Paniti Sukumvanich

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Abstract Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial–mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Twice daily template-based interstitial brachytherapy for gynecologic cancers: What is the optimal dose?

Several factors of template-based interstitial brachytherapy in gynecologic cancers, including large tumor size, invasion into adjacent organs or fistula, dose heterogeneity, and twice daily fractionation cause inherent dose-escalation effects, potentially increasing toxicity. This study reports a single-institutional dose escalation experience in twice daily template-based interstitial brachytherapy treatments to demonstrate tumor control and toxicity outcomes, with the hypothesis that with image-based planning dose-escalation with interstitial brachytherapy is safe and efficacious. Patients treated with template-based interstitial brachytherapy at our institution from 2006 to 2022 were identified. Over time, HDR brachytherapy boost dose at our institution has been dose-escalated from 18.75 Gy in 5 fractions to 27.5 Gy in 5 fractions. Local control and survival outcomes were analyzed using the Kaplan-Meier method and log-rank test to compare between groups. Formal tumor control probability (TCP) analysis was performed using logistic dose-response modeling. 214 patients were identified with median follow-up of 28.1 months (IQR 8.2-58.7). Total HDR dose correlated significantly with local and locoregional control when analyzed as a continuous variable, and when dichotomized around median dose of 25 Gy (p = 0.024). TCP analysis showed a dose-response effect between HR CTV D90 and local control in the entire cohort, and separately in cervical and vaginal cancer subsets. The actuarial 5-year incidence of grade 3 or worse toxicity was 6.1%, and there was no significant association between toxicity and total HDR dose or HR CTV D90. In patient treated with twice-daily template-based interstitial brachytherapy for gynecologic cancers brachytherapy dose correlates with local control with no significant association between brachytherapy dose and toxicity, thus suggesting room for dose-escalation.