Yoshikazu Nagase

SLFN11 is a BRCA Independent Biomarker for the Response to Platinum-Based Chemotherapy in High-Grade Serous Ovarian Cancer and Clear Cell Ovarian Carcinoma

Abstract BRCA1/2 mutations are robust biomarkers for platinum-based chemotherapy in epithelial ovarian cancers. However, BRCA1/2 mutations in clear cell ovarian carcinoma (CCC) are less frequent compared with high-grade serous ovarian cancer (HGSC). The discovery of biomarkers that can be applied to CCC is an unmet need in chemotherapy. Schlafen 11 (SLFN11) has attracted attention as a novel sensitizer for DNA-damaging agents including platinum. In this study, we investigated the utility of SLFN11 in HGSC and CCC for platinum-based chemotherapy. SLFN11 expression was analyzed retrospectively by IHC across 326 ovarian cancer samples. The clinicopathologic significance of SLFN11 expression was analyzed across 57 advanced HGSC as a discovery set, 96 advanced HGSC as a validation set, and 57 advanced CCC cases, all of whom received platinum-based chemotherapy. BRCA1/2 mutation was analyzed using targeted-gene sequencing. In the HGSC cohort, the SLFN11-positive and BRCA mutation group showed significantly longer whereas the SLFN11-negative and BRCA wild-type group showed significantly shorter progression-free survival and overall survival. Moreover, SLFN11-positive HGSC shrunk significantly better than SLFN11-negative HGSC after neoadjuvant chemotherapy. Comparable results were obtained with CCC but without consideration of BRCA1/2 mutation due to a small population. Multivariate analysis identified SLFN11 as an independent factor for better survival in HGSC and CCC. The SLFN11-dependent sensitivity to platinum and PARP inhibitors were validated with genetically modified non-HGSC ovarian cancer cell lines. Our study reveals that SLFN11 predicts platinum sensitivity in HGSC and CCC independently of BRCA1/2 mutation status, indicating that SLFN11 assessment can guide treatment selection in HGSC and CCC.

Identifying the possible candidate population for adjuvant radiotherapy de-escalation for intermediate-risk cervical cancer.

To explore whether there is a possible candidate population for treatment de-escalation with active surveillance without adjuvant radiotherapy for patients with stage IB cervical cancer meeting the intermediate-risk criteria. This retrospective cohort study queried the Commission-on-Cancer's National Cancer Database in the United States. The study population included 1133 patients with node-negative, parametria-free, surgical margin-uninvolved, stage IB intermediate-risk cervical cancer (tumor size 2-4 cm with lymphovascular space invasion, or tumor size of >4 cm regardless of lymphovascular space invasion) who had primary radical hysterectomy and lymph node evaluation from 2010 to 2022. Exposure was adjuvant radiotherapy status: external beam radiotherapy with or without chemotherapy (n = 642) or active surveillance without radiotherapy (n = 491). The main outcome measure was overall survival, assessed in a propensity score inverse probability of treatment weighting cohort. At the whole-cohort level, hazard ratio (HR) for all-cause mortality comparing adjuvant radiotherapy de-escalation to adjuvant radiotherapy was 1.31 (95% confidence interval [CI] 0.92 to 1.86, p = .13). When stratified by histology type, adjuvant radiotherapy de-escalation was associated with increased all-cause mortality risk in squamous cell carcinoma (HR 1.55, 95% CI 1.02 to 2.34, p = .038) but not in adenocarcinoma or adenosquamous carcinoma (HR, 0.90; 95% CI 0.46 to 1.75, p = .75). When stratified by tumor differentiation, adjuvant radiotherapy de-escalation was associated with increased all-cause mortality risk in poorly-differentiated tumors (HR, 2.11; 95% CI 1.29 to 3.42, p =.003) but not in well- to moderately-differentiated tumors (HR, 0.83; 95% CI 0.50 to 1.37, p = .47). The results of this cohort study in the United States suggest that overall survival benefits of adjuvant radiotherapy for study-defined intermediate-risk stage IB cervical cancer may vary based on histology type and tumor differentiation. Specifically, patients with squamous cell carcinoma or poorly-differentiated tumors benefited from receiving adjuvant radiotherapy, while those with adenocarcinoma/adenosquamous carcinoma or well- to moderately-differentiated tumors did not. Whether there may be candidates for treatment de-escalation in intermediate-risk cervical cancer warrants further investigation with a prospective design.