Mutations in BRCA2 and taxane resistance in prostate cancer

Sci Rep. 2017 Jul 4;7(1):4574. doi: 10.1038/s41598-017-04897-x.

Abstract

Mutations in BRCA1 or BRCA2 define a subset of prostate cancer patients. Herein, we address the question whether BRCA1/2 mutations have a predictive impact on chemotherapy with docetaxel, a widely used drug in patients with metastatic castration resistant prostate cancer (mCRPC). Fifty-three men treated with docetaxel for mCRPC were tested for somatic BRCA1/2 mutations of the primary tumor. In a subgroup of patients, BRCA1/2 protein expression was tested as a potential surrogate marker for BRCA1/2 inactivation. Eight of 53 patients (15.1%) harbored a deleterious BRCA2 mutation. No BRCA1 mutation was found. Patients with a BRCA2 mutation showed a response rate of 25% to docetaxel in comparison to 71.1% in men with wildtype BRCA2 (p = 0.019). While the time to develop castration resistance was similar in both subgroups, the overall survival was significantly shorter in patients harboring a BRCA2 mutation. No correlation between the BRCA1/2 protein expression and the response to docetaxel was found. While the presence of a BRCA2 mutation does not preclude a response to docetaxel, there is overall a significant correlation between BRCA2 inactivation and a poor response rate. Our results suggest that a close oncological monitoring of patients with BRCA2 mutations for taxane resistance is warranted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor*
  • Bridged-Ring Compounds / pharmacology*
  • Bridged-Ring Compounds / therapeutic use
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression
  • Genes, BRCA1
  • Genes, BRCA2*
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • Male
  • Mutation Rate
  • Mutation*
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Prostatic Neoplasms / diagnosis
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / therapy
  • Retrospective Studies
  • Taxoids / pharmacology*
  • Taxoids / therapeutic use
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Bridged-Ring Compounds
  • Taxoids
  • taxane