Abstract
BackgroundBody 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).MethodsIn 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.ResultsWe 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.ConclusionsThe 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.
Highlights
Body mass index (BMI) is largely investigated as a prognostic and predictive factor in triple-negative breast cancer (TNBC)
We have recently reported on the association between elevated levels of phosphorylated H2A Histone Family Member X (γ-H2AX), a marker of DNA double-strand breaks that activate the AtaxiaTelangiectasia Mutated (ATM)-Checkpoint Kinase 2 (Chk2) pathway, and reduced pathological complete response rate in TNBC patients treated with neoadjuvant chemotherapy (NACT) [18]
The sample size was slightly smaller compared with the original cohort [18], consistently with our previous results, elevated Phosphorylated H2A Histone Family Member X (γ-H2AX) levels retained significant association with reduced pathological complete response (pCR) rate (p = 0.015), and a suggestion towards an association between phosphorylated checkpoint kinase 1 (pChk1) and pCR was observed (p = 0.057)
Summary
Body mass index (BMI) is largely investigated as a prognostic and predictive factor in triple-negative breast cancer (TNBC). We 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). Obesity is increasingly designated as a risk factor for triple-negative BC (TNBC) [3,4,5,6,7,8]. Abnormalities have been described in the expression profiles of various adipokines and cytokines [9]. This abnormal status leads to the activation of oncogenic intracellular molecular networks in cancer cells, such as the JAK2/ STAT3, MAPK/ERK, PI3K/AKT and NF-kB pathways [9]. The low chronic tissue inflammation status that accompanies obesity enhances the activity of some factors, such as hypoxia-inducible factor 1α (HIF1α), which in turn promotes angiogenesis and acquisition of cancer stem-like traits [10,11,12]
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