Multiomics of HER2-low triple-negative breast cancer identifies a receptor tyrosine kinase–relevant subgroup with therapeutic prospects
Lie Chen, Cui-Cui Liu, Si-Yuan Zhu, Jing-Yu Ge, Yu-Fei Chen, Ding Ma, Zhi-Ming Shao, Ke-Da Yu
Lie Chen, Cui-Cui Liu, Si-Yuan Zhu, Jing-Yu Ge, Yu-Fei Chen, Ding Ma, Zhi-Ming Shao, Ke-Da Yu
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Research Article Oncology

Multiomics of HER2-low triple-negative breast cancer identifies a receptor tyrosine kinase–relevant subgroup with therapeutic prospects

Abstract

To provide complementary information and reveal the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multiomics study of hormone receptor–negative (HR–) and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified 3 subgroups: basal-like, receptor tyrosine kinase–relevant (TKR), and mesenchymal stem–like. These 3 subgroups had distinct features and potential therapeutic targets and were validated in external data sets. Interestingly, the TKR subgroup (which exists in both HR+ and HR– breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab–drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.

Authors

Lie Chen, Cui-Cui Liu, Si-Yuan Zhu, Jing-Yu Ge, Yu-Fei Chen, Ding Ma, Zhi-Ming Shao, Ke-Da Yu

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Figure 5

Construction of the HRD signature in the BSL subgroup to predict prognosis.

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Construction of the HRD signature in the BSL subgroup to predict prognos...
(A) Distribution of intrinsic BSL subtypes among the BSL, TKR, and MSL subgroups of HER2-low TNBC from the FUSCC (left) and TCGA (right) data sets (χ2 test and Fisher’s exact test). (B) Distribution of HRD scores in BSL and other subgroups with BRCA mutation status from the FUSCC data set (left; Mann-Whitney test); distribution of HRD scores in BSL and other subgroups from the TCGA data set (right; Student’s t test). (C) RFS of BSL patients in the high-HRD versus low-HRD groups (top; log-rank test); AUC of time-dependent ROC analysis (bottom). (D) ssGSEA of the BSL subgroup of HER2-low TNBC based on GO data sets are shown in the heatmap. (E) Volcano plot illustrating DEGs between the bottom 25% and top 25% of HRD scores in BSL. (F) RFS of BSL patients (with HRD scores) with high HRDR score versus low HRDR score groups (left; log-rank test); AUC of time-dependent ROC analysis (right). (G) Correlational analysis was performed between HRDR scores and HRD scores in BSL based on the FUSCC data set. (H) RFS of total BSL patients (with and without HRD scores) with high HRDR score versus low HRDR score groups (left; log-rank test); AUC of time-dependent ROC analysis. Statistical significance was set at P < 0.05. Val, value.