PAM50 HER2-enriched Phenotype as a Predictor of Response to Dual HER2 Blockade in HER2-positive Early Breast Cancer

PAMELA is a non-randomized, open label, multicentric translational research study of neoadjuvant dual HER2 blockade therapy without chemotherapy. Although efficacy and safety will be investigated, the primary goal is to identify profiles predictive of clinical benefit from targeted therapy. Eligible patients must be women with untreated primary HER2-overexpressing and/or amplified breast tumors of more than 1 cm in diameter amenable to definitive surgery (stage I-IIIA). The PAMELA study is designed to test the hypothesis that the PAM50 HER2-E subtype is able to predict clinical response to neoadjuvant dual HER2 blockade with lapatinib and trastuzumab, with or without endocrine therapy, assessed by pathological complete response in the breast (pCRB) rate at the time of surgery, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy. Patients will first undergo screening, tumor measurement, and mandatory collection of core tumor biopsies for central determination of HER2 and HR status. These biopsies will be used to determine gene expression patterns once the patient is included in the study. Patients will be treated with dual HER2 blockade consisting of lapatinib and trastuzumab for a total of 18 weeks. Patients who are HR-positive will also be given endocrine therapy, letrozole or tamoxifen depending on their menopausal status, for the same 18 weeks. If tumor progression is observed by ultrasound (US) at week 6, tumors will be identified as resistant, and paclitaxel will be added to dual HER2 blockade, maintaining trastuzumab at the same original dose and reducing lapatinib dose for safety reasons. In those patients with HR-positive disease, endocrine therapy will be withdrawn in order to avoid its adverse interactions with chemotherapy. Two weeks after the first administration of study medication, all patients will undergo mandatory repeat tumor tissue acquisition that will be used for secondary endpoint assessment. Post treatment tissue acquisition will be obtained at the time of surgery from the specimen excised. US of the breast and axillary lymph nodes will be performed at baseline, Day 14, week 6, and prior to surgery, and will be correlated with pCR. If tumor progression is observed on week 6, the US will be repeated on week 10 to discard the progression continues despite the addition of paclitaxel at neoadjuvant regimen. Mammography is required at baseline and prior to surgery, but will not be used for the objective response assessment. Treatment will be given until definitive surgery, clinical signs of disease progression after paclitaxel addition, unacceptable toxicity or withdrawal of patient consent. Breast surgery will be carried out 1 to 3 weeks after completion of dual HER2 blockade with or without endocrine therapy, and 2 to 3 weeks after completion of paclitaxel plus dual HER2 blockade, should it had been initiated for progressive disease. Following surgical excision, adjuvant treatment will be as per investigator´s choice and local standards of care outside the scope of this protocol. End of study is 30 days (±14 days) after surgery with a safety follow-up visit.