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

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.

• Authors: Patrizia Vici, Anna Di Benedetto, Cristiana Ercolani, Laura Pizzuti, Luigi Di Lauro, Domenico Sergi, Francesca Sperati, Irene Terrenato, Rosanna Dattilo, Claudio Botti, Alessandra Fabi, Maria Teresa Ramieri, Lucia Mentuccia, Camilla Marinelli, Laura Iezzi, Teresa Gamucci, Clara Natoli, Ilio Vitale, Maddalena Barba, Marcella Mottolese, Ruggero De Maria, Marcello Maugeri-Saccà
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 40 Pg. 42773-80 (Dec 15 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26544894 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• H2AX protein, human
• Histones
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (analysis)
• Checkpoint Kinase 1
• Chemotherapy, Adjuvant
• DNA Damage (genetics)
• DNA Repair (genetics)
• Drug Resistance, Neoplasm (genetics)
• Female
• Histones (analysis, biosynthesis)
• Humans
• Immunohistochemistry
• Middle Aged
• Neoadjuvant Therapy
• Phosphorylation
• Predictive Value of Tests
• Protein Kinases (analysis, biosynthesis)
• Retrospective Studies
• Treatment Outcome
• Triple Negative Breast Neoplasms (drug therapy, genetics)