Combining Homologous Recombination-Deficient Testing and Functional RAD51 Analysis Enhances the Prediction of Poly(ADP-Ribose) Polymerase Inhibitor Sensitivity.

PURPOSE: To meet the urgent need for accessible homologous recombination-deficient (HRD) test options, we validated a laboratory-developed test (LDT) and a functional RAD51 assay to assess patients with ovarian cancer and predict the clinical benefit of poly(ADP-ribose) polymerase inhibitor therapy. METHODS: Optimization of the LDT cutoff and validation on the basis of samples from 91 patients enrolled in the ENGOT-ov24/NSGO-AVANOVA1&2 trial (ClinicalTrials.gov identifier: NCT02354131), previously subjected to commercial CDx HRD testing (CDx). RAD51 foci analysis was performed and tumors with ≥five foci/nucleus were classified as RAD51-positive (homologous recombination-proficient). RESULTS: The optimal LDT cutoff is 54. Comparing CDx genome instability score and LDT HRD scores show a Spearman's correlation of rho = 0.764 (P < .0001). Cross-tabulation analysis shows that the sensitivity of the LDT HRD score is 86% and of the LDT HRD status is 91.8% (Fisher's exact test P < .001). Survival analysis on progression-free survival (PFS) of LDT-assessed patients show a Cox regression P < .05. RAD51 assays show a correlation between low RAD51 foci detection (<20% RAD51+ cells) and significantly prolonged PFS (P < .001). CONCLUSION: The robust concordance between the open standard LDT and the CDx, especially the correlation with PFS, warrants future validation and implementation of the open standard LDT for HRD testing in diagnostic settings.

Comparative Assessment of Diagnostic Homologous Recombination Deficiency-Associated Mutational Signatures in Ovarian Cancer.

PURPOSE: Homologous recombination (HR) deficiency (HRD) is one of the key determinants of PARP inhibitor response in ovarian cancer, and its accurate detection in tumor biopsies is expected to improve the efficacy of this therapy. Because HRD induces a wide array of genomic aberrations, mutational signatures may serve as a companion diagnostic to identify PARP inhibitor-responsive cases. EXPERIMENTAL DESIGN: From the The Cancer Genome Atlas (TCGA) whole-exome sequencing (WES) data, we extracted different types of mutational signature-based HRD measures, such as the HRD score, genome-wide LOH, and HRDetect trained on ovarian and breast cancer-specific sequencing data. We compared their performance to identify BRCA1/2-deficient cases in the TCGA ovarian cancer cohort and predict survival benefit in platinum-treated, BRCA1/2 wild-type ovarian cancer. RESULTS: We found that the HRD score, which is based on large chromosomal alterations alone, performed similarly well to an ovarian cancer-specific HRDetect, which incorporates mutations on a finer scale as well (AUC = 0.823 vs. AUC = 0.837). In an independent cohort these two methods were equally accurate predicting long-term survival after platinum treatment (AUC = 0.787 vs. AUC = 0.823). We also found that HRDetect trained on ovarian cancer was more accurate than HRDetect trained on breast cancer data (AUC = 0.837 vs. AUC = 0.795; P = 0.0072). CONCLUSIONS: When WES data are available, methods that quantify only large chromosomal alterations such as the HRD score and HRDetect that captures a wider array of HRD-induced genomic aberrations are equally efficient identifying HRD ovarian cancer cases.

Major clinical research advances in gynecologic cancer in 2017.

In 2017, 10 topics were selected as major clinical research advances in gynecologic oncology. For cervical cancer, efficacy and safety analysis results of a 9-valent human papillomavirus (HPV) vaccine and long-term impact of reduced dose of quadrivalent vaccine were updated. Brief introduction of KEYNOTE trials of pembrolizumab, a monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, followed. Tailored surveillance programs for gynecologic cancer related with Lynch syndrome and update on sentinel lymph node mapping were reviewed for uterine corpus cancer. For ovarian cancer, 5 topics were selected including poly(ADP-ribose) polymerases inhibitors and immunotherapy. The other potential practice changers covered in this review were lymphadenectomy in advanced disease, secondary cytoreductive surgery in recurrent disease, weekly dose-dense regimen for first-line chemotherapy, incorporation of bevacizumab maintenance in platinum-sensitive recurrent disease, and effect of platinum-free interval prolongation. Conflicting opinions of academic societies on periodic pelvic examination were introduced in conjunction with relevant literature review. For the field of radiation oncology, results of 2 big trials, The Postoperative Radiation Therapy in Endometrial Carcinoma-3 and Gynecologic Oncology Group-258, for endometrial cancer and recent advance in high-dose-rate brachytherapy for cervical cancer were reported. Topics for breast cancer covered adjuvant capecitabine after preoperative chemotherapy, adjuvant pertuzumab and trastuzumab in early human epidermal growth factor receptor 2-positive disease, olaparib for metastatic cancer in patients with a germline BRCA mutation, 20-year risks of recurrence after stopping endocrine therapy at 5 years, and contemporary hormonal contraception and the risk of breast cancer.