Given that HCQ is well tolerated and is currently in clinical trials to reverse hormonal and cytotoxic drug resistance14, 61, we first propose a Phase II clinical trial (in the neoadjuvant setting) in postmenopausal advanced ER+/HER2− breast cancer patients, treating them with the combination of low-dose palbociclib (75 mg kg−1 per day), HCQ and letrozole using surrogate biomarkers such as Ki67 staining. The gene discussed is ESR1; the disease is breast cancer.