Jung-Yun Lee

Efficacy of Chemotherapy Following Prior PARP-Inhibitor Treatment in Patients with Ovarian Cancer

Purpose Considering the current lack of consensus on post–poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) treatment strategies, this study aimed to evaluate the efficacy of subsequent therapy and compare the outcomes of regimes in patients with recurrent ovarian cancer after PARPi treatment.Materials and Methods This multi-center retrospective cohort study analyzed data on patients diagnosed with ovarian cancer between January 2012 and June 2023 who had previously used PARPi after first- to fourth-line platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS), which was the interval between recurrence after using PARPi and subsequent recurrence in the case of recurrence.Results Of 318 patients, 147/318 (46.2%) recurred after the PARPi maintenance. Patients were categorized into groups based on subsequent therapy except non-treated (11/147, 7.5%): platinum-based chemotherapy (89/147, 60.5%), non-platinum-based chemotherapy (21/147, 14.3%), other treatments (26/147, 17.7%), and the median PFS (mPFS) for each group were 7.3, 4.8, and 11.4 months, respectively. Among the platinum-based chemotherapy group, the gemcitabine+carboplatin regimen demonstrated a longer mPFS (10.1 months) than the other regimens (6.6 months, p=0.019). In non-platinum-based chemotherapy, no statistically significant differences were observed among the regimens. And, in the other therapy group, where the proportion of patients with oligometastasis was as high as 88.5%, no significant differences were observed among the therapies, including other modalities.Conclusion In the subsequent chemotherapy of recurrent ovarian cancer after platinum-based chemotherapy and PARPi, the gemcitabine+carboplatin regimen demonstrated a potential to delay recurrence more effectively compared to other therapies.

Neoadjuvant Chemotherapy with Dual Immune Checkpoint Inhibitors for Advanced-Stage Ovarian Cancer: Final Analysis of TRU-D Phase II Nonrandomized Clinical Trial

Abstract Purpose: This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival, and neoadjuvant outcomes of neoadjuvant chemotherapy (NAC) combined with dual immune checkpoint inhibitors in advanced-stage epithelial ovarian cancer (EOC). Patients and Methods: Between June 2019 and July 2021, 45 patients with unresectable stage III to IV EOC were enrolled. The patients received three cycles of NAC combined with durvalumab and tremelimumab. All patients underwent interval debulking surgery and received three cycles of durvalumab and adjuvant chemotherapy, followed by 12 cycles of durvalumab as maintenance therapy. The primary endpoint was the 12-month progression-free survival (PFS) rate; the secondary endpoints were the objective response rate after NAC, a chemotherapy response score, pathologic complete response, overall survival, and safety. The preplanned exploratory analyses assessed the lymphocyte infiltration, PD-L1 expression, and genomic profiles of pretreatment tumors. Results: The 12-month PFS rate was 65.9% [95% confidence interval (CI), 52.8–not estimated (NE)], whereas the 24- and 30-month PFS rates were 38.6% (95% CI, 26.7–NE) and 36.4% (95% CI, 24.7–NE), respectively. After NAC, the objective response rate was 86.7%, whereas 14 patients (31.1%) had a chemotherapy response score of three, and five (11.1%) achieved pathologic complete response. The 30-month overall survival rate was 87.7%. The most common grade ≥3 adverse event was neutropenia (26.7%). In an exploratory analysis, patients with pre-NAC tumors showing PD-L1 (combined positive score) ≥1, high Mutation Signature 3, and a high extracellular matrix signature demonstrated improved PFS outcomes. Conclusions: NAC combined with dual immune checkpoint inhibitors is feasible for advanced-stage EOC and shows promising activity with a durable clinical response.

Clinical practice guidelines for ovarian cancer: an update to the Korean Society of Gynecologic Oncology guidelines

We updated the Korean Society of Gynecologic Oncology (KSGO) practice guideline for the management of ovarian cancer as version 5.1. The ovarian cancer guideline team of the KSGO published announced the fifth version (version 5.0) of its clinical practice guidelines for the management of ovarian cancer in December 2023. In version 5.0, the selection of the key questions and the systematic reviews were based on the data available up to December 2022. Therefore, we updated the guidelines version 5.0 with newly accumulated clinical data and added 5 new key questions reflecting the latest insights in the field of ovarian cancer between 2023 and 2024. For each question, recommendation was provided together with corresponding level of evidence and grade of recommendation, all established through expert consensus.

Gynecologic oncology in 2024: breakthrough trials and evolving treatment strategies for cervical, uterine corpus, and ovarian cancers

This review summarized the results of clinical trials in 2024 that were believed to have a significant impact on clinical practice in the field of gynecologic oncology. The SHAPE trial, INTERLACE and KEYNOTE-A18 trials, and BEATcc and COMPASSION-16 trials were included in early-stage, locally advanced, and recurrent/metastatic cervical cancer, respectively. For uterine corpus cancer, updated survival data of the four trials (NRG-GY018, RUBY, AtTEnd, DUO-E) for endometrial cancer and the first survival data of LMS-04 trial for leiomyosarcoma were described. For ovarian cancer, the final overall survival results of PRIMA study were followed by DUO-O, ATHENA-combo, and FIRST-ENGOT-OV44 trial in different disease conditions. Finally, the results of DESTINY-PanTumor02, a basket trial of trastuzumab deruxtecan, were briefly addressed.

OPERA: a phase II trial of oregovomab plus non-platinum chemotherapy in PARP inhibitor/platinum-resistant ovarian cancer

A consensus regarding subsequent therapeutic strategies for patients with platinum- and poly (ADP-ribose) polymerase inhibitor (PARPi)-resistant ovarian cancer is lacking. These patients typically receive non-platinum-based chemotherapy; however, survival outcomes remain poor. Compared with chemotherapy alone, combination therapy with novel target agents can provide additional benefits to these patients. Oregovomab, an investigational murine monoclonal antibody against CA-125, has shown promising efficacy in a phase II study in patients with recurrent ovarian cancer. Herein, we described the rationale and design of OPERA/KGOG 3065/APGOT-OV6, a multicenter, investigator-initiated, two-cohort, single-arm phase II trial, aimed at examining the efficacy of oregovomab plus non-platinum-based chemotherapy in patients with PARPi/platinum-resistant ovarian cancer. The primary end point was the objective response rate, according to RECIST 1.1.

Major clinical research advances in gynecologic cancer in 2023: a tumultuous year for endometrial cancer

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs. In 2023, the field of endometrial cancer treatment witnessed a landmark year, marked by several practice-changing outcomes with immune checkpoint inhibitors and the reliable efficacy of PARP inhibitors and ADCs.

Anti–4-1BB×PDL1 Bispecific Antibody Reinvigorates Tumor-Specific Exhausted CD8+ T Cells and Enhances the Efficacy of Anti-PD1 Blockade

Abstract Purpose: To overcome the limited efficacy of immune checkpoint blockade, there is a need to find novel cancer immunotherapeutic strategies for the optimal treatment of cancer. The novel anti–4-1BB×PDL1 bispecific antibody—ABL503 (also known as TJ-L14B)—was designed to simultaneously target PDL1 and 4-1BB and demonstrated strong antitumor T-cell responses without considerable toxicity. In this study, we investigated the mechanisms by which the combination of ABL503 and anti-PD1 blockade affected the reinvigoration of exhausted tumor-infiltrating CD8+ T cells (CD8+ TIL) and antitumor efficacy. Experimental Design: Single-cell suspensions of hepatocellular carcinoma and ovarian cancer tissues from treatment-naïve patients were used for immunophenotyping of CD8+ TILs and in vitro functional assays. Humanized hPD1/hPDL1/h4-1BB triple–knock-in mice were used to evaluate the effects of ABL503 and anti-PD1 blockade in vivo. Results: We observed that ABL503 successfully restored the functions of 4-1BB+ exhausted CD8+ TILs, which were enriched for tumor-specific T cells but unresponsive to anti-PD1 blockade. Importantly, compared with anti-PD1 blockade alone, the combination of ABL503 and anti-PD1 blockade further enhanced the functional restoration of human CD8+ TILs in vitro. Consistently, the combination of ABL503 with anti-PD1 in vivo significantly alleviated tumor growth and induced enhanced infiltration and activation of CD8+ TILs. Conclusions: ABL503, a PDL1 and 4-1BB dual-targeting bispecific antibody, elicits pronounced additive tumor growth inhibition, with increased infiltration and functionality of exhausted CD8+ T cells, which in turn enhances the anticancer effects of anti-PD1 blockade. These promising findings suggest that ABL503 (TJ-L14B) in combination with PD1 inhibitors will likely further enhance therapeutic benefit in clinical trials. See related commentary by Molero-Glez et al., p. 3971

