Elizabeth H. Stover

Endometrial Cancer Risk Among Germline BRCA1/2 Pathogenic Variant Carriers: Review of Our Current Understanding and Next Steps

PURPOSE To review the literature exploring endometrial cancer (EC) risk among surgical candidates with germline BRCA1/2 pathogenic variants (PVs) to guide decisions around risk-reducing (rr) hysterectomy in this population. DESIGN A comprehensive review was conducted of the current literature that influences clinical practice and informs expert consensus. We present our understanding of EC risk among BRCA1/2 PV carriers, the risk-modifying factors specific to this patient population, and the available research technology that may guide clinical practice in the future. Limitations of the existing literature are outlined. RESULTS Patients with BRCA1/2 PVs, those with a personal history of tamoxifen use, those who desire long-term hormone replacement therapy, and/or have an elevated BMI are at higher risk of EC, primarily endometrioid EC and/or uterine papillary serous carcinoma, and may benefit from rr-hysterectomy. Although prescriptive clinical guidelines specific to BRCA1/2 PV carriers could inform decisions around rr-hysterectomy, limitations of the current literature prevent more definitive guidance at this time. A large population-based study of a contemporary cohort of BRCA1/2 PV carriers with lifetime follow-up compared with cancer-gene negative controls would advance this topic and facilitate care decisions. CONCLUSION This review validates a potential role for rr-hysterectomy to address EC risk among surgical candidates with BRCA1/2 PVs. Evidence-based clinical guidelines for rr-hysterectomy in BRCA1/2 PV carriers are essential to ensure equitable access to this preventive measure, supporting insurance coverage for patients with either BRCA1 or BRCA2 PVs to pursue rr-hysterectomy. Overall, this review highlights the complexity of EC risk in BRCA1/2 PV carriers and offers a comprehensive framework to shared decision making to inform rr-hysterectomy for BRCA1/2 PV carriers.

Improved T-cell Immunity Following Neoadjuvant Chemotherapy in Ovarian Cancer

Abstract Purpose: Although local tissue-based immune responses are critical for elucidating direct tumor–immune cell interactions, peripheral immune responses are increasingly recognized as occupying an important role in anticancer immunity. We evaluated serial blood samples from patients with advanced epithelial ovarian cancer (EOC) undergoing standard-of-care neoadjuvant carboplatin and paclitaxel chemotherapy (including dexamethasone for prophylaxis of paclitaxel-associated hypersensitivity reactions) to characterize the evolution of the peripheral immune cell function and composition across the course of therapy. Experimental Design: Serial blood samples from 10 patients with advanced high-grade serous ovarian cancer treated with neoadjuvant chemotherapy (NACT) were collected before the initiation of chemotherapy, after the third and sixth cycles, and approximately 2 months after completion of chemotherapy. T-cell function was evaluated using ex vivo IFNγ ELISpot assays, and the dynamics of T-cell repertoire and immune cell composition were assessed using bulk and single-cell RNA sequencing (RNAseq). Results: T cells exhibited an improved response to viral antigens after NACT, which paralleled the decrease in CA125 levels. Single-cell analysis revealed increased numbers of memory T-cell receptor (TCR) clonotypes and increased central memory CD8+ and regulatory T cells throughout chemotherapy. Finally, administration of NACT was associated with increased monocyte frequency and expression of HLA class II and antigen presentation genes; single-cell RNAseq analyses showed that although driven largely by classical monocytes, increased class II gene expression was a feature observed across monocyte subpopulations after chemotherapy. Conclusions: NACT may alleviate tumor-associated immunosuppression by reducing tumor burden and may enhance antigen processing and presentation. These findings have implications for the successful combinatorial applications of immune checkpoint blockade and therapeutic vaccine approaches in EOC.

Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses

PURPOSE The multicenter, open-label, randomized phase 2 NCI-9944 study ( NCT02595892 ) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.