Tmax) was 3 hours. The long terminal elimination half-life (T1/2 ∼ 35 hours) supports once-daily dosing regimen. The exposure to niraparib showed linear and dose-proportional pharmacokinetics, whereas other PK parameters such as Tmax, T1/2, and accumulation ratio were dose independent. Population PK analysis indicated that there was no effect of race on niraparib PK parameters, whereas baseline body weight had a modest impact on niraparib exposure. Grade 3/4 treatment-emergent adverse events (TEAEs; reported in ≥10% of patients) included platelet count decreased (a total of five patients who were all from the 300-mg group) and neutrophil count decreased. The TEAEs were manageable after dose modification. Conclusion The PK profile of niraparib in Chinese patients is consistent with that in white patients. Niraparib is safe and well tolerated in Chinese patients with ovarian cancer.

Combination therapy for platinum-resistant ovarian cancer: a novel at-home regimen with envafolimab, lenvatinib, and etoposide

Abstract Background Effective and tolerable treatment for patients with platinum-resistant recurrent ovarian cancer remains a great challenge in clinical practice. This study aimed to evaluate the efficacy and safety of envafolimab, the first subcutaneously administered programmed death ligand 1 (PD-L1) inhibitor, combined with lenvatinib and etoposide in patients with platinum-resistant recurrent ovarian cancer. Methods This was an open-label, single-arm, phase 2 trial (ENLEN-OC-001). Patients with platinum-resistant recurrent ovarian cancer were eligible for inclusion who were administered envafolimab subcutaneously on day 1 and lenvatinib and etoposide orally on days 1-14, with 21 days as a cycle. After 6-10 cycles, envafolimab and lenvatinib were taken as maintenance therapy until intolerable toxicity, disease progression, withdrawal of consent, or finishing 24 months of treatment. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results Of the screened 28 patients, 21 were included, with 18 being assessed for the efficacy and safety. The ORR was 44.4% (95% CI 21.5%-69.2%), and the DCR was 83.3% (95% CI 58.6%-96.4%). The median PFS was 10.2 months (95% CI 5.6-not applicable [NA]), and the median OS was 21.3 months (95% CI 6.8-NA). The most common grade 3/4 adverse events were leukopenia (27.8%) and thrombocytopenia (16.7%). No serious adverse events or treatment-related deaths were reported. No changes were observed in the depression, anxiety, and quality of life following treatment. Conclusion Envafolimab combined with lenvatinib and etoposide showed promising efficacy and tolerable safety for patients with platinum-resistant recurrent ovarian cancer. ClinicalTrials.gov identifier NCT05422183

The cervical cancer screening and precancer treatment journey: a qualitative study of experiences among Zambian women living with and without HIV

Abstract Background Zambia has the third highest cervical cancer incidence rate globally, and it remains the leading cause of cancer-related death among women. We explored the experiences of Zambian women who accessed cervical cancer screening and precancer treatment services to understand factors influencing care-seeking and access across urban, peri-urban, and rural settings. Methods In 2020, we conducted eight focus group discussions with women living with and without Human Immunodeficiency Virus (HIV) who underwent cervical cancer screening between 2016 and 2020. To explore their care journey, participants were grouped by screening outcome—those with cervical precancerous lesions and those without. We also conducted 18 in-depth interviews with healthcare workers providing antiretroviral treatment, cervical cancer screening, or precancer treatment at government health facilities. Transcripts were coded and analyzed using thematic analysis. Results Care-seeking unfolded across five stages: recognition of need to screen, hesitation and consultation, screening, result interpretation, and treatment. Women were generally knowledgeable about cervical cancer and sought screening promptly, though some delayed due to fear. Social networks and interactions with healthcare workers facilitated screening, while logistical and financial barriers, along with delays in histopathology services particularly in rural areas, hindered access to timely diagnosis and treatment. Conclusion Improving cervical cancer screening and precancer treatment in Zambia requires addressing systemic inefficiencies by strengthening laboratory capacity, decentralizing diagnostics, and training healthcare workers to provide respectful, consistent counselling. Expanding community engagement to counter misinformation, leveraging social networks, and providing financial protection are also critical to ensuring timely, equitable, and reassuring care.

Prevalence and associated factors of persistent precancerous lesions among women treated for cervical lesions in Addis Ababa, Ethiopia

Abstract Background Cervical cancer is one of the leading causes of cancer-related deaths among Ethiopian women, despite being largely preventable. Women treated for precancerous cervical lesions remain at elevated risk of developing invasive cancer, yet little is known about the burden and predictors of persistent lesions following treatment in resource-limited settings. Materials and Methods We conducted a cross-sectional study among 242 women who underwent ablative or excisional therapy for precancerous cervical lesions at 3 clinics in Addis Ababa between November 2022 and December 2023. Data were collected using structured questionnaires and clinical records. Logistic regression analysis was used to identify factors associated with persistent lesions, reported as adjusted odds ratios (AORs) with 95% CIs. Results Of the 242 women treated, 104 (43.0%; 95% CI, 37.2-49.6%) experienced persistent lesions within 1 year. Persistent lesion rates were highest among women initially screened with a Pap smear (97.4%) compared to visual inspection with acetic acid (VIA) (21.9%) and HPV DNA testing (14.7%). Independent predictors of persistent lesions included an age of ≥50 years (AOR = 5.4; 95% CI, 1.56-18.93), being married (AOR = 2.5; 95% CI, 1.15-5.44), an HIV-positive status (AOR = 5.0; 95% CI, 1.41-20.3), and Pap smear as the initial screening modality (AOR = 4.9; 95% CI, 1.04-23.15). Conclusion Nearly half of the women treated for precancerous cervical lesions experienced persistent disease within 1 year, particularly those who were older, married, HIV-positive, or initially screened by Pap smear. These findings raise concerns about the effectiveness of current treatment and screening strategies.

Different prognosis for stage IIB cervical cancer patients with unilateral or bilateral parametrial invasion treated with concurrent chemoradiotherapy

Abstract Objective To compare the survival difference between 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer (CC) patients with unilateral parametrial invasion (UL) and bilateral parametrial invasion (BL) disease, and explore the significant role of parametrial invasion (PI) in prognosis prediction. Methods A total of 506 stage IIB CC patients were identified from the multi-center study, and patients were divided into UL and BL groups according to gynecological and radiological examination. Survival outcomes were estimated and compared between 2 groups before and after propensity scoring matching (PSM). The role of upper 2/3 vaginal invasion (VI) in impacting survival probability was also assessed. The random forest (RF) model was constructed and validated to select important features related to survival outcomes and predict prognosis for these patients. The SHapley Additive exPlanation (SHAP) was further introduced to provide a better understanding toward the findings from the RF model. Results Significant better 5-year overall survival (OS) was observed among patients with UL disease whether before (BL: 61.7% [95% CI: 57.0%-66.4%]; UL: 84.8% [95% CI: 82.4%-87.2%]; HR = 2.83, 95% CI: 1.90-4.20, P < 0.001) or after PSM (BL: 61.3% [95% CI: 56.6%-66.0%]; UL: 81.2% [95% CI: 77.3%-85.1%]; HR = 2.51, 95% CI: 1.56-4.04, P < 0.001). Similar findings could also be observed in terms of progression-free survival (PFS). The presence of VI didn’t significantly impair the survival probability, whether in the UL or BL group (all P > 0.05). RF model was constructed, which possessed decent predictive ability both in the training (area under the receiver operating characteristic curve [AUC] = 0.893; 95% CI: 0.874-0.912) and validation cohort (AUC = 0.879; 95% CI: 0.801-0.957). PI was identified to be the paramount feature in affecting the survival outcomes for stage IIB CC patients through the Beeswarm summary plot and bar chart in SHAP analysis. Conclusion Our findings demonstrated that 2018 FIGO stage IIB CC patients with BL disease had a worse prognosis than those with UL disease, and PI was the most significant feature in prognosis prediction for these patients.

The risk of radiation-associated second cancer in patients with cervical cancer following radiotherapy from 1975 to 2019

Abstract Background Radiation-associated second primary malignancies (SPMs) are a significant risk factor affecting the quality of life in long-term cervical cancer survivors. However, the impact of brachytherapy-boost and advanced radiotherapy techniques on the risk of radiation-related SPMs remains unclear. Methods We utilized data from the Surveillance, Epidemiology, and End Results (SEER) database (1975-2019) to assess the risk of radiation-associated SPMs among cervical cancer patients. Radiation-associated second solid and hematologic malignancies were defined as those diagnosed in survivors living for ≥5 and ≥2 years, respectively. The fine-gray sub-distribution hazard model was employed to compare the risk of SPMs across different groups. Results External beam radiation therapy (EBRT) was associated with an increased risk of pelvic SPMs (sub-distribution hazard ratio [sHR] = 2.13; P < .001). However, no increased risk was observed for extra-pelvic or hematologic SPMs. For radiotherapy-treated patients, the 15-year cumulative incidence of overall pelvic SPMs significantly declined from 3.92% in 1975-1994 to 2.85% in 1995-2006 (sHR = 0.87; P = .036), further decreasing to 2.27% after 2001 compared to those treated in 1975-2001 (sHR = 0.59; P = .030). Brachytherapy alone increased the risk of pelvic SPMs (sHR = 3.04; P < .001), but the combination of brachytherapy with EBRT did not further elevate the risk of pelvic SPMs (sHR = 1.35; P = .092). Conclusions The risk of radiation-associated pelvic SPMs has diminished over the past 40 years, and the combination of brachytherapy with EBRT did not further increase the risk of SPMs among cervical cancer patients.

Prevalence and Associations of Beta2-Microglobulin Mutations in MSI-H/dMMR Cancers

AbstractMicrosatellite instability (MSI) has emerged as an important predictor of sensitivity for immunotherapy-based strategies. β-2-Microglobulin (B2M) contains microsatellites within the coding regions and is prone to somatic changes in MSI/mismatch repair deficiency (MSI/dMMR) tumors. To delineate prevalence and associations of B2M mutations in MSI-H/dMMR cancers, we investigated the mutational profile of B2M and clinical and pathological features in gastric cancer (GC), colorectal cancer (CRC), and endometrial cancer (EC) with a high incidence of microsatellite instability-high (MSI-H)/dMMR. Formalin-fixed paraffin-embedded (FFPE) tumor tissues along with matched normal tissues were collected from 108 MSI/dMMR patients with GC, CRC, and EC. Genomic profiling of tissue and blood samples were assessed next-generation sequencing (NGS). Immunohistochemistry (IHC) was used to examine the presence or absence of B2M protein. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. NGS assay revealed that genes involved in chromatin regulation, the PI3K pathway, the WNT pathway, and mismatch repair were extensively altered in the MSI-H cohort. Signature 6 and 26, 2 of 4 mutational signatures associated with defective DNA mismatch repair, featured with high numbers of small insertion/deletions (INDEL) dominated in all 3 types of cancer. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. Tumor mutational burden (TMB) was significantly higher in the patients carrying MSI-H/dMMR tumors with B2M mutation than that in patients with wild-type B2M (P = .026).The frame shift alteration occurring at the exonic microsatellite sties caused loss of function of B2M gene. In addition, a case with CRC carrying indels in B2M gene resisted the ICI treatment was reported. In conclusion, patients carrying MSI-H/dMMR tumors with B2M mutation showed significantly higher TMB. Prescription of ICIs should be thoroughly evaluated for these patients.

Safety and quality of life with maintenance olaparib plus bevacizumab in older patients with ovarian cancer: subgroup analysis of PAOLA‑1/ENGOT-ov25

Abstract Background In PAOLA-1/ENGOT-ov25, the addition of olaparib to bevacizumab maintenance improved overall survival in patients with newly diagnosed advanced ovarian cancer. We describe the safety profile and quality of life (QoL) of this combination in older patients in PAOLA-1. Methods Safety (CTCAE v4.03) and QoL (EORTC QoL Questionnaires Core 30 and Ovarian 28) data were collected. We compared safety by age (≥70 vs <70 years) in the olaparib-containing arm. QoL by treatment arm was assessed in older patients. Geriatric features, including Geriatric Vulnerability Score (GVS), were also gathered. Results Of 806 patients randomized, 142 were ≥70 years old (olaparib-containing arm: n = 104; placebo arm: n = 38). Older patients treated with olaparib exhibited a similar safety profile to younger patients, except for higher rates of all grades of lymphopenia and grade ≥3 hypertension (31.7% vs 21.6%, P =.032 and 26.9% vs 16.7%, P =.019, respectively). No hematological malignancy was reported. Two years after randomization, mean Global Health Status and cognitive functioning seemed better with olaparib than bevacizumab alone (adjusted mean difference: +4.47 points [95% CI, −0.49 to 9.42] and +4.82 [−0.57 to 10.21], respectively), and other QoL items were similar between arms. In the olaparib-containing arm, older patients with baseline GVS ≥ 1 (n = 48) exhibited increased toxicity and poorer QoL than those with GVS of 0 (n = 34). Conclusion Among older patients in PAOLA-1, olaparib plus bevacizumab had a manageable safety profile and no adverse impact on QoL. Additional data are required to confirm these results in more vulnerable patients. (ClinicalTrials.gov Identifier: NCT02477644).