The effectiveness of CA125 and HE4 as clinical prognostic markers in epithelial ovarian cancer patients with BRCA mutation

To investigate the efficacy of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in predicting survival outcomes based on breast cancer gene (BRCA) mutational status in epithelial ovarian cancer. Medical records of 448 patients diagnosed with epithelial ovarian cancer at a single tertiary institution in Korea were retrospectively analyzed. Area under the curve, sensitivity, specificity, and accuracy were assessed using the CA125 and HE4 values after surgery and 3 cycles of chemotherapy to predict 1-year survival based on the BRCA mutational status. Kaplan-Meier analysis was used to obtain progression-free and overall survival to evaluate CA125 and HE4 effectiveness in predicting survival outcomes. A total of 423 patients were analyzed, including 180 (42.6%) who underwent interval debulking surgery (IDS) and 243 (57.4%) who underwent primary debulking surgery (PDS). BRCA mutations were observed in 37 (15.2%) and 44 (22.4%) patients in the PDS and IDS groups, respectively. CA125 and HE4 normalization demonstrated the highest specificity in patients with or without BRCA mutations, with specificities of 97.1% and 99.1% in the PDS group and 78.6% and 86.2% in the IDS group, respectively. Normalizing HE4 alone may be an effective prognostic marker, with an area under the curve of 0.774 and specificity of 75.0%, in patients with BRCA mutations. Normalizing both biomarkers emerged as the most effective predictive marker for the 1-year recurrence rate, regardless of BRCA mutational status. A negative HE4 value can be a useful predictor for 1-year recurrence-free survival in patients with BRCA mutations.

Chemotherapy response score no longer predicts survival outcomes in high-grade serous ovarian cancer patients with BRCA mutation and/or maintenance therapy

We aimed to revalidate the chemotherapy response score (CRS) system as a prognostic factor for ovarian cancer patients with breast cancer gene ( A retrospective analysis was performed using medical records of patients with high-grade serous carcinoma who received neoadjuvant chemotherapy followed by interval debulking surgery between January 2007 and December 2021 at 5 tertiary medical institutions in South Korea. At each hospital, pathologists independently assessed each slide of omental tissues obtained from surgery using the CRS system. Progression-free survival (PFS) and overall survival (OS) values were obtained using Kaplan-Meier analysis to evaluate the effect of Of 466 patients, CRS may not be a prognostic factor in patients with

Clinical guidelines for ovarian cancer: the Korean Society of Gynecologic Oncology guidelines

Since the latest practice guidelines for ovarian cancer were developed by the Korean Society of Gynecologic Oncology (KSGO) in 2021, many studies have examined the efficacy and safety of various treatments for epithelial ovarian cancer (EOC). Therefore, the need to develop recommendations for EOC treatments has been raised. This study searched the literature using 4 key items and the Population, Intervention, Comparison, and Outcome: the efficacy and safety of poly-ADP ribose polymerase inhibitors in newly diagnosed advanced EOC; the efficacy and safety of intraperitoneal plus intravenous chemotherapy in optimally debulked advanced EOC; the efficacy and safety of secondary cytoreductive surgery in platinum-sensitive recurrent ovarian cancer; and the efficacy and safety of the addition of bevacizumab to platinum-based chemotherapy in first platinum-sensitive recurrent EOC patients who received prior bevacizumab. The evidence for these recommendations, according to each key question, was evaluated using a systematic review and meta-analysis. The committee of ovarian cancer of the KSGO developed updated guidelines for treatments of EOC.

Serial Circulating Tumor DNA Analysis with a Tumor-Naïve Next-Generation Sequencing Panel Detects Minimal Residual Disease and Predicts Outcome in Ovarian Cancer

Abstract Circulating tumor DNA (ctDNA) may aid in personalizing ovarian cancer therapeutic options. Here, we aimed to assess the clinical utility of serial ctDNA testing using tumor-naïve, small-sized next-generation sequencing (NGS) panels. A total of 296 patients, including 201 with ovarian cancer and 95 with benign or borderline disease, were enrolled. Samples were collected at baseline (initial diagnosis or surgery) and every 3 months after that, resulting in a total of 811 blood samples. Patients received adjuvant therapy based on the current standard of care. Cell-free DNA was extracted and sequenced using an NGS panel of 9 genes: TP53, BRCA1, BRCA2, ARID1A, CCNE1, KRAS, MYC, PIK3CA, and PTEN. Pathogenic somatic mutations were identified in 69.2% (139/201) of patients with ovarian cancer at baseline but not in those with benign or borderline disease. Detection of ctDNA at baseline and/or at 6 months follow-up was predictive of progression-free survival (PFS). PFS was significantly poorer in patients with detectable pathogenic mutations at baseline that persisted at follow-up than in patients that converted from having detectable ctDNA at baseline to being undetectable at follow-up; survival did not differ between patients without pathogenic ctDNA mutations in baseline or follow-up samples and those that converted from ctDNA positive to negative. Disease recurrence was also detected earlier with ctDNA than with conventional radiologic assessment or CA125 monitoring. These findings demonstrate that serial ctDNA testing could effectively monitor patients and detect minimal residual disease, facilitating early detection of disease progression and tailoring of adjuvant therapies for ovarian cancer treatment. Significance: In ovarian cancer, serial circulating tumor DNA testing is a highly predictive marker of patient survival, with a significantly improved recurrence detection lead time compared with conventional monitoring tools.

Reply to: Comments on “Randomized, two‐arm, non‐comparative phase 2 study of olaparib plus cediranib or durvalumab in HRR‐mutated, platinum‐resistant ovarian cancer: A substudy of KGOG 3045”

Phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer: primary analysis in the original cohort of KGOG3046/TRU-D

Background This study assessed the antitumor activity and safety of durvalumab plus tremelimumab combined with neoadjuvant chemotherapy (NAC) in patients newly diagnosed with advanced ovarian cancer. Here, we report the primary endpoint of the original cohort of the KGOG 3046/TRU-D study. Methods In this investigator-initiated single-arm, phase II trial, patients with stage IIIC-IVB ovarian cancer were administered three cycles of durvalumab (1500 mg) and tremelimumab (75 mg) with NAC, followed by interval debulking surgery (IDS). After surgery, three cycles of durvalumab (1120 mg) and adjuvant chemotherapy followed by durvalumab maintenance (1120 mg [total 12 cycles]) were administered. The primary endpoint of the study was 12-month progression-free survival (PFS) rate. Results Twenty-three patients were enrolled. The median patient age was 60 years (range 44–77 years), and most patients presented with high-grade serous carcinoma (87.0%) and stage IV disease (87.0%). At the time of data cut-off on January 17, 2023, the median follow-up duration was 29.2 months (range 12.0–42.2). The 12-month, 24-month, and 30 month PFS rates were 63.6%, 45.0%, and 40.0%, respectively. All patients underwent IDS, with an R0 resection rate of 73.9%, and 17.4% achieved pathological complete response. Skin rashes were the most common treatment-related adverse events (TRAEs, 69.6%). However, all TRAEs completely resolved after steroid use. Conclusion This study showed promising activity with a durable clinical response, supporting the potential of NAC with dual immune checkpoint blockade in advanced-stage ovarian cancer. Trial registration number NCT03899610.

