Pamela Soberanis Pina

Methodical Manipulation of the TME in Ovarian Cancer

SummaryThe complex interplay between ovarian cancer cells and the tumor microenvironment (TME) modulates progression, with dynamic cellular interactions influenced by external modulators, including neoadjuvant chemotherapy (NACT). A recent article described the alterations within the TME following NACT, either with or without bevacizumab, in ovarian cancer.See related article by Tavira et al., p. 176

Electronic malignant bowel obstruction symptom monitoring smartphone application for patients with gynecologic cancers

Genomic Landscape of ctDNA and Real-World Outcomes in Advanced Endometrial Cancer

Abstract Purpose: ctDNA is a novel technique extensively studied in solid tumors, although not currently well defined in endometrial cancer. Experimental Design: A de-identified retrospective analysis of 1,988 patients with advanced/recurrent endometrial cancer was performed. In addition, an analysis of a real-world evidence cohort was completed (n = 1,266). Patients underwent ctDNA testing using Guardant360 during routine clinical care. The objective was to describe and assess molecular landscape using ctDNA. Results: Among 1,988 ctDNA samples, at least one somatic alteration was detected in 91.6% (n = 1,821). Most frequently altered genes were TP53 (64%), PIK3CA (29%), PTEN (25%), ARID1A (20%), and KRAS (14%). Overall, 18.5% had amplifications, with the majority identified in CCNE1 (40.9%), PIK3CA (22%), and EGFR (19.3%). From the real-world evidence cohort, those with TP53 mutations had a worse overall survival (OS) versus those without TP53 mutations (P = 0.02) and those with TP53 comutations had an inferior OS in comparison with TP53-mutated only (P = 0.016). Amongst these, patients with a PIK3CA comutation (P = 0.012) and CCNE1 amplification (P = 0.01) had an inferior OS compared with those with only TP53 mutations. Fifty-seven patients with newly diagnosed endometrial cancer had at least two serial ctDNA samples showing evolution in detected variants compared with baseline samples, with TP53 being the most frequent change. Conclusions: This study is one of the largest cohorts of ctDNA currently reported in endometrial cancer. The presence of TP53 mutation and other comutations detected by ctDNA have a negative effect on outcomes. This report suggests that ctDNA analysis is feasible and could become a useful biomarker for endometrial cancer.

Circulating human papillomavirus DNA sequencing as a biomarker of response in advanced cervical cancer

Despite intense multi-modal treatment, the prognosis for advanced cervical cancer remains poor. The recent increase in cervical cancer cases worldwide highlights an urgent need for clinically validated biomarkers to guide patient management. Our pilot study investigates the utility of human papillomavirus (HPV) circulating tumor deoxy ribonucleic acid (ctDNA) in metastatic and recurrent cervical cancer. We investigated the association of HPV ctDNA levels, early kinetics, and detection of viral-host integration sites with response and outcomes. Serial plasma samples were prospectively collected from 21 patients with metastatic/recurrent cervical cancer. HPV ctDNA genotyping and quantification were conducted using a previously validated hybrid capture next-generation sequencing-based method. Mutation profiles within ctDNA were investigated simultaneously using a bespoke panel. In addition, high-confidence HPV integration was detected and quantified in ctDNA using SearcHPV. Differences in progression-free survival and overall survival were also evaluated between patients with high-confidence integration sites detected at baseline and those with low or no-confidence integration sites using the Kaplan-Meier method and log-rank tests to compare groups. This pilot study cohort included 21 patients with HPV-associated cervical cancer. Treatments included front-line platinum-based chemotherapy without (n = 4) or with (n = 5) bevacizumab, bevacizumab monotherapy (n = 2), or subsequent therapy (n = 7). A total of 3 previously treated patients were included to study HPV kinetics during observation. At baseline, HPV ctDNA was detected in 20 of 21 patients (95.2%). From baseline to the first assessment, a change in HPV ctDNA was significantly associated with type of response in patients on treatment (n = 18) (p = .049) and across all patients (n = 21) (p = .008). A total of 26 unique mutations were detected in either plasma or tissue. Of these, 11 of 26 were only detected in plasma, 9 of 26 were only detected in tissue, and 6 of 26 were detected in plasma and tissue. Patients with a high-confidence HPV integration site detected within ctDNA at baseline have inferior overall survival compared with patients with low-confidence or undetectable integration. In this pilot study, a decrease in HPV ctDNA was associated with response to treatment in metastatic and recurrent cervical cancer. HPV site integration and mutation-based ctDNA may have application to personalized therapy and should be evaluated in larger studies.

