Background Chemotherapy added to anti-HER2 agents (H) is the treatment of choice in patients with HER2+ early breast cancer. However, HER2+ tumours are clinically and biologically heterogeneous, and treatment response varies significantly by hormone receptor (HR) status and molecular subtype. Predictive biomarkers are needed in this context. This study assessed whether an RB-1 loss of function gene signature (RBsig) is predictive of response to neoadjuvant chemotherapy in combination with trastuzumab, lapatinib or both, within the NeoALTTO trial. Methods We collected RNA-sequencing data from pretreatment biopsies derived from the NeoALTTO trial. RBsig expression was computed retrospectively and correlated with pathological complete response (pCR) using receiver-operating characteristic (ROC) curves. The RBsig was dichotomised as High/Low in correspondence to the 25th percentile. Reported p values resulted from Fisher's exact test. Results Of 455 NeoALTTO patients, 244 were eligible for this substudy (HR+ n = 129; HR- n = 115). Overall, pCR rate was significantly higher in patients with RBsig High tumours than those with RBsig Low (35% versus 18% respectively; p = 0.01). The area under the ROC curve (AUC) was 0.60 (95% CI 0.52-0.67). A remarkably low pCR rate of 11% was seen in HR+/RBsig Low patients versus 28% in HR+/RBsig High. Conclusions These results indicate RBsig may add valuable information to HER2 and HR expression, which may in turn inform treatment choices. HR+/HER2+/RBsig Low breast cancers exhibited the poorest pathological response following chemotherapy plus H. Accordingly, in such patients, endocrine therapy in combination with H and, possibly, a CDK4/6 inhibitor, may potentially prove to be a more effective treatment.

中文翻译：

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RB-1 功能基因特征缺失作为预测对新辅助化疗加抗 HER2 药物反应的工具：NeoALTTO 试验的子研究 (BIG 1-06)。

背景 添加抗 HER2 药物 (H) 的化学疗法是 HER2+ 早期乳腺癌患者的首选治疗方法。然而，HER2+ 肿瘤在临床和生物学上具有异质性，治疗反应因激素受体 (HR) 状态和分子亚型而异。在这种情况下需要预测性生物标志物。本研究评估了在 NeoALTTO 试验中，RB-1 功能基因特征缺失 (RBsig) 是否可预测新辅助化疗联合曲妥珠单抗、拉帕替尼或两者的反应。方法 我们从来自 NeoALTTO 试验的预处理活检中收集 RNA 测序数据。RBsig 表​​达是回顾性计算的，并使用接受者操作特征 (ROC) 曲线与病理完全缓解 (pCR) 相关联。RBsig 根据第 25 个百分位分为高/低。报告的 p 值来自 Fisher 精确检验。结果 在 455 名 NeoALTTO 患者中，244 名符合该子研究的条件（HR+ n = 129；HR- n = 115）。总体而言，RBsig High 肿瘤患者的 pCR 率显着高于 RBsig Low 患者（分别为 35% 和 18%；p = 0.01）。ROC 曲线下面积 (AUC) 为 0.60 (95% CI 0.52-0.67)。HR+/RBsig Low 患者的 pCR 率非常低，为 11%，而 HR+/RBsig High 患者为 28%。结论 这些结果表明 RBsig 可能会为 HER2 和 HR 表达增加有价值的信息，这反过来可能会为治疗选择提供信息。HR+/HER2+/RBsig 低乳腺癌在化疗加 H 后表现出最差的病理反应。因此，在这些患者中，