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

PURPOSE Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)–directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non–small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. METHODS This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

Initial experience with the da Vinci SP robot-assisted surgical staging of endometrial cancer: a retrospective comparison with conventional laparotomy

To compare the perioperative outcomes of surgical staging performed using conventional laparotomy (LT) or the da Vinci SP robotic system (SP) in patients with endometrial cancer. We retrospectively analyzed 180 patients with stage I-III endometrial cancer who underwent surgical staging using LT (n = 126) or SP (n = 54) at the Yonsei Cancer Center between November 2018 and December 2022. Propensity score matching (PSM) was performed to mitigate potential confounding biases. Fifty-one pairs of patients were matched by PSM. SP required longer total operation time than LT (221 vs. 142 min in SP vs. LT, respectively, p < 0.001). However, estimated blood loss and postoperative hemoglobin change were lower in SP than in LT (30 vs. 100 mL, p < 0.001; 0.6 vs. 1.6 g/dL, p < 0.001 for SP vs. LT respectively). Furthermore, postoperative minor complications (13.7% in SP vs. 33.3% in LT, p = 0.02), perioperative transfusion rate (0% in SP vs. 11.8% in LT, p = 0.03), and postoperative hospital stay (2 days for SP vs. 8 days for LT, p < 0.001) were lower in SP than in LT. Although the patient-controlled analgesia administration rate was lower in SP (13.8% in SP vs. 100% in LT, p < 0.001), the median postoperative pain score at 6, 12, and 24 h after surgery was lower in SP than in LT (2 vs. 3, p = 0.002; 2 vs. 3, p = 0.005; 2 vs. 3, p = 0.001 for SP vs. LT, respectively). Although SP required longer total operation time, it demonstrated several advantages over LT in endometrial cancer staging.

Modifying surgical extents in patients with preoperatively presumed early-stage endometrial cancer based on ProMisE classification: a retrospective, single-center study

This study aimed to explore differences in disease extent based on the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classification and to establish personalized staging surgery strategies in patients with preoperatively presumed uterus-confined endometrial cancer. In this retrospective, single-center study, we reviewed the medical records of patients with endometrial cancer. These patients were classified according to the ProMisE classification based on tissue samples obtained from dilation and curettage or staging surgeries, and the disease extent was analyzed based on pathologic reports. A total of 345 patients were clinically estimated to be in stage 1/2 before staging surgery, with immunohistochemistry (IHC) results available. This cohort included 332 patients (96.2%) with clinical stage 1 and 13 patients (3.8%) with stage 2 based on the 2009 FIGO staging system. Among these, 81 patients (23.5%) were assigned to an mismatch repair deficient group (MMRd), 33 (9.6%) to an abnormal p53 group, and 123 (71.1%) to a no specific molecular profile (NSMP) group. Overall, 13 patients had nodal metastasis, with a higher rate observed in the abnormal p53 group (1.2%, 12.1%, and 2.2% for the MMRd, abnormal p53, and NSMP groups, respectively, p=0.013). One patient (0.3%) had parametrial metastasis and four (1.1%) had peritoneal metastasis. Patients with abnormal p53 IHC results exhibited a higher likelihood of lymph node metastasis, even when initially presumed to be at an early stage. For the abnormal p53 group, proactive lymphadenectomy surgery appears beneficial for accurate staging and establishing a subsequent treatment plan.

Genomic Profiling in Patients with Endometrial Cancer by Deep Sequencing of Vaginal Swabs and Plasma

Abstract Purpose: Endometrial cancer is a common gynecologic malignancy that lacks effective noninvasive screening tools as traditional approaches rely on invasive biopsies. In this large prospective study, we evaluated a novel approach combining vaginal swab DNA and plasma-based ctDNA for genomic profiling to provide a comprehensive framework for diagnosis, prognosis, and disease monitoring. Experimental Design: Adult patients with diverse stages of endometrial cancer, preneoplastic disease, and benign endometrial conditions were prospectively recruited over 2 years. Paired vaginal swab DNA and plasma-based ctDNA were collected preoperatively, and additional plasma samples were obtained at multiple time points postoperatively. Deep next-generation sequencing targeting 101 genes was performed, achieving an average depth exceeding 40,000×. Results: A total of 191 patients contributed 388 samples. Vaginal swab DNA demonstrated 77.7% sensitivity and 96.6% specificity. PTEN mutations were associated with favorable prognosis (HR: 0.27; 95% confidence interval, 0.092–0.77), and TP53 mutations were associated with poor prognosis (HR: 3.7; 95% confidence interval, 1.4–10). A novel classification system based on the mutational profile of PTEN/TP53 identified distinct prognostic groups. Plasma-based ctDNA was significantly associated with stage, lymphovascular invasion, and prognosis (P &amp;lt; 0.01 for all). Patients with preoperative positive plasma-based ctDNA results exhibited poorer outcomes (P &amp;lt; 0.01), whereas postoperative positive ctDNA results enabled early detection of recurrence. Conclusions: These two noninvasive methods play distinct, complementary roles in the management of endometrial cancer. Vaginal swab DNA and novel PTEN/TP53-based classification have distinct prognostic advantages over existing frameworks. Plasma-based ctDNA provides dynamic insights into recurrence risk and disease progression.

Is presumed clinical stage I endometrial cancer using PET-CT and MRI accurate in predicting surgical staging?

To evaluate upstaging, lymph node (LN) metastasis, and recurrence in patients with presumed stage I endometrial cancer using preoperative magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT). Retrospective review of 422 patients with presumed clinical stage I endometrial cancer diagnosed via MRI and PET-CT (July 2014-June 2023). Surgical staging included pelvic lymph nodes (PLNs) and para-aortic lymph nodes (PALNs), classifying patients as low/intermediate- or high-risk groups. Post-operative upstaging rate was 14.5% (8.8% low/intermediate-risk vs. 22.8% high-risk, p2 cm on MRI (OR=2.9; 95% CI=0.8-9.9) increased LN metastasis risk. Median 48.5-month follow-up showed an 8.1% overall recurrence rate (4.0% low/intermediate-risk vs. 14.0% high-risk, p<0.001), with 2.4% nodal recurrences (1.2% low/intermediate-risk vs. 4.1% high-risk). High-risk patients had significant upstaging, LN metastasis, and recurrence rates. Even in low/intermediate-risk groups, some patients exhibited LN metastasis and nodal recurrence, underscoring the importance of comprehensive surgical staging, including PALN evaluation, for precise diagnosis and treatment.

A phase II study of induction PD-1 blockade (nivolumab) in patients with surgically completely resectable mismatch repair deficient endometrial cancer (NIVEC)

Mismatch repair deficient (MMRd) tumors are known to be highly immunogenic and of great interest for immune checkpoint inhibitor. However, there is no data about the complete response (CR) rate of programmed cell death protein 1 (PD-1) blockade and surgery in subjects with MMRd surgically resectable endometrial cancer. In this regard, we suggest a window of opportunity study of induction PD-1 blockade (nivolumab) in patients with surgically resectable MMRd endometrial cancer. This is a multicenter, single-arm phase II trial. A total of 30 surgically resectable MMRd endometrial cancer patients will be enrolled. Inclusion criteria include clinical stage I-IIIC2, tumor specimen that demonstrates MMRd by immunohistochemistry or microsatellite instability. Exclusion criteria include multiple primary cancers, residual adverse effects of prior therapy or effects of surgery. Patients are treated with nivolumab 480 mg intravenously every 4 weeks up to 6 months followed by standard surgery and/or adjuvant treatment. The primary endpoint of the study is clinical CR rate or pathological CR rate after treatment of nivolumab. Secondary endpoints include objective response rate, progression-free survival, overall survival, and adverse events. Correlative studies include genomic characterization of tumors, assessment of immune infiltration of tumor microenvironment, and serial circulating cell-free DNA and immune biomarkers. ClinicalTrials.gov Identifier: NCT05795244.

Comparison of oncological outcomes between sentinel lymph node biopsy and complete lymphadenectomy for endometrial cancer

AbstractAimSentinel lymph node (SLN) mapping allows node‐negative patients to be spared from the surgical comorbidities associated with total lymphadenectomy. This study aimed to evaluate the oncological outcomes of SLN biopsy versus complete lymph node dissection in patients with early‐stage endometrial carcinoma.MethodsRetrospective analyses were performed in patients with pathologically confirmed endometrioid endometrial carcinoma, who underwent minimally invasive surgical staging with SLN biopsy or complete lymph node dissection at Yonsei Cancer Center between 2015 and 2019.ResultsA total of 301 patients were included in this study. Eighty‐two patients underwent SLN biopsy, while 219 underwent complete lymph node dissection. There were no significant differences in patient characteristics between the two groups. In terms of operative characteristics, the SLN biopsy‐only group had a significantly shorter surgical duration (p &lt; 0.001) than the lymphadenectomy group. The mean follow‐up period was 41.4 months. There were no differences in progression‐free survival (PFS) and overall survival (OS) between the two groups (SLN biopsy vs. complete lymph node dissection; p = 0.798 and 0.301, respectively). Multivariate analysis revealed that SLN biopsy was not an independent prognostic factor for PFS or OS.ConclusionOur results showed that SLN biopsy provided oncological outcomes similar to those of lymphadenectomy.