Impact of lymphadenectomy and intra-operative tumor rupture on survival in early-stage mucinous ovarian cancers

Mucinous ovarian carcinoma is a rare subtype of epithelial ovarian cancer with scarce literature guiding its management. We aimed to investigate the optimal surgical management of clinical stage I mucinous ovarian carcinoma by examining the prognostic significance of lymphadenectomy and intra-operative rupture on patient survival. We conducted a retrospective cohort study of all pathology-reviewed invasive mucinous ovarian carcinomas diagnosed between 1999 and 2019 at two tertiary care cancer centers. Baseline demographics, surgical management details, and outcomes were collected. Five-year overall survival, recurrence-free survival, and the association of lymphadenectomy and intra-operative rupture on survival were examined. Of 170 women with mucinous ovarian carcinoma, 149 (88%) had clinical stage I disease. Forty-eight (32%; n=149) patients had a pelvic and/or para-aortic lymphadenectomy, but only 1 patient with grade 2 disease was upstaged due to positive pelvic lymph nodes. Intra-operative tumor rupture was documented in 52 cases (35%). On multivariable analysis, after adjusting for age, final stage, and use of adjuvant chemotherapy, there was no significant association between intra-operative rupture with overall survival (HR 2.2 (0.6-8.0); p=0.3) or recurrence-free survival (HR 1.3 (0.5-3.3); p=0.6), or lymphadenectomy with overall survival (HR 0.9 (0.3-2.8); p=0.9) or recurrence-free survival (HR 1.2 (0.5-3.0); p=0.7). Advanced stage was the only factor that was significantly associated with survival. In clinical stage I mucinous ovarian carcinoma, systematic lymphadenectomy has low utility, as very few patients are upstaged and recurrence typically occurs in the peritoneum. Furthermore, intra-operative rupture does not appear to independently confer a worse survival, and therefore these women may not benefit from adjuvant treatment based on rupture alone.

Overcoming PARP inhibitor resistance in ovarian cancer

Ovarian cancer (OC) is one of the most lethal tumors in women, mostly diagnosed at advanced stages. Standard of care is based on surgery and platinum-based chemotherapy which provides high rates of response, although most patients will relapse. Poly(ADP-ribose) polymerase inhibitors (PARPi) have recently been incorporated in the treatment strategy for high-grade OC, particularly for those with defects in DNA repair pathways (homologous repair deficiency (HRd)). However, some tumor cells may not respond and some others will develop mechanisms of resistance to adapt. The most known mechanism of PARPi resistance is the reversion of HRd to homologous repair proficiency driven by epigenetic and genetic changes. Ongoing research is exploring different agents that are trying to re-sensitize tumor cells,overcome or bypass resistance to PARPi. Current investigations are focused on agents that target replication stress and DNA repair pathways, improve drug delivery, and target other cross-talk pathways. A crucial challenge in practice will be to identify and select patients for the appropriate therapy or combination strategies. However, efforts are needed to decrease overlapping toxicity and define the correct schedule timing of dosing to maximize the therapeutic index.

A phase I study of the Wee1 kinase inhibitor adavosertib (AZD1775) in combination with chemoradiation in cervical, upper vaginal, and uterine cancers

Wee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aimed to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers. A multi-institutional, open-label phase I trial was designed to assess dose escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45-50 Gy in 1.8-2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m Ten patients were enrolled (nine locally advanced cervical and one endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg by mouth daily on days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level -1 (adavosertib 100 mg by mouth daily on days 3 and 5), one out of five patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. The overall response rate at 4 months was 71.4%, including four complete responses. At 2 years follow-up, 86% of patients were alive and progression-free. The recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising, yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities.

Proactive assessment of patient reported outcomes in ovarian cancer studies: a systematic review and call for action in future studies

This systematic review aims to evaluate the proactive or real-time assessment of patient reported outcomes in studies involving patients with ovarian cancer undergoing systemic therapy. PubMed, Embase, and Cochrane databases were searched (from database inception until February 2022), and prospective ovarian cancer studies (experimental or observational) that incorporated patient reported outcomes, including quality of life, were included. The primary objective was to assess the ratio of studies incorporating real-time use of patient reported outcomes among those studies performing patient reported outcomes. A secondary objective was to describe the patient reported outcome reporting. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 checklist was followed. Descriptive statistics were used. 3071 articles were screened, with 117 included in the final analysis. Studies were published between 1990 and 2022, and consisted of 35 735 patients (median 140 patients per study; interquartile range 58-415). Median time from patient enrollment initiation to study publication was 7 years (range 1-15). Most studies were experimental/clinical trials (n=93, 79%) followed by observational (n=23, 20%). Therapeutic strategies were assessed in 98% (91/93) of experimental studies, most frequently chemotherapy (n=53, 58%), followed by antiangiogenics or poly-ADP ribose polymerase (PARP) inhibitors (n=8, 9%, each). Patient reported outcomes were the primary endpoint in 7.5% (7/93) and 83% (19/23) of experimental and observational studies, respectively. The ratio of real-time patient reported outcomes assessment/ evaluation was 0.9% (1/117). Completion of patient reported outcome questionnaires involves time and effort for patients with ovarian cancer. Responses to these questionnaires were only assessed in real time in <1% of analyzed studies. Efforts should be made to incorporate proactive assessment of patient reported outcomes to optimize patient care and safety.

