Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma.
Tibor A Zwimpfer,
Sian Fereday,
Ahwan Pandey,
Dinuka Ariyaratne,
Madawa W Jayawardana,
Laura Twomey,
Céline M Laumont,
Catherine J Kennedy,
Adelyn Bolithon,
Nicola S Meagher,
Katy Milne,
Phineas Hamilton,
Jennifer Alsop,
Antonis C Antoniou,
George Au-Yeung,
Matthias W Beckmann,
Amy Berrington de Gonzalez,
Christiani Bisinotto,
Freya Blome,
Clara Bodelon,
Jessica Boros,
Alison H Brand,
Michael E Carney,
Alicia Cazorla-Jiménez,
Derek S Chiu,
Elizabeth L Christie,
Anita Chudecka-Głaz,
Penny Coulson,
Kara L Cushing-Haugen,
Cezary Cybulski,
Kathleen M Darcy,
Cath David,
Trent Davidson,
Arif B Ekici,
Esther Elishaev,
Julius Emons,
Tobias Engler,
Rhonda Farrell,
Anna Fischer,
Montserrat García-Closas,
Aleksandra Gentry-Maharaj,
Prafull Ghatage,
Rosalind Glasspool,
Philipp Harter,
Andreas D Hartkopf,
Arndt Hartmann,
Sebastian Heikaus,
Brenda Y Hernandez,
Anusha Hettiaratchi,
Sabine Heublein,
David G Huntsman,
Mercedes Jimenez-Linan,
Michael E Jones,
Eunyoung Kang,
Ewa Kaznowska,
Tomasz Kluz,
Felix K F Kommoss,
Gottfried Konecny,
Roy F P M Kruitwagen,
Jessica Kwon,
Diether Lambrechts,
Cheng-Han Lee,
Jenny Lester,
Samuel C Y Leung,
Yee Leung,
Anna Linder,
Jolanta Lissowska,
Liselore Loverix,
Jan Lubiński,
Constantina Mateoiu,
Iain A McNeish,
Malak Moubarak,
Gregg S Nelson,
Nikilyn Nevins,
Alexander B Olawaiye,
Siel Olbrecht,
Sandra Orsulic,
Ana Osorio,
Carmel M Quinn,
Ganendra Raj Mohan,
Isabelle Ray-Coquard,
Cristina Rodríguez-Antona,
Patricia Roxburgh,
Matthias Ruebner,
Stuart G Salfinger,
Spinder Samra,
Minouk J Schoemaker,
Hans-Peter Sinn,
Gabe S Sonke,
Linda Steele,
Colin J R Stewart,
Aline Talhouk,
Adeline Tan,
Christopher M Tarney,
Sarah E Taylor,
Koen K Van de Vijver,
Maaike A van der Aa,
Toon Van Gorp,
Els Van Nieuwenhuysen,
Lilian Van-Wagensveld,
Andrea E Wahner-Hendrickson,
Christina Walter,
Chen Wang,
Julia Welz,
Nicolas Wentzensen,
Lynne R Wilkens,
Stacey J Winham,
Boris Winterhoff,
Michael S Anglesio,
Andrew Berchuck,
Francisco J Candido Dos Reis,
Paul A Cohen,
Thomas P Conrads,
Philip Crowe,
Jennifer A Doherty,
Peter A Fasching,
Renée T Fortner,
María J García,
Simon A Gayther,
Marc T Goodman,
Jacek Gronwald,
Holly R Harris,
Florian Heitz,
Hugo M Horlings,
Beth Y Karlan,
Linda E Kelemen,
G Larry Maxwell,
Usha Menon,
Francesmary Modugno,
Susan L Neuhausen,
Joellen M Schildkraut,
Annette Staebler,
Karin Sundfeldt,
Anthony J Swerdlow,
Ignace Vergote,
Anna H Wu,
James D Brenton,
Paul D P Pharoah,
Celeste Leigh Pearce,
Malcolm C Pike,
Ellen L Goode,
Susan J Ramus,
Martin Köbel,
Brad H Nelson,
Anna DeFazio,
Michael L Friedlander,
David D L Bowtell,
Dale W Garsed
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.