Risk assessment in a Chinese cohort of 96 318 females undergoing opportunistic cervical cancer screening

Abstract Objective To assess CIN3+ risk in a Chinese cohort of outpatients undergoing contesting screening and to evaluate the portability of the American Society for Colposcopy and Cervical Pathology (ASCCP) risk-based management, which was primarily developed using data from the Kaiser Permanente of Northern California (KPNC) cohort. Methods Females aged 25-65 years who were screened with cytology and high-risk human papillomavirus (hrHPV) co-testing between 2011 and 2020 at Wuhan Union Hospital (WHUH) were retrospectively studied. The risks of immediate and 3-year CIN3+ were estimated via prevalence-incidence mixture models. Portability was evaluated via the ratio of the observation risk in the WHUH cohort to the expected risk in the KPNC cohort (O/E) and its 95% CI. Results A total of 96 318 females were included, and 16.83% of the women tested hrHPV-positive at initial screening, who had a CIN3+ immediate risk of 14.14%. The CIN3+ immediate risk varied between subgroups of positive HPV16 (34.09%), HPV18 (13.38%), other HPV types (6.71%), and negative hrHPV (0.12%). Compared to the KPNC cohort, our cohort exhibited a significantly higher CIN3+ immediate risk (1.42% vs 0.46%; O/E, 3.09; 95% CI, 2.92-3.26) and disproportionately increased cancer immediate risks in most subgroups requiring immediate colposcopy or treatment, as well as higher 3-year CIN3+ risks in women with hrHPV-negative ASC-US/NILM. Yet, the action threshold suggested by ASCCP, a CIN3+ immediate risk of 4%, showed good portability to our cohort. Conclusions Despite the higher risks in our cohort, the ASCCP clinical action threshold remains portable. For women with minimal abnormalities or normal results, shortened follow-up intervals should be considered.

Predictive role of ARID1A and B2M mutations and the antigen presentation pathway in the efficacy of definitive chemoradiotherapy for cervical cancer

Abstract Background and purpose Definitive chemoradiotherapy (dCRT) is the standard treatment for locally advanced cervical cancer (LACC), yet patients experience considerable variability in disease-free survival (DFS). This study aimed to identify molecular biomarkers associated with response to dCRT in cervical cancer. Materials and methods: We retrospectively analyzed targeted next-generation sequencing data from tumor biopsy samples of 31 patients diagnosed with FIGO stage IIB–IVA LACC. Genetic alterations in cancer-related genes and pathways were assessed to determine associations with DFS. Immune cell infiltration and gene expression were analyzed using data from The Cancer Genome Atlas. Results Genetic alterations were frequently detected in PIK3CA (45.2%), EP300 (25.8%), RB1 (19.4%), FBXW7 (19.4%), and FAT1 (16.1%). Multivariate analysis identified mutations in ARID1A and B2M as independent predictors of poor DFS. Alterations in the antigen processing and presentation pathway were also associated with reduced survival rates. Patients with ARID1A and B2M mutations exhibited decreased immune cell infiltration and impaired antigen presentation, indicating a compromised immune response. Conclusion ARID1A and B2M mutations may serve as potential biomarkers for predicting treatment outcomes in cervical cancer patients undergoing dCRT. Testing for these mutations could help identify patients at higher risk of poor outcomes, guiding personalized treatment strategies to improve survival rates.

De-escalating first-line treatment in stage IVB or recurrent cervical cancer: outcomes of immunotherapy alone and systemic review

Abstract Introduction Chemo-immunotherapy (IO) is the preferred first-line treatment for stage IVB or recurrent cervical cancer. However, limited data exist on the efficacy and safety of using IO-alone as a de-escalation strategy. We report outcomes from a case series of selected patients treated with IO-alone and review the feasibility of de-escalating first-line treatment. Methods The authors conducted a literature review using Google Scholar and PubMed to identify reports using IO-alone as a de-escalation strategy across malignancies published between 1999 and December 2024 and also reviewed a cervical cancer database from a tertiary academic to identify patients with stage IVB or recurrent disease treated with IO-alone. The authors used the Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS). Results Among 582 patients treated between 2015 and 2021, 18 met the inclusion criteria. The median age was 43 years (range 28-84); 67% had squamous cell carcinoma, 11% adenocarcinoma, and 80% expressed PD-L1. CPS scores were <1 in 20%, 1--10 in 33%, and >10 in 47%. Most patients had oligo-metastatic disease (83%). Treatment with IO-alone began a median of 7 months after platinum-based chemotherapy. Indications included prior adjuvant (44%) or neoadjuvant (22%) chemotherapy, clinical trial participation (11%), or patient preference (22%). Median PFS and OS were 27 months and 82 months, respectively. Conclusions These findings support the need for clinical trials evaluating IO-alone as a first-line treatment option for de-escalation in stage IVB or recurrent cervical cancer. Biomarker development is needed to better identify candidates for personalized therapy.

Barriers to adherence to cervical cancer screening care in Northern Tanzania

Abstract Background Cervical cancer disproportionately affects women in low- and middle-income countries compared to those in high-income countries because of the difference in quality and effectiveness of cervical cancer screening programs. An essential part of effective cervical cancer prevention is the continuum of care for a woman with a suspicious cervical lesion (SCL) consisting of appropriate treatment and, in Tanzania, a follow-up screening one year after treatment. This study aimed at identifying factors associated with non-adherence to the scheduled follow-up after treatment of a SCL. Additionally, the cervical cancer screening results one year after treatment were evaluated. Methods A total of 219 clients treated for a SCL between 2017 and 2021 from 8 centres in the Kilimanjaro region were interviewed. Contact and medical information of the clients was obtained at the facilities. Additionally, 11 in-depth interviews with healthcare providers were conducted. Results In the quantitative study, 143 (65.3%) clients treated for suspicious cervical lesions adhered to the recommended follow-up appointment. Significant factors associated with poor adherence were individual barriers such as failure to understand why they should return and access barriers to the health facility. The health workers mentioned a lack of awareness and financial challenges regarding transportation. Conclusion The complete journey of high-risk women needs attention, otherwise the primary screening will not be effective. Additional efforts are needed to address knowledge gaps and socio-economic problems during the follow-up.

Predictors of advanced-stage presentation among patients with a diagnosis of breast and cervical cancer in Ethiopia

Abstract Background Breast and cervical cancers are the most common causes of cancer incidence and mortality in women in Africa. Women with breast and cervical cancers in Sub-Saharan Africa are frequently diagnosed with their disease at advanced stages. Delays in seeking health, diagnosis, and treatment are contributing factors to high mortality in Ethiopia. This study aimed to assess predictors of advanced stage presentation among patients with breast and cervical cancer attending public hospitals in Addis Ababa, Ethiopia. Methods A cross-sectional study was conducted with a total of 418 patients at Tikur Anbessa specialized hospital and Saint Pauls’ Hospital Millennium Medical College from October to November 2021. Stages III and IV were considered advanced stages. Data were collected by reviewing medical records and face-to-face interviews with a structured questionnaire. Bivariate and multivariable analyses were performed to examine the association between independent and outcome variables. Results A total of 269 patients with breast cancer and 149 patients with cervical cancer were included in the study, and the mean age was 44 years (SD = 10.9 years) and 50 years (SD = 11.2) years, respectively. About 66.9% of breast cancers and 71.1% of cervical cancers were diagnosed at an advanced disease stage. Rural residence (adjusted odds ratio [AOR] = 2.041, 95% CI, 1.108-3.758), indirect referral (AOR = 3.8, 95% CI, 1.485-9.946), financial difficulty (AOR = 10, 95% CI,1.859-56.495), and cancer screening recommended during their visit (AOR = 4.029 95% CI, 1.658-10.102) were independent predictors of advanced-stage presentation. Conclusions This study revealed a high prevalence of advanced-stage breast and cervical cancer diagnosis in Ethiopia, like data collected 10 years ago, despite the introduction of a cancer control plan in 2015. For better implementation, interventions should aim to improve referral pathways, adapt screening and early detection services, and increase cancer awareness at the community level in a culturally accepted way.

Triage performance of DNA methylation for women with high-risk human papillomavirus infection

Abstract Objective DNA methylation is a promising biomarker for cervical cancer screening. This study aimed to validate the triage performance of cytological DNA methylation for detecting cervical intraepithelial neoplasia of grade 3 or worse (CIN3+) in women with high-risk human papillomavirus (hrHPV) infection from a large prospective cohort undergoing opportunistic screening in China (METHY3). Methods The triage performance for detecting CIN3+ lesions was compared between HPV16/18 genotyping, a liquid-based cytology (LBC) test, and the PAX1 and JAM3 methylation (PAX1m/JAM3m) test according to cervical pathologic outcomes. Among the 4394 women infected with hrHPV, 1105 had definitive cervical histological findings that were analyzed. Results For detecting CIN3+, the specificity of HPV16/18(+), the LBC result of ≥atypical squamous cells of undetermined significance (ASCUS), and PAX1m/JAM3m(+) was 66.4%, 23.9%, and 89.6%, respectively, with odds ratios of 4.24 (95% confidence interval [CI], 2.85-6.40), 4.44 (2.27-10.1), and 18.5 (12.1-28.7) (P < .001), respectively. PAX1m/JAM3m(+) had the highest area under the receiver operating characteristic curve (0.790, 95% CI, 0.747-0.832) in the whole cohort and in women of various ages. PAX1m/JAM3m (+) was detected in all patients with cancer (n = 28). Compared with HPV16/18 genotyping and the LBC test, PAX1m/JAM3m testing reduced referrals to colposcopy by 20.64 percentage points and 61.18 percentage points, respectively. Conclusions PAX1 m /JAM3 m testing is highly specific for detecting CIN3+. As a triage biomarker, it is superior to HPV 16/18 genotyping and LBC testing for women with hrHPV infection.

Barriers to adherence of posttreatment follow-up after positive primary cervical cancer screening in Ethiopia: a mixed-methods study

Abstract Background Even though it is preventable, cervical cancer contributes significantly to cancer-related mortality among Ethiopian women. Follow-up visits after treatment of precancerous lesions are essential to monitor lesion recurrence. In our previous study, we found a level of adherence to follow-up of 44.7%, but the reasons for low adherence have not been comprehensively explored within the Ethiopian context. This study aimed to identify these reasons by interviewing 167 women who had missed their follow-up appointments as well as 30 health professionals with experience in the field. Methods The study employed a mixed-methods approach: Quantitative data were collected through a telephone questionnaire conducted with 167 women who had a positive visual inspection with acetic acid (VIA) and had missed their follow-up appointments. Subsequently, in-depth interviews were conducted with 30 healthcare professionals, and an inductive content analysis was carried out. Results In the patient interviews, the reasons given most often were “lack of information about the follow-up” (35; 21.1%), “forgetting the appointment” (30; 18.1%), and “not seeing the need for follow-up” (24; 14.5%). Healthcare professionals identified various reasons such as lack of knowledge, living in a remote area/changing living area, forgetfulness, fear, poor counseling, a shortage of trained healthcare providers to give counseling and follow-up, and reminder-related barriers. Conclusion Lack of knowledge, forgetfulness, poor health-seeking behavior, and a lack of reminders were identified as barriers contributing to the low uptake of rescreening. Further interventions should target these by creating community awareness, improving patient counseling, tracing patients in need of follow-up, and making reminder calls or using SMS.

Pegylated liposomal doxorubicin in partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer: a prospective study

Abstract Background This study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) for patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer. Methods Patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer were recruited in this prospective, open-label, single-arm, multicenter study. Eligible patients were given 4-6 cycles of PLD (40 mg/m2 on day 1, every 4 weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life, and safety. Exploratory endpoints included the change trend of CA125 and platinum-free interval. Results Between June 2017 and November 2020, 167 eligible patients were included in the full analysis set. The median PFS and OS were 6.8 months (95% CI, 4.4-9.3 months) and 19.1 months (95% CI, 15.0-23.3 months), respectively. The ORR and DCR were 32.3% and 60.5%, respectively. The ORR (62.3 vs 22.5%) and DCR (84.9 vs 60.7%) of patients with a CA125 decrease after the first cycle were significantly higher than those without a CA125 decrease (all P < .05). Grade ≥ 3 and serious adverse events were reported in 9.9% and 3.9% of patients, respectively. No treatment-related death was observed. Conclusion PLD showed promising efficacy and manageable tolerability in patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer. ClinicalTrials.gov Identifier: Chinese Clinical Trial Registry, ChiCTR1900022962.

Treatment, outcomes, and resource utilization among patients with metastatic breast and advanced epithelial ovarian cancer, by BRCA1/2 and HRD status

Abstract Background Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis) are indicated for treatment of tumors with breast cancer susceptibility genes BRCA1/2 mutations and homologous recombination deficiency (HRD). Little is known about differences in care by BRCA1/2 and HRD status for breast and ovarian cancers. Methods We investigated clinical characteristics, treatment, clinical outcomes, and health-care resource utilization by BRCA1/2 or HRD status among patients diagnosed between 2018-2020 with HER2-negative metastatic breast (mBC) and advanced epithelial ovarian cancer (aEOC) in the United States community healthcare setting. Results The study included 314 patients with mBC and 465 with aEOC. Patients with mBC carrying a BRCA1/2 mutation were younger and had a higher proportion of triple negative cancer than non-carriers (50% vs 38%). Only 8% of eligible patients received a PARPi in first-line (1L) and 18% in second-line (2L) of treatment for mBC. In aEOC, patients with HRD were younger and a higher proportion received 1L maintenance treatment with a PARPi than patients with non-HRD tumors (95% vs 66%). In aEOC, patients without HRD had greater healthcare resource use. Patients with BRCA-mutated tumors had poorer overall survival (OS); there were no differences in OS by HRD status in aEOC. Conclusion This study demonstrated differences in treatment by BRCA1/2 and HRD status. There was low PARPi uptake among patients with BRCA-mutated mBC but not among patients with aEOC. In aEOC, the cost to “treat all” may outweigh benefits; identifying patients without HRD likely to benefit from PARPis is needed.

