Abstract
Abstract Introduction: Autophagy, a lysosome-mediated degradation and recycling process, functions as an adaptive survival response during various stressful conditions including hypoxia and chemotherapy. The cysteine protease ATG4B, an important component of the autophagy pathway, is becoming a promising therapeutic target, but its value as a prognostic marker in breast cancer has not been investigated yet. Our recent studies established a novel association between ATG4B and HER2 positive breast cancer. Objective: The aim of this study was to investigate the prognostic value of ATG4B in different breast cancer subtypes using a large population-based cohort. Methods/Experimental Design: We evaluated ATG4B cytoplasmic expression by immunohistochemistry on tissue microarrays constructed from a cohort of 2003 breast cancer patients seen at the British Columbia Cancer Agency. For this large, well-characterized cohort detailed clinical information was available, including age, histology, tumor grade, tumor size, lymph node status, type of local and adjuvant systemic therapy, and dates of first recurrence and death. Median follow-up time was 12.4 years. ATG4B expression was scored by two independent observers using a categorized H-score system. Survival analyses were performed using the Kaplan-Meier function and Cox proportional hazards regression models to evaluate the association of ATG4B expression with breast cancer-specific survival, stratified by intrinsic subtype. Results: ATG4B expression was significantly lower in basal-like vs. non-basal (p<0.001), basal vs. HER2 overexpressed (p=0.0029), and triple-negative vs. non-triple-negative (p<0.001) breast cancer subtypes. In HER2 positive breast cancers, high (H-score >200) ATG4B expression was significantly associated with poor overall survival (hazard ratio (HR) =1.90, 95% confidence interval (CI) =1.10 to 3.27, p=0.033), disease specific survival (HR=2.23, CI =1.23 to 4.04, p=0.016), and relapse-free survival (HR=1.92, CI=1.09 to 3.39, p=0.037). However, in Luminal A breast cancers, high (H-score>150) ATG4B expression was strongly associated with improved overall survival (HR=0.71, CI=0.55 to 0.93, p=0.012) and disease-specific survival (HR=0.43, CI=0.26 to 0.67, p=0.00009). Conclusion: High ATG4B expression is a poor prognostic marker in HER2 positive breast cancer, but a favorable prognostic factor in the Luminal A subtype. Validation analyses are planned on a further set of 1989 cases. Citation Format: Svetlana Bortnik, Basile Tessier Cloutier, Jamie Magrill, Samuel Leung, Aline Talhouk, Karen Gelmon, Stephen Yip, Tony NG, Torsten Nielsen, Sharon Gorski. Evaluation of the prognostic value of ATG4B expression in different breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4722. doi:10.1158/1538-7445.AM2017-4722
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