Background Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage Human Epidermal growth factor Receptor 2 (HER2)-positive Breast Cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty Acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models. Methods Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival (EFS) in 180 patients enrolled in the phase 3 trial NeoALTTO, which randomized stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pre-treatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase 2 trial NeoSphere. Results In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse EFS in patients treated with trastuzumab-based therapy (HR: 1.72, 95% CI: 1.20–2.46), but not with lapatinib- (HR: 1.02, 95% CI: 0.68–1.53) or trastuzumab-lapatinib-based (HR: 1.08, 95% CI: 0.60–1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient Disease-Free Survival (DFS) both in the whole study cohort (HR = 1.197, 95% CI: 1.002–1.428) and in patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI: 1.049–1.568). Conclusion High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy.

中文翻译：

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CD36 表达对接受曲妥珠单抗新辅助治疗的 HER2 阳性乳腺癌患者的预测作用

背景 尽管在接受（新）辅助抗 HER2 治疗的早期人类表皮生长因子受体 2 (HER2) 阳性乳腺癌 (HER2+ BC) 患者中鉴定与长期临床结果相关的生物标志物已付出巨大努力，但尚无可靠的证据到目前为止已经确定了预测因素。脂肪酸摄取是一种由跨膜转运蛋白 CD36 介导的过程，最近已成为临床前 HER2+ BC 模型中抗 HER2 治疗耐药性的潜在决定因素。方法 在这里，我们调查了 180 名参加 3 期试验 NeoALTTO 的患者的基线瘤内 CD36 基因表达与无事件生存 (EFS) 之间的关联，该试验将 II-III 期 HER2+ BC 患者随机分配接受新辅助拉帕替尼、曲妥珠单抗或拉帕替尼-曲妥珠单抗联合化疗。为此，我们选择了可获得治疗前全转录组数据的 NeoALTTO 试验患者。主要研究结果在参加新辅助 2 期试验 NeoSphere 的独立患者队列中得到验证。结果 在 180 名 NeoALTTO 患者中，肿瘤内 CD36 高表达与接受基于曲妥珠单抗治疗的患者的 EFS 较差独立相关（HR：1.72，95% CI：1.20-2.46），但与拉帕替尼无关（HR：1.02，95%） CI：0.68–1.53）或基于曲妥珠单抗-拉帕替尼（HR：1.08，95% CI：0.60–1.94）的治疗。在接受评估的 331 名 NeoSphere 患者中，在整个研究队列（HR = 1.197，95% CI：1.002–1.428）和接受基于曲妥珠单抗的新辅助治疗的患者中，高 CD36 表达与较差的患者无病生存期 (DFS) 独立相关（HR = 1.282，95% CI：1.049–1.568）。