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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

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

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