Hypoxia-Inducible Factor-1 Alpha Expression Is Predictive of Pathological Complete Response in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy

Abstract

To demonstrate the value of hypoxia-inducible factor-1α (HIF-1α) in predicting response in patients with breast cancer receiving standard neoadjuvant chemotherapy (NAC). Methods: Ninety-five women enrolled in two prospective studies underwent biopsies for the histopathological diagnosis of breast carcinoma before receiving NAC, based on anthracyclines and taxanes. For expression of HIF-1α, EGFR, pAKT and pMAPK, tumor samples were analyzed by immunohistochemistry in tissues microarrays. Standard statistical methods (Pearson chi-square test, Fisher exact test, Kruskal–Wallis test, Mann–Whitney test and Kaplan–Meier method) were used to study the association of HIF-1α with tumor response, survival and other clinicopathologic variables/biomarkers. Results: HIF-1α expression was positive in 35 (39.7%) cases and was significantly associated to complete pathological response (pCR) (p = 0.014). HIF-1α expression was correlated positively with tumor grade (p = 0.015) and Ki-67 expression (p = 0.001) and negativity with progesterone receptors (PR) (p = 0.04) and luminal A phenotype expression (p = 0.005). No correlation was found between HIF-1α expression and EGFR, pAKT and pMAPK. In terms of survival, HIF-1α expression was associated with a significantly shorter disease-free survival (p = 0.013), being identified as an independent prognostic factor in multivariate analysis. Conclusions: Overexpression of HIF-1α is a predictor of pCR and shorter DFS; it would be valuable to confirm these results in prospective studies.

Harnessing adrenergic blockade in stress-promoted TNBC in vitro and solid tumor in vivo: disrupting HIF-1α and GSK-3β/β-catenin driven resistance to doxorubicin

“…Genome-wide association studies show that HIF-1α and its target genes are upregulated in breast cancer, and clinical data suggest that, compared to hormone responsive and HER-2 positive breast cancers, TNBCs are particularly enriched for HIF-1 and its target genes ( Ma et al, 2022 ). Their high protein levels in primary breast cancer tumor biopsies are independently associated with poor prognostic outcomes ( Ramírez-Tortosa et al, 2022 ; Tutzauer et al, 2022 ). Importantly, residual breast cancer cells surviving chemotherapy display stem-like traits ( Creighton et al, 2009 ) and knocking down HIF-1α in these cells dampens their tumor-initiating capacity ( Xiang et al, 2014 ).…”