TRacking Adaptation, Dormancy and awakening with multi-Omics (traditiom)

Patients diagnosed with estrogen receptor positive breast cancer (ER+ BC) receive five or more years of adjuvant endocrine therapies (ETs). Adjuvant ETs delay relapse by targeting clinically undetectable micro-metastatic deposits​​, yet 50% of patients receiving ET relapse up to decades after surgery​​. The mechanisms driving these clinical dynamics are largely unknown but likely involve dormancy​​. We developed two approaches to study the fate of dormant cells in long-term experiments. Firstly, we analysed samples from a cohort of late relapses (10-35 yrs.) and in parallel we longitudinally profiled a rare cohort of patients treated with 16-44 months of neoadjuvant ETs until progression. This allowed us to dissect the contribution of genetic and transcriptional changes to tumour awakening. Next, we developed an in vitro evolutionary study to systematically record adaptive strategies of individual lineages in unperturbed parallel experiments through several months. Collectively our data demonstrate that ETs induce a non-genetic cell state transition into dormancy in a stochastically selected subset of cancer cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably and sequentially in the absence of detectable genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs with profound implications for breast cancer.