title: Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer.
abstract: Understanding the molecular underpinnings of sensitivity to specific therapies will advance the goal of precision medicine in prostate cancer (PCa). We identified three patients with metastatic castration-resistant PCa (mCRPC) who achieved an exceptional response to platinum chemotherapy (not first-line treatment for PCa), despite disease progression on prior standard therapies. Using targeted next-generation sequencing on the primary and metastatic tumors, we found that all three patients had biallelic inactivation of BRCA2, a tumor suppressor gene critical for homologous DNA repair. Notably, two had germline BRCA2 mutations, including a patient without compelling family history who was diagnosed at age 66 yr. The third patient had somatic BRCA2 homozygous copy loss. Biallelic BRCA2 inactivation in mCRPC warrants further exploration as a predictive biomarker for sensitivity to platinum chemotherapy.
authors.affiliation: Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Cheng
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Pritchard
authors.affiliation: Northstar Lodge Cancer Center, Yakima, WA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boyd
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA. Electronic address: rbmontgo@uw.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Montgomery
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary / Q000628:therapy*; D000368:Aged; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D017024:Chemotherapy, Adjuvant; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D024522:Genes, BRCA2; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011468:Prostatectomy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D016190:Carboplatin
keywords: BRCA2; Carboplatin; DNA repair; Platinum; Prostate cancer; mCRPC