Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma
Tibor A. Zwimpfer(Peter MacCallum Cancer Centre), Sián Fereday(The University of Melbourne), Ahwan Pandey(Peter MacCallum Cancer Centre), Dinuka Ariyaratne(Peter MacCallum Cancer Centre), Madawa Jayawardana(The University of Melbourne), Laura Twomey(Peter MacCallum Cancer Centre), Céline M. Laumont, Catherine J. Kennedy(The University of Sydney), Adelyn Bolithon(Cancer Institute of New South Wales), Nicola S. Meagher(The University of Sydney), Katy Milne, Phineas T. Hamilton, Jennifer Alsop(University of Cambridge), Antonis C. Antoniou(University of Cambridge), George Au-Yeung(The University of Melbourne), Matthias W. Beckmann(Comprehensive Cancer Center Erlangen), Amy Berrington de González(Institute of Cancer Research), Christiani Bisinotto(Universidade de São Paulo), Freya Blome(University of Tübingen), Clara Bodelon(American Cancer Society), Jessica Boros(The University of Sydney), Alison H. Brand(The University of Sydney), Michael E. Carney(University of Hawaiʻi at Mānoa), Alicia Cazorla(Hospital Universitario Fundación Jiménez Díaz), Derek S. Chiu(Vancouver General Hospital), Elizabeth L. Christie(The University of Melbourne), Anita Chudecka-Głaz(Pomeranian Medical University), Penny Coulson(Institute of Cancer Research), Kara L. Cushing-Haugen(Fred Hutch Cancer Center), Cezary Cybulski(Mississippi State University), Kathleen M. Darcy(Henry M. Jackson Foundation), Cath David(Royal Hospital for Women), Trent Davidson(New South Wales Department of Health), Arif B. Ekici(Comprehensive Cancer Center Erlangen), Esther Elishaev(University of Pittsburgh), Julius Emons(Comprehensive Cancer Center Erlangen), Tobias Engler, Rhonda Farrell(The University of Sydney), Anna Fischer(University of Tübingen), Montserrat Garcia-Closas(Institute of Cancer Research), Aleksandra Gentry-Maharaj(MRC Clinical Trials Unit at UCL), P. Ghatage(University of Calgary), Rosalind Glasspool(Beatson West of Scotland Cancer Centre), Philipp Harter(Kliniken Essen-Mitte), AD Hartkopf(University Hospital Ulm), A Hartmann(Universitätsklinikum Erlangen), Sebastian Heikaus(Kliniken Essen-Mitte), Brenda Hernandez(University of Hawaiʻi at Mānoa), Anusha Hettiaratchi(St Vincent's Clinic), Sabine Heublein(Heidelberg University), David G. Huntsman(University of British Columbia), M. Jimenez-Linan(Addenbrooke's Hospital), Michael E. Jones(Institute of Cancer Research), E. Kang(Seoul National University Bundang Hospital), Ewa Kaznowska(University of Rzeszów), Tomasz Kluz(University of Rzeszów), F. Kommoss(Heidelberg University), Gottfried E. Konecny(University of California, Los Angeles), Roy F.P.M. Kruitwagen(Maastricht University Medical Centre), Jessica J Kwon(University of British Columbia), Diether Lambrechts(VIB-KU Leuven Center for Cancer Biology), Cheng-Han Lee(University of Alberta), Jenny Lester(University of California, Los Angeles), Samuel Leung(Vancouver General Hospital), Yee Leung(The University of Western Australia), Anna Linder(University of Gothenburg), Jolanta Lissowska(National Institute of Oncology), Liselore Loverix, Jan Lubiński(Pomeranian Medical University), Constantina Mateoiu(University of Gothenburg), Iain A. McNeish(Ovarian Cancer Action), Malak Moubarak Moubarak(Kliniken Essen-Mitte), G. Nelson(University of Calgary), Nikilyn Nevins(The University of Sydney), A. Olawaiye(University of Pittsburgh), Siel Olbrecht, Sandra Oršulić(University of California, Los Angeles), Ana Osorio(Centre for Biomedical Network Research on Rare