Abstract SP012: Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine signaling inhibitors

Abstract

Abstract Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionary trajectories of early stage breast cancer tumors using serial tumor biopsies from a clinical trial of preoperative endocrine therapy alone (letrozole) or in combination with the cell cycle inhibitor ribociclib. Applying hierarchical regression and Gaussian process mathematical modelling, we classified each tumor by whether it shrinks or persists with therapy and determined cancer phenotypes related to evolution of resistance and cell cycle transcriptional rewiring. We found that all patients’ tumors undergo subclonal evolution during therapy, irrespective of the clinical response. However, tumors subjected to endocrine therapy alone showed reduced diversity over time, those facing combination therapy exhibited increased diversity. Despite different diversity, single nuclei RNA sequencing uncovered common phenotypic changes in tumor cells that persist following treatment. In these tumors, accelerated loss of estrogen signaling is convergent with up-regulation of the JNK pathway, while persistent tumors that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. Cell cycle reconstruction identified that these tumors can rebound during combination therapy treatment, indicating stronger selection and promotion of a proliferative state. These results indicate that combination therapy in early stage ER+ breast cancers with ER and CDK inhibition drives rapid evolution of resistance via a shift from estrogen signaling to alternative growth factor receptor mediated proliferation and JNK signaling activation, concordant with a bypass in the G1 checkpoint. Citation Format: JI Griffiths, J Chen, PA Cosgrove, A O'Dea, P Sharma, CX Ma, M Trivedi, K Kalinsky, KB Wisinski, R O'Reagan, I Makhoul, LM Spring, A Bardia, FR Adler, AL Cohen, JT Chang, QJ Khan, AH Bild. Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine signaling inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP012.