Background: Despite the great efficacy of anti HER2-agents, HER2+ metastatic breast cancer remains incurable and in need of additional options. Palbociclib, a CDK4/6 inhibitor, has demonstrated unprecedented clinical activity in HER2-/ER+ disease. Its potential in HER2+ disease, however, remains to be explored. Preclinical evidence suggests a potentially complementary role with trastuzumab based on their effects on the cell cycle. Our hypothesis is that the addition of palbociclib to trastuzumab-based therapy could offer clinical benefit in this population. Moreover, given that the expression of ER dictates two biologically different HER2+ subgroups, we will explore this activity accordingly, in addition to endocrine therapy. Methods: This is an exploratory, prospective, open-label, multicenter trial of palbociclib plus trastuzumab. Patients must have histologically confirmed HER2+ adenocarcinoma of the breast and have received 2-4 lines of anti-HER2-containing regimens for their advanced disease. The study is based on a Simon 2-stage design comprising three cohorts: cohort A includes ER- patients and cohorts B1 and B2, ER+ patients. All patients receive trastuzumab with an 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks, and 200 mg daily palbociclib for 2 weeks, with 1 week off. Additionally, patients in cohort B2 receive 2.5 mg daily letrozole. A 2-cycle safety run-in with the first 6 patients of each regimen will be performed. The primary objective is to assess clinical efficacy measured as progression-free survival rate at 6 months (PFS6). Assuming an increase of at least 20% in PFS6 by the addition of palbociclib +/- letrozole to trastuzumab, PFS6 should be ≥ 50% for a cohort to be successful, and proceed to stage 2. According to this, it will be necessary to include 15 patients in each cohort in stage 1. In stage 2, each cohort may continue for up to 46 patients. A treatment regimen will be considered efficacious if ≥ 18 patients are progression-free at 6 months, with an 80% power and α = 0.05. Based on this, a maximum of 138 patients may be included. Translational research searching for predictive biomarkers will be implemented. Clinical trial information: 2014-005006-38.