Predictive Biomarkers for Adjuvant Capecitabine Benefit in Early-Stage Triple-Negative Breast Cancer in the FinXX Clinical Trial

• Published in: Clinical cancer research 2020-06, Vol.26 (11), p.2603-2614
• Main Authors: Asleh, Karama, Brauer, Heather Ann, Sullivan, Amy, Lauttia, Susanna, Lindman, Henrik, Nielsen, Torsten O, Joensuu, Heikki, Thompson, E Aubrey, Chumsri, Saranya
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1945

Recent studies have demonstrated a benefit of adjuvant capecitabine in early breast cancer, particularly in patients with triple-negative breast cancer (TNBC). However, TNBC is heterogeneous and more precise predictive biomarkers are needed. Tumor tissues collected from TNBC patients in the FinXX trial, randomized to adjuvant anthracycline-taxane-based chemotherapy with or without capecitabine, were analyzed using a 770-gene panel targeting multiple biological mechanisms and additional 30-custom genes related to capecitabine metabolism. Hypothesis-generating exploratory analyses were performed to assess biomarker expression in relation to treatment effect using the Cox regression model and interaction tests adjusted for multiplicity. One hundred eleven TNBC samples were evaluable (57 without capecitabine and 54 with capecitabine). The median follow-up was 10.2 years. Multivariate analysis showed significant improvement in recurrence-free survival (RFS) favoring capecitabine in four biologically important genes and metagenes, including cytotoxic cells [hazard ratio (HR) = 0.38; 95% confidence intervals (CI), 0.16-0.86, -interaction = 0.01], endothelial (HR = 0.67; 95% CI, 0.20-2.22, -interaction = 0.02), mast cells (HR = 0.78; 95% CI, 0.49-1.27, -interaction = 0.04), and (HR = 0.31; 95% CI, 0.12-0.81, -interaction = 0.03). Furthermore, we identified 38 single genes that were significantly associated with capecitabine benefit, and these were dominated by immune response pathway and enzymes involved in activating capecitabine to fluorouracil, including . However, these results were not significant when adjusted for multiple testing. Genes and metagenes related to antitumor immunity, immune response, and capecitabine activation could identify TNBC patients who are more likely to benefit from adjuvant capecitabine. Given the reduced power to observe significant findings when correcting for multiplicity, our findings provide the basis for future hypothesis-testing validation studies on larger clinical trials.