Multimodal assessment of exceptional responders refines subtyping-directed precision treatment in HR+/HER2– breast cancer
Yi Xiao, Fan Yang, Ying-Jia Qi, Li Chen, Hang Zhang, Si-Wei Zhang, Rui Shan, Liang Huang, Jun-Jie Li, Yi-Zhou Jiang, Zhi-Ming Shao
Yi Xiao, Fan Yang, Ying-Jia Qi, Li Chen, Hang Zhang, Si-Wei Zhang, Rui Shan, Liang Huang, Jun-Jie Li, Yi-Zhou Jiang, Zhi-Ming Shao
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Clinical Research and Public Health Cell biology Clinical Research Oncology

Multimodal assessment of exceptional responders refines subtyping-directed precision treatment in HR+/HER2– breast cancer

Abstract

BACKGROUND We previously defined 4 hormone receptor+/human epidermal growth factor receptor 2– (HR+/HER2–) subtypes: SNF1 canonical luminal, SNF2 immunogenic, SNF3 proliferative, and SNF4 RTK driven. The FASCINATE-N proof-of-concept trial demonstrated that subtyping-directed precision treatment improves pathologic complete response in locally advanced HR+/HER2– breast cancer, yet efficacy remains suboptimal.METHODS We integrated transcriptomic, genomic, digital pathology, and clinical data from this trial (n = 230) and focused on exceptional responders to explore opportunities for refining treatment strategies.RESULTS In SNF1, we uncovered that perineural invasion diminished endocrine therapy efficacy, suggesting the potential benefit of incorporating perineural blockade. Digital pathology and spatial transcriptomics identified that the spatial architecture of the tumor-stromal-immune interface influenced apatinib efficacy in SNF4, highlighting the importance of interfering with the tumor microenvironment. In the SNF3 group, exceptionally well responders exhibited multiple mutations in DNA repair genes and cell cycle activation, correlating with the efficacy of poly (ADP-ribose) polymerase and CDK4/6 inhibitors. Additionally, we illustrated that lymphatic vessel infiltration was linked to improved immunotherapy outcomes in HR+/HER2– SNF2 tumors.CONCLUSION Overall, our study emphasizes the importance of multimodal assessments in optimizing precision treatments for HR+/HER2– breast cancer.FUNDING National Natural Science Foundation of China, grant numbers U25C2032, 82441028, and 82573645; The Shanghai Key Laboratory of Breast Cancer, grant number 12DZ2260100; The Human Phenome Data Center of Fudan University.TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT05582499.

Authors

Yi Xiao, Fan Yang, Ying-Jia Qi, Li Chen, Hang Zhang, Si-Wei Zhang, Rui Shan, Liang Huang, Jun-Jie Li, Yi-Zhou Jiang, Zhi-Ming Shao

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Figure 2

Expression of molecular biomarkers across the FASCINATE-N multiomics cohort.

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Expression of molecular biomarkers across the FASCINATE-N multiomics coh...
(A) Subtype-specific feature scores of specific molecular features in 4 SNF subtypes. ER, estrogen receptor. (B) Expression level or single-sample gene set enrichment analysis (ssGSEA) scores of representative biomarkers in 4 SNF subtypes. P values were calculated via the Welch’s t test. Box plots show the interquartile range, median (line), and minimum and maximum (whiskers). FPKM, fragments per kilobase of transcript per million mapped reads.