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.
Highlights
Triple-negative breast cancer (TNBC) accounts for approximately 20% of all breast cancer (BC) cases, and represents the most aggressive BC subtype [1]
The predictive ability of γ-H2AX levels was observed in the univariate logistic regression model (γ-H2AXhigh vs γ-H2AXlow: Odds Ratio (OR) 4.51, 95% Confidence Interval (CI): 1.39–14.66, p = 0.012) (Table 3), and maintained in the multivariate model (γ-H2AXhigh vs γ-H2AXlow: OR 5.07, 95% CI: 1.28–20.09, p = 0.021) (Table 3)
Sensitivity analysis carried out by removing 13 patients whose tumors changed hormone receptor status during Neoadjuvant chemotherapy (NACT) further confirmed the predictive ability of γ-H2AXhigh (Table 4)
Summary
Triple-negative breast cancer (TNBC) accounts for approximately 20% of all breast cancer (BC) cases, and represents the most aggressive BC subtype [1]. The complexity of the DDR has been the focus of intense preclinical investigations, and nowadays we have a fairly detailed picture of the molecular events that are triggered in cancer cells challenged with chemotherapy [8]. Despite these achievements, from a clinical perspective the analyses of the DDR have historically been confined to a handful of distal effectors acting in the context of specific repair avenues, and they have been overall inconclusive [9]. Novel biomarkers such as RAD51 and the so-called genomic scars, which presumably reflect the underlying state of DNA repair, were proposed, renewing the enthusiasm surrounding the clinical development of DDR-associated endpoints to foresee the efficacy of chemotherapy [10,11,12,13]
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