Mismatch repair, p53, and L1 cell adhesion molecule status influence the response to chemotherapy in advanced and recurrent endometrial cancer

Abstract Objective This study aimed to identify the recurrence and survival rates according to the mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) status in patients with advanced and recurrent endometrial cancer (EC) receiving systemic chemotherapy. Methods This single-center retrospective cohort study included chemotherapy-naïve patients with advanced-stage (III/IV) or recurrent EC between January 2015 and June 2022 ( n  = 156), who were administered chemotherapy as adjuvant therapy or first-line palliative treatment. MMR and p53 status were assessed, and L1CAM was tested using immunohistochemistry in the p53-wild and MMR-proficient (p53wt/pMMR) group. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Results Of the 156 patients, 62 (39.7%), 53 (34.0%), and 41 (26.3%) had p53wt/pMMR, abnormal p53 (p53abn), and MMR-deficient (dMMR) tumors, respectively. PFS and OS were longest in dMMR, followed by p53wt/pMMR, and were the least in p53abn tumors (PFS: p  = 0.0006, OS: p  = 0.0013). After p53wt/pMMR was classified according to positive or negative L1CAM status, the L1CAM negative group exhibited significantly shorter survival rates than the L1CAM positive group (PFS: p  = 0.0001, OS: p  = 0.0027). p53abn tumors were independent prognostic factors for poor PFS (PFS: p  = 0.039 on multivariable analysis). Conclusion In chemotherapy-naïve patients with advanced and recurrent EC, there was a better prognosis in the order of MMR-D, p53wt/pMMR, and p53abn tumors after chemotherapy. L1CAM status is useful as a new marker to stratify p53wt/pMMR in advanced and recurrent groups.

RAD51/geminin/γH2AX immunohistochemical expression predicts platinum-based chemotherapy response in ovarian high-grade serous carcinoma

The RAD51 assay is a recently developed functional assay for homologous recombination deficiency (HRD) that reflects real-time HRD status. We aimed to identify the applicability and predictive value of RAD51 immunohistochemical expression in pre- and post-neoadjuvant chemotherapy (NAC) samples of ovarian high-grade serous carcinoma (HGSC). We evaluated the immunohistochemical expression of RAD51/geminin/γH2AX in ovarian HGSC before and after NAC. In pre-NAC tumors (n=51), 74.5% (39/51) showed at least 25% of γH2AX-positive tumor cells, suggesting endogenous DNA damage. The RAD51-high group (41.0%, 16/39) showed significantly worse progression-free survival (PFS) compared to the RAD51-low group (51.3%, 20/39) (p High RAD51 expression was significantly associated with worse PFS in HGSC, and post-NAC RAD51 status showed higher association than pre-NAC RAD51 status. Moreover, RAD51 status can be evaluated in a significant proportion of treatment-naïve HGSC samples. As RAD51 status dynamically changes, sequential follow-up of RAD51 status might reflect the biological behavior of HGSCs.

Phase II randomized study of dostarlimab alone or with bevacizumab versus non-platinum chemotherapy in recurrent gynecological clear cell carcinoma (DOVE/APGOT-OV7/ENGOT-ov80)

Recurrent gynecological clear cell carcinoma (rGCCC) has a low objective response rate (ORR) to chemotherapy. Previous preclinical and clinical data suggest a potential synergy between immune checkpoint inhibitors and bevacizumab in rGCCC. Dostarlimab, a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1), combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. This study will investigate the efficacy of dostarlimab +/- bevacizumab in rGCCC. DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/- bevacizumab with standard chemotherapy in rGCCC. We will enroll 198 patients with rGCCC and assign them to one of three groups in a 1:1:1 ratio: arm A (dostarlimab monotherapy), B (dostarlimab + bevacizumab), and C (investigator's choice of chemotherapy [weekly paclitaxel, pegylated liposomal doxorubicin, doxorubicin, or gemcitabine]). Patients with disease progression in arm A or C will be allowed to cross over to arm B. Stratification factors include prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina, or vulva; up to five prior lines of therapy; disease progression within 12 months after platinum-based chemotherapy; and measurable disease. Key exclusion criteria are prior treatment with an anti-PD-1, anti-programmed death-ligand 1, or anti-programmed death-ligand 2 agent. The primary endpoint is progression-free survival determined by investigators. Secondary endpoints are ORR, disease control rate, clinical benefit rate, progression-free survival 2, overall survival, and toxicity. Exploratory objectives include immune biomarkers. ClinicalTrials.gov Identifier: NCT06023862.

Frequency of peripheral PD-1+regulatory T cells is associated with treatment responses to PARP inhibitor maintenance in patients with epithelial ovarian cancer

Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis) are becoming the standard of care for epithelial ovarian cancer (EOC). Recently, clinical trials of triple maintenance therapy (PARPi+anti-angiogenic agent+anti-PD-1/L1) are actively ongoing. Here, we investigated the immunological effects of PARPi or triple maintenance therapy on T cells and their impact on clinical responses. We collected serial blood from EOC patients receiving PARPi therapy (cohort 1: PARPi, n = 49; cohort 2: olaparib+bevacizumab+pembrolizumab, n = 31). Peripheral T cells were analyzed using flow cytometry and compared according to the PARPi response. Progression-free survival (PFS) was assessed according to prognostic biomarkers identified in a comparative analysis. Regulatory T cells (Tregs) were suppressed by PARPi therapy, whereas PD-1 was not significantly changed. Short PFS group exhibited a higher percentage of baseline PD-1 PARPi suppresses Tregs, but does not affect PD-1 expression. Adding anti-PD-1 to PARPi decreases PD-1

Triplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4

AbstractIn this multicenter, open-label, single-arm, Phase II study with Simon two-stage optimum design (NCT04361370), we investigate the efficacy and safety of triplet maintenance (olaparib, pembrolizumab, bevacizumab) in patients with platinum-sensitive recurrent ovarian cancer who are wild-type for BRCA 1/2. A total of 44 patients were enrolled, and the median follow-up duration was 22.9 months (interquartile range: 17.4–24.7). The primary outcome was 6-months progression-free survival (PFS), which was 88.6% (95% confidence interval [CI] 75.4–96.2), meeting the pre-specified primary endpoint. The secondary outcomes reported here include median PFS, 12-months PFS, and overall survival and safety. The median PFS was 22.4 months (20.4–∞), with a 12-months PFS rate of 84.0% (95% CI 69.3–92.0). The median overall survival was 28.6 months (27.3–∞). The combination demonstrated tolerable toxicity with manageable side effects. Other secondary outcomes include time-to-progression, time to subsequent treatment, time to second treatment and PFS2; however, this data is not reported, as treatment is still ongoing in a majority of patients. Exploratory analysis shows that patients who were homologous recombination deficiency-positive or had a programmed death-ligand 1 combined positive score ≥1 showed a favorable response (P = 0.043 and P &lt; 0.001, respectively). Thus, triplet maintenance shows durable efficacy with tolerable safety in patients with platinum-sensitive recurrence.

