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 4

Spatial structures influence the efficacy of apatinib in SNF4 HR+/HER2– breast cancers.

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Spatial structures influence the efficacy of apatinib in SNF4 HR+/HER2– ...
(A) Overview of enrollment, sequencing, and treatment efficacy of patients with the SNF4 subtype of HR+/HER2– breast cancer. (B) Box plot showing the relative pathway ssGSEA scores for pathways between pCR and non-pCR patients. (C) Workflow for extracting morphological, texture, and topological features of WSIs from baseline biopsy using sc-MTOP. (D) Comparisons of cell type proportions extracted from WSIs between pCR and non-pCR patients, with exceptional nonresponders highlighted. P values were calculated via unpaired Student’s t test. (E) Heatmap showing scaled pathological feature expression between the pCR and non-pCR patients. (F) Bar plot comparing the topological features between pCR and non-pCR patients, with exceptional nonresponders highlighted. P values were calculated via unpaired Student’s t test. (G) MRI of STE236 and NST543 at baseline, after 6 weeks, and after 12 weeks of neoadjuvant therapy. (H) Representative WSIs showing the topological features between 2 exceptional responders (STE236 and NST543), with different colored lines representing different types of cell connections. (I) Heatmap showing immune cycle pathways in lymphocytes across tissue regions. (J) Design and cellular landscape of CosMx-SMI profiling. Tumor samples from 5 HR+/HER2– breast cancer patients were analyzed by CosMx-SMI, identifying major cell populations. (K) Cytotoxic effector gene expression in tumor-infiltrated versus stroma-restricted T cells. (L and M) Representative images showing the GZMB expression in T cells adjacent to tumor cells or cancer-associated fibroblasts. (N) Schematic overview of the analysis of SNF4 arm. Box plots show the interquartile range, median (line), and minimum and maximum (whiskers). PCb, nab-paclitaxel, carboplatin; NAT, neoadjuvant therapy; I, immune cells; N, normal cells; S, stroma cells; T, tumor cells; SD, stable disease; PD, progressive disease; WSI, whole-slide image; GZMB, granzyme B; CAF, cancer-associated fibroblast.