Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis
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Patrizia Vici1,*, Anna Di Benedetto2,*, Cristiana Ercolani2, Laura Pizzuti1, Luigi Di Lauro1, Domenico Sergi1, Francesca Sperati3, Irene Terrenato3, Rosanna Dattilo4, Claudio Botti5, Alessandra Fabi6, Maria Teresa Ramieri7, Lucia Mentuccia8, Camilla Marinelli9, Laura Iezzi10, Teresa Gamucci8, Clara Natoli10, Ilio Vitale4,11, Maddalena Barba1,4, Marcella Mottolese2, Ruggero De Maria4, Marcello Maugeri-Saccà1,4
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
*These authors have contributed equally to this work
Marcello Maugeri-Saccà, e-mail: [email protected]
Ruggero De Maria, e-mail: [email protected]
Keywords: DNA damage and repair, triple-negative breast cancer, pathological complete response
Received: September 09, 2015 Accepted: October 05, 2015 Published: October 17, 2015
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.
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