Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium.
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Nat Commun. 2023 Nov 3;14(1):7053. doi: 10.1038/s41467-023-42635-2.
The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.
在接受新辅助治疗的患者中识别预后标志物对于优化 HER2 阳性乳腺癌的治疗至关重要，免疫微环境是一个关键因素。在这里，我们在两项 III 期试验 NeoALTTO 和 CALGB 40601 中研究了 B 和 T 细胞受体 (BCR 和 TCR) 库的复杂性，评估了新辅助紫杉醇联合曲妥珠单抗和/或拉帕替尼治疗 HER2 阳性乳腺癌的疗效。根据激素受体状态和 PAM50 亚型，BCR 特征（尤其是读长和克隆数、均匀度和基尼指数）具有异质性。此外，描述克隆扩增的 BCR 指标，即均匀度和基尼指数，是独立的预后因素。我们提出了一种在 NeoALTTO 中开发并在 CALGB 40601 中验证的模型，该模型可以通过整合激素受体和临床淋巴结状态、乳腺病理完全缓解 (pCR)、基质肿瘤浸润淋巴细胞水平（%）和 BCR 库均匀度来预测无事件生存 (EFS)。源自该模型并包含这些变量的预后评分 HER2-EveNT 可识别出 5 年 EFS ＞90%的患者，并且对于未达到 pCR 的患者，尽管存在残留疾病，但可以识别出免疫富集肿瘤的亚组，其预后极好。
