Data from Concurrent RB1 Loss and <i>BRCA</i> Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
Authors: Saner Flurina A.M. , Takahashi Kazuaki , Budden Timothy , Pandey Ahwan , Ariyaratne Dinuka , Zwimpfer Tibor A. , Meagher Nicola S. , Fereday Sian , Twomey Laura , Pishas Kathleen I. , Hoang Therese , Bolithon Adelyn , Traficante Nadia , Alsop Kathryn , Christie Elizabeth L. , Kang Eun-Young , Nelson Gregg S. , Ghatage Prafull , Lee Cheng-Han , Riggan Marjorie J. , Alsop Jennifer , Beckmann Matthias W. , Boros Jessica , Brand Alison H. , Brooks-Wilson Angela , Carney Michael E. , Coulson Penny , Courtney-Brooks Madeleine , Cushing-Haugen Kara L. , Cybulski Cezary , El-Bahrawy Mona A. , Elishaev Esther , Erber Ramona , Gayther Simon A. , Gentry-Maharaj Aleksandra , Gilks C. Blake , Harnett Paul R. , Harris Holly R. , Hartmann Arndt , Hein Alexander , Hendley Joy , Hernandez Brenda Y. , Jakubowska Anna , Jimenez-Linan Mercedes , Jones Michael E. , Kaufmann Scott H. , Kennedy Catherine J. , Kluz Tomasz , Koziak Jennifer M. , Kristjansdottir Björg , Le Nhu D. , Lener Marcin , Lester Jenny , Lubiński Jan , Mateoiu Constantina , Orsulic Sandra , Ruebner Matthias , Schoemaker Minouk J. , Shah Mitul , Sharma Raghwa , Sherman Mark E. , Shvetsov Yurii B. , Soong T. Rinda , Steed Helen , Sukumvanich Paniti , Talhouk Aline , Taylor Sarah E. , Vierkant Robert A. , Wang Chen , Widschwendter Martin , Wilkens Lynne R. , Winham Stacey J. , Anglesio Michael S. , Berchuck Andrew , Brenton James D. , Campbell Ian , Cook Linda S. , Doherty Jennifer A. , Fasching Peter A. , Fortner Renée T. , Goodman Marc T. , Gronwald Jacek , Huntsman David G. , Karlan Beth Y. , Kelemen Linda E. , Menon Usha , Modugno Francesmary , Pharoah Paul D.P. , Schildkraut Joellen M. , Sundfeldt Karin , Swerdlow Anthony J. , Goode Ellen L. , DeFazio Anna , Köbel Martin , Ramus Susan J. , Bowtell David D.L. , Garsed Dale W. 
Published: August 2024

<div>AbstractPurpose:<p>The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of <i>BRCA1</i> or <i>BRCA2</i> (<i>BRCA</i>) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).</p>Experimental Design:<p>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 <i>BRCA</i> status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8<sup>+</sup> lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted <i>RB1</i> in HGSC cells with and without <i>BRCA1</i> 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 <i>BRCA</i> deficiency and <i>RB1</i> loss.</p>Results:<p>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 <i>BRCA</i> variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic <i>BRCA</i> variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in <i>BRCA1</i>-altered cells with <i>RB1</i> knockout. Combined <i>RB1</i> loss and <i>BRCA</i> deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial–mesenchymal transition. CD8<sup>+</sup> lymphocytes were most prevalent in <i>BRCA</i>-deficient HGSC with co-loss of <i>RB1</i>.</p>Conclusions:<p>Co-occurrence of RB1 loss and <i>BRCA</i> deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.</p></div>