BACKGROUND: Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC). METHODS: Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2). CONCLUSIONS: g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.
BACKGROUND: Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC). METHODS: Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2). CONCLUSIONS: g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.
Authors: Debyani Chakravarty; Jianjiong Gao; Sarah M Phillips; Ritika Kundra; Hongxin Zhang; Jiaojiao Wang; Julia E Rudolph; Rona Yaeger; Tara Soumerai; Moriah H Nissan; Matthew T Chang; Sarat Chandarlapaty; Tiffany A Traina; Paul K Paik; Alan L Ho; Feras M Hantash; Andrew Grupe; Shrujal S Baxi; Margaret K Callahan; Alexandra Snyder; Ping Chi; Daniel Danila; Mrinal Gounder; James J Harding; Matthew D Hellmann; Gopa Iyer; Yelena Janjigian; Thomas Kaley; Douglas A Levine; Maeve Lowery; Antonio Omuro; Michael A Postow; Dana Rathkopf; Alexander N Shoushtari; Neerav Shukla; Martin Voss; Ederlinda Paraiso; Ahmet Zehir; Michael F Berger; Barry S Taylor; Leonard B Saltz; Gregory J Riely; Marc Ladanyi; David M Hyman; José Baselga; Paul Sabbatini; David B Solit; Nikolaus Schultz Journal: JCO Precis Oncol Date: 2017-05-16
Authors: Siân Jones; Xiaosong Zhang; D Williams Parsons; Jimmy Cheng-Ho Lin; Rebecca J Leary; Philipp Angenendt; Parminder Mankoo; Hannah Carter; Hirohiko Kamiyama; Antonio Jimeno; Seung-Mo Hong; Baojin Fu; Ming-Tseh Lin; Eric S Calhoun; Mihoko Kamiyama; Kimberly Walter; Tatiana Nikolskaya; Yuri Nikolsky; James Hartigan; Douglas R Smith; Manuel Hidalgo; Steven D Leach; Alison P Klein; Elizabeth M Jaffee; Michael Goggins; Anirban Maitra; Christine Iacobuzio-Donahue; James R Eshleman; Scott E Kern; Ralph H Hruban; Rachel Karchin; Nickolas Papadopoulos; Giovanni Parmigiani; Bert Vogelstein; Victor E Velculescu; Kenneth W Kinzler Journal: Science Date: 2008-09-04 Impact factor: 47.728
Authors: Ashton A Connor; Robert E Denroche; Gun Ho Jang; Lee Timms; Sangeetha N Kalimuthu; Iris Selander; Treasa McPherson; Gavin W Wilson; Michelle A Chan-Seng-Yue; Ivan Borozan; Vincent Ferretti; Robert C Grant; Ilinca M Lungu; Eithne Costello; William Greenhalf; Daniel Palmer; Paula Ghaneh; John P Neoptolemos; Markus Buchler; Gloria Petersen; Sarah Thayer; Michael A Hollingsworth; Alana Sherker; Daniel Durocher; Neesha Dhani; David Hedley; Stefano Serra; Aaron Pollett; Michael H A Roehrl; Prashant Bavi; John M S Bartlett; Sean Cleary; Julie M Wilson; Ludmil B Alexandrov; Malcolm Moore; Bradly G Wouters; John D McPherson; Faiyaz Notta; Lincoln D Stein; Steven Gallinger Journal: JAMA Oncol Date: 2017-06-01 Impact factor: 31.777
Authors: Brian A Dougherty; Zhongwu Lai; Darren R Hodgson; Maria C M Orr; Matthew Hawryluk; James Sun; Roman Yelensky; Stuart K Spencer; Jane D Robertson; Tony W Ho; Anitra Fielding; Jonathan A Ledermann; J Carl Barrett Journal: Oncotarget Date: 2017-07-04
