Mayu Yunokawa

Universal tumor testing is increasingly recommended for Lynch syndrome (LS). However, data involving younger Japanese patients are still limited. This study aimed to prospectively evaluate the prevalence and clinicopathologic profile of DNA mismatch repair (MMR)-deficient (dMMR) endometrial cancers (EC) in patients aged under 50 years, and characterize immunohistochemical (IHC) loss patterns and genetic testing results. Patients with EC aged under 50 years who consented to study participation were prospectively enrolled at a single Japanese institution. Diagnostic specimens underwent MMR IHC (MLH1, MSH2, MSH6, and PMS2). Clinicopathologic variables were compared between proficient MMR (pMMR) and dMMR. Among 111 patients, 26 (23.4%) had dMMR. Grades differed when dichotomized as G1 versus G2-G3 (p < 0.01). FIGO stage distribution also varied between groups (p = 0.035). Among dMMR tumors, IHC patterns were loss of MLH1/PMS2 (n = 12), loss of MSH2/MSH6 (n = 8), and isolated loss of MSH6 (n = 6). Of the 12 (46.2%) patients with dMMR who underwent germline testing, 9 had LS (MLH1/PMS2 loss: 3/5; MSH2/MSH6 loss: 4/4; MSH6 isolated loss: 2/3). The overall dMMR prevalence in this young cohort was comparable to that in all-age series from multiple regions. This represents a minimum prevalence of LS in the overall study cohort, as germline testing was performed only in a subset of patients with dMMR tumors. In this prospective Japanese cohort, approximately one in four patients with EC had dMMR, with clinicopathologic features skewing toward a higher grade. Notably, many dMMR tumors were grade 2-3, suggesting that a substantial proportion of patients may fall outside the conventional criteria for fertility-sparing treatment.

Background: The optimal approach for early-stage ovarian cancer detection remains unclear, particularly in patients with hereditary breast and ovarian cancer (HBOC). As ovarian cancer in HBOC is often thought to originate from the fallopian tube fimbriae, endometrial cytology may play a role in detecting early-stage disease. This retrospective study aimed to assess the positive rate of endometrial cytology and compare to cervical cytology in ovarian cancer patients with patients with BRCA1/2 germline pathogenic variants (gPV). Methods: Patients with genetically confirmed BRCA1/2 gPV diagnosed with ovarian, fallopian tube, or primary peritoneal cancer from May 1998 to April 2024 at our institution were included. Those who underwent endometrial and cervical cytology prior to initial treatment were eligible for this analysis. The positive rates for each cytology type were evaluated. Results: A total of 154 patients with BRCA1/2 gPV were enrolled, 118 underwent both endometrial and cervical cytology. The positive rate for endometrial cytology was significantly higher than that for cervical cytology (36.4% vs. 15.3%; p < 0.001). Additionally, a correlation was observed between the positive rate of endometrial cytology and cancer stage (Stage I 16.6%, Stage II 25%, Stage III 41.5%, Stage IV 58.6%; r = 0.9895). Conclusion: In this retrospective study, the positive rate of endometrial cytology surpassed that of cervical cytology. Endometrial cytology may play a role as a potential surveillance tool for women with BRCA1/2 gPV, even at early stages of ovarian cancer.

Background: The optimal timing of cytoreductive surgery for advanced high-grade serous carcinoma (HGSC) remains a critical unmet question in the modern era of platinum-based chemotherapy and PARP inhibitor (PARPi) maintenance. To address this gap, we compared outcomes following primary debulking surgery (PDS) versus interval debulking surgery (IDS) in a uniformly treated, contemporary cohort. Methods: Patients with FIGO stage IIIB–IVB HGSC treated between 2019 and 2023 were retrospectively analyzed. Baseline tumor burden was assessed using detailed radiologic and laparoscopic evaluations, including both presurgical and intraoperative assessments. Progression-free survival (PFS) and overall survival (OS) were examined using multivariable Cox proportional hazards models and reported as adjusted hazard ratios (aHRs). Subgroup analyses were rigorously conducted according to residual disease status and BRCA mutation status. Results: Among 221 patients (PDS, n = 60; IDS, n = 151), the median follow-up was 40 months. In the overall cohort, adjusted PFS and OS did not differ significantly between the PDS and IDS groups (PFS: aHR, 1.15; 95%CI, 0.67–1.98; OS: aHR, 1.24; 95%CI, 0.54–2.83). Outcomes were comparable among patients achieving R0 resection. Notably, BRCA-mutated patients demonstrated a substantial survival advantage with PDS (BRCA-mutated PFS: aHR, 3.34; 95%CI, 1.06–16.67; OS: aHR, 6.07; 95%CI, 2.13–∞), whereas BRCA wild-type patients showed no significant difference between surgical strategies. Conclusions: The findings suggest that BRCA-mutated patients may derive a survival benefit from PDS, whereas surgical timing had a limited impact on BRCA wild-type disease. This result underscores the importance of integrating molecular profiling, particularly BRCA mutation status, with surgical assessment to guide optimal and personalized treatment strategies in the PARPi era.

Shoji T, et al. J Gynecol Oncol. 2026 ;37:e150. https://doi.org/10.3802/jgo.2026.37.e150

Toyohara Y, et al. J Gynecol Oncol. 2026 ;37:e82. https://doi.org/10.3802/jgo.2026.37.e82

Background: Existing circulating cell-free DNA (cfDNA) assays are primarily centralized, requiring specialized sample handling and transportation. Implementing a flexible, decentralized sequencing system at point of care, with minimal technical oversight, can enhance turnaround times and patient access to genomic profiling. In this study, we aimed to evaluate the clinical feasibility of an automated and decentralized cfDNA next-generation sequencing (NGS) assay for identifying actionable alterations in advanced solid tumors. Methods: Genomic profiling of plasma cfDNA from 298 patients with advanced solid tumors was conducted using an automated NGS assay. We assessed concordance of tumor mutations detected in plasma cfDNA and patient-matched tumor tissues analyzed by an FDA-approved assay, investigating clinical factors influencing circulating tumor DNA (ctDNA) aberration (mut-ctDNA) detection sensitivity. Results: Sequencing success rates for cfDNA genomic profiling was significantly higher than archived tumor tissue (99% vs 96%). Mut-ctDNA detection rates ranged from 20% to 67% across different solid tumors. Targetable or resistance alterations were found in 18% of the patients. About 72% of the patients showed concordant alterations from tissue and plasma. The level of concordance was associated with the cancer type, tumor burden, and metastatic location. Notably, 63 plasma-only alterations were identified in 18% of patients and were more frequently observed in those with prior targeted treatments (24%) compared to chemotherapy (10%). Conclusions: This study underscores the clinical feasibility of an automated, decentralized cfDNA genomic profiling approach. It emphasizes the importance of considering confounding clinical factors when selecting plasma- or tissue-based profiling assay. Such an approach holds promise for enhancing patient access to timely genomic profiling and targeted therapy selection.

Takekuma M, et al. J Gynecol Oncol. 2025 May;36:e116. https://doi.org/10.3802/jgo.2025.36.e116