Randomized, two‐arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR‐mutated, platinum‐resistant ovarian cancer: A substudy of KGOG 3045

AbstractChoosing an optimal concomitant drug for combination with poly‐ADP ribose polymerase (PARP) inhibitor based on patient‐specific biomarker status may help increase to improve treatment efficacy in patients with ovarian cancer. However, the efficacy and safety of different PARP inhibitor‐based combinations in patients with homologous recombination repair (HRR) mutations have not been evaluated in ovarian cancer. In this sub‐study of Korean Gynecologic Oncology Group (KGOG) 3045, we compared the efficacy and safety of two olaparib‐based combinations and biomarkers of patients with platinum‐resistant ovarian cancer with HRR gene mutations. Patients were randomized to receive either olaparib (200 mg twice a day) + cediranib (30 mg daily) (Arm 1, n = 16) or olaparib (300 mg) + durvalumab (1,500 mg once every 4 weeks) (Arm 2, n = 14). The objective response rates for Arm 1 and Arm 2 were 50.0% and 42.9%, respectively. Most patients (83.3%) had BRCA mutations, which were similarly distributed between arms. Grade 3 or 4 treatment‐related adverse events were observed in 37.5% and 35.7% of the patients, respectively, but all were managed properly. A high vascular endothelial growth factor signature was associated with favorable outcomes in Arm 1, whereas immune markers (PD‐L1 expression [CPS ≥10], CD8, neutrophil‐to‐lymphocyte ratio and platelet‐to‐lymphocyte ratio) were associated with favorable outcomes in Arm 2. The activation of homologous recombination pathway upon disease progression was associated with poor response to subsequent therapy. Based on comprehensive biomarker profiling, including immunohistochemistry, whole‐exome and RNA sequencing and whole blood‐based analyses, we identified biomarkers that could help inform which of the two combination strategies is appropriate given a patient's biomarker status. Our findings have the potential to improve treatment outcome for patients with ovarian cancer in the PARP inhibitor era.

Application of precision medicine based on next-generation sequencing and immunohistochemistry in ovarian cancer: a real-world experience

To evaluate the landscape of gene alterations and immunohistochemistry (IHC) profiles of patients with ovarian cancer for targeted therapy and investigate the real-world experience of applying precision medicine. Patients diagnosed with ovarian cancer between January 2015 and May 2021 at Severance Hospital and who underwent tumor next-generation sequencing (NGS) were reviewed. Data on germline mutation, IHC markers for mismatch repair deficiency (MMRd), programmed death ligand 1 (PD-L1) expression, and human epidermal growth factor receptor 2 (HER2) expression were acquired. The use of matched therapy and its clinical outcomes were evaluated. Of the 512 patients who underwent tumor NGS, 403 underwent panel-based germline testing. In patients who underwent both tests, tumor NGS identified 39 patients (9.7%) with A comprehensive review of germline mutation, IHC, and tumor NGS helped identify candidates for precision therapy in patients with ovarian cancer, a proportion of whom received matched therapy.

Investigation of PARP Inhibitor Resistance Based on Serially Collected Circulating Tumor DNA in Patients With BRCA -Mutated Ovarian Cancer

Abstract Purpose: Patient-specific molecular alterations leading to PARP inhibitor (PARPi) resistance are relatively unexplored. In this study, we analyzed serially collected circulating tumor DNA (ctDNA) from patients with BRCA1/2 mutations who received PARPis to investigate the resistance mechanisms and their significance in postprogression treatment response and survival. Experimental Design: Patients were prospectively enrolled between January 2018 and December 2021 (NCT05458973). Whole-blood samples were obtained before PARPi administration and serially every 3 months until progression. ctDNA was extracted from the samples and sequenced with a 531-gene panel; gene sets for each resistance mechanism were curated. Results: Fifty-four patients were included in this analysis. Mutation profiles of genes in pre-PARPi samples indicating a high tumor mutational burden and alterations in genes associated with replication fork stabilization and drug efflux were associated with poor progression-free survival on PARPis. BRCA hypomorphism and reversion were found in 1 and 3 patients, respectively. Among 29 patients with matched samples, mutational heterogeneity increased postprogression on PARPis, showing at least one postspecific mutation in 89.7% of the patients. These mutations indicate non-exclusive acquired resistance mechanisms—homologous recombination repair restoration (28%), replication fork stability (34%), upregulated survival pathway (41%), target loss (10%), and drug efflux (3%). We observed poor progression-free survival with subsequent chemotherapy in patients with homologous recombination repair restoration (P = 0.003) and those with the simultaneous involvement of two or more resistance mechanisms (P = 0.040). Conclusions: Analysis of serial ctDNAs highlighted multiple acquired resistance mechanisms, providing valuable insights for improving postprogression treatment and survival.

Major clinical research advances in gynecologic cancer in 2022: highlight on late-line PARP inhibitor withdrawal in ovarian cancer, the impact of ARIEL-4, and SOLO-3

In the 2022 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Ovarian cancer: long-term follow-up data, new poly (ADP-ribose) polymerase (PARP) inhibitors, overall survival (OS) issues with PARP inhibitor monotherapy, hyperthermic intraperitoneal chemotherapy, immunotherapy, and antibody-drug conjugate; 2) Cervical cancer: surgery in early stage disease, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Corpus cancer: follow-up regimen, immune checkpoint inhibitor, WEE1 inhibitor, selective inhibitor of nuclear export. A special note was made on the withdrawal of PARP inhibitor from the market for heavily pretreated ovarian cancer patients based on the final OS results of ARIEL-4 and SOLO-3 due to concerns of increased risk of death.

4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39+ CD8 T cells from primary and metastatic sites of epithelial ovarian cancers

Background Responses to immunotherapy vary between different cancer types and sites. Here, we aimed to investigate features of exhaustion and activation in tumor-infiltrating CD8 T cells at both the primary and metastatic sites in epithelial ovarian cancer. Methods Tumor tissues and peripheral blood were obtained from 65 patients with ovarian cancer. From these samples, we isolated tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells. These cells were used for immunophenotype using multicolor flow cytometry, gene expression profile using RNA sequencing and ex vivo functional restoration assays. Results We found that CD39+ CD8 TILs were enriched with tumor-specific CD8 TILs, and that the activation status of these cells was determined by the differential programmed cell death protein 1 (PD-1) expression level. CD39+ CD8 TILs with high PD-1 expression (PD-1high) exhibited features of highly tumor-reactive and terminally exhausted phenotypes. Notably, PD-1high CD39+ CD8 TILs showed similar characteristics in terms of T-cell exhaustion and activation between the primary and metastatic sites. Among co-stimulatory receptors, 4-1BB was exclusively overexpressed in CD39+ CD8 TILs, especially on PD-1high cells, and 4-1BB-expressing cells displayed immunophenotypes indicating higher degrees of T-cell activation and proliferation, and less exhaustion, compared with cells not expressing 4-1BB. Importantly, 4-1BB agonistic antibodies further enhanced the anti-PD-1-mediated reinvigoration of exhausted CD8 TILs from both primary and metastatic sites. Conclusion Severely exhausted PD-1high CD39+ CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers.

Role of diagnostic laparoscopy in deciding primary treatment in advanced-stage ovarian cancer

We evaluated the usefulness of preoperative diagnostic laparoscopy for treatment planning in patients with advanced-stage ovarian cancer. We retrospectively analyzed 614 patients diagnosed with advanced-stage ovarian cancer between January 2010 and May 2018. Primary debulking surgery (PDS) or neoadjuvant chemotherapy (NAC) followed by interval debulking surgery were selected based on preoperative laparoscopic (Group 1, n=192) and computed tomography findings (Group 2, n=422). The primary outcomes in the PDS and NAC groups were suboptimal cytoreduction (residual disease >1 cm) rate and non-high-grade serous carcinoma (non-HGSC) rate, respectively. The patients who underwent PDS in group 1 and group 2 were 49 (25.5%) and 279 (66.1%), respectively. The suboptimal cytoreduction rate after PDS was lower in Group 1 than in Group 2 (2.0% vs 11.1%, p=0.023). Moreover, Group 1 showed a tendency toward a lower proportion of non-HGSC patients who underwent NAC than that in Group 2 (9.1% vs. 15.4%, p=0.069). Further, Group 1 showed lower rates of postoperative morbidity than Group 2 (5.2% vs. 10.4%, p=0.033). However, Kaplan-Meier analysis showed no significant differences in survival outcomes between the 2 groups. Diagnostic laparoscopy reduced the suboptimal cytoreduction rate in the PDS group and the implementation rate of NAC in non-HGSC patients. Moreover, it reduced postoperative morbidity without affecting survival in both groups. Thus, diagnostic laparoscopy is a valuable diagnostic tool for determining the primary treatment.

