The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer

Abstract

Objective: Hypoxia-associated biomarkers profiling may provide information for prognosis, staging, and subsequent therapy. We aim to evaluate whether the quantitative gene and protein expression of hypoxic response tumor markers-carbonic anhydrase IX (CAIX) and hypoxia-inducible factor 1 alpha (HIF1A)-may have a role in predicting survival in advanced breast cancer of Indonesian population. Methods: Tumor tissues and peripheral blood samples were collected from treatment-naïve locally advanced (LABC) or metastatic breast cancer patients (MBC) at Wahidin Sudirohusodo General Hospital (Makassar, South Sulawesi) and its referral network hospitals from July 2017 to March 2019. The level of mRNA (of blood and tumor tissue samples) and soluble protein (of blood samples) of CAIX and HIF1A were measured by RT-qPCR and ELISA methods, respectively, besides the standard histopathological grading and molecular subtype assessment. The CAIX and HIF1A expression, patients' age, tumor characteristics, surgery status, and neoadjuvant chemotherapy drug classes were further involved in survival analyses for overall survival (OS) and progression-free survival (PFS). Results: Forty (30 LABC, 10 MBC) eligible patients examined were 21 hormone-receptors positives (15 Luminal A, 6 Luminal B) and 19 hormone-receptors negatives (10 HER2-enriched, 9 triple-negative). The CAIX blood mRNA and CAIX soluble protein levels in hormone-receptors negative patients were higher than in hormone-receptor-positive patients (p < 0.05). In univariate analysis, both CAIX and HIF1A levels predict OS (except HIF1A protein) with CAIX tissue mRNA has the highest hazard ratio (HR 8.04, 95%CI:2.45-26.39), but not PFS. Cox proportional hazard model confirmed that CAIX tissue mRNA is the independent predictor of OS (HR 6.10, 95%CI: 1.16-32.13) along with surgical status and tumor advancement type (LABC or MBC). Conclusions: CAIX mRNA expression of tumor tissue in treatment-naïve advanced breast cancer has a predictive value for OS.

Expression profile of interleukin-6, 4-hydroxy-2-nonenal, and hypoxia-inducible factor 1-α in women with breast cancer and their association with clinicopathological parameters

“…No significant difference was found between HIF-1α serum levels in different molecular subtypes of BC. This finding supports the study of Gunawan et al [14], who found that the levels of HIF-1α mRNA and soluble HIF-1α protein in tissues and blood were similar in different molecular subtypes, and that no association was found. Our results also agree with the findings of Nie et al [69], who reported that there is no significant difference of HIF-1α in the different molecular subtypes.…”

“…This finding supports the study of Gunawan et al . [ 14 ], who found that the levels of HIF-1α mRNA and soluble HIF-1α protein in tissues and blood were similar in different molecular subtypes, and that no association was found. Our results also agree with the findings of Nie et al .…”

“…Hypoxia-inducible factor 1-α (HIF-1α) is a transcription factor implicated in carcinogenesis and in the metastatic propagation of tumour cells [ 13 ]. In BC, cells react to oxygen reduction by activating HIF-1α, regulating multiple genes involved in metastatic progression [ 14 ].…”

Serum immuno-oncology markers carry independent prognostic information in patients with newly diagnosed metastatic breast cancer, from a prospective observational study

“…Similarly, we observed that elevated serum levels of CAIX showed significant correlation with worse OS in both uni-and multivariable analyses, in agreement with its association with visceral metastases and with what has previously been shown for MBC patients [33][34][35]. After FDR correction, there was still strong evidence for correlation to OS in UV analyses, whereas the evidence for correlation to OS in MV analysis was weaker.…”

The therapeutic importance of acid-base balance

“…It is noteworthy that a high level of net endogenous acid production was associated with higher mortality in breast-cancer recurrence in a cohort of early stage breast cancer survivors [418] . Moreover, acid-treatment of melanoma cells selects for more invasive phenotypes [419] and the extent of upregulation of various ABTs and CAs can be an adverse prognostic factor (e.g., [420] , [421] , [422] ).…”