Abstract
Despite the availability of multiple human epidermal growth factor receptor 2–targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1–positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.
Highlights
Amplification and overexpression of ERBB2 encoding the human epidermal growth factor receptor 2 (HER2) distinguishes a subtype of breast cancers that accounts for approximately one-fifth of all invasive breast cancer cases [1]
We found that trastuzumab and pertuzumab treatment resistance was linked to survival of subpopulations of cancer cells able to regulate angiogenesis and epithelial-to-mesenchymal transition (EMT), while leading to elimination of cells with active translation, protein folding, and ER stress response linked to apoptosis
Our single-cell in situ analyses show that the frequency of cells with resistance-conferring PIK3CA mutation is higher in untreated samples of patients who did not respond to trastuzumab/chemotherapy combination, and in those patients, the subpopulations with PIK3CA mutation and ERBB2 amplification expanded after treatment
Summary
Amplification and overexpression of ERBB2 encoding the human epidermal growth factor receptor 2 (HER2) distinguishes a subtype of breast cancers that accounts for approximately one-fifth of all invasive breast cancer cases [1]. Inhibition of HER2 was one of the first examples for targeted cancer therapy based on the development and use of the anti-HER2 antibody trastuzumab [2]. Over the past 2 decades, the combination of trastuzumab with chemotherapy became a standard of care for patients with HER2+ breast cancer Even though this targeted approach substantially improves the disease-free and overall survival of patients with HER2+ breast cancer, virtually all patients with advanced HER2+ disease will eventually develop resistance and progressive disease. Several potential mechanisms of resistance to HER2-targeted therapy have been identified from preclinical and clinical studies These include genetic alterations, such as mutations in PI3K catalytic subunit α (PIK3CA) and ERBB2 leading to constitutive activation of downstream signaling pathways [5]. Despite accumulating knowledge in this area, the actual molecular changes driving resistance in human cancers have not been definitively demonstrated, and accurate predictions of the likelihood of resistance based on diagnostic biopsy profiles are not yet feasible
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