Purpose: 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. Experimental Design: 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. Results: 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, P -interaction = 0.01], endothelial (HR = 0.67; 95% CI, 0.20–2.22, P -interaction = 0.02), mast cells (HR = 0.78; 95% CI, 0.49–1.27, P -interaction = 0.04), and PDL2 (HR = 0.31; 95% CI, 0.12–0.81, P -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 TYMP . However, these results were not significant when adjusted for multiple testing. Conclusions: 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.

中文翻译：

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FinXX 临床试验中卡培他滨辅助治疗早期三阴性乳腺癌的预测生物标志物。

目的：最近的研究表明，卡培他滨辅助治疗对早期乳腺癌有益，尤其是在三阴性乳腺癌 (TNBC) 患者中。然而，TNBC 是异质的，需要更精确的预测生物标志物。实验设计：在 FinXX 试验中从 TNBC 患者收集的肿瘤组织，随机接受基于蒽环类紫杉烷的辅助化疗，加或不加卡培他滨，使用针对多种生物学机制的 770 个基因面板和额外的 30 个与卡培他滨代谢相关的定制基因进行分析. 进行假设生成探索性分析以使用 Cox 回归模型和针对多重性调整的相互作用测试评估与治疗效果相关的生物标志物表达。结果：111 个 TNBC 样本是可评估的（57 个不含卡培他滨，54 个含卡培他滨）。中位随访时间为 10.2 年。多变量分析显示，卡培他滨在包括细胞毒性细胞在内的四种生物学重要基因和元基因中显着改善无复发生存率 (RFS) [风险比 (HR) = 0.38；95% 置信区间 (CI)，0.16–0.86，P 相互作用 = 0.01]，内皮细胞（HR = 0.67；95% CI，0.20–2.22，P 相互作用 = 0.02），肥大细胞（HR = 0.78；95% CI , 0.49–1.27, P -interaction = 0.04), 和 PDL2 (HR = 0.31; 95% CI, 0.12–0.81, P -interaction = 0.03)。此外，我们确定了 38 个与卡培他滨获益显着相关的单基因，这些基因主要由免疫反应途径和参与将卡培他滨激活为氟尿嘧啶的酶（包括 TYMP）主导。然而，当针对多重测试进行调整时，这些结果并不显着。结论：与抗肿瘤免疫、免疫反应和卡培他滨激活相关的基因和宏基因可以识别更有可能从卡培他滨辅助治疗中获益的 TNBC 患者。鉴于在校正多重性时观察显着结果的能力降低，我们的研究结果为未来更大的临床试验的假设检验验证研究提供了基础。