Background: Despite the high efficacy of anti HER2-agents, HER2-positive (HER2+) metastatic breast cancer (BC) remains incurable and in need of additional options. In this context, CDK4/6 inhibition combined with anti-HER2 therapy is currently being explored in phase II/III trials. Preclinical evidence from different HER2+ BC models have shown that CDK4/6 inhibition leads to deep cytostatic arrest and inhibition of its invasive properties, underlining the role of CDK4/6 in HER2 signaling. Moreover, Identification of the luminal subtype in HER2+/HR+ disease might be important since the median IC50 of palbociclib (P) in HER2+ BC cell lines falling into the luminal subtype is lower than in non-luminal HER2+ cell lines (47.5 vs. 300 nM). We have recently reported that PAM50 luminal subtype predicts progression‐free survival (PFS) in HER2+/HR+ advanced BC treated with P and trastuzumab (T) compared to non-luminal disease (10.37 vs. 3.53 months, p-value = 0.023). PATRICIA is a Simon 2‐Stage study to evaluate the efficacy of combining T plus P, +/- letrozole (L), assessed by PFS in heavily pretreated HER2+ patients. Methods: Postmenopausal HER2+ patients who had received 2‐4 prior lines of anti-HER2-based regimens are included in 3 cohorts: A: HR‐negative; B1: HR+, receiving both T and P; B2: HR+, receiving T, P and L. P is administered at 200 mg/day for 14 days of 21‐day cycles. T and L are administered at usual doses. The primary objective is to assess clinical efficacy measured as PFS at 6 months (PFS6). Assuming an increase of at least 20% in PFS6 by the addition of P +/‐ L to T, PFS6 should be ≥30% for a cohort to be successful and proceed to stage 2. Thus, it will be necessary to include 15 patients in each cohort in stage 1. In stage 2, each cohort may continue recruitment for up to 46 patients. Translational research for predictive biomarkers will be implemented. To date, 55 patients, 15 in A and 20 in each B cohort, have been included in 14 sites across Spain. The 1^st stage efficacy analysis was performed for B cohorts, leading 2^nd stage accrual began in September 2017. Cohort A stage 1 effectiveness analysis is intended for June 2018. Clinical trial information: NCT02448420