Artificial Intelligence and Machine Learning to Guide CDK4/6 Inhibitor Rechallenge in Breast Cancer.

This is a phase II, open-label, randomized controlled single-site study to assess the clinical utility of an artificial intelligence model, called palbo-VNN, to guide treatment selection in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) advanced (unresectable or metastatic) breast cancer who have progressed after prior treatment with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. The investigators hypothesize that: (1) the model will be able to predict who will respond to a second CDK4/6 inhibitors combined with fulvestrant (Faslodex); and (2) that the participants treated with a second CDK4/6 inhibitors plus fulvestrant will have better outcomes (longer progression free survival, higher overall response rate, higher clinical benefit rate, and better quality of life) than the participants treated based on the physician's choice. Next-generation sequencing of the tumor will be performed using biopsies obtained after the first CDK4/6 inhibitor treatment and within six months of study enrollment. The next-generation sequencing data will be analyzed with the palbo-VNN model. Participants with tumors predicted to respond to a second CDK4/6 inhibitor (CDK4/6i sensitive) will be randomized. Half of the randomized participants will receive a second CDK4/6 inhibitor plus fulvestrant; the other half will receive the treatment of physician's choice, excluding CDK4/6 inhibitors. After 6 months of therapy, the investigators will evaluate the progression free survival rate of the randomized participants, as well as other measures of efficacy, such as overall response rate, clinical benefit rate, and quality of life. They will also do studies to correlate treatment efficacy with molecular alterations of the tumor. These correlative studies may allow to improve the predictive ability of the palbo-VNN model in the future. The investigators will also evaluate treatment safety.