Clinical Significance of ARID1A and ANXA1 in HER-2 Positive Breast Cancer.

Rita Silva-Oliveira,Ana Lameirinhas,Paula Lopes,Filipa Ferreira Pereira,Susana Palma De Sousa,Rui Henrique,Luís Antunes,Ana Teresa Martins,Carmen Jerónimo,Vera Constâncio,Sofia Salta,Inês Caldas-Ribeiro,Sara Petronilho,Fernando Castro

doi:10.3390/jcm9123911

Rita Silva-Oliveira, Ana Lameirinhas + Show 12 more

Open Access

https://doi.org/10.3390/jcm9123911

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Abstract

Background: trastuzumab is considered the standard of care for human epidermal growth factor receptor-2 (HER-2+) breast cancer patients. Regardless of the benefits of its use, many early-stage patients eventually recur, and usually, the disease progresses within a year. Since about half of the HER-2+ patients do not respond to trastuzumab, new biomarkers of prognosis and prediction are warranted to allow a better patient stratification. Annexin A1 (ANXA1) was previously reported to contribute to trastuzumab resistance through AKT activation. An association between adenine thymine-rich interactive domain 1A (ARID1A) loss and ANXA1 upregulation was also previously suggested by others. Methods: in this study, we examined tissue samples from 215 HER-2+ breast cancer patients to investigate the value of ARID1A and ANXA1 protein levels in trastuzumab response prediction and patient outcome. Expression of ARID1A and ANXA1 were assessed by immunohistochemistry. Results: contrary to what was expected, no inverse association was found between ARID1A and ANXA1 expression. HER-2+ (non-luminal) tumours displayed higher ANXA1 expression than luminal B-like (HER-2+) tumours. Concerning trastuzumab resistance, ARID1A and ANXA1 proteins did not demonstrate predictive value as biomarkers. Nevertheless, an association was depicted between ANXA1 expression and breast cancer mortality and relapse. Conclusions: overall, our results suggest that ANXA1 may be a useful prognostic marker in HER-2+ patients. Additionally, its ability to discriminate between HER-2+ (non-luminal) and luminal B-like (HER-2+) patients might assist in patient stratification regarding treatment strategy.

Highlights

Breast cancer (BrC) is the most common cancer and the leading cause of cancer-related death among women, being responsible for high morbidity and mortality rates
Since our cohort was comprised of two distinct molecular subtypes, we assessed if luminal B-like (HER-2+) and human epidermal growth factor receptor-2 (HER-2)+ displayed different survival, but no differences were depicted
Since the small number of HER-2+ patients (n = 48) would compromise the statistical power, cumulative incidence analysis was performed for all patients and not stratified by molecular subtype

Summary

Introduction

Breast cancer (BrC) is the most common cancer and the leading cause of cancer-related death among women, being responsible for high morbidity and mortality rates. This constitutes as a health issue and economic burden worldwide [1]. Despite having different prognosis and treatment strategies, patients with luminal B-like (HER-2 positive) and HER-2 positive (non-luminal) BrC receive trastuzumab therapy [5]. Trastuzumab is a monoclonal antibody directed to the extracellular domain of the HER-2 protein [3] It was approved in 1998 for the treatment of HER-2 positive (HER-2+) metastatic BrC (MBC), having revolutionized the precision medicine for this disease and becoming a standard of care in the HER-2+ disease [6]. Being usually well-tolerated, patients may experience cardiac dysfunction, which is further exacerbated when administered concomitantly with anthracyclines [5]

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