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

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

Author information

  • 1Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 2Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 3Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 4Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 5Department of Surgery, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 6Division of Medical Oncology A, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 7Division of Pathology, ASL Frosinone, Frosinone, Italy.
  • 8Medical Oncology Unit, ASL Frosinone, Frosinone, Italy.
  • 9Division of Pathology, "SS. Annunziata Hospital", Chieti, Italy.
  • 10Department of Experimental and Clinical Sciences, University "G. d'Annunzio", Chieti, Italy.
  • 11Department of Biology, University of Rome "Tor Vergata", Rome, Italy.

Abstract

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

PMID:
26544894
PMCID:
PMC4767469
DOI:
10.18632/oncotarget.6001
[PubMed - indexed for MEDLINE]
Free PMC Article
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