The Relationship between Common Genetic Markers of Breast Cancer Risk and Chemotherapy-Induced Toxicity: A Case-Control Study

PLoS One. 2016 Jul 8;11(7):e0158984. doi: 10.1371/journal.pone.0158984. eCollection 2016.

Abstract

Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / mortality
  • Disease-Free Survival
  • Female
  • Humans
  • Middle Aged
  • Neutropenia* / chemically induced
  • Neutropenia* / genetics
  • Neutropenia* / metabolism
  • Neutropenia* / mortality
  • Pharmacogenomic Testing
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Survival Rate

Substances

  • Biomarkers, Tumor