Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium.
IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy.
Nat Commun. 2024 Nov 29;15(1):10402. doi: 10.1038/s41467-024-54621-3.
In HER2-positive breast cancer, clinical outcome and sensitivity to HER2-targeted therapies are influenced by both tumor and microenvironment features. However, we are currently unable to depict the molecular heterogeneity of this disease with sufficient granularity. Here, by performing gene expression profiling in HER2-positive breast cancers from patients receiving adjuvant trastuzumab in the ALTTO clinical trial (NCT00490139), we identify and characterize five molecular subtypes associated with the risk of distant recurrence: immune-enriched, proliferative/metabolic-enriched, mesenchymal/stroma-enriched, luminal, and ERBB2-dependent. Additionally, we validate the biological profiles of the subtypes and explore their prognostic/predictive value in external cohorts, namely the NeoALTTO trial (NCT00553358), SCAN-B (NCT02306096), I-SPY2 (NCT01042379), METABRIC and TCGA. Immune-enriched tumors present better survival outcomes, in contrast to mesenchymal/stroma-enriched and proliferative/metabolic-enriched tumors, while luminal and ERBB2-dependent tumors are characterized by low and high rates of pathological complete response, respectively. Of note, these molecular subtypes provide the rationale for treatment approaches leveraging the heterogeneous biology of HER2-positive breast cancer.
在 HER2 阳性乳腺癌中，肿瘤和微环境特征均会影响临床结局和对 HER2 靶向治疗的敏感性。然而，我们目前还无法充分细致地描绘出这种疾病的分子异质性。在此，我们通过对接受辅助曲妥珠单抗治疗的 ALTTO 临床试验（NCT00490139）中 HER2 阳性乳腺癌患者进行基因表达谱分析，确定并描述了与远处复发风险相关的五种分子亚型：免疫富集型、增殖/代谢富集型、间质/基质富集型、管腔型和 ERBB2 依赖性。此外，我们验证了这些亚型的生物学特征，并在外部队列（NeoALTTO 试验、SCAN-B、I-SPY2、METABRIC 和 TCGA）中探索了它们的预后/预测价值。与间质/基质富集型和增殖/代谢富集型相比，免疫富集型肿瘤具有更好的生存结局，而管腔型和 ERBB2 依赖性肿瘤则分别表现出较低和较高的病理完全缓解率。值得注意的是，这些分子亚型为利用 HER2 阳性乳腺癌的异质性生物学提供了治疗方法的依据。
