Body mass index modifies the relationship between γ-H2AX, a DNA damage biomarker, and pathological complete response in triple-negative breast cancer

BMC Cancer. 2017 Feb 6;17(1):101. doi: 10.1186/s12885-016-3045-z.


Background: Body mass index (BMI) is largely investigated as a prognostic and predictive factor in triple-negative breast cancer (TNBC). Overweight and obesity are linked to a variety of pathways regulating tumor-promoting functions, including the DNA damage response (DDR). The DDR physiologically safeguards genome integrity but, in a neoplastic background, it is aberrantly engaged and protects cancer cells from chemotherapy. We herein verified the role of BMI on a previously assessed association between DDR biomarkers and pathological complete response (pCR) in TNBC patients treated with neoadjuvant chemotherapy (NACT).

Methods: In this retrospective analysis 54 TNBC patients treated with NACT were included. The relationship between DDR biomarkers, namely phosphorylated H2A Histone Family Member X (γ-H2AX) and phosphorylated checkpoint kinase 1 (pChk1), and pCR was reconsidered in light of BMI data. The Pearson's Chi-squared test of independence (2-tailed) and the Fisher Exact test were employed to assess the relationship between clinical-molecular variables and pCR. Uni- and multivariate logistic regression models were used to identify variables impacting pCR. Internal validation was carried out.

Results: We observed a significant association between elevated levels of the two DDR biomarkers and pCR in patients with BMI < 25 (p = 0.009 and p = 0.022 for γ-H2AX and pChk1, respectively), but not in their heavier counterpart. Results regarding γ-H2AX were confirmed in uni- and multivariate models and, again, for leaner patients only (γ-H2AXhigh vs γ-H2AXlow: OR 10.83, 95% CI: 1.79-65.55, p = 0.009). The consistency of this finding was confirmed upon internal validation.

Conclusions: The predictive significance of γ-H2AX varies according to BMI status. Indeed, elevated levels of γ-H2AX seemed associated with lower pCR rate only in leaner patients, whereas differences in pCR rate according to γ-H2AX levels were not appreciable in heavier patients. Larger investigations are warranted concerning the potential role of BMI as effect modifier of the relationship between DDR-related biomarkers and clinical outcomes in TNBC.

Keywords: Body mass index; Chk1; Double-strand breaks; Pathological complete response; Triple-negative breast cancer; γ-H2AX.

MeSH terms

  • Body Mass Index*
  • Checkpoint Kinase 1 / analysis*
  • Checkpoint Kinase 1 / chemistry
  • Checkpoint Kinase 1 / metabolism
  • DNA Damage*
  • Female
  • Histones / analysis*
  • Histones / metabolism
  • Humans
  • Middle Aged
  • Neoadjuvant Therapy*
  • Obesity / complications
  • Phosphorylation
  • Retrospective Studies
  • Triple Negative Breast Neoplasms / complications
  • Triple Negative Breast Neoplasms / diagnosis
  • Triple Negative Breast Neoplasms / pathology*
  • Triple Negative Breast Neoplasms / therapy


  • H2AX protein, human
  • Histones
  • CHEK1 protein, human
  • Checkpoint Kinase 1