Major clinical research advances in gynecologic cancer in 2019

In 2019, 12 topics were selected as the major research advances in gynecologic oncology. Herein, we first opted to introduce the significant clinical activity of pembrolizumab in women with advanced cervical cancer based on the results of the phase 2 KEYNOTE-158 trial. Thereafter, we reviewed 5 topics, including systemic lymphadenectomy in the advanced stage with no gross residual tumor, secondary cytoreductive surgery in recurrent ovarian cancer according to the results of Gynecologic Oncology Group-213 trial, dose-dense weekly paclitaxel scheduling as first-line chemotherapy, the utility of intraperitoneal therapy in the advanced stage, and an update on poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Additionally, we conducted a thorough review of emerging data from several clinical trials on PARP inhibitors according to drug, target population, and combined usage. For uterine corpus cancer, we reviewed adjuvant therapy for high-risk disease and chemotherapy in advanced/recurrent disease. For the field of radiation oncology, we discussed the utility of neoadjuvant chemotherapy added to chemoradiotherapy and the treatment of radiation-induced cystitis using hyperbaric oxygen. Finally, we discussed the use of individualized therapy with humanized monoclonal antibodies (trastuzumab emtansine and sacituzumab govitecan-hziy) and combination therapy (fulvestrant plus alpesilib, fulvestrant plus anastrozole, and ribociclib plus endocrine therapy) for women with advanced breast cancer.

A Single-Center, Retrospective Study of Bevacizumab-Containing Neoadjuvant Chemotherapy followed by Interval Debulking Surgery for Ovarian Cancer

We evaluated whether adding bevacizumab to current platinum-based chemotherapy could improve clinical outcomes without affecting safety. We retrospectively reviewed medical records of patients with pathologically confirmed ovarian cancer who received neoadjuvant chemotherapy (NAC) at Yonsei Cancer Hospital. We divided the patients into groups based on the use of bevacizumab for NAC (CP group: carboplatin+paclitaxel vs. BCP group: bevacizumab+carboplatin+paclitaxel) and compared patient characteristics, responses to NAC, and surgical and survival outcomes between the two groups. Overall, 88 patients in the CP group and 16 patients in the BCP group received NAC. The primary endpoint was survival outcomes. Complete resection rate after interval debulking surgery (IDS), cancer antigen 125 (CA-125) normalization after NAC, and chemotherapy response score were secondary endpoints. After NAC treatment, all patients underwent IDS. There were no significant differences in adverse events during NAC or postoperative complications between the two groups ( Bevacizumab-containing NAC might be safe and provide longer PFS than chemotherapy alone in patients with advanced ovarian cancer. However, further study is necessary to investigate the impact of bevacizumab-containing NAC on OS.

Comparison between weekly versus 3-weekly paclitaxel in combination with carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer

To compare the efficacy and toxicity of dose-dense weekly paclitaxel and 3-weekly carboplatin (ddPC) as neoadjuvant chemotherapy (NAC) with the standard 3-weekly regimen. A retrospective study of patients diagnosed with stage IIIc and IV ovarian cancer who received at least one cycle of NAC followed by interval debulking surgery between August 2015 and January 2018 was conducted. Patient characteristics, clinical and pathological response to NAC, surgical and survival outcome, and adverse event were compared. A total of 23 patients in the ddPC group and 50 patients in the standard group received a median of 3 cycles of NAC. Rate of grade ≥3 neutropenia was significantly higher in the ddPC group than the standard (82.6% vs. 22.0%, p<0.001). Patients in the ddPC group underwent dose-reduction more frequently (34.8% vs. 4.00%, p=0.001). Normalization of cancer antigen-125 post-NAC occurred more frequently in the ddPC group (73.9% vs. 46.0%, p=0.030). No residual disease rate (43.5% vs. 60.0%, p=0.188) and chemotherapy response score of 3 (34.8% vs. 26.0%, p=0.441) were not statistically different between two groups. There was no statistical difference in progression free survival (PFS) at 2 years (36.3% vs. 28.4%, p=0.454). Cox proportional hazard model showed that ddPC was not a significant determinant of PFS (p=0.816). There was no difference between both regimens in terms of NAC response and survival outcomes. However, ddPC group showed higher hematologic toxicity requiring dose reduction.

Genomic profiling of the residual disease of advanced high‐grade serous ovarian cancer after neoadjuvant chemotherapy

The goal of our study was to demonstrate the spectrum of genomic alterations present in the residual disease of patients with advanced high‐grade serous ovarian cancer (HGSOC) after neoadjuvant chemotherapy (NAC), including matched pretreatment biopsies. During the study period between 2006 and 2017, we collected pre‐NAC and post‐NAC tumor tissue samples from patients with advanced HGSOC. We performed combined next‐generation sequencing and immunohistochemistry to identify actionable targets and pathway activation in post‐NAC residual tumors. We also examined whether post‐NAC profiling of residual HGSOC identified targetable molecular lesions in the chemotherapy‐resistant component of tumors. Among 102 post‐NAC samples, 41 (40%) of patients had mutations in homologous recombination repair (HRR) genes (HRR deficiency). Patients with HRR mutations had higher tumor mutation burdens (p &lt; 0.001) and higher alterations in the PI3K–AKT–mTOR pathway (p = 0.004) than patients without these HRR mutations. Nevertheless, we found no significant differences in progression‐free survival (p = 0.662) and overall survival (OS; p = 0.828) between the two groups. Most patients (91%) had alterations in at least one of the targetable pathways, and those patients with cell cycle (p = 0.004) and PI3K–AKT–mTOR signaling (p = 0.005) pathway alterations had poorer OS (Bonferroni‐corrected threshold = 0.0083, 0.05/6). We showed the genomic landscape of tumor cells remaining in advanced HGSOC after NAC. Once validated, these data can help inform biomarker‐driven adjuvant studies in targeting residual tumors to improve the outcomes of patients with advanced HGSOC after NAC.

A single-arm, phase II study of niraparib and bevacizumab maintenance therapy in platinum-sensitive, recurrent ovarian cancer patients previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial

Given the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therapy in platinum-sensitive ovarian cancer patients who were previously treated with a PARPi. The KGOG 3056/NIRVANA-R is a multi-centre, investigator-initiated, single-arm, phase II trial of patients with platinum-sensitive recurrent ovarian cancer recruited from seven KGOG sites. This study included patients with platinum-sensitive recurrent epithelial ovarian cancer who received at least 2 previous courses of platinum-containing therapy and had been treated with a PARPi. Mucinous histology type was excluded. Patients who had responded to the last platinum regimen (either complete or partial response) were eligible to participate in this study. Forty-four patients will be recruited. All enrolled patients are treated with niraparib and bevacizumab for maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint of the study is 6-month progression-free survival rate. Accrual is expected to be completed in 2022, followed by presentation of results in 2023. ClinicalTrials.gov Identifier: NCT04734665.

CT-Based Fagotti Scoring System for Non-Invasive Prediction of Cytoreduction Surgery Outcome in Patients with Advanced Ovarian Cancer

To construct a CT-based Fagotti scoring system by analyzing the correlations between laparoscopic findings and CT features in patients with advanced ovarian cancer. This retrospective cohort study included patients diagnosed with stage III/IV ovarian cancer who underwent diagnostic laparoscopy and debulking surgery between January 2010 and June 2018. Two radiologists independently reviewed preoperative CT scans and assessed ten CT features known as predictors of suboptimal cytoreduction. Correlation analysis between ten CT features and seven laparoscopic parameters based on the Fagotti scoring system was performed using Spearman's correlation. Variable selection and model construction were performed by logistic regression with the least absolute shrinkage and selection operator method using a predictive index value (PIV) ≥ 8 as an indicator of suboptimal cytoreduction. The final CT-based scoring system was internally validated using 5-fold cross-validation. A total of 157 patients (median age, 56 years; range, 27-79 years) were evaluated. Among 120 (76.4%) patients with a PIV ≥ 8, 105 patients received neoadjuvant chemotherapy followed by interval debulking surgery, and the optimal cytoreduction rate was 90.5% (95 of 105). Among 37 (23.6%) patients with PIV < 8, 29 patients underwent primary debulking surgery, and the optimal cytoreduction rate was 93.1% (27 of 29). CT features showing significant correlations with PIV ≥ 8 were mesenteric involvement, gastro-transverse mesocolon-splenic space involvement, diaphragmatic involvement, and para-aortic lymphadenopathy. The area under the receiver operating curve of the final model for prediction of PIV ≥ 8 was 0.72 (95% confidence interval: 0.62-0.82). Central tumor burden and upper abdominal spread features on preoperative CT were identified as distinct predictive factors for high PIV on diagnostic laparoscopy. The CT-based PIV prediction model might be useful for patient stratification before cytoreduction surgery for advanced ovarian cancer.

