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

Laura Spugnesi1, Michele Gabriele1, Rosa Scarpitta1

  • 1Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.

Genes, Chromosomes & Cancer
|June 22, 2016
PubMed

Insights

Triple negative breast cancer (TNBC) patients with DNA repair gene defects, beyond BRCA1, show improved response to neoadjuvant anthracyclines/taxanes therapy. This highlights potential biomarkers for personalized treatment strategies in TNBC.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Triple negative breast cancer (TNBC) is molecularly heterogeneous, with some cases mimicking BRCA-mutated tumors (BRCAness) due to DNA repair defects.
  • These TNBC subtypes have a high recurrence risk despite potential response to alkylating agents.
  • Biomarkers for DNA repair deficiency are crucial for optimizing neoadjuvant therapy in TNBC.

Purpose of the Study:

  • To investigate the correlation between mutations in DNA repair genes and response to neoadjuvant anthracyclines/taxanes therapy in TNBC patients.
  • To identify potential germline genetic alterations associated with treatment efficacy.
  • To explore the role of DNA repair gene mutations beyond BRCA1 in TNBC.

Main Methods:

  • Next-generation sequencing of a 24-gene panel (DNA repair and breast cancer predisposition) was performed on DNA from 19 TNBC patients.
  • Patients were undergoing neoadjuvant therapy with anthracyclines/taxanes.
  • In silico tools were used to predict the deleteriousness of detected variants of unknown significance (VUS).

Main Results:

  • Pathogenic mutations in DNA repair genes (BRCA1, PALB2, RAD51C) were identified in 26% (5/19) of patients.
  • Two patients had probable pathogenic missense variants, and five had VUS predicted to be deleterious.
  • Germline mutations in DNA repair genes were significantly associated with a positive response to neoadjuvant therapy.

Conclusions:

  • A distinct subgroup of TNBC patients possesses germline defects in DNA repair genes, other than BRCA1.
  • These patients demonstrate a favorable response to neoadjuvant anthracyclines/taxanes therapy.
  • Identifying these DNA repair deficiencies can guide personalized treatment approaches for TNBC.

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