Background: Resistance to endocrine therapy in patients (pts) with breast cancer remains a major clinical concern. Preclinical studies suggest that complete blockade of the hormone receptor (HR) combined with the inhibition of HER family members may be necessary to overcome resistance and improve clinical outcome in HR-positive and HER2-positive breast cancer (BC). The combination of pertuzumab (P) and trastuzumab (H) with docetaxel significantly improves patient outcome by blocking, more efficiently and completely, the HER signalling pathway. This benefit, however, may be smaller in HR-positive patients. PERTAIN is the first clinical trial to study whether a more potent blockade of the HER pathway with P and H in combination with endocrine therapy may restore or enhance endocrine sensitivity of HER2-positive BC and provide an effective treatment option in pts with HER2-positive and HR-positive MBC. Methods: PERTAIN is a multicenter, open-label, Phase II trial for post-menopausal women with HER2- and HR-positive BC, studying the efficacy of the combination of P plus H with an aromatase inhibitor (AI) as first-line therapy for MBC. Pts will be randomized 1:1 to Arm 1 (P: 840 mg loading dose, 420 mg q3w IV; H: 8 mg/kg loading dose, 6 mg/kg q3w IV; AI [anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H + AI at same dose as Arm 1). Pts in either arm may also receive induction chemotherapy (docetaxel or paclitaxel) for up to 18 weeks at the investigator’s discretion. Study medication will be administered until disease progression or unacceptable toxicity. Pts must not have previously been treated with anti-HER2 agents except H and/or lapatinib in the (neo)adjuvant setting, and must have no CNS involvement or clinically significant cardiovascular disease. The primary endpoint is PFS, and secondary endpoints include overall survival, overall response rate, clinical benefit rate, duration of response, time to response, safety and tolerability, and quality of life. The study opened in January 2012 and will recruit 250 pts. Analysis of the primary endpoint will be performed after 165 PFS events using the Kaplan-Meier approach.