TY - JOUR
T1 - Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy
T2 - An exploratory analysis
AU - Vici, Patrizia
AU - Di Benedetto, Anna
AU - Ercolani, Cristiana
AU - Pizzuti, Laura
AU - Di Lauro, Luigi
AU - Sergi, Domenico
AU - Sperati, Francesca
AU - Terrenato, Irene
AU - Dattilo, Rosanna
AU - Botti, Claudio
AU - Fabi, Alessandra
AU - Ramieri, Maria Teresa
AU - Mentuccia, Lucia
AU - Marinelli, Camilla
AU - Iezzi, Laura
AU - Gamucci, Teresa
AU - Natoli, Clara
AU - Vitale, Ilio
AU - Barba, Maddalena
AU - Mottolese, Marcella
AU - Maria, Ruggero De
AU - Maugeri-Saccà, Marcello
PY - 2015
Y1 - 2015
N2 - 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 (f-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. f-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 f-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 f-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 f-H2AX levels was observed (p <0.001). Overall, f-H2AX showed ability to predict pCR in TNBC and deserves larger, prospective studies.
AB - 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 (f-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. f-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 f-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 f-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 f-H2AX levels was observed (p <0.001). Overall, f-H2AX showed ability to predict pCR in TNBC and deserves larger, prospective studies.
KW - DNA damage and repair
KW - Pathological complete response
KW - Triple-negative breast cancer
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U2 - 10.18632/oncotarget.6001
DO - 10.18632/oncotarget.6001
M3 - Article
AN - SCOPUS:84952342480
VL - 6
SP - 42773
EP - 42780
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 40
ER -