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

// Patrizia Vici 1, * , Anna Di Benedetto 2, * , Cristiana Ercolani 2 , Laura Pizzuti 1 , Luigi Di Lauro 1 , Domenico Sergi 1 , Francesca Sperati 3 , Irene Terrenato 3 , Rosanna Dattilo 4 , Claudio Botti 5 , Alessandra Fabi 6 , Maria Teresa Ramieri 7 , Lucia Mentuccia 8 , Camilla Marinelli 9 , Laura Iezzi 10 , Teresa Gamucci 8 , Clara Natoli 10 , Ilio Vitale 4, 11 , Maddalena Barba 1, 4 , Marcella Mottolese 2 , Ruggero De Maria 4 , Marcello Maugeri-Sacca 1, 4 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 * These authors have contributed equally to this work Correspondence to: Marcello Maugeri-Sacca, e-mail: maugeri@ifo.it Ruggero De Maria, e-mail: demaria@ifo.it Keywords: DNA damage and repair, triple-negative breast cancer, pathological complete response Received: September 09, 2015      Accepted: October 05, 2015      Published: October 17, 2015 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.