Real-World Delivery of Rucaparib to Patients with Ovarian Cancer: Recommendations Based on an Integrated Safety Analysis of ARIEL2 and Study 10

Abstract Treatment options for women with recurrent ovarian cancer who have received two or more prior lines of chemotherapy have recently expanded with the U.S. Food and Drug Administration (FDA) and European Commission (EC) approvals of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. As more oncologists begin to use rucaparib and other PARP inhibitors as part of routine clinical practice, awareness of possible side effects and how to adequately manage toxicities is crucial. In this review, we summarize the safety and tolerability of rucaparib reported in an integrated safety analysis that supported the FDA's initial approval of rucaparib in the treatment setting. Additionally, drawing on clinical data and our personal experience with rucaparib, we provide our recommendations on the management of common side effects observed with rucaparib, including anemia, blood creatinine elevations, alanine aminotransferase and aspartate aminotransferase elevations, thrombocytopenia, gastrointestinal-related events (e.g., nausea, vomiting), and asthenia and fatigue. These side effects, many of which appear to be class effects of PARP inhibitors, are often self-limiting and can be managed with adequate interventions such as treatment interruption and/or dose reduction and the use of supportive therapies. Supportive therapies may include blood transfusions for patients with anemia, prophylactic medications to prevent nausea and vomiting, or behavioral interventions to mitigate fatigue. Understanding and appropriate management of potential side effects associated with rucaparib may allow patients with ovarian cancer to continue to benefit from rucaparib treatment.

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation

Abstract Lessons Learned Background Cediranib, a vascular endothelial growth factor receptor inhibitor, suppresses expression of BRCA1/2 and RAD51 inducing homologous recombination DNA repair deficiency (HRD) in several cancer cell lines and xenograft models [1]. Olaparib provides a clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPDAC) with germline BRCA mutation (gBRCAmt) [2]. We hypothesized that cediranib induces HRD in the absence of gBRCAmt and synergizes with olaparib, resulting in an objective response in patients with mPDAC. Methods Patients with mPDAC with at least one prior systemic chemotherapy were enrolled. Patients with known gBRCAmt were excluded. Patients took cediranib 30 mg daily and olaparib 200 mg twice daily, orally. The primary endpoint was objective response (OR) rate. Results Nineteen patients received the study drugs. Seven patients came off treatment before the first restaging scan: six because of clinical progression and one because of an adverse event. No OR was observed. Six patients had stable disease (SD) as a best overall response. The median duration of SD was 3.1 months. The median overall survival was 3.4 months. Common treatment-related adverse events were fatigue, hypertension, and diarrhea. Conclusion Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.

A European, Observational, Prospective Trial of Trabectedin Plus Pegylated Liposomal Doxorubicin in Patients with Platinum-Sensitive Ovarian Cancer

Abstract Purpose The noninterventional, prospective NIMES-ROC phase IV study (NCT02825420) evaluated trabectedin plus pegylated liposomal doxorubicin (PLD) in real-life clinical practice. Patients and Methods Eligible participants included adults with platinum-sensitive recurrent ovarian cancer (PS-ROC) who had received one or more cycles of trabectedin/PLD before inclusion according to the marketing authorization. The primary endpoint was progression-free survival (PFS) according to investigator criteria. Results Two hundred eighteen patients from five European countries were evaluated, 72.5% of whom were pretreated with at least two prior chemotherapy lines and received a median of six cycles of trabectedin/PLD (range: 1–24). Median PFS was 9.46 months (95% confidence interval [CI], 7.9–10.9), and median overall survival (OS) was 23.56 months (95% CI, 18.1–34.1). Patients not pretreated with an antiangiogenic drug obtained larger median PFS (p < .007) and OS (p < .048), largely owning to differences between the two populations. Twenty-four patients (11.0%) had a complete response, and 57 patients (26.1%) achieved a partial response for an objective response rate (ORR) of 37.2%. Fifty-nine patients (27.1%) had disease stabilization for a disease control rate of 64.2%. No statistically significant difference in PFS, OS, or ORR was observed by BRCA1/2 status and platinum sensitivity. Most common grade 3/4 adverse events (AEs) were neutropenia (30.3%), anemia (6.4%), thrombocytopenia (5.5%), and asthenia (5.0%). No deaths attributed to treatment-related AEs or unexpected AEs occurred. Conclusion The combination of trabectedin/PLD represents a clinically meaningful and safe option for patients with PS-ROC regardless of prior treatment with an antiangiogenic drug, being comparable with previously observed outcomes in selected and less pretreated patients from clinical trials. Implications for Practice This noninterventional, prospective study, conducted in 57 reference sites across Europe, consistently confirmed that trabectedin plus pegylated liposomal doxorubicin (PLD) in routine clinical practice represents a clinically meaningful and safe option for women with platinum-sensitive recurrent ovarian cancer. Although the study population represented a heterogeneous, older, and more pretreated population than those in prospective clinical trials, the combination of trabectedin plus PLD induced comparable clinical benefits, with a similar and manageable safety profile. Overall, these findings show that trabectedin in combination with PLD maintains antitumor activity when administered to heavily pretreated patients in real-life clinical practice.

Exceptional Response of Cryoablation Followed by Pembrolizumab in a Patient with Metastatic Cervical Carcinosarcoma with High Tumor Mutational Burden: A Case Report

Abstract Cervical carcinosarcoma is an extremely rare type of neoplasm that lacks standard of care. Preclinical and clinical evidence has suggested that cryoablation in combination with immunotherapy may result in a synergistic effect, generating a more robust immune response to distant lesions. A few clinical trials have evaluated the efficacy of such combination treatment in a variety of solid tumors, but with conflicting results. This report describes the first clinical efficacy of cryoablation followed by pembrolizumab observed in a patient with tumor mutational burden (TMB)-high metastatic cervical carcinosarcoma that was negative for programmed cell death protein 1 expression, microsatellite instability stable, and had mutations in DNA polymerase epsilon (POLE). She had achieved complete response (CR) after 3 months of pembrolizumab treatment and had maintained CR as of the time of submission of this manuscript, with a progression-free survival of 11 months and counting. The case exhibited an exceptional response to cryoablation followed by pembrolizumab, potentially attributed to mutations in POLE, which lead to an extremely high TMB. This report paves the avenue for establishing treatment regimens for patients with TMB-high cervical carcinosarcoma. Key Points Owing to its rarity, cervical carcinosarcoma has not been well characterized, and currently, there is no standard of care for this disease. This report describes the first case of clinical efficacy of cryoablation followed by pembrolizumab observed in a patient with tumor mutational burden-high metastatic cervical carcinosarcoma. The case exhibited an exceptional response (maintained CR as of the time of submission of this article: 11 months) to cryoablation followed by pembrolizumab. This is the first POLE-mutated cervical carcinosarcoma case.

Cervical Cancer in Sub-Saharan Africa: A Multinational Population-Based Cohort Study of Care and Guideline Adherence

Abstract Background Cervical cancer (CC) is the most common female cancer in many countries of sub-Saharan Africa (SSA). We assessed treatment guideline adherence and its association with overall survival (OS). Methods Our observational study covered nine population-based cancer registries in eight countries: Benin, Ethiopia, Ivory Coast, Kenya, Mali, Mozambique, Uganda, and Zimbabwe. Random samples of 44–125 patients diagnosed from 2010 to 2016 were selected in each. Cancer-directed therapy (CDT) was evaluated for degree of adherence to National Comprehensive Cancer Network (U.S.) Guidelines. Results Of 632 patients, 15.8% received CDT with curative potential: 5.2% guideline-adherent, 2.4% with minor deviations, and 8.2% with major deviations. CDT was not documented or was without curative potential in 22%; 15.7% were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IV disease. Adherence was not assessed in 46.9% (no stage or follow-up documented, 11.9%, or records not traced, 35.1%). The largest share of guideline-adherent CDT was observed in Nairobi (49%) and the smallest in Maputo (4%). In patients with FIGO stage I–III disease (n = 190), minor and major guideline deviations were associated with impaired OS (hazard rate ratio [HRR], 1.73; 95% confidence interval [CI], 0.36–8.37; HRR, 1.97; CI, 0.59–6.56, respectively). CDT without curative potential (HRR, 3.88; CI, 1.19–12.71) and no CDT (HRR, 9.43; CI, 3.03–29.33) showed substantially worse survival. Conclusion We found that only one in six patients with cervical cancer in SSA received CDT with curative potential. At least one-fifth and possibly up to two-thirds of women never accessed CDT, despite curable disease, resulting in impaired OS. Investments into more radiotherapy, chemotherapy, and surgical training could change the fatal outcomes of many patients. Implications for Practice Despite evidence-based interventions including guideline-adherent treatment for cervical cancer (CC), there is huge disparity in survival across the globe. This comprehensive multinational population-based registry study aimed to assess the status quo of presentation, treatment guideline adherence, and survival in eight countries. Patients across sub-Saharan Africa present in late stages, and treatment guideline adherence is remarkably low. Both factors were associated with unfavorable survival. This report warns about the inability of most women with cervical cancer in sub-Saharan Africa to access timely and high-quality diagnostic and treatment services, serving as guidance to institutions and policy makers. With regard to clinical practice, there might be cancer-directed treatment options that, although not fully guideline adherent, have relevant survival benefit. Others should perhaps not be chosen even under resource-constrained circumstances.

Burden of Cancer and Utilization of Local Surgical Treatment Services in Rural Hospitals of Ethiopia: A Retrospective Assessment from 2014 to 2019

Abstract Background Global cancer estimations for Ethiopia announced 77 352 new cases in 2020 based on the only population-based registry in Addis Ababa. This study characterizes cancer patients in rural Ethiopia at 8 primary and secondary hospitals between 2014 and 2019. Patients and Methods All clinically or pathologically confirmed cancer cases that were diagnosed between 1 May 2014 and 29 April 2019 were included. A structured data extraction tool was used to retrospectively review patients’ charts and descriptive analysis was done. Results A total of 1298 cancer cases were identified, of which three-fourths were females with a median age of 42 years. Breast (38%) and cervical (29%) cancers were the most common among females, while prostate (19%) and oesophageal cancers (16%) were the most common among males. Only 39% of tumors were pathologically confirmed. Nearly two-thirds of the cases were diagnosed at an advanced stage. Surgery was the only accessible treatment option for more than half of the cancer patients, and systemic treatment (except endocrine) was rarely available. One in 5 patients did not receive the recommended surgical procedure, half due to patient refusal or lack of the patient returning to the hospital. Conclusion The pattern of cancer diagnoses in rural hospitals shows an exceptionally high burden in women in their middle-ages due to breast and cervical cancers. Advanced stage presentation, lack of pathology services, and unavailability of most systemic treatment options were common. The surgery was offered to nearly 60% of the patients, showing the significant efforts of health workers to reduce sufferings.

Sarcoid-like reactions in patients treated with checkpoint inhibitors for advanced solid tumors

Abstract Importance While new intrathoracic adenopathy in a patient with cancer can represent progression of disease, the differential diagnosis is broad. Sarcoid-like reactions (SLR) remain an underreported source of lymphadenopathy in patients treated with immune checkpoint inhibitors (ICI), with limited reports in patients with cancers other than melanoma. Objective To characterize SLRs among patients treated with ICI for advanced solid tumors. Methods Data were collected on the clinical, pathologic, and radiographic presentation of patients treated with ICI who developed clinical or imaging findings suggestive of an SLR, including the presence of hilar or mediastinal lymphadenopathy, cutaneous/subcutaneous involvement, and/or worsening of existing sarcoidosis on ICI. Results Twelve patients were identified as having experienced an SLR. While 6 patients had melanoma, SLRs were also observed among patients with lung, gynecologic, and genitourinary cancers, including high-grade serous ovarian carcinoma, and an angiomyolipoma. Median time from initiation of ICI to diagnosis of an SLR was 3.4 months (range: 1.8-9.1). All but one patient (92%) were deemed to have had a radiographic response to ICI. Conclusions and relevance Clinicians should maintain the awareness of the possibility of SLRs in patients receiving ICI, particularly in patients whose scans show evidence of “mixed” response, with decreases in certain lesions coupled with new/increasing intrathoracic lymphadenopathy and/or other systemic signs of sarcoid.