A single-arm phase II study of olaparib maintenance with pembrolizumab and bevacizumab in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer (OPEB-01)

The optimal treatment of ClinicalTrials.gov Identifier: NCT04361370, Clinical Research Information Service Identifier: KCT0005144.

Major clinical research advances in gynecologic cancer in 2021

In the 2021 series, we not only summarized the major clinical research advances in gynecologic oncology but also added discussions to every part, based on communications at the conference. A review of cervical cancer included adjuvant treatments such as radiation and chemoradiation (concurrent or sequential) after radical hysterectomy in early cervical cancer, and immune checkpoint inhibitors in advanced, recurrent, and metastatic disease. Ovarian cancer research included studies of secondary cytoreductive surgery in platinum-sensitive recurrent ovarian cancer, and various trials of immune checkpoint inhibitors with or without vascular endothelial growth factor inhibitors and conventional chemotherapy. The rechallenge of poly (ADP-ribose) polymerase inhibitor maintenance in heavily pretreated ovarian cancer were also addressed. For uterine corpus cancer, dostarlimab (anti-programmed cell death protein 1 antibody) alone, or a tyrosine kinase inhibitor in combination with pembrolizumab for advanced, metastatic, or recurrent endometrial cancer were reviewed. The survival differences between the intensive and minimalist follow-up protocols were also described. In this review, we compared salpingectomy with delayed oophorectomy and salpingo-oophorectomy in terms of quality of life in BRCA 1 and 2 pathogenic variant carriers.

PARP inhibitors in ovarian cancer: overcoming resistance with combination strategies

The use of PARP inhibitors (PARPi) in patients with epithelial ovarian cancer is expanding, with the transition from use in recurrent disease to the first-line setting. This is accompanied with an increasing population of patients who develop acquired PARPi resistance. Coupled with those patients with primary PARPi resistance, there is an urgent need to better understand mechanisms of resistance and identify means to overcome this resistance. Combination therapy offers the potential to overcome innate and acquired resistance, by either working synergistically with PARPi or by restoring homologous recombination deficiency, targeting the homologous recombination repair pathway through an alternate strategy. We discuss mechanisms of PARPi resistance and data on novel combinations which may restore PARPi sensitivity.

Biomarker-guided targeted therapy in platinum-resistant ovarian cancer (AMBITION; KGOG 3045): a multicentre, open-label, five-arm, uncontrolled, umbrella trial

Management of heavily pre-treated platinum-resistant ovarian cancer remains a therapeutic challenge. Outcomes are poor with non-platinum, single-agent chemotherapy (CT); however, molecularly targeted anticancer therapies provide new options. This open-label, investigator-initiated, phase 2 umbrella trial (NCT03699449) enrolled patients with platinum-resistant ovarian cancer (at least 2 prior lines of CT and Eastern Cooperative Oncology Group 0/1) to receive combination therapy based on homologous recombination deficiency (HRD) and programmed death ligand 1 (PD-L1) status determined by archival tumour sample assessment. HRD-positive patients were randomised to either olaparib 200mg bid tablet + cediranib 30mg qd (arm 1) or olaparib 300mg bid tablet + durvalumab 1,500mg q4w (arm 2). HRD-negative patients were allocated to either durvalumab 1,500 mg q4w + pegylated liposomal doxorubicin (PLD) or topotecan or weekly paclitaxel (6 cycles; arm 3, those with PD-L1 expression) or durvalumab 1,500 mg q4w + tremelimumab 75mg q4w (4 doses) + PLD or topotecan or weekly paclitaxel (4 cycles; arm 4, those without PD-L1 expression). Arm 5 (durvalumab 1,500 mg q4w + tremelimumab 300mg [1 dose] + weekly paclitaxel [60 mg/m² D1,8,15 q4w for 4 cycles] was initiated after arm 4 completed. The primary endpoint was objective response rate (ORR; Response Evaluation Criteria in Solid Tumours 1.1). Between Dec 2018 and Oct 2020, 70 patients (median 57 years; median 3 prior treatment lines [range 2-10]) were treated (n=16, 14, 5, 18, and 17, respectively). Overall ORR was 37.1% (26/70, 95% confidence interval=25.9, 49.5); 2 achieved complete response. ORR was 50%, 42.9%, 20%, 33.3%, and 29.4%, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 37.5%, 35.7%, 20%, 66.7%, and 35.3% of patients, respectively. No TRAEs leading to treatment discontinuation and no grade 5 TRAEs were observed. This study, the first biomarker-driven umbrella trial in platinum-resistant recurrent ovarian cancer, suggests clinical utility with biomarker-driven targeted therapy. All treatment combinations were manageable, and without unexpected toxicities. ClinicalTrials.gov Identifier: NCT03699449.

Prognostic value of complete metabolic response on 18F-FDG-PET/CT after three cycles of neoadjuvant chemotherapy in advanced high-grade serous ovarian cancer

We investigated the prognostic value of complete metabolic response (CMR) on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) after 3 cycles of neoadjuvant chemotherapy (NAC) in advanced high-grade serous ovarian cancer (HGSC). PET/CT at baseline and after 3 cycles of NAC were performed; peak standardized uptakes were measured. PET parameters were compared with NAC parameter: cancer antigen-125 (CA-125) normalization before interval debulking surgery (IDS) and chemotherapy response score (CRS) to predict platinum-sensitivity. Kaplan-Meier analysis was used to determine correlations between PET parameters and survival. Prognostic factors were obtained by multivariate Cox regression analysis. Between 2007 and 2020, 102 patients were recruited: 19 (18.6%) were designated as CMR group and 83 (81.4%) as non-CMR group. CMR after 3 cycles of NAC showed the highest accuracy in predicting platinum-sensitivity (area under the curve [AUC]=0.729; 95% confidence interval [CI]=0.552-0.823; p=0.017), compared with CA-125 normalization before IDS (AUC=0.626; 95% CI=0.542-0.758; p=0.010) and CRS (AUC=0.613; 95% CI=0.490-0.735; p=0.080). CMR demonstrated better prognosis than non-CMR in progression-free survival (PFS) (median PFS, 23.9 months vs. 16.4 months; p=0.021) and overall survival (OS) (median OS, not reached vs. 69.7 months; p=0.025). In multivariate analysis, CMR was associated with a lower risk of recurrence (adjusted hazard ratio [aHR]=0.50; 95% CI=0.27-0.92; p=0.027) and death (aHR=0.23; 95% CI=0.05-0.99; p=0.048). CMR after 3 cycles of NAC can be a prognostic factor for both recurrence and death in advanced HGSC.

Time for enhancing government-led primary prevention of cervical cancer

Major clinical advances in gynecologic cancer in 2025: from de-escalation strategies to precision therapies beyond BRCA

The landscape of gynecologic cancer management has continued to evolve substantially in 2025, driven by major clinical advances spanning surgical, radiation, and systemic therapies. Recent progress in precision oncology has expanded therapeutic options beyond the

Phase II randomized study of first-line carboplatin and paclitaxel in combination with pembrolizumab, followed by maintenance pembrolizumab alone or with nesuparib, in mismatch-repair proficient, advanced or recurrent endometrial cancer (PENELOPE).

