Citations 2
Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma
Garsed, Dale W. , Pandey, Ahwan , Ariyaratne, Dinuka , Laumont, Céline M. , Hamilton, Phineas T. , Alsop, Jennifer , Antoniou, Antonis C. , Au‐Yeung, George , Beckmann, Matthias W. , González, Amy Berrington de , Bisinotto, Christiani, Blome, Freya , Bodelón, Clara , Boros, Jessica , Brand, Alison H. , Carney, Michael E., Coulson, Penny , Cushing‐Haugen, Kara L. , Cybulski, Cezary, Darcy, Kathleen M. , David, C. W. Mabey, Davidson, Trent , Emons, Julius , Farrell, Rhonda , Gentry-Maharaj, Aleksandra, Harter, Philipp, Hartmann, Arndt, Heikaus, Sebastian, Hettiaratchi, Anusha , Heublein, Sabine , Huntsman, David G. , Jimenez-Linan, Mercedes , Jones, Michael E. , Kang, Eunyoung , Konecny, Gottfried E. , Kruitwagen, Rutgerus, Kwon, Jessica, Lambrechts, Diether , Lester, Jenny, Leung, Samuel , Leung, Yee , Loverix, Liselore , Mateoiu, Constantina , McNeish, Iain A. , Nevins, Nikilyn, Olawaiye, Alexander , Oršulić, Sandra , Osório, Ana , Quinn, Carmel M. , Mohan, Ganendra Raj , Ruebner, Matthias , Salfinger, Stuart , Samra, Spinder , Stewart, Colin J.R. , Talhouk, Aline , Tan, Adeline , Tarney, Christopher M., Aa, Maaike AVan Der, Gorp, Toon Van , Nieuwenhuysen, Els Van, Wagensveld, Lilian van , Wahner-Hendrickson, Andrea E., Walter, Christina B., Welz, Julia , Wentzensen, Nicolas , Winterhoff, Boris , Berchuck, Andrew, Fasching, Peter A. , Gayther, Simon A. , Kelemen, Linda E. , Maxwell, G. Larry , Menon, Usha , Modugno, Francesmary, Schildkraut, Joellen M. , Staebler, Annette , Swedlow, Anthony, Vergote, Ignace , Wu, Anna H. , Pearce, Celeste Leigh, Pike, M. C., Goode, Ellen L. , Bowtell, David D.L. , Lambrechts, Diether , Garsed, Dale W , Fereday, Sian , Pandey, Ahwan , Ariyaratne, Dinuka , Kennedy, Catherine J , Milne, Katy , Berrington de Gonzalez, Amy , Blome, Freya , Bodelon, Clara , Christie, Elizabeth L , Ekici, Arif B , Ghatage, Prafull , Hettiaratchi, Anusha , Jones, Michael E , Kommoss, Felix , Lambrechts, Diether , Lee, Cheng-Han , Leung, Yee , Linder, Anna , McNeish, Iain A , Nelson, Gregg S , Nevins, Nikilyn , Ray-Coquard, Isabelle L. , Roxburgh, Patricia , Van de Vijver, Koen , Wahner-Hendrickson, Andrea, Wang, Chen , Wentzensen, Nicolas , Winham, Stacey J , Anglesio, Michael S , Cohen, Paul , Conrads, Thomas , Fasching, Peter A , Horlings, Hugo , Karlan, Beth Y , Menon, Usha , Neuhausen, Susan L. , Brenton, James D , Pharoah, Paul D P , Goode, Ellen L , Ramus, Susan J , Köbel, Martin , Nelson, Brad H , Fazio, Anna de , Friedlander, Michael , Lambrechts, Diether , Brand, Alison H , Bowtell, David D , Goodman, Marc T , Zwimpfer, Tibor A. , Fereday, Sián , Jayawardana, Madawa , Twomey, Laura , Kennedy, Catherine J. , Bolithon, Adelyn , Meagher, Nicola S. , Milne, Katy , Cazorla, Alicia , Chiu, Derek S , Christie, Elizabeth L. , Chudecka-Glaz, Anita Monika , Ekici, Arif B. , Elishaev, Esther , Engler, Tobias , Fischer, Anna, García‐Closas, Montserrat , Gentry‐Maharaj, Aleksandra , Glasspool, Rosalind , Hartkopf, Andreas D , Hernandez, Brenda Y. , Kaznowska, Ewa B. , Kluz, Tomasz , Kruitwagen, Roy F.P.M. , Kwon, Jessica, Lee, Cheng‐Han , Lester, Jenny, Leung, Samuel, Linder, Anna , Lissowska, Jolanta , Lubiński, Jan , Moubarak, Malak , Nelson, Gregg , Olbrecht, Siel , Rodríguez‐Antona, Cristina , Schoemaker, Minouk J. , Sinn, Hans‐Peter , Sonke, Gabe S. , Steele, Linda, Taylor, Sarah E , Nieuwenhuysen, Els Van , Wang, Chen , Wilkens, Lynne R. , Winham, Stacey J. , Anglesio, Michael S. , Reis, Francisco José Cândido dos , Cohen, Paul A. , Crowe, Philip John , Doherty, Jennifer A. , Fortner, Renée T. , García, María J. , Goodman, Marc T. , Gronwald, Jacek , Harris, Holly R. , Heitz, Florian , Karlan, Beth Y. , Sundfeldt, Karin , Brenton, James D. , Pharoah, Paul D.P. , Ramus, Susan J. , Köbel, Martin , Nelson, Brad H. , DeFazio, Anna , Friedländer, Michael
No container title available | October 3, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.
The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas
Heinze, Karolin , Cairns, Evan S. , Thornton, Shelby , Harris, Bronwyn , Milne, Katy , Grube, Marcel , Meyer, Charlotte , Karnezis, Anthony N. , Fereday, Sián , Garsed, Dale W. , Leung, Samuel , Harter, Philipp , Bowtell, David D.L. , Goode, Ellen L. , Pike, Malcolm C. , Ramus, Susan J. , Pearce, Celeste Leigh , Staebler, Annette , Kommoss, Stefan , Talhouk, Aline , Anglesio, Michael S. , Leung, Samuel C Y , Chiu, Derek S , Moubarak, Malak , Harter, Philipp , Heitz, Florian , McAlpine, Jessica N , Fazio, Anna de , Bowtell, David D , Goode, Ellen L , Pike, Malcolm C , Ramus, Susan J , Pearce, Celeste Leigh , Staebler, Annette , Köbel, Martin , Kommoss, Stefan , Talhouk, Aline , Nelson, Brad H , Anglesio, Michael S , Karnezis, Anthony , Fereday, Sian , Garsed, Dale W , Milne, Katy , Heitz, Florian , McAlpine, Jessica N. , DeFazio, Anna , Köbel, Martin , Nelson, Brad H.
Clinical Cancer Research | June 20, 2023 | Volume: 29 | Issue: 17 | Pages: 3471-3483
Abstract Purpose: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. Experimental Design: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. Results: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P > 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0; 95% confidence interval, 1.1–14.7; P < 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. Conclusions: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.