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.
Vici, P., Di Benedetto, A., Ercolani, C., Pizzuti, L., Di Lauro, L., Sergi, D., Sperati, F., Terrenato, I., Dattilo, R., Botti, C., Fabi, A., Ramieri, M. T., Mentuccia, L., Marinelli, C., Iezzi, L., Gamucci, T., Natoli, C., Vitale, I., Barba, M., Mottolese, M., De Maria Marchiano, R., Maugeri-Saccà, M., Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis, <<ONCOTARGET>>, 2015; 6 (40): 42773-42780. [doi:10.18632/oncotarget.6001] [http://hdl.handle.net/10807/112054]
Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis
Gamucci, Teresa;Vitale, Ilio;De Maria Marchiano, Ruggero;
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 (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.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
