Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis

Oncotarget. 2015 Dec 15;6(40):42773-80. doi: 10.18632/oncotarget.6001.


Response of cancer cells to chemotherapy-induced DNA damage is regulated by the ATM-Chk2 and ATR-Chk1 pathways. We investigated the association between phosphorylated H2AX (γ-H2AX), a marker of DNA double-strand breaks that trigger the ATM-Chk2 cascade, and phosphorylated Chk1 (pChk1), with pathological complete response (pCR) in triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy. γ-H2AX and pChk1 were retrospectively assessed by immunohistochemistry in a series of pretreatment biopsies related to 66 patients. In fifty-three tumors hormone receptor status was negative in both the diagnostic biopsies and residual cancers, whereas in 13 cases there was a slight hormone receptor expression that changed after chemotherapy. Internal validation was carried out. In the entire cohort elevated levels of γ-H2AX, but not pChk1, were associated with reduced pCR rate (p = 0.009). The association tested significant in both uni- and multivariate logistic regression models (OR 4.51, 95% CI: 1.39-14.66, p = 0.012, and OR 5.07, 95% CI: 1.28-20.09, p = 0.021, respectively). Internal validation supported the predictive value of the model. The predictive ability of γ-H2AX was further confirmed in the multivariate model after exclusion of tumors that underwent changes in hormone receptor status during chemotherapy (OR 7.07, 95% CI: 1.39-36.02, p = 0.018). Finally, in residual diseases a significant decrease of γ-H2AX levels was observed (p < 0.001). Overall, γ-H2AX showed ability to predict pCR in TNBC and deserves larger, prospective studies.

Keywords: DNA damage and repair; pathological complete response; triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / analysis*
  • Checkpoint Kinase 1
  • Chemotherapy, Adjuvant
  • DNA Damage / genetics*
  • DNA Repair / genetics*
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Histones / analysis
  • Histones / biosynthesis
  • Humans
  • Immunohistochemistry
  • Middle Aged
  • Neoadjuvant Therapy
  • Phosphorylation
  • Predictive Value of Tests
  • Protein Kinases / analysis
  • Protein Kinases / biosynthesis
  • Retrospective Studies
  • Treatment Outcome
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / genetics


  • Biomarkers, Tumor
  • H2AX protein, human
  • Histones
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1