Germline mutations in DNA repair genes may predict neoadjuvant therapy response in triple negative breast patients

Genes Chromosomes Cancer. 2016 Dec;55(12):915-924. doi: 10.1002/gcc.22389. Epub 2016 Jul 26.


Triple negative breast cancers (TNBCs) represent about 15-20% of all breast cancer cases and are characterized by a complex molecular heterogeneity. Some TNBCs exhibit clinical and pathological properties similar to BRCA-mutated tumors, without actually bearing a mutation in BRCA genes. This "BRCAness" phenotype may be explained by germline mutations in other genes involved in DNA repair. Although respond to chemotherapy with alkylating agents, they have a high risk of recurrence and progression. Some studies have shown the efficacy of neoadjuvant therapy in TNBC patients with DNA repair defects, but proper biomarkers of DNA repair deficiency are still needed. Here, we investigated if mutations in DNA repair genes may be correlated with anthracyclines/taxanes neoadjuvant therapy response. DNA from 19 TNBC patients undergoing neoadjuvant therapy were subjected to next generation sequencing of a panel of 24 genes in DNA repair and breast cancer predisposition. In this study, 5 of 19 patients (26%) carried a pathogenic mutation in BRCA1, PALB2, RAD51C and two patients carried a probable pathogenic missense variant. Moreover, VUS (Variants of Unknown Significance) in other genes, predicted to be deleterious by in silico tools, were detected in five patients. Germline mutations in DNA repair genes were found to be associated with the group of TNBC patients who responded to therapy. We conclude that a subgroup of TNBC patients have defects in DNA repair genes, other than BRCA1, and such patients respond favourably to neoadjuvant anthracyclines/taxanes therapy. © 2016 Wiley Periodicals, Inc.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • BRCA1 Protein / genetics
  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • DNA Repair / drug effects
  • DNA Repair / genetics
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / genetics
  • Fanconi Anemia Complementation Group N Protein
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease
  • Germ-Line Mutation / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Middle Aged
  • Neoadjuvant Therapy*
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Nuclear Proteins / genetics
  • Prognosis
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Suppressor Proteins / genetics


  • BRCA1 Protein
  • BRCA1 protein, human
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • Nuclear Proteins
  • PALB2 protein, human
  • RAD51C protein, human
  • Tumor Suppressor Proteins
  • DNA Repair Enzymes