Authors: Ahmet Zehir; Ryma Benayed; Ronak H Shah; Aijazuddin Syed; Sumit Middha; Hyunjae R Kim; Preethi Srinivasan; Jianjiong Gao; Debyani Chakravarty; Sean M Devlin; Matthew D Hellmann; David A Barron; Alison M Schram; Meera Hameed; Snjezana Dogan; Dara S Ross; Jaclyn F Hechtman; Deborah F DeLair; JinJuan Yao; Diana L Mandelker; Donavan T Cheng; Raghu Chandramohan; Abhinita S Mohanty; Ryan N Ptashkin; Gowtham Jayakumaran; Meera Prasad; Mustafa H Syed; Anoop Balakrishnan Rema; Zhen Y Liu; Khedoudja Nafa; Laetitia Borsu; Justyna Sadowska; Jacklyn Casanova; Ruben Bacares; Iwona J Kiecka; Anna Razumova; Julie B Son; Lisa Stewart; Tessara Baldi; Kerry A Mullaney; Hikmat Al-Ahmadie; Efsevia Vakiani; Adam A Abeshouse; Alexander V Penson; Philip Jonsson; Niedzica Camacho; Matthew T Chang; Helen H Won; Benjamin E Gross; Ritika Kundra; Zachary J Heins; Hsiao-Wei Chen; Sarah Phillips; Hongxin Zhang; Jiaojiao Wang; Angelica Ochoa; Jonathan Wills; Michael Eubank; Stacy B Thomas; Stuart M Gardos; Dalicia N Reales; Jesse Galle; Robert Durany; Roy Cambria; Wassim Abida; Andrea Cercek; Darren R Feldman; Mrinal M Gounder; A Ari Hakimi; James J Harding; Gopa Iyer; Yelena Y Janjigian; Emmet J Jordan; Ciara M Kelly; Maeve A Lowery; Luc G T Morris; Antonio M Omuro; Nitya Raj; Pedram Razavi; Alexander N Shoushtari; Neerav Shukla; Tara E Soumerai; Anna M Varghese; Rona Yaeger; Jonathan Coleman; Bernard Bochner; Gregory J Riely; Leonard B Saltz; Howard I Scher; Paul J Sabbatini; Mark E Robson; David S Klimstra; Barry S Taylor; Jose Baselga; Nikolaus Schultz; David M Hyman; Maria E Arcila; David B Solit; Marc Ladanyi; Michael F Berger Journal: Nat Med Date: 2017-05-08 Impact factor: 53.440
Authors: Rachna T Shroff; Andrew Hendifar; Robert R McWilliams; Ravit Geva; Ron Epelbaum; Lindsey Rolfe; Sandra Goble; Kevin K Lin; Andrew V Biankin; Heidi Giordano; Robert H Vonderheide; Susan M Domchek Journal: JCO Precis Oncol Date: 2018-05-16
Authors: Muhammet Ozer; Megha Ranganathan; Nicolas Lecomte; Juan M Schvartzman; Henry S Walch; Walid K Chatila; Jungeui Hong; Maria I Carlo; Michael F Walsh; Margaret Sheehan; Diana Mandelker; Ozge Ceyhan-Birsoy; Anna Maio; Yelena Kemel; Christine A Iacobuzio-Donahue; Eileen M O'Reilly; Kenneth H Yu Journal: JCO Precis Oncol Date: 2022-06
Authors: Mohamad Dbouk; Bryson W Katona; Randall E Brand; Amitabh Chak; Sapna Syngal; James J Farrell; Fay Kastrinos; Elena M Stoffel; Amanda L Blackford; Anil K Rustgi; Beth Dudley; Linda S Lee; Ankit Chhoda; Richard Kwon; Gregory G Ginsberg; Alison P Klein; Ihab Kamel; Ralph H Hruban; Jin He; Eun Ji Shin; Anne Marie Lennon; Marcia Irene Canto; Michael Goggins Journal: J Clin Oncol Date: 2022-06-15 Impact factor: 50.717