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.
Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer
Hamilton, Phineas T. , Phung, Minh Tung , Stevens, Donald L.I., Kalaria, Shreena , Laumont, Céline M. , Moss, Elena, Alimujiang, Aliya , Meagher, Nicola S. , Hendley, Joy , Goode, Ellen L. , Shen, Hui , Richardson, Jean , Deurloo, Cindy McKinnon, Chase, Anne, Grout, Bronwyn, Cushing‐Haugen, Kara L. , Anglesio, Michael S. , Huntsman, David G. , Talhouk, Aline , Hanley, Gillian E. , Alsop, Jennifer , Jimenez-Linan, Mercedes , Boros, Jessica , Brand, Alison H. , Sharma, Raghwa , Hecht, Jonathan L. , Sasamoto, Naoko , Terry, Kathryn L. , Lester, Jenny, Carney, Michael E. , Goodman, Marc T. , Fasching, Peter A., Bisinotto, Christiani, Le, Nhu D. , Menon, Usha , García, María J. , Rodríguez‐Antona, Cristina , Farrington, Kyo , Kelemen, Linda E. , Kommoss, Stefan , Staebler, Annette , Garsed, Dale W. , Piskorz, Anna , Bowtell, David D.L. , Ramus, Susan J. , Pike, Malcolm C., Pearce, Celeste Leigh , Ramus, Susan J , Rodríguez-Antona, Cristina , Menon, Usha , Anglesio, Michael S , Brand, Alison H , Bowtell, David D , Garsed, Dale W , Goodman, Marc T , Phung, Minh Tung , Nelson, Brad H. , Milne, Katy , Harris, Bronwyn, Thornton, Shelby , Singh, Karanvir , Bolithon, Adelyn , Fereday, Sián , Kennedy, Catherine J. , Ariyaratne, Dinuka , Alsop, Kathryn , Traficante, Nadia , Karnezis, Anthony N. , Chase, Anne, Doherty, Jennifer A. , Harris, Holly R. , Heinze, Karolin , Pharoah, Paul D.P. , Harnett, Paul R. , Karlan, Beth Y. , Hernandez, Brenda Y. , Wilkens, Lynne R. , Behrens, Sabine , Fortner, Renée T. , Reis, Francisco José Cândido dos , Ghatage, Prafull , Köbel, Martin , Elishaev, Esther , Modugno, Francesmary , Cook, Linda S. , Gentry‐Maharaj, Aleksandra , Brenton, James D. , DeFazio, Anna
Journal of Clinical Investigation | October 29, 2024 | Volume: 134 | Issue: 24 | Pages: No page available
BACKGROUND Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment. METHODS We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5–7.99 years; n = 433) and short-term survivors (STS; 2–4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1 + cells, and PD-L1 + cells) and epithelial content. RESULTS Positive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8 + T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSION The tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada’s Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.