The impact of inter-cycle treatment delays on overall survival in patients with advanced-stage ovarian cancer

Abstract Introduction Chemotherapy forms the cornerstone of systemic treatment for advanced ovarian cancer, extending overall survival; however, drug-related toxicity can lead to treatment delays, potentially diminishing treatment efficacy. This study evaluated the impact of treatment delays on all-cause mortality of patients with ovarian cancer, to better inform decisions on patient management. Methods This retrospective, population-based cohort study included 1517 women with advanced-stage ovarian cancer, receiving first-line adjuvant or neoadjuvant chemotherapy in 2014 and 2015. The frequency of inter-cycle delays >7 days was calculated using drug administration dates. Kaplan-Meier estimates were used to compare 2-year overall survival (OS) between patients who were delayed and those treated to schedule. Cox proportional hazards regression was used to investigate the impact of treatment delay on all-cause mortality. Inverse probability of treatment weighting propensity scores were used to adjust for confounding variables. Results Delays >7 days occurred in 35.3% of patients. Two-year OS probability was 62.7% in patients who experienced treatment delays >7 days (95% CI, 58.7-66.9) compared to 69.1% in those treated to schedule (95% CI, 66.2-72.0). Delays were not significantly associated with all-cause mortality when adjusted for confounders (HR 1.00 95% CI, 0.83-1.20, P = .9). Conclusions Delays to chemotherapy treatment were not significantly associated with worsened survival in patients with advanced-stage ovarian cancer. These results can inform clinical decision making that prioritize toxicity management and quality of life for those treated with chemotherapy.

Adherence to Treatment and Follow-Up of Precancerous Cervical Lesions in Ethiopia

Abstract Background In Ethiopia, both incidence and mortality of cervical cancer are relatively high. Screening services, which were implemented during the past few years, are currently being expanded. The World Health Organization recommends patients with a positive VIA (visual inspection with acetic acid) result should immediately receive treatment followed by rescreening after 1 year as precancerous lesions can reoccur or become residential despite treatment. Materials and Methods Screening logbooks dating between 2017 and 2020 were retrospectively reviewed in 14 health facilities of Addis Ababa and Oromia region. Data for 741 women with a VIA-positive result were extracted and those women were asked to participate in a questionnaire-based phone interview to gain insights about adherence to treatment and follow-up. Data were analyzed using descriptive methods and then fitted into 2 generalized linear models to test variables for an influence on adherence to follow up. Results Around 13 800 women had received a VIA screening, of which approximately 820 (5.9%) were VIA positive. While over 90% of women with a positive screen received treatment, only about half of the treated patients returned for a follow-up examination. After treatment, 31 women had a VIA-positive re-screen. We found that educational status, age over 40, no/incorrect follow-up appointment, health facility-related barriers, and use of reminders are important drivers of adherence to follow up. Conclusion Our results revealed that adherence to treatment after VIA positive screening is relatively high whereas adherence to follow up recommendations still needs improvement. Reminders like appointment cards and phone calls can effectively reduce the loss of follow-up.

FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA-Mutated Metastatic Castrate-Resistant Prostate Cancer

Abstract The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%–57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3–4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. Implications for Practice The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug.

Bridging adjuvant treatment gaps: low and intermediate risk endometrial carcinoma patients care in Salah Azaiez Institute in Tunisia

Abstract Background The management of low- and intermediate-risk endometrial carcinoma (EC) at the Salah Azaiez Institute (SAI) has evolved with international recommendations and the advent of the molecular era. We lack access to molecular profiling; consequently, both undertreatment and overtreatment are observed. This study explores how adherence to international recommendations affects clinical outcomes. Methods We performed a retrospective analytic study including 180 women with stage I–II low-, low-intermediate-, and high-intermediate-risk EC treated at SAI between 2015 and 2020, with at least 3 years of follow-up. Ethical approval and patient consent were obtained; for telephone interviews, verbal consent was secured. We selected 60 women per risk group from a larger pool to ensure comparability. Eleven histopathologic slides exhibiting lymphovascular space invasion (LVSI) were reviewed independently by 2 experienced pathologists to distinguish focal from extensive LVSI; no slides without LVSI were reexamined. Risk stratification followed the 2020 ESGO–ESTRO–ESP guidelines, and adjuvant treatments were assessed according to the 2021 ESGO–ESTRO recommendations. Pelvic lymphadenectomy was the standard nodal assessment; sentinel lymph node (SLN) mapping was not available during the study period. Results Median age was 60 years (range 35–69). After histopathologic review, 51.1% of tumors were grade 2, 54.5% had under 50% myometrial invasion, 8.3% had extensive LVSI, and 3.9% had focal LVSI. Forty-seven per cent of patients received guideline-concordant therapy, 47% were over-treated, and 6% were under-treated. Over-treated women had a 7.9-fold higher risk of death and a 6.6-fold higher risk of recurrence than appropriately treated women. Under-treatment was not a significant prognostic factor. Overtreatment and guideline-concordant therapy were both associated with higher rates of gastrointestinal, genitourinary, and sexual toxicities. Conclusion Limited access to molecular profiling constrains personalized care in Tunisia. Strict adherence to current guidelines is essential to avoid unnecessary toxicity, and the integration of molecular classification and SLN mapping should be prioritized.

“Showing some care”: interest-holders’ perspectives on addressing health-related social conditions in ovarian cancer

Abstract Background Health-related social conditions (HRSCs) are modifiable factors affecting ovarian cancer outcomes. How best to manage HRSCs as part of ovarian cancer care remains unclear. We sought interest-holder perspectives on HRSC assessment and assistance to inform integration of social care with gynecologic oncology practice. Methods In this qualitative descriptive study, we conducted individual, semi-structured interviews with patients with ovarian cancer, their caregivers, and oncology clinicians from an academic medical center. We solicited thoughts on HRSC assessment and assistance, including whether and how HRSC discussions should occur, as well as opinions on a 20-item HRSC assessment and a community resource referral document. We analyzed data using the Rigorous and Accelerated Data Reduction (RADaR) technique. Results Participants (n = 14) included 5 patients with ovarian cancer, 4 caregivers, and 5 clinicians. Patients and caregivers were open to HRSC conversations with clinicians from various disciplines if undertaken with empathy, respect, and active listening. In addition to common HRSCs like food insecurity and housing instability, participants endorsed attending to religion/spirituality and assessing for financial hardship, interpersonal violence, psychological support, and neighborhood safety. Patients and clinicians characterized the HRSC screening questions as straightforward and in-depth. All participants felt the community resource referral document was well-organized and helpful. Conclusion Even in the context of a life-threatening disease, participants affected by and caring for patients with ovarian cancer regard social conditions as relevant to cancer care. Our findings inform practical considerations of who, what, when, where, why, and how HRSC assessment and assistance can be undertaken in oncology.

A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma

Abstract Background ONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients. Methods This single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies. Results Twenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor–positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n = 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets. Conclusion ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).

Next-Generation Sequencing in the Diagnosis of Metastatic Lesions: Reclassification of a Glioblastoma as an Endometrial Cancer Metastasis to the Brain

Abstract Endometrial cancer is the most common gynecologic cancer in the U.S., but metastasis to the brain is rare, and diagnosis can be challenging. Traditional tools for determining if a tumor is a primary or metastatic lesion include pan-imaging, histopathologic studies, and immunohistochemistry. Molecular testing with next-generation sequencing has been increasingly used to augment these tests. We present a case of a patient who initially presented with a brain lesion diagnosed as glioblastoma on histology and immunohistochemistry, but whose diagnosis was later changed to metastasis from an endometrial primary based on molecular findings. The two tumors shared a common microsatellite instability signature and 51 DNA variants, including oncogenic driver mutations KRAS p.G13D, PIK3CA p.E545A, and PTEN p.I135V and p.K267Rfs*9. This highlights the power of molecular analysis in making the diagnosis in cases of rare metastases. Key Points Brain metastasis from endometrial primary is rare, and histopathological features may be augmented with molecular analysis to aid in diagnosis. Comparison of the molecular makeup of the primary endometrial lesion with the metastatic lesion may reveal high-risk molecular features that may be indicative of metastatic potential.

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab

AbstractBackgroundThe combination of lenvatinib plus pembrolizumab has shown efficacy in treatment of advanced endometrial carcinoma (that is not microsatellite instability–high or mismatch repair deficient) following prior systemic therapy in any setting in the open-label, single-arm, phase Ib/II Study 111/KEYNOTE-146. With the exception of hypothyroidism, the safety profile of the combination was comparable to that of each monotherapy. Given the medical complexity and fragility of patients with endometrial carcinoma, further characterization of adverse reactions (ARs) associated with treatment will help health care professionals to optimize treatment with lenvatinib plus pembrolizumab combination therapy.Patients and MethodsIn Study 111/KEYNOTE-146, patients received lenvatinib at a starting dose of 20 mg orally once daily and pembrolizumab 200 mg intravenously every 3 weeks. Selected ARs (hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria) were chosen for detailed post hoc analyses.ResultsMedian times to first onset of the selected ARs in this analysis all occurred within the first 10 weeks of treatment. Of the selected ARs, grade ≥3 severity of fatigue, hypertension, and nausea occurred in ≥5% of patients. Overall incidence of hypothyroidism was 51%, primarily of grade 2 severity (46%). Most of the ARs assessed were managed with a combination of study drug dose modifications and concomitant medications.ConclusionNo new safety signals were identified and the toxicity profile in this study was manageable with supportive medications, dose interruptions, and/or lenvatinib dose reductions. This analysis provides AR management guidance for patients with endometrial cancer receiving lenvatinib plus pembrolizumab combination therapy.Implications for PracticeLenvatinib plus pembrolizumab has shown efficacy in the treatment of patients with advanced endometrial carcinoma (that is, not microsatellite instability–high or mismatch repair deficient) following at least one prior systemic therapy in any setting. Patients may experience toxicity associated with this combination, including adverse reactions of hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria. These adverse reactions may be managed with a combination of concomitant supportive care medications and judicious lenvatinib dose modifications. This article provides context and guidance for the recognition and management of adverse reactions in patients receiving lenvatinib plus pembrolizumab.

A Durable Response to Pembrolizumab in a Patient with Uterine Serous Carcinoma and Lynch Syndrome due to the MSH6 Germline Mutation

Abstract Pembrolizumab, a programmed death 1 ligand (PD-1) checkpoint inhibitor, has elicited responses in mismatch repair (MMR)–deficient advanced solid tumors, leading to its agnostic approval by the US Food and Drug Administration in 2017 when no other therapeutic options are available. However, there are still insufficient data on the response to checkpoint inhibitors in advanced endometrial cancer related to Lynch syndrome (LS) and, specifically, in uterine serous carcinoma, which is uncommon in LS. Here we report a case of metastatic uterine serous carcinoma due to a germline MSH6 mutation (Lynch syndrome) that was discovered because of a patient's tumor MMR deficiency. The patient was started on first-line pembrolizumab in 2018 and sustained a partial response. She remains asymptomatic and progression free for more than 2 years. Tumor sequencing showed a high mutational burden and an upstream somatic mutation in the same gene, p.F1088fs. Immunohistochemical staining was negative for PD-L1 expression. We discuss clinical characteristics of the patient, molecular features of her tumor, and the mechanism of her tumor response. We also discuss the duration of immunotherapy in her case. Our case demonstrated a partial response and a long-term remission from the frontline single-agent pembrolizumab in a woman with metastatic uterine serous carcinoma and Lynch syndrome due to a germline MSH6 gene mutation. Our experience suggests a potential significant clinical benefit of checkpoint inhibitors used as single agents early on in the treatment of MMR-deficient/high microsatellite instability/hypermutated uterine cancers in women with Lynch syndrome. Key Points Even though checkpoint inhibitors are effective in mismatch repair-deficient endometrial cancer, it is unknown whether the response to them differs between women with endometrial cancer due to germline mutations in a mismatch repair gene (Lynch syndrome) and women with sporadic endometrial cancer. In our case, a patient with Lynch syndrome and recurrent mismatch repair-deficient serous endometrial cancer achieved a durable remission on the first-line therapy with the checkpoint inhibitor pembrolizumab and remains progression free after more than 2 years. Based on our observation and the data, suggesting the stronger immune activation in women with Lynch syndrome–associated endometrial cancer, we propose to use checkpoint inhibitor monotherapy early in the course of their treatment and stratify patients for the presence of Lynch syndrome in clinical trials.

Supporting our survivors: an evaluation of the facilitators and barriers to advocacy in cervical and breast cancer survivors

Abstract Purpose This study aimed to evaluate the facilitators and barriers to self-advocacy and advocacy in the community of cervical and breast cancer survivors. Methods A mixed-methods approach was used to collect data from patients with breast and cervical cancer. Qualitative interviews were conducted after presenting for routine oncologic follow-up appointments All interviews were transcribed and coded by two separate investigators. The Female Self-Advocacy in Cancer Survivorship Scale (FSACS) was administered and demographic data were collected to quantitatively evaluate self-advocacy behaviors and socioeconomic characteristics in the two groups. Results Twenty-one patients were interviewed: 11 cervical cancer (CC) patients and 10 breast cancer (BC) patients. The median age was 47 years, with approximately half having early-stage disease and half having advanced or recurrent disease. The facilitators to self-advocacy included being open with their support system, wanting more information, and being determined to fight. Barriers to self-advocacy included fear, not opening up to family and friends, and not wanting additional information. Facilitators to advocacy in the community were talking with their children about their diagnosis, having an interest in support groups, and a desire to help. Barriers to community advocacy included not always feeling supported, a lack of confidence, and a lack of understanding of their disease process. CC participants scored lower on the FSACS survey compared to BC patients, with mean scores of 95 and 107, respectively. Conclusions Facilitators to advocacy involve having a strong social network and a determination to fight or desire to help. Barriers include fear, lack of confidence, and lack of knowledge. Increasing resources to encourage social connection, education, and advocacy opportunities can positively impact cancer survivors well-being.