Gestational trophoblastic neoplasia: does centralization of care impact clinical management?

International societies advocate for gestational trophoblastic neoplasia referral to designated expert centers. This study assessed the impact of centralization of trophoblastic care on clinical outcomes. A centralized program was implemented in 2018 at two affiliated academic hospitals, Princess Margaret Cancer Center and Mount Sinai Hospital. A retrospective analysis of patients treated between 2000 and 2022 was performed and the clinical outcomes were compared before (2000-2017) and after (2018-2022) centralization. Statistical analyses were performed with significance set as p<0.05. A total of 94 patients with trophoblastic neoplasia were included: 60 pre-centralization and 34 post-centralization, 79.8% low-risk and 18.1% high-risk. Centralization led to significant improvement for: (1) accurate score documentation (from 37.9% to 89.3%,); (2) contraception counseling (from 67.2% to 96.7%); (3) median time from diagnosis to chemotherapy (from 9 days to 1 day); and (4) incomplete follow-up (from 20.7% to 3.3%) (all p<0.05). First-line chemotherapy for low-risk neoplasia was dactinomycin in 47.9% and 87.0% pre- and post-centralization, respectively (p=0.005). The median number of chemotherapy cycles decreased from seven to four (p=0.01), and the median number of consolidation cycles increased from two to three (p<0.001). Serum human chorionic gonadotropin (hCG) levels of 10 000-100 000 IU/L were significantly associated with longer time to hCG normalization and higher risk of resistance to first-line chemotherapy compared with hCG levels <1000 IU/L. Centralization of trophoblastic neoplasia care leads to greater guideline compliance, faster chemotherapy initiation, fewer chemotherapy cycles with optimized consolidation, and enhanced surveillance completion. This supports the establishment of trophoblastic neoplasia expert centers.

Preclinical Combination Targeting VEGF and PI3K in a Rare, Aggressive Mixed Endometrial Carcinoma: An Applied Case Report

Abstract We report a rare case of a young patient (VENUS 167) initially diagnosed with grade 1 endometrioid endometrial cancer, which, following endocrine treatment, presented with mixed aggressive carcinoma with three distinct histologic patterns: grade 1 endometrioid, large cell neuroendocrine, and undifferentiated carcinoma. The surgical specimen at the time of disease progression was used to establish OPTO.85, a patient-derived organoid (PDO), followed by a corresponding organoid-derived xenograft (ODX). Multi-omic analyses confirmed that OPTO.85 accurately reflected the patient’s tumor characteristics. Whole-exome sequencing analysis identified oncogenic alterations in PIK3CA, ARID1A, and CTNNB1. Further RNA sequencing and assay for transposase-accessible chromatin using sequencing analyses revealed enrichment in VEGF and Wnt signaling pathways, suggesting therapeutic vulnerabilities. A high-throughput drug screen was conducted using ApexBio-approved and epigenetic drug libraries, along with kinase inhibitor and tool compound libraries developed at the Ontario Institute of Cancer Research. The OPTO.85 PDO exhibited sensitivity to PI3K inhibitors and responsiveness to VEGF inhibition. Cediranib demonstrated synergy with BKM120, significantly reducing organoid growth. This combination also showed in vivo efficacy in the ODX model, in which dual inhibitors significantly suppressed tumor growth compared with single compounds. This case exemplifies the impact of genomic profiling and patient-derived models in identifying actionable molecular changes in rare cancers with limited therapeutic options and poor prognosis. It highlights that high-throughput sequencing for individual patient tumors and generation of patient-derived models are feasible in endometrial cancer. This preclinical model may assist clinical decision and personalized therapy requiring validation in prospective studies. Significance: This study characterizes a rare aggressive mixed endometrial carcinoma that developed after hormonal therapy. Patient-derived organoid and xenograft models revealed actionable targets in the VEGF and PI3K pathways. Combined cediranib and BKM120 treatment showed synergistic antitumor effects in vitro and in vivo. These findings highlight the potential of integrating molecular profiling and drug testing to guide personalized therapies in rare and recurrent endometrial cancers.