Diseases), Carmel M. Quinn(St Vincent's Clinic), G. Raj K. A. Mohan(St John of God Subiaco Hospital), Isabelle Ray-Coquard(Université Claude Bernard Lyon 1), Cristina Rodriguez-Antona(Instituto de Investigaciones Biomédicas Sols-Morreale), Patricia Roxburgh(University of Glasgow), M Ruebner(Comprehensive Cancer Center Erlangen), Stuart Salfinger(St John of God Subiaco Hospital), Spinder Samra(The University of Sydney), Minouk J. Schoemaker(Institute of Cancer Research), Hans-Peter Sinn(Heidelberg University), Gabe S. Sonke(The Netherlands Cancer Institute), Linda Steele(City of Hope), Colin J. R. Stewart(The University of Western Australia), Aline Talhouk(University of British Columbia), Adeline Tan(The University of Western Australia), Christopher M. Tarney(Walter Reed National Military Medical Center), Sarah E. Taylor(University of Pittsburgh), Koen Van de Vijver(Antwerp University Hospital), Maaike A. van der Aa(Netherlands Comprehensive Cancer Organisation), Toon Van Gorp(KU Leuven), Els Van Nieuwenhuysen, Lilian Van-Wagensveld(Maastricht University Medical Centre), Andrea E. Wahner-Hendrickson(Mayo Clinic in Arizona), Christina Walter, Chen Wang(Mayo Clinic in Florida), Julia Welz(Kliniken Essen-Mitte), Nicolas Wentzensen(National Cancer Institute), Lynne R. Wilkens(University of Hawaiʻi at Mānoa), Stacey J. Winham(Mayo Clinic in Florida), Boris Winterhoff(University of Minnesota), M. S. Anglesio(University of British Columbia), A Berchuck(Duke Medical Center), Francisco J. Candido dos Reis(Universidade de São Paulo), Paul A. Cohen(The University of Western Australia), Thomas P. Conrads(Inova Health System), Philip Crowe(UNSW Sydney), Jennifer A. Doherty(University of Utah), Peter A. Fasching(Comprehensive Cancer Center Erlangen), Renée T. Fortner(Norwegian Institute of Public Health), María J. García(Instituto de Investigación en Ciencias de la Alimentación), Simon A. Gayther(The University of Texas at San Antonio Health Science Center), Marc T. Goodman(Cedars-Sinai Medical Center), J. Gronwald(Pomeranian Medical University), Holly R. Harris(University of Washington), Florian Heitz(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Hugo M. Horlings(Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital), Beth Y. Karlan(University of California, Los Angeles), Linda E. Kelemen(South Carolina Department of Health and Environmental Control), G. Larry Maxwell(Inova Health System), Usha Menon(MRC Clinical Trials Unit at UCL), Francesmary Modugno(University of Pittsburgh), Susan L. Neuhausen(City of Hope), Joellen M. Schildkraut(Emory University), Annette Staebler(University of Tübingen), Karin Sundfeldt(University of Gothenburg), A. J. SWERDLOW(Institute of Cancer Research), Ignace Vergote, Anna H. Wu(University of Southern California), James D. Brenton(University of Cambridge), Paul D. P. Pharoah(Cedars-Sinai Medical Center), Celeste Leigh Pearce(University of Michigan), Malcolm C. Pike(University of Southern California), Ellen L. Goode(Mayo Clinic in Florida), Susan J. Ramus(Cancer Institute of New South Wales), Martin Köbel(University of Calgary), Brad H. Nelson(University of British Columbia), Anna DeFazio(The University of Sydney), Michael L. Friedlander(New South Wales Department of Health), David D.L. Bowtell(The University of Melbourne), Dale W. Garsed(Peter MacCallum Cancer Centre)
Cited by 0Open Access
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 poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.
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