Clinicopathological and immune characterization of mismatch repair deficient endocervical adenocarcinoma

Abstract Endocervical adenocarcinoma (ECA) is reported increasingly often in young women, and this aggressive disease lacks effective methods of targeted therapy. Since mismatch repair deficiency (dMMR) is an important biomarker for predicting response to immune checkpoint inhibitors, it is important to investigate the clinicopathological features and immune microenvironment of dMMR ECAs. We assessed 617 ECAs from representative tissue microarray sections, gathered clinicopathologic information, reviewed histological characteristics, and performed immunohistochemical staining for MMR, programmed cell death 1 (PD-L1), and other immune markers. Of 617 ECA samples, 20 (3.2%) cases had dMMR. Among them, loss of MMR-related proteins expression was observed in 17/562 (3.0%) human papilloma virus-associated (HPVA) adenocarcinoma and 3/55 (5.5%) non-HPV-associated (NHPVA) adenocarcinoma. In NHPVA cohort, dMMR status was observed in 3 (3/14, 15.0%) patients with clear cells. dMMR ECAs had a higher tendency to have a family history of cancer, larger tumor size, p16 negative, HPV E6/E7 mRNA in situ hybridization (HPV E6/E7 RNAscope) negative, and lower ki-67 index. Among the morphological variables evaluated, poor differentiation, necrosis, stromal tumor-infiltrating lymphocytes, peritumoral lymphocytes, and lymphoid follicles were easily recognized in the dMMR ECAs. In addition, dMMR ECAs had higher CD3+, CD8+, CD38+, CD68+ and PD-1+ immune cells. A relatively high prevalence of PD-L1 expression was observed in dMMR ECAs. dMMR ECAs were significantly more likely to present with a tumor-infiltrating lymphocytes -high/PD-L1-positive status. In conclusion, dMMR ECAs have some specific morphological features and a critical impact on the immune microenvironment, which may provide insights into improving responses to immunotherapy-included comprehensive treatment for ECAs in the future.

Immunotherapy May Improve Tumor Sensitivity to Palliative Chemotherapy in Platinum Resistant Ovarian Cancer

AbstractOvarian cancer is the second most common gynecologic cancer in the US and ranks among the top 10 causes of female cancer-related deaths. Platinum-resistant disease carries a particularly poor prognosis and leaves patients with limited remaining therapeutic options. Patients with platinum-resistant disease have significantly lower response rates to additional chemotherapy, with estimates as low as 10%-25%. We hypothesize that in patients with platinum-resistant ovarian cancer, treatment with immunotherapy followed by cytotoxic chemotherapy with antiangiogenic therapy results in prolonged survival without compromising quality of life. Our experience of 3 patients with recurrent, metastatic platinum-resistant ovarian cancer treated with immunotherapy followed by anti-angiogenic treatment plus chemotherapy resulted in progression-free survival durations significantly above previously published averages. Further studies evaluating the role of immunotherapy followed by chemotherapy in combination with drugs targeting angiogenesis are needed and may provide a long-sought after breakthrough for advancing survival in platinum-resistant ovarian cancer.

Financial Toxicity: Unveiling the Burden of Cancer Care on Patients in Rwanda

Abstract Introduction Cancer is a major public health problem in Rwanda and other low- and middle-income countries (LMICs). While there have been some improvements in access to cancer treatment, the cost of care has increased, leading to financial toxicity and treatment barriers for many patients. This study explores the financial toxicity of cancer care in Rwanda. Methods This prospective cross-sectional study was conducted at 3 referral hospitals in Rwanda, which deliver most of the country’s cancer care. Data were collected over 6 months from June 1 to December 1, 2022 by trained research assistants (RAs) using a modified validated data collection tool. RAs interviewed consecutive eligible patients with breast cancer, cervical cancer, colorectal cancer, Hodgkin’s and non-Hodgkin’s lymphoma who were on active systemic therapy. The study aimed to identify sources of financial burden. Data were analyzed using descriptive statistics. Results 239 patients were included; 75% (n = 180/239) were female and mean age was 51 years. Breast, cervix, and colorectal cancers were the most common diagnoses (42%, 100/239; 24%, 58/239; and 24%, 57/239, respectively) and 54% (n = 129/239) were diagnosed with advanced stage (stages III-IV). Financial burden was high; 44% (n = 106/239) of respondents sold property, 29% (n = 70/239) asked for charity from public, family, or friends, and 16% (n = 37/239) took loans with interest to fund cancer treatment. Conclusion Despite health insurance which covers many elements of cancer care, a substantial proportion of patients on anti-cancer treatment in Rwanda experience major financial toxicity. Novel health financing solutions are needed to ensure accessible and affordable cancer care.

PARP inhibitors in gastric cancer: unlocking precision oncology

Abstract Gastric cancer (GC) demonstrates frequent alterations in homologous recombination repair (HRR) genes, and preclinical studies have demonstrated a clear synthetic lethality between HRR deficiency (HRD) and PARPi. While such preclinical synthetic lethality has translated into clinical benefits of PARPi in patients with HRD breast, ovarian, pancreatic, or prostate cancer, the therapeutic role of PARPi in GC remains unclear due to molecular heterogeneity and lack of validated biomarkers for patient selection. This review summarizes the mechanistic foundation for PARPi sensitivity in HRR-deficient GC tumors and evaluates emerging biomarkers, including genomic instability scores, RAD51 foci formation, mutational signatures, and candidate genes such as BRCA1/2, PALB2, and BARD1. We highlight key clinical trials and ongoing research aimed at refining patient selection, optimizing combination strategies, and identifying predictive biomarkers. Improving biomarkers to identify bona fide HRD is essential to optimizing PARPi as a valuable treatment option for patients with GC. We outline a pathway for biomarker-guided adoption of PARPi in GC management. Early-phase clinical trials of PARPi monotherapy in GC have yielded limited efficacy, likely due to variable HRD status and other mechanisms of primary resistance. Combining PARPi with chemotherapy, immune checkpoint inhibitors, or anti-angiogenic agents offers strategies to potentially increase the tumor susceptibility to PARPi and overcome resistance.

Delayed Versus Immediate Start of Chemotherapy in Asymptomatic Patients With Advanced Cancer: A Meta-Analysis

Abstract Background Due to increased use of imaging, advanced stages of cancer are increasingly being diagnosed in an early, asymptomatic phase. Traditionally, chemotherapy is started immediately in these patients. However, a strategy wherein chemotherapy is withheld until symptoms occur may be beneficial for patients in terms of quality of life (QOL). A systematic review regarding optimal timing of chemotherapy including survival and QOL is lacking. Methods We systematically searched PubMed, EMBASE, and Cochrane for studies investigating the timing of start of chemotherapy in asymptomatic patients with advanced cancer. Overall survival (OS) was abstracted as primary, QOL, and toxicity as secondary outcomes. A meta-analysis was performed on OS. QOL was described using the global health status derived from the EORTC-QLQ-C30 questionnaire and toxicity as grade 3-4 adverse events. Results Overall, 919 patients from 4 randomized controlled trials and 1 retrospective study were included. The included studies investigated colorectal cancer (n = 3), ovarian cancer (n = 1), and gastric cancer (n = 1). Pooled analysis demonstrated no significant differences in OS between delayed and immediate start of chemotherapy (pooled HR: 1.05, 95% CI, 0.90-1.22, P = .52). QOL, evaluated in 3 studies, suggested a better QOL in the delayed treatment group. Toxicity, evaluated in 2 studies, did not differ significantly between groups. Conclusion This meta-analysis confirms the need for prospective studies on timing of start of chemotherapy in asymptomatic patients with advanced cancer. The limited evidence available suggests that delayed start of chemotherapy, once symptoms occur, as compared to immediate start in asymptomatic patients does not worsen OS while it may preserve QOL.

Development of tele-lifestyle-based multidisciplinary survivorship program for gynecologic oncology practice

Abstract We assessed the recruitment and retention of a short 8-week telemedicine-based group peri-habilitation program for gynecologic cancer survivors. Multidisciplinary team included: a gynecologic oncologist with additional board certification by the American College of Lifestyle Medicine, cancer-specific nutritionist, culinary medicine chef, physical therapist, exercise physiologists, mental health counselor, body image aesthetician, pelvic floor therapist, and sex therapist. Pre- and post-self-administered questionnaires assessed conformity to lifestyle medicine pillars and a general medical symptom questionnaire (MSQ). Recruitment was suboptimal (11.7%). Neither provider referrals nor flyers sufficiently directed patients to the program, but those that completed the program expressed meaningful impact on lifestyle behavioral change and improved quality-of-life across multiple parameters including MSQ (40.0 vs 20.75) and 85% participants reported compliance with recommendations. This pilot program suggests that a multidisciplinary tele-lifestyle-based survivorship program beyond just diet and exercise to improve quality-of-life in gynecologic cancer survivors, though novel and well received, needs physician buy-in and enhanced marketing strategies.

Neoadjuvant Chemotherapy Followed by Vaginal Radical Trachelectomy as Fertility-Preserving Treatment for Patients with FIGO 2018 Stage 1B2 Cervical Cancer

Abstract Background Standard treatment for International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (i.e., tumor size between 2 and 4 cm) is a radical hysterectomy (RH) with pelvic lymph node dissection (PLND). We evaluated the oncological and fertility outcomes treatment in patients receiving a fertility-sparing alternative consisting of neoadjuvant chemotherapy (NACT) followed by vaginal radical trachelectomy (VRT). Methods Patients with stage 1B2 cervical cancer who wished to preserve fertility were included from September 2009 to September 2018. NACT consisted of 6-week cycles of cisplatin or carboplatin with paclitaxel. If tumor size decreased to 2 cm or smaller, NACT was followed by a robot-assisted PLND and VRT. Results Eighteen patients were included. Median follow-up time was 49.7 months (range 11.4–110.8). Median tumor size was 32 mm (range 22–40 mm). Complete remission after NACT occurred in seven women. Four women had a poor response on NACT. Three underwent RH with PLND; one received chemoradiation after PLND instead of VRT because of positive lymph nodes. The remaining 14 patients received VRT 3–4 weeks after NACT. Four recurrences occurred: three after NACT and VRT and one after NACT and RH. Median time to recurrence was 20.8 months (range 17.0–105.7). Three recurrences occurred in women with adenocarcinoma with lymph vascular space invasion (LVSI). In four women fertility could not be preserved. To date, four women had six pregnancies, including three live births born at term, two first trimester miscarriages, and one currently ongoing pregnancy. Conclusion NACT and VRT in women with stage 1B2 cervical cancer showed promising results. In 78% fertility was preserved. However, patients with poor response on NACT and with adenocarcinoma and/or LVSI were possibly at risk for recurrence. Long-term results in relation to fertility and oncological outcome are needed to corroborate these findings. Implications for Practice Standard treatment for women with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (tumor size 2–4 cm) is a radical hysterectomy and pelvic lymph node dissection (PLND). However, many of these women are young and wish to preserve fertility. Data on fertility-sparing treatment options are sparse, but neoadjuvant chemotherapy followed by a vaginal radical trachelectomy and PLND could be an alternative. Since 2009 we performed an observational cohort study in which 18 women opted for this treatment in our center. In 14 women fertility could be preserved. In four patients the tumor recurred. In four women six pregnancies occurred. After careful selection this treatment could be a good fertility-sparing treatment option.

An Indirect Comparison of the Efficacy and Safety of Dostarlimab and Doxorubicin for the Treatment of Advanced and Recurrent Endometrial Cancer

Abstract Background There is no clear standard of care for advanced/recurrent endometrial cancer (EC) following platinum-based therapy. Dostarlimab is approved for patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) advanced/recurrent EC. This indirect treatment comparison (ITC) assessed dostarlimab efficacy and safety from the single-arm GARNET (NCT02715284) trial compared with doxorubicin from ZoptEC (NCT01767155). Patients and Methods Patient-level data and study variables from GARNET Cohort A1 (dMMR/MSI-H EC) and the ZoptEC doxorubicin control arm were merged. Patients were matched based on eligibility criteria (main analysis population). Safety population included all patients who received treatment. The primary efficacy comparison outcome, overall survival (OS), was calculated using a Cox proportional hazards model, with adjusted stabilized inverse probability of treatment weighting. Modified assessment-scheduled matching Kaplan--Meier analysis was used for progression-free survival (PFS) and time to deterioration (TTD) in quality of life (QoL). Results In the main analysis population, median (95% CI) OS was not reached (NR; 18.0 months--NR) for dostarlimab (n = 92) and was 11.2 (10.0-13.1) months for doxorubicin (n = 233; HR: 0.41 [95% CI: 0.28-0.61]); median PFS was 12.2 (3.3-NR) and 4.9 (4.1-6.6) months, respectively. Median TTD in QoL was NR (2.5-NR; n = 61) and 4.5 (4.1-5.4; n = 188) months, respectively. Similar rates of adverse events (AEs, 11.6% vs 15.3%) and serious AEs (34.1% vs 30.1%) were observed with dostarlimab (n = 129) and doxorubicin (n = 249). Grade ≥3 AEs occurred in 48.1% vs 78.3%, respectively. Conclusion This ITC suggests a favorable benefit:risk profile for dostarlimab in patients with dMMR/MSI-H advanced/recurrent EC.

