“Longitudinal and multimodal auditing of tumor adaptation to CDK4/6 inhibitors in HR+ metastatic breast cancers”

Abstract

CDK4/6 inhibitors (CDK4/6i) have transformed the treatment of hormone receptor-positive (HR+), HER2-negative (HR+) breast cancers as they are effective across all clinicopathological, age, and ethnicity subgroups for metastatic HR+ breast cancer. In metastatic ER+ breast cancer, CDK4/6i lead to strong and consistent improvement in survival across different lines of therapy. To understand how metastatic HR+ breast cancers become refractory to CDK4/6i, we have created a multimodal and longitudinal tumor atlas to investigate therapeutic adaptations in malignant cells and in the tumor immune microenvironment. This atlas is part of the NCI Cancer Moonshot Human Tumor Atlas Network and includes seven pairs of pre- and on-progression biopsies from five metastatic HR+ breast cancer patients treated with CDK4/6i. Biopsies were profiled with bulk genomics, transcriptomics, and proteomics as well as single-cell ATAC-seq and multiplex tissue imaging for spatial, single-cell resolution. These molecular datasets were then linked with detailed clinical metadata to create an atlas for understanding tumor adaptations during therapy. Analysis of our atlas datasets revealed a diverse but tractable set of tumor adaptations to CDK4/6i therapy. Malignant cells adapted to therapy via mTORC1 activation, cell cycle bypass, and increased replication stress. The tumor immune microenvironment displayed evidence of both immune activation and immune suppression, including increased PD-1 expression, features of T cell dysfunction, and CD163+macrophage infiltration. Together, our metastatic ER+ breast cancer atlas represents a rich multimodal resource to understand tumor therapeutic adaptations to CDK4/6i therapy.