Although recent clinical trials proved survival benefit from the addition of immune checkpoint inhibitors to standard chemotherapy, treatment of mismatch repair-proficient (pMMR) advanced or recurrent endometrial cancer (arEC) is challenging. As poly(ADP-ribose) polymerase (PARP) inhibitors enhance the effects of immune checkpoint inhibitors when combined, improvement of survival is expected by dual maintenance in this population. The PENELOPE trial will investigate the efficacy and safety of dual maintenance with nesuparib, an orally active PARP1/2 and tankyrase 1/2 inhibitor, and pembrolizumab after paclitaxel/carboplatin plus pembrolizumab (TCP) treatment in patients with pMMR arEC. In this multicenter, randomized, open-label, non-comparative phase II trial, patients with pMMR arEC, naïve to first-line chemotherapy, will be enrolled. Six patients will be enrolled in stage 1 (safety run-in) and treated with TCP for 6 cycles followed by dual maintenance with nesuparib and pembrolizumab. The study will proceed to stage 2 (dose expansion) if less than 33% of patients in stage 1 experience a dose-limiting toxicity. Otherwise, additional patients will be enrolled in stage 1 at a lower dose level. In stage 2, 80 patients will be randomized (1:1) to: arm A) TCP followed by maintenance with pembrolizumab; arm B) TCP followed by dual maintenance with nesuparib and pembrolizumab. Patients are planned to receive maintenance treatment up to 14 cycles every 6 weeks. Primary endpoint is investigator-assessed progression-free survival (Response Evaluation Criteria in Solid Tumors 1.1) of each arm vs. historical control, which is the placebo arm for pMMR patients in the NRG-GY018 study, and key secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and safety. Enrollment began in Q4 2024. ClinicalTrials.gov Identifier: NCT06502743.

Primary Analysis of EPIK-O/ENGOT-ov61: Alpelisib Plus Olaparib Versus Chemotherapy in Platinum-Resistant or Platinum-Refractory High-Grade Serous Ovarian Cancer Without BRCA Mutation

PURPOSE Patients with platinum-resistant/platinum-refractory high-grade serous ovarian cancer (HGSOC) without a BRCA mutation have poor prognosis and limited treatment options. We report efficacy and biomarker data from EPIK-O, which investigated alpelisib + olaparib versus single-agent chemotherapy in these patients. PATIENTS AND METHODS EPIK-O was an open-label, phase III trial that randomly assigned patients with platinum-resistant/platinum-refractory HGSOC with no germline or known somatic BRCA mutation 1:1 to alpelisib 200 mg once daily + olaparib 200 mg twice daily or treatment of physician's choice (TPC; paclitaxel 80 mg/m 2 once weekly or pegylated liposomal doxorubicin 40-50 mg/m 2 once every 28 days). Patients had 1-3 previous systemic therapies. Previous bevacizumab was required (unless contraindicated); previous poly(adenosine diphosphate-ribose) polymerase inhibitors were allowed. Primary end point was progression-free survival (PFS) per RECIST 1.1 (blinded independent review committee [BIRC]). Secondary efficacy end points included overall response rate (ORR; per BIRC), duration of response (per BIRC), and overall survival (OS; key secondary end point). RESULTS A total of 358 patients (alpelisib + olaparib [n = 180], TPC [n = 178]) were included. The median follow-up time was 9.3 months. At data cutoff (April 21, 2023), 33 (18.3%) and 30 (16.9%) patients remained on treatment with alpelisib + olaparib and TPC, respectively. The median PFS (BIRC) was 3.6 versus 3.9 months (hazard ratio [HR], 1.14 [95% CI, 0.88 to 1.48]; one-sided P = .84) for alpelisib + olaparib versus TPC. The ORR was 15.6% (95% CI, 10.6% to 21.7%) versus 13.5% (95% CI, 8.8% to 19.4%). The median OS was 10.0 versus 10.6 months (HR, 1.22; 95% CI, 0.87 to 1.71). The safety profile of alpelisib + olaparib was consistent with that observed for the individual agents. CONCLUSION The primary objective, PFS improvement, was not met in EPIK-O. No new or unexpected adverse events were observed. Biomarker analyses provided new insights for responders to alpelisib + olaparib.

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)–deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P &lt; .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1–positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

A Three-arm Randomized Phase II Study of Dostarlimab Alone or With Bevacizumab Versus Nonplatinum Chemotherapy in Recurrent Gynecological Clear Cell Carcinoma: DOVE (APGOT-OV7/ ENGOT-ov80 Study)

Multicenter, randomized, open-label, phase II clinical study comparing Dostarlimab +/- Bevacizumab with standard chemotherapy in patients with gynecological clear cell carcinoma. 198 subjects will be enrolled in this study and will be assigned to three groups in a 1:1:1 ratio. 1. Group A: Dostarlimab monotherapy * First 3 cycles: Dostalimab 500mg every 3 weeks, IV * 4 cycles \~ up to 24 months: Dostalimab 1000mg every 6 weeks, IV 2. Group B: Dostarlimab + Bevacizumab combination therapy * First 3 cycles: Dostalimab 500mg every 3 weeks, IV * 4 cycles \~ up to 24 months: Dostalimab 1000mg every 6 weeks, IV * Bevacizumab administered IV at 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity 3. Group C: General chemotherapy (one of Pegylated liposomal doxorubicin, Doxorubicin, Paclitaxel, and Gemcitabine)

Study of Induction PD-1 Blockade (Nivolumab) in Patients With Surgically Complete Resectable Mismatch Repair Deficient Endometrial Cancer (NIVEC)

phase 2 clinical trial to confirm the pathological complete response rate of PD-1 blocker use in patients with Mismatch Repair Deficiency(MMRd) endometrial cancer that can be completely resected surgically.

Niraparib and Bevacizumab Maintenance Therapy in Platinum-sensitive Recurrent Ovarian Cancer Patients Previously Treated With a PARP Inhibitor

This study is phase II, open label, clinical trial to determine the efficacy of Niraparib re-treatment with Bevacizumab of assessment progression-free survival(6 months PFS rate) with platinum-sensitive recurrent ovarian cancer patients previously treated with a PARP inhibitor.

Olaparib Maintenance With Pembrolizumab & Bevacizumab in BRCA Non-mutated Patients With Platinum-sensitive Recurrent Ovarian Cancer

This study is phase II, open label, clinical trial to determine the efficacy of Olaparib maintenance with Bevacizumab and Pembrolizumab by assessment progression-free survival(6 months PFS rate) in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer.

A Phase II Study of Neoadjuvant Chemotherapy Plus Durvalumab (MEDI4736) and Tremelimumab in Advanced-stage Ovarian Cancer (TRU-D)

The primary objective of this trial is to evaluate the synergistic effects of durvalumab and tremelimumab plus chemotherapy in advanced-stage ovarian cancer. Ovarian cancer is the deadliest gynecologic cancer. The current standard therapy is surgical cytoreduction followed by taxane-platinum combination chemotherapy. However, most patients with advanced-stage ovarian cancer will experience a relapse of disease. Therefore, there is an urgent need to improve outcomes of patients with this aggressive cancer. Research hypothesis: Adding durvalumab and tremelimumab to current neoadjuvant chemotherapy (front-line therapy) in advanced-stage ovarian cancer can increase response rate and improve patient's outcome such as progression-free survival and overall survival with minimal effects on safety.

An uMbrella Study of BIomarker-driven Targeted Therapy In Patients With Platinum-resistant Recurrent OvariaN Cancer(AMBITION)

This study is a pilot study of biomarker-driven targeted therapy in patients with platinum-resistant recurrent ovarian cancer. More specifically, this is a randomized, multi-center, open label, phase II study for Homologous Recombination Deficiency(HRD)+ patients and a biomarker-driven multiple-arm phase II study for Homologous Recombination Deficiency(HRD)- patients. This study will consist of a number of study modules (substudies), each evaluating the antitumor activity of targeted agents in patients whose tumors express specific phenotype relevant to the molecules under investigation.

Circulating Tumor DNA and BRCA Reversion Mutation in Advanced or Recurrent Ovarian Cancer Patients With Germline Mutation.

Increasing number of ovarian cancer patients are receiving PARP inhibitor as maintenance or salvage therapy. Predictive factors to PARP inhibitor other than BRCA mutation or HRD status as well as specific resistance mechanism are unknown. Thus, the objective of this study was to prospectively collect serial blood samples in ovarian cancer patients with germline BRCA mutation who receive PARP inhibitor. We investigated circulating tumor DNA (ctDNA) before patients are started on PARP inhibitor and every 3 months thereafter until progression on PARP inhibitor. Through assessment of the changes in ctDNA mutational landscape, we aimed to investigate resistance mechanism to PARP inhibitor including BRCA reversion mutation.