Risk of myelodysplastic syndrome and acute myeloid leukemia related to PARP inhibitor maintenance line in real-world ovarian cancer patients

Abstract Objective To estimate the risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) secondary to PARP inhibitors (PARPi), based on the line of treatment, in real-world ovarian cancer (OC) patients. Methods Using the TriNetX platform, we compared a cohort (experimental A) of 3402 OC patients treated with first-line maintenance PARPi to a control cohort of 1653 OC patients treated with platinum-based chemotherapy without PARPi. Experimental group B included 356 OC patients treated with PARPi after a platinum-sensitive relapse and was compared to a control cohort of 1503 patients who had not received PARPi after 2 lines of platinum-based chemotherapy. The cohorts were propensity score matched (PSM) 1:1 (experimental A vs control 1 and experimental B vs control 2) for age, race, bevacizumab treatment, and genetic susceptibility to neoplasms. A hazard ratio (HR) was used to compare the incidence of MDS and AML between the matched cohorts. Results In the first-line setting, 2 groups of 1346 matched OC patients (mean age 59.8 ± 10.2 SD) were evaluated. The overall incidence of MDS or AML was 1.9% and 0.1% in the experimental A and control groups, respectively (HR = 2.46; 95% CI 1.27-4.75, P = .006). For the platinum-­sensitive relapse setting, the HR was 1.76 (95% CI 0.42-7.37, P = .432). No significant differences were observed between the various PARPi used. Conclusions Our study indicates that PARPi may increase the risk of MDS or AML after first-line maintenance treatment. No significant differences were found across the types of PARPi used.

Left Ventricular Ejection Fraction in Patients With Ovarian Cancer Treated With Avelumab, Pegylated Liposomal Doxorubicin, or Both

Abstract In the phase III JAVELIN Ovarian 200 trial, 566 patients with platinum-resistant/refractory ovarian cancer were randomized 1:1:1 to receive avelumab alone, avelumab plus pegylated liposomal doxorubicin (PLD), or PLD alone. Cardiac monitoring was included for all patients. We report left ventricular ejection fraction (LVEF) data from the trial. Grade ≥3 cardiac adverse events (AEs) occurred in 4 (2.1%), 1 (0.5%), and 0 patients in the avelumab, combination, and PLD arms, respectively. LVEF decreases of ≥10% to below institutional lower limit of normal at any time during treatment were observed in 1 (0.8%), 3 (1.9%), and 2 (1.5%) patients, respectively; 4 had subsequent assessments, and these showed transient decreases. No patient had a cardiovascular AE related to LVEF decrease. This analysis is, to our knowledge, the first analysis of LVEF in patients receiving immune checkpoint inhibitors. ClinicalTrials.gov Identifier NCT02580058.

KRAS-Mutated, Estrogen Receptor-Positive Low-Grade Serous Ovarian Cancer: Unraveling an Exceptional Response Mystery

Abstract We report on a woman with aggressive estrogen receptor-positive, KRAS-mutated ovarian cancer who achieved a remarkable response to combination therapy with the MEK inhibitor (trametinib) and the aromatase inhibitor (letrozole), even though the disease had failed to respond to a combination of a PI3K inhibitor and different MEK inhibitor, as well as to trametinib and the estrogen modulator, tamoxifen, and to letrozole by itself. The mechanism of action for exceptional response was elucidated by in vitro experiments that demonstrated that the fact that tamoxifen can have an agonistic effect in addition to antagonist activity, whereas letrozole results only in estrogen depletion was crucial to the response achieved when letrozole was combined with an MEK inhibitor. Our current observations indicate that subtle variations in mechanisms of action of outwardly similar regimens may have a major impact on outcome and that such translational knowledge is critical for optimizing a precision medicine strategy. Key Points This report describes the remarkable response of a patient with KRAS-mutated, estrogen receptor-positive low-grade serous ovarian cancer treated with trametinib (MEK inhibitor) and letrozole (aromatase inhibitor), despite prior progression on similar agents including tamoxifen (estrogen modulator). In vitro investigation revealed that tamoxifen can have agonistic in addition to antagonistic effects, which could be the reason for the patient not responding to the combination of trametinib and tamoxifen. The current observations suggest that drugs with different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.

Response to Nivolumab and Ipilimumab in Microsatellite Instability-High (MSI-H) Cervical Carcinoma with Acquired Resistance to Pembrolizumab: A Case Report and Literature Review

Abstract As the use of immune checkpoint inhibitors (ICIs) in treating a variety of cancer types has increased in recent years, so too have the number of reports on patients acquiring resistance to these therapies. Overcoming acquired resistance to immunotherapy remains an important need in the field of immuno-oncology. Herein, we present a case that suggests sequential administration of combination immunotherapy may be beneficial to advanced cervical cancer patients exhibiting acquired resistance to mono-immunotherapy. The patient’s tumor is microsatellite instability-high (MSI-H), which is an important biomarker in predicting ICI response. Results from recent interim prospective studies using combination immunotherapy (eg, nivolumab and ipilimumab) with anti-PD-1 plus anti-CTLA-4 inhibitor following progression on anti-PD-1 inhibitors (eg, nivolumab) have shown anti-tumor activity in patients with advanced melanoma and metastatic urothelial carcinoma. We also introduce retrospective studies and case reports/case series of dual checkpoint inhibition with anti-PD-1 inhibitor plus anti-CTLA-4 inhibitor after progression on prior anti-PD/PD-L1 monotherapy. To date, there has been no prospective study on the use of combined anti-PD-1 and anti-CTLA-4 therapy at the time of progression on anti-PD-1 therapy in patients with MSI-H tumors or advanced cervical cancer. In this report, we provide evidence that supports future investigations into such treatments.

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis

Abstract Background Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. Methods To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. Clinical Report and Results We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered. Conclusion uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.

Association Between Pathologic Chemotherapy Response Score and Pattern of Recurrence in Advanced High-Grade Serous Ovarian Cancer

Abstract Background Chemotherapy Response Score (CRS) is a three-tier histopathologic system evaluating response to neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC). Methods We evaluated recurrence patterns and survival outcomes in advanced-stage HGSOC patients treated with NACT and interval debulking surgery (IDS) between 2015 and 2024. Results Among 238 patients, CRS3 was most frequent (43.3%) and was associated higher complete cytoreduction (CC0) rates (93%) compared to CRS2 (81%) and CRS1 (57%) (p < 0.001). Median follow-up was 35 months (IQR 12.6–42.2). Median progression-free survival (PFS) was 40.4 months for CRS3, 23.4 for CRS2, and 21.5 for CRS1 (p = 0.001). Among 109 (45.7%) patients who relapsed, 25 (23%) presented with oligometastatic disease (≤5 lesions), more frequently in CRS3 (46%) than CRS2 (8.9%) or CRS1 (15%) (p < 0.001). Specifically, peritoneal (p = 0.002) and nodal (p = 0.05) oligorecurrences were more common in the CRS3 group. CRS3 predicted oligometastatic recurrence (OR = 4.89; p = 0.008) and was associated with increased use of locoregional therapies (surgery or radiotherapy) at relapse (p = 0.014). Median overall survival (OS) was 93.9, 37.2, and 31.7 months for CRS3, CRS2, and CRS1, respectively (p < 0.001). Conclusions CRS3 predicts lower recurrence risk, increased rates of oligometastatic relapse, and greater use of locoregional treatments in patients with recurrent HGSOC after NACT and IDS.

Weekly Carboplatin and Paclitaxel: A Retrospective Comparison with the Three-Weekly Schedule in First-Line Treatment of Ovarian Cancer

Abstract Background Conventional first-line combination therapy for ovarian cancer comprises 6 cycles of adjuvant or neoadjuvant carboplatin (AUC5-6) with paclitaxel (175 mg/m2) every 3 weeks (PC-3W). Weekly scheduling of paclitaxel may maximize its antiangiogenic effect and reduce adverse effects. We compared the efficacy and safety of PC-3W with a modified protocol of weekly paclitaxel 80 mg/m2 and weekly carboplatin AUC2 administered on days 1, 8, and 15 in a 28-day cycle (i.e., with 1 week off-treatment [PC-W]). Materials and Methods Medical records of consecutive patients treated between 2000 and 2018 were reviewed; 707 patients were analyzed for demographic and clinical characteristics, effectiveness and toxicity. Results PC-3W was administered to 402 patients (median age, 60.5 years) and PC-W to 305 patients (median age, 62.5 years). Most patients (91.4%) were diagnosed at stage III–IV. Notwithstanding a higher proportion of residual disease and older patients in the PC-W group, median progression-free survival was 21.4 months and 13.2 months for PC-W and PC-3W, respectively; median overall survival was 75.2 and 54.0 months for PC-W and PC-3W, respectively. Cox proportional hazards model indicated improved survival for patients treated with PC-W (hazard ratio, 0.54). Similar results were observed for older patients diagnosed at ≥75 years. PC-W demonstrated a better safety profile, with lower incidence of neuropathy, neutropenia, and alopecia. Conclusion PC-W is as active and better tolerated than the standard PC-3W regimen. PC-W may serve as an alternative option for elderly or frail patients. Implications for Practice Weekly scheduling of paclitaxel 80 mg/m2 and carboplatin AUC2, administered on days 1, 8, and 15 in a 28-day cycle (PC-W) for first-line therapy for advanced ovarian cancer, is as active and better tolerated than the standard regimen of carboplatin and paclitaxel (175 mg/m2) every 3 weeks (PC-3W). It is possible that the weekly holiday on day 21 in the PC-W regimen may ensure better completion rates (which may result in treatment delays for toxicity in PC-3W). The results of this retrospective analysis highlight the weekly regimen as a valid treatment option, especially for elderly patients and those with significant comorbidities.

Phase II Trials of Iniparib (BSI-201) in Combination with Gemcitabine and Carboplatin in Patients with Recurrent Ovarian Cancer

AbstractBackgroundIniparib (BSI-201), a novel anticancer agent thought to have poly(ADP-ribose) polymerase (PARP) inhibitory activity and synergy with both gemcitabine and carboplatin (GC) was evaluated in 2 cohorts with GC.MethodsParallel multicenter, single-arm, phase II studies using a Simon two-stage design. Eligible patients had a histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and demonstration of platinum-sensitive (≥6 months [mo]) or -resistant disease (relapse 2-6 mo post-platinum). Carboplatin (AUC 4 IV day 1), gemcitabine (1000 mg/m2 IV days 1 and 8), and iniparib (5.6 mg/kg IV days 1, 4, 8, and 11) were given on a 21-day cycle.ResultsThe overall response rate (ORR RECIST 1.0) in platinum sensitive disease was 66% (95% CI, 49-80) with a higher response rate in the 15 pts with germline BRCA mutations (gBRCAmut) (73%). Median PFS was 9.9 (95% CI, 8.2-11.3) months. In the platinum resistant population the ORR was 26% (95% CI, 14-42), however in the 11 pts for whom BRCA mutation was present, the best overall response was PR in 5 (46%). Median PFS was 6.8 months (range, 5.7-7.7 months). Notably, among the 17 CA-125-response-evaluable patients who did not achieve tumor response, 7 (41.2%) patients had a CA125 response, and 93% has clinical benefit (CR + PR + SD). The GCI combination was generally well tolerated despite a high incidence of thrombocytopenia and neutropenia, with no new toxicities.ConclusionsGiven the subsequent lack of efficacy demonstrated for iniparib in breast cancer, these are studies of GC and demonstrate a higher than traditionally appreciated activity in patients with platinum-sensitive and -resistant recurrent ovarian cancer, especially in patients that harbor a BRCA mutation, resetting the benchmark for efficacy in phase II trials. (ClinicalTrials.gov Identifiers: NCT01033292 & NCT01033123).

Clinical Characteristics and Mutation Analyses of Ovarian Sertoli-Leydig Cell Tumors

AbstractBackgroundThere are limited studies on Sertoli-Leydig cell tumors (SLCTs) and no data in the population of Chinese patients with SLCTs from the genetic level. In addition, previous studies on SLCTs have focused exclusively on mutations in the DICER1 gene and no data exists on the genetic landscape of SLCTs.MethodsPatients with moderately or poorly differentiated SLCTs who underwent surgical resection between January 2012 and October 2018 in our institution were recruited. Whole exome sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue and peripheral blood or normal tissue samples.ResultsSeventeen patients were recruited with 19 tumor samples. The rate of tumor-associated germline mutations was 6 of 17 (35.3%), and that of DICER1 germline mutations was 4 of 17 (23.5%). Regarding clinical relapse, patients with germline tumor-associated mutations had significantly poorer prognosis than those without (p = .007), and those with germline DICER1 mutations were relatively more likely to exhibit clinical relapse, although not to a significant degree (p = .069). Regarding somatic mutations, firstly, the subclone evolution analysis demonstrated that the two tumors on the contralateral ovary were primary tumors, respectively. Secondly, somatic mutations were most commonly found in CDC27 (10/19, 52.6%), DICER1 (4/19, 21.1%), and MUC22 (4/19, 21.1%). And the analysis of cancer cell fractions showed that DICER1 mutations were correlated with tumorigenesis of SLCTs. The rates of germline and somatic DICER1 mutations were higher in patients who were younger than 18 years than those in older patients (p = .022 and p = .001, respectively).ConclusionOur study indicates that genetic testing may have important clinical significance for patients with SLCTs, particularly for younger patients.Implications for PracticeBilateral ovarian Sertoli-Leydig cell tumors were verified to be primary tumors from the genetic perspective. The rates of germline and somatic DICER1 mutations were 4 of 17 (23.5%) and 4 of 19 (21.1%), respectively. The rates of germline and somatic DICER1 mutations were higher in patients who were younger than 18 years than those in older patients (p = .022 and p = .001, respectively).

