ImportanceBiologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plus ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer (EBC).ObjectiveTo define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41.Design, Setting, and ParticipantsIn this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023.Main Outcomes and MeasuresThe association of clinical variables and gene expression biomarkers with pCR and EFS were studied by logistic regression and Cox analyses.ResultsIn the pooled analysis, of 758 women, median age was 49 years, 12% were Asian, 6% Black, and 75% were White. Overall, pCR results were associated with EFS in the ERBB2-enriched (hazard ratio [HR], 0.45; 95% CI, 0.29-0.70; P < .001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P = .03) subtypes but not in luminal A or B tumors. Dual trastuzumab plus lapatinib blockade over trastuzumab alone had a trend toward EFS benefit in the intention-to-treat population; however, in the ERBB2-enriched subtype there was a significant and independent EFS benefit of trastuzumab plus lapatinib vs trastuzumab alone (HR, 0.47; 95% CI, 0.27-0.83; P = .009). Overall, 275 of 618 gene expression signatures (44.5%) were significantly associated with pCR and 9 of 618 (1.5%) with EFS. The ERBB2/HER2 amplicon and multiple immune signatures were significantly associated with pCR. Luminal-related signatures were associated with lower pCR rates but better EFS, especially among patients with residual disease and independent of hormone receptor status. There was significant adjusted HR for pCR ranging from 0.45 to 0.81 (higher pCR) and 1.21-1.94 (lower pCR rate); significant adjusted HR for EFS ranged from 0.71 to 0.94.Conclusions and relevanceIn patients with ERBB2/HER2-positive EBC, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates.

中文翻译：

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早期 ERBB2/HER2 阳性乳腺癌的肿瘤内在亚型和基因表达特征

重要性生物学特征可能影响新辅助化疗后的病理完全缓解 (pCR) 和无事件生存 (EFS)ERBB2/HER2封锁ERBB2/HER2-阳性早期乳腺癌 (EBC)。目的在 CALGB 40601、NeoALTTO 和 NSABP B-41 等 3 项 3 期试验的汇总分析中，通过内在亚型和其他基因表达特征来定义 pCR 和 EFS 之间的定量关联。设置和参与者在这项回顾性汇总分析中，1289 名 EBC 患者接受了化疗加曲妥珠单抗、拉帕替尼或联合用药，合并中位随访时间为 5.5 年。通过 RNA 测序获得基因表达谱，并计算了内在亚型和 618 个基因表达特征。数据分析于2020年6月1日至2023年1月1日进行。主要结果和措施通过逻辑回归和Cox分析研究临床变量和基因表达生物标志物与pCR和EFS的关联。结果在汇总分析中，758名女性，中位年龄为 49 岁，其中 12% 为亚裔，6% 为黑人，75% 为白人。总体而言，pCR 结果与富含 ERBB2 的 EFS 相关（风险比 [HR]，0.45；95% CI，0.29-0.70；磷< .001）和类基础（HR，0.19；95% CI，0.04-0.86；磷=。03) 亚型，但不在管腔 A 或 B 肿瘤中。与单独使用曲妥珠单抗相比，曲妥珠单抗联合拉帕替尼阻断在意向治疗人群中具有 EFS 获益的趋势；然而，在富含 ERBB2 的亚型中，曲妥珠单抗加拉帕替尼与单用曲妥珠单抗相比，具有显着且独立的 EFS 获益（HR，0.47；95% CI，0.27-0.83；磷=.009）。总体而言，618 个基因表达特征中的 275 个（44.5%）与 pCR 显着相关，618 个基因表达特征中的 9 个（1.5%）与 EFS 显着相关。这ERBB2/HER2扩增子和多重免疫特征与 pCR 显着相关。 Luminal 相关特征与较低的 pCR 率和较好的 EFS 相关，尤其是在有残留疾病且与激素受体状态无关的患者中。 pCR 的 HR 有显着调整，范围为 0.45 至 0.81（较高的 pCR）和 1.21-1.94（较低的 pCR 率）； EFS 的显着调整 HR 范围为 0.71 至 0.94。 结论和相关性ERBB2/HER2-阳性 EBC、pCR 和 EFS 之间的关联因肿瘤内在亚型而异，以及双重治疗的益处ERBB2/HER2封锁仅限于富含 ERBB2 的肿瘤。免疫激活特征与较高的 pCR 率和更好的 EFS 一致相关，而管腔特征与较低的 pCR 率相关。