Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, NC.
Department of Genetics, University of North Carolina, Chapel Hill, NC.
J Clin Oncol. 2020 Dec 10;38(35):4184-4193. doi: 10.1200/JCO.20.01276. Epub 2020 Oct 23.
CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival.
Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples.
One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS.
In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.
CALGB 40601 评估了新辅助化疗中双重与单一人表皮生长因子受体 2（HER2）靶向药物联合应用是否增加了病理完全缓解（pCR）。在这里，我们报告无复发生存（RFS）、总生存（OS）和预测 pCR 和生存的基因表达特征。
305 例未经治疗的 II 期和 III 期 HER2 阳性乳腺癌患者被随机分配接受每周紫杉醇联合曲妥珠单抗加拉帕替尼（THL）、曲妥珠单抗（TH）或拉帕替尼（TL）治疗。主要终点为 pCR，次要终点包括 RFS、OS 和基因表达分析。对 264 例预处理样本进行了 mRNA 测序。
118 例患者被随机分配至 THL 组，120 例患者分配至 TH 组，67 例患者分配至 TL 组。在超过 7 年的随访中，THL 的 RFS 和 OS 显著优于 TH（RFS 风险比，0.32；95%CI，0.14 至 0.71；P=0.005；OS 风险比，0.34；95%CI，0.12 至 0.94；P=0.037），而 TH 与 TL 之间无差异。在之前描述的 688 个基因表达特征中，有 215 个与 pCR 显著相关，45 个与 RFS 相关，只有 22 个与 pCR 和 RFS 均相关（3.2%）。具体而言，有 8 个免疫特征与更高的 pCR 率和更好的 RFS 相关。在残留疾病患者中，免疫球蛋白 G 特征是一个独立的预后良好因素，而与更高 pCR 率相关的 HER2 富集特征则显示出较短的 RFS。
在 CALGB 40601 中，双重 HER2 靶向治疗可显著提高 RFS 和 OS 获益。内在亚型和免疫特征的整合可预测 pCR 和 RFS，包括总体和残留疾病组。这些方法可能为 HER2 阳性乳腺癌的合理升级和降级治疗策略提供依据。