Clinicopathologic Characteristics and Impact of Oophorectomy for Ovarian Metastases from Colorectal Cancer

Abstract Background As survival with metastatic colorectal cancer (CRC) and imaging modalities improve, detection of ovarian metastases may be increasing. The ovary may serve as a sanctuary site for malignant cells; however, there is a paucity of data regarding the role for oophorectomy. Methods This is a single-institution retrospective study of patients with CRC with ovarian metastases from 2009 to 2017. We evaluated patient, disease, and treatment related factors associated with overall survival (OS) from initial diagnosis of metastatic CRC. Results Of 108 patients assessed, the median age was 50, 19% had localized disease at initial presentation, 64% had ovarian metastases at initial CRC diagnosis, and 77% underwent oophorectomy. Median OS was 29.6 months across all patients, and it was 36.7 months in patients who underwent oophorectomy versus 25.0 months in patients who did not (hazard ratio [HR] 0.54). In multivariate analysis, the effect of oophorectomy on OS suggested protection but was not statistically significant (HR 0.57). Resection of primary tumor was performed in 71% of patients, which was independently associated with improved OS (HR 0.21). Twelve patients (11%) remained alive at 5 years after diagnosis of metastatic disease. Conclusion Although it has been previously reported that patients with CRC with ovarian metastases have poor prognosis, the median OS for this cohort was comparable to existing OS data for patients with metastatic CRC. In patients treated with chemotherapy, we did not find the ovarian metastasis to frequently serve as a sanctuary site of disease. However, we found that in carefully selected patients, oophorectomy may confer a survival benefit. Implications for Practice In colorectal cancer (CRC) ovarian metastasis is not necessarily associated with worse prognosis than metastasis to other sites. In carefully selected patients with ovarian metastases from CRC, oophorectomy may confer a survival benefit. Specifically, development of ovarian metastasis early in the disease course, resection of the primary tumor, and limited extraovarian metastatic disease are clinical features that are potentially associated with benefit from oophorectomy. A subset of patients with ovarian metastasis from CRC have potential to become long-term survivors (>5 years).

A Large, Multicenter, Retrospective Study on Efficacy and Safety of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Ovarian Cancer (MITO RT1 Study): A Collaboration of MITO, AIRO GYN, and MaNGO Groups

Abstract Background Recent studies have reported improvement of outcomes (progression-free survival, overall survival, and prolongation of androgen deprivation treatment-free survival) with stereotactic body radiotherapy (SBRT) in non-small cell lung cancer and prostate cancer. The aim of this retrospective, multicenter study (MITO RT-01) was to define activity and safety of SBRT in a very large, real-world data set of patients with metastatic, persistent, and recurrent ovarian cancer (MPR-OC). Materials and Methods The endpoints of the study were the rate of complete response (CR) to SBRT and the 24-month actuarial local control (LC) rate on “per-lesion” basis. The secondary endpoints were acute and late toxicities and the 24-month actuarial late toxicity-free survival. Objective response rate (ORR) included CR and partial response (PR). Clinical benefit (CB) included ORR and stable disease (SD). Toxicity was evaluated by the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) and Common Terminology Criteria for Adverse Events (CTCAE) scales, according to center policy. Logistic and Cox regression were used for the uni- and multivariate analysis of factors predicting clinical CR and actuarial outcomes. Results CR, PR, and SD were observed in 291 (65.2%), 106 (23.8%), and 33 (7.4%) lesions, giving a rate of CB of 96.4%. Patient aged ≤60 years, planning target volume (PTV) ≤18 cm3, lymph node disease, and biologically effective dose α/β10 > 70 Gy were associated with higher chance of CR in the multivariate analysis. With a median follow-up of 22 months (range, 3–120), the 24-month actuarial LC rate was 81.9%. Achievement of CR and total dose >25 Gy were associated with better LC rate in the multivariate analysis. Mild toxicity was experienced in 54 (20.7%) patients; of 63 side effects, 48 were grade 1, and 15 were grade 2. The 24-month late toxicity-free survival rate was 95.1%. Conclusions This study confirms the activity and safety of SBRT in patients with MPR-OC and identifies clinical and treatment parameters able to predict CR and LC rate.

GBAS Regulates the Proliferation and Metastasis of Ovarian Cancer Cells by Combining with eEF1A1

Abstract Background The glioblastoma-amplified sequence (GBAS) is a newly identified gene that is amplified in approximately 40% of glioblastomas. This article probes into the expression, prognostic significance, and possible pathways of GBAS in ovarian cancer (OC). Method Immunohistochemical methods were used to evaluate the expression level of GBAS in OC and its relationship with clinicopathological characteristics and prognosis. Glioblastoma-amplified sequence shRNA was designed to transfect into OC cell lines to silence GBAS expression, then detect the proliferation, apoptosis, and migration ability of the cell. Furthermore, an in vitro tumor formation experiment in mice was constructed to prove the effect of GBAS expression on the growth of OC in vivo. To further study the regulation mechanism of GBAS, we performed co-immunoprecipitation (Co-IP) and shotgun LC-MS mass spectrometry identification. Results Immunohistochemistry indicated that GBAS was markedly overexpressed in OC compared with normal ovarian tissue and was associated with lymph node metastasis. Inhibition of GBAS expression can significantly reduce OC cell proliferation, colony formation, promote cell apoptosis, and reduce the ability of cell migration and invasion. In vivo tumor formation experiments showed that the size and weight of tumors in mice after GBAS expression knockdown was significantly smaller. Glioblastoma-amplified sequence may be combined with elongation factor 1 alpha 1 (eEF1A1) to achieve its regulation in OC. Bioinformatics analysis data indicate that GBAS may be a key regulator of mitochondria-associated pathways, therefore controlling cancer progression. MicroRNA-27b, MicroRNA-23a, and MicroRNA-590 may directly targeting GBAS affects the biological behavior of OC cells. Conclusion The glioblastoma-amplified sequence may regulate the proliferation and metastasis of OC cells by combining with eEF1A1.

Homologous Recombination Deficiency: Concepts, Definitions, and Assays

AbstractBackgroundHomologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting.MethodsFriends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status.ResultsThis publication provides findings from the group’s discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community.ConclusionOverall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.

Cervical Cancer in Young Women: Do They Have a Worse Prognosis? A Retrospective Cohort Analysis in a Population of Mexico

Abstract Background Cervical cancer (CC) is a global problem; it is among the five leading causes of cancer death in women. Several studies have examined the association between age and disease prognosis; however, controversy still exists. The objective of the present study is to determine if age at diagnosis has an impact on overall survival (OS) and disease-free survival (DFS). Materials and Methods Retrospective cohort of 2,982 patients with CC treated at the National Cancer Institute of Mexico from 2005 to 2015. We collected demographic, clinical, and treatment data, as well as current status, of 2 groups: women under and over 40 years of age. We calculated OS and DFS rates with Kaplan-Meier estimates. Cox proportional hazards modeling was used to determine risks. Results The median follow-up time was 26.5 months (percentile [P]25–P75, 11–60.23). When comparing DFS, OS, stage, and histologic subtype between young patients <40 and adult patients >40, we did not observe any difference. We found that in both groups, locally advanced and advanced stage, neuroendocrine subtype, hydronephrosis, and positive inguinal lymph nodes increased the risks of death and recurrence. Having been pregnant was identified as protective factor in DFS (hazard ratio, 0.54; 95% confidence interval, 0.04–0.71). Conclusion We corroborated that age at diagnosis is not a prognostic factor for decreased or increased OS or DFS, and in both groups, the stage, histologic subtype, hydronephrosis, and node involvement were identified as factors adverse to OS and DFS, and pregnancy history was a protective factor in DFS. Implications for Practice The present study directly affects everyday clinical practice because it allows us to focus on the most relevant prognostic factors in patients with cervical cancer. When planning treatment and follow-up, clinicians should focus on stage at diagnosis, histologic subtype, hydronephrosis, and distant metastasis instead of patients’ age. They should also be aware of any previous pregnancies and poor response, or nonresponse, to treatment, which results in disease progression and persistence. Paying attention to these factors affecting overall survival and disease-free survival will help treat patients better and increase their chances of survival and improve their quality of life.

Anal cancer incidence among women with a history of vulvar cancer by histology, age, and time since diagnosis

Abstract Women with a history of vulvar cancer face a high risk of anal cancer; however, incidence according to histology, age-at, and time since vulvar cancer diagnosis remains unexplored. Using data from SEER-8 and SEER-17 registries, we identified 21,230 women with vulvar cancer, with 154,825 person-years follow-up from 1975 to 2021. We observed 95 anal cancer cases, resulting in an incidence of 61.4 per 100,000 person-years (95% CI, 49.6-75.0). Incidence was higher among women with vulvar squamous cell carcinoma (SCC) (78.7; 95% CI, 62.9-97.1) than vulvar non-SCC (19.8; 95% CI, 9.0-37.6). The highest incidence (>100 per 100,000) was observed in women <45 years old with vulvar SCC and those >10 years post-diagnosis. These findings could inform anal cancer screening guidelines, as women with vulvar cancer, particularly those diagnosed with SCC, may substantially benefit from heightened surveillance or targeted screening.

Adjuvant treatment strategy evolution and risk stratification for hormone receptor-positive, human epidermal growth factor receptor-2 negative early breast cancer in China

Abstract Background Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2−) early breast cancer (EBC) with high-risk clinicopathological features face an increased risk of recurrence. This study explored the evolving treatment landscape and clinical outcomes in patients with EBC using a nationwide database. Patients and Methods The study cohort comprised HR+/HER2−, stages 1-3, patients with EBC who underwent surgery and received adjuvant endocrine therapy (AET) from January 2013 to March 2021. High-risk patients were defined by ≥4 positive axillary lymph nodes, or 1-3 positive lymph node(s) with at least one high-risk feature (histologic grade 3, tumor size ≥5 cm, or Ki-67 ≥20%). A low-risk cohort included patients not meeting the criteria. Survival analysis was conducted with a cutoff of September 2021. Results The study included 4088 eligible patients (1310 high-risk patients and 2778 low-risk patients). High-risk patients were more likely to receive adjuvant chemotherapy and radiotherapy compared to low-risk patients. From 2013 to 2021, an increasing proportion of patients received aromatase inhibitors and ovarian function suppression as part of their AET. The 2-, 5-, and 7-year invasive disease-free survival for high-risk cohort were 90.67%, 75.26%, and 57.10%, respectively, these rates were notably higher for low-risk cohort at 97.14%, 89.85%, and 84.83%. High-risk patients demonstrated a higher risk of recurrence or death compared with low-risk patients (hazard ratio, 2.38; 95% CI, 1.82-3.12). Conclusion In the setting of standard or even intensive AET, patients with EBC with high-risk features still present high recurrence risk, highlighting the urgent need for innovative adjuvant treatment strategies.

Risk Stratification of Early-Stage Cervical Cancer with Intermediate-Risk Factors: Model Development and Validation Based on Machine Learning Algorithm

Abstract Background Adjuvant therapy for patients with cervical cancer (CC) with intermediate-risk factors remains controversial. The objectives of the present study are to assess the prognoses of patients with early-stage CC with pathological intermediate-risk factors and to provide a reference for adjuvant therapy choice. Materials and Methods This retrospective study included 481 patients with stage IB–IIA CC. Cox proportional hazards regression analysis, machine learning (ML) algorithms, Kaplan-Meier analysis, and the area under the receiver operating characteristic curve (AUC) were used to develop and validate prediction models for disease-free survival (DFS) and overall survival (OS). Results A total of 35 (7.3%) patients experienced recurrence, and 20 (4.2%) patients died. Two prediction models were built for DFS and OS using clinical information, including age, lymphovascular space invasion, stromal invasion, tumor size, and adjuvant treatment. Patients were divided into high-risk or low-risk groups according to the risk score cutoff value. The Kaplan-Meier analysis showed significant differences in DFS (p = .001) and OS (p = .011) between the two risk groups. In the traditional Sedlis criteria groups, there were no significant differences in DFS or OS (p > .05). In the ML-based validation, the best AUCs of DFS at 2 and 5 years were 0.69/0.69, and the best AUCs of OS at 2 and 5 years were 0.88/0.63. Conclusion Two prognostic assessment models were successfully established, and risk grouping stratified the prognostic risk of patients with CC with pathological intermediate-risk factors. Evaluation of long-term survival will be needed to corroborate these findings. Implications for Practice The Sedlis criteria are intermediate-risk factors used to guide postoperative adjuvant treatment in patients with cervical cancer. However, for patients meeting the Sedlis criteria, the choice of adjuvant therapy remains controversial. This study developed two prognostic models based on pathological intermediate-risk factors. According to the risk score obtained by the prediction model, patients can be further divided into groups with high or low risk of recurrence and death. The prognostic models developed in this study can be used in clinical practice to stratify prognostic risk and provide more individualized adjuvant therapy choices to patients with early-stage cervical cancer.

