Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine
therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic
deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown
mechanisms likely involving dormancy. To investigate genetic and transcriptional changes
underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled
a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed
an in vitro evolutionary study to record the adaptive strategies of individual lineages
in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic
cell state transitions into dormancy in a stochastic subset of cells via epigenetic
reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the
absence of recurrent 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.This study advances
the understanding of therapy-induced dormancy with potential clinical implications
for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine
treatment by entering a dormant state characterized by strong heterochromatinization
with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation
of cancer cells to ETs.