Acceptability, Utility, and Cost of a Mobile Health Cancer Screening Education Application for Training Primary Care Physicians in India

Abstract Purpose Mobile health (mHealth)–based oncology education can be a powerful tool for providing cancer screening knowledge to physicians, as mobile technology is widely available and inexpensive. We developed a mobile application (M-OncoED) to educate physicians on cancer screening and tested the acceptability, utility, and cost of two different approaches to recruit physicians. Methods M-OncoED was designed to perform pre- and postlearning assessments through the in-built quizzes; present case studies and educational materials for cervical, breast, and oral cancer screening; collect responses to interactive queries; document module completion; send reminders and alerts; and track user metrics, including number of sessions to complete each module and time spent per session. We tested two recruitment approaches: a broad-scale recruitment group, for which we relied on e-mails, messaging apps (e.g., WhatsApp), and phone calls, and the targeted recruitment group, for which we conducted a face-to-face meeting for the initial invitation. Results Overall, about 35% of those invited in the targeted group completed the course compared with about 3% in the broad-based recruitment group. The targeted recruitment approach was more cost-efficient ($55.33 vs. $109.43 per person). Cervical cancer screening knowledge increased by about 30 percentage points, and breast cancer screening knowledge increased by 10 percentage points. There was no change in knowledge for oral cancer scorings. Conclusion This study has demonstrated the feasibility and utility of using an mHealth app to educate physicians. A more intensive hands-on recruitment approach is likely required to engage physicians to download and complete the app. Future studies should assess the impact of mHealth tools on physician behavior and patient outcomes. Implications for Practice Mobile health (mHealth)–based oncology education can be a powerful tool for providing cancer screening knowledge to physicians, as mobile technology is widely available and inexpensive. This study has demonstrated the feasibility and utility of using an mHealth app to educate physicians and illustrates the type of recruitment approach (face-to-face) that is likely required to incentivize physicians to download the app and complete the training.

Unmet Needs in Oncology Clinical Research and Treatment in Africa: Focus on Ghana

Abstract Cancer incidence is increasing worldwide and is a major cause of mortality. The relative magnitude of the increase is remarkably high in low human development index (HDI; 95%) and medium HDI (64%) countries. On the African continent, a corresponding increase in cancer burden is predicted, particularly for sub-Saharan Africa. Current epidemiologic data indicate that mortality rates of certain cancers, such as breast and cervical cancers, in sub-Saharan Africa are the highest in the world, and the cancer risks are broadly comparable to the risks in high-income countries, such as the United States and Europe. Although emerging data alludes to the unique genetic profile of cancer in African populations, most cancer therapies are introduced to Africa without confirmatory clinical trials. Therefore, there is an increasing need for clinical trials directed toward prevention, screening, diagnosis, and identification of innovative treatments in the African context. This review will discuss the increasing cancer burden in Africa, with a particular focus on Ghana, unmet clinical needs in cancer, current medical systems, clinical trial regulatory systems, and challenges to clinical trial recruitment.

Clinical Implication of Simultaneous Intensity-modulated Radiotherapy Boost to Tumor Bed for Cervical Cancer with Full-thickness Stromal Invasion

Abstract Objective The objective of this study was to retrospectively explore the clinical implications of simultaneous intensity-modulated radiotherapy (IMRT) boost to the tumor bed in cervical cancer with full-thickness stromal invasion (FTSI). Patients and Methods Patients diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB and IIA cervical cancer with confirmed FTSI were included. Patients received pelvic IMRT from a dose of 50.4 Gy in 28 fractions with (or without) a simultaneous integrated boost (SIB) to 58.8 Gy in 28 fractions for the tumor bed. The progression-free survival (PFS), overall survival (OS), and pelvic-PFS (p-PFS) were analyzed using the Kaplan–Meier method, and independent prognostic factors were explored by Cox regression analyses. Results Patients without a tumor bed boost had a poor prognosis. The 5-year OS was 81.3% versus 58.3% and the 5-year PFS rates were 75.0% versus 57.6% (boost vs non-boost). The FIGO stage, pathology, adjuvant chemotherapy, and tumor bed boost were independent factors affecting both the 5-year OS and PFS. Subgroup analysis showed that the SIB group had a higher 5-year OS, PFS, and p-PFS for different stages, lymph node status, and risk groups than the non-SIB group. Recurrence occurred in 268 of 910 (29.5%) patients without SIB and 49 of 293 (16.7%) with SIB. Among patients with recurrence, 113 of 282 (40.1%) in the non-boost group compared with 14 of 51 (23.0%) patients in the boost group had a pelvic recurrence. Tumor bed boost resulted in an increase in the mean radiation dose to the intestine, rectum, and bladder, although there were no differences in the rates of acute and late toxicities between the 2 groups. Conclusion Tumor bed boost by external beam radiotherapy (EBRT) is an effective and safe method for patients with FTSI and risk factors. Compared with the standard prophylactic radiation, tumor bed boost by EBRT was not associated with increased acute and late toxicities.

Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications

Abstract Homologous recombination (HR) is a highly accurate DNA repair mechanism. Several HR genes are established cancer susceptibility genes with clinically actionable pathogenic variants (PVs). Classically, BRCA1 and BRCA2 germline PVs are associated with significant breast and ovarian cancer risks. Patients with BRCA1 or BRCA2 PVs display worse clinical outcomes but respond better to platinum-based chemotherapies and poly-ADP ribose polymerase inhibitors, a trait termed “BRCAness.” With the advent of whole-exome sequencing and multigene panels, PVs in other HR genes are increasingly identified among familial cancers. As such, several genes such as PALB2 are reclassified as cancer predisposition genes. But evidence for cancer risks remains unclear for many others. In this review, we will discuss cancer predispositions and treatment implications beyond BRCA1 and BRCA2, with a focus on 24 HR genes: 53BP1, ATM, ATR, ATRIP, BARD1, BLM, BRIP1, DMC1, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RIF1, RMI1, RMI2, RPA1, TOP3A, TOPBP1, XRCC2, and XRCC3. Implications for Practice This review provides a comprehensive reference for readers to quickly identify potential cancer predisposing homologous recombination (HR) genes, and to generate research questions for genes with inconclusive evidence. This review also evaluates the “BRCAness” of each HR member. Clinicians can refer to these discussions to identify potential candidates for future clinical trials.

eNose technologies in the detection of cancer: a systematic review and meta-analysis

Abstract Background In 2004, researchers in the United Kingdom were able to train six dogs to distinguish between urine samples from bladder cancer patients and healthy controls using smell, achieving a detection rate of 41% (95% confidence interval [CI]: 23-58%), far above the 14% expected by chance. After numerous subsequent studies validated that the odor of breath and urine samples could be used by dogs to detect cancer, researchers pivoted to electronic noses (eNoses), sensor-based systems that mimic the sense of smell using arrays of chemical detectors. In this study, we review the potential efficacy of eNoses in the detection of selected cancer types in human biological samples. Methods We identified and performed a meta-analysis on 37 studies of eNose technology, comprising 1 365 cancer patients and 2 249 control subjects. We calculated the pooled sensitivity and specificity stratified by cancer type, sample type, and sensor type. Meta-regressions were conducted on these variables as well as the number of sensors used in the sensor array. Results All six cancer types analyzed—breast, colorectal, gastric, lung, ovarian, and prostate—achieved pooled sensitivities and specificities above 70%, with most around 85%. The overall pooled sensitivity was 85.9% (95% CI: 82.3-88.9%) and specificity was 83.6% (95% CI: 78.6-87.7%). Meta-regression revealed that the number of sensors in the sensor arrays, up to 15 sensors, was predictive of sensitivity with PFDR < 0.001. Conclusion This analysis found that eNoses constitute a promising tool in the early detection of cancer. However, more research is necessary before it can be introduced into clinical settings.

Endometrial Cancer: Who Lives, Who Dies, Can We Improve Their Story?

Abstract Background Endometrial cancer (EC) is the most common gynecologic cancer in the U.S. The objective of this cohort study was to characterize the clinical and pathologic features that are associated with endometrial cancer–specific death for women cared for at a single National Cancer Institute–designated comprehensive cancer center. Patients, Materials, and Methods This is a retrospective cohort from 2014 to 2017 including all women who had a hysterectomy for EC. Charts were reviewed for clinical and pathologic data, focusing on survival outcomes. Results Seven hundred seventy-one patients with EC underwent hysterectomy with 760 informative for outcomes. Seventy-six (10%) deaths were related to their EC; 62 women died from recurrent EC. Nonendometrioid histology and advanced stage were predictors of recurrence and EC death. Among patients with endometrioid ECs, mismatch repair status was significantly associated with EC-specific survival (relative risk = 4.8; 95% confidence interval, 2.3–10.3; p < .0001). Most patients with EC who recurred died of their disease 62/83 (74.7%). Nearly half of the patients that recurred (27/62) had no additional therapy at the time of recurrence. Overall survival was significantly longer for those women who had additional treatment at the time of recurrence; however, the improvement in overall survival with therapy at recurrence was largely attributable to effects in those women who were adjuvant therapy naïve. Conclusion Although there is benefit of treatment at the time of recurrence for treatment-naïve women; only approximately half of patients were able to receive therapy. There is an urgent need for continued efforts for more effective EC therapy in both the front-line and recurrent setting as well as early identification of cancer diagnosis and recurrence. Implications for Practice Approximately 10% of patients died of their endometrial cancer. Most deaths were from recurrent disease; however, almost 20% of endometrial cancer deaths were within 120 days of surgery. Although treatment at the time of recurrence improves overall survival, only approximately half of patients will receive therapy at the time of recurrence. Traditional prognostic features like histology and stage remain important to predict risk of recurrence, and newer biomarkers, such as mismatch repair status, may improve risk stratification and targeted therapy. There remains an urgent need for improved therapy and early detection of diagnosis and recurrence.

Real-world effectiveness and safety of hyperthermic intraperitoneal chemotherapy and intraperitoneal chemotherapy in ovarian cancer

Abstract Background Both hyperthermic intraperitoneal chemotherapy (HIPEC) and conventional intraperitoneal chemotherapy (IP) have shown survival benefits in ovarian cancer (OC), but direct comparisons between the two perfusion modalities are lacking. This study aimed to compare effectiveness and safety between HIPEC and conventional IP in OC. Methods This retrospective real-world study analyzed 606 patients with stages II-IV OC who received HIPEC or IP following cytoreductive surgery between 2013 and 2024. The primary endpoint was progression-free survival. Overall survival and adverse events were secondary endpoints. The study used inverse probability of treatment propensity-score weighting. We also conducted sensitivity analyses to evaluate result robustness and subgroup analyses to explore potential effect modification. Results After a median follow-up of 26 months, disease progression occurred in 40.6% of patients in the HIPEC group and 55.0% in the IP group (hazard ratio [HR] 0.79; P = .103). Mortality rates were 13.2% and 22.5%, respectively (HR 0.83; P = .434), showing no significant differences in progression and survival between the two groups. Exploratory subgroup analyses suggested a trend toward improved progression-free outcomes with HIPEC, particularly among patients with BRCA wild-type or BRCA1-mutated tumors and early postoperative perfusion. Hypoalbuminemia was the most common event in both groups (HIPEC 27.2%; IP 15.6%). HIPEC group had more abdominal distension and wound dehiscence, whereas IP patients experienced nausea and rash more frequently. Conclusions HIPEC did not significantly improve survival over conventional IP in the overall population, but showed greater benefit in specific subgroups, underscoring the importance of individualized intraperitoneal chemotherapy strategies in OC.

Attitudes toward large language model-based Artificial Intelligence systems as an information source for shared decision-making in radiation oncology

Abstract Background Implementing structured shared decision-making (SDM) requires high-quality, reliable patient information. In radiation oncology, patients often have limited knowledge and misconceptions about therapy and side effects, affecting their decision-making. Large language model-based AI systems (LLMs) may help by providing evidence-based information in accessible language, but successful implementation depends on the willingness of patients and health care professionals (HCPs) to adopt these technologies. Methods A survey was conducted among patients undergoing radiation therapy and HCPs between 03/2024 and 02/2025. Data was collected using structured electronic questionnaires (32 items for patients, 35 for HCPs). The survey assessed sociodemographic characteristics, the status of SDM in oncology, sources of information relevant to SDM, and current and anticipated LLM applications. Data were analyzed using descriptive statistics and logistic regression analysis. Results The internet was the prime information source for patients (n = 400). Regarding current use of LLMs, a large discrepancy between patients and HCPs (n = 200) was observed (18.2% vs 69.5%). Although 77% of HCPs believed that patients will rely on LLMs in the future, only 29.1% of patients agreed. Most patients (65.8%) stated that even as LLMs improve, they will continue to trust physicians more; 46% of HCPs shared this view. Only 16.5% of patients were convinced that LLMs provide all relevant data for SDM in cancer care. Familiarity with technology was the strongest predictor of LLM use among patients. Conclusion Only a minority of radiation oncology patients currently use LLMs, and many remain skeptical about their future role—contrasting with the more optimistic expectations of HCPs.