www.thelancet.com/oncology Published online February 23, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30021-9 1 Articles HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial Antonio Llombart-Cussac, Javier Cortés, Laia Paré, Patricia Galván, Begoña Bermejo, Noelia Martínez, Maria Vidal, Sònia Pernas, Rafael López, Montserrat Muñoz, Paolo Nuciforo, Serafín Morales, Mafalda Oliveira, Lorena de la Peña, Alexandra Peláez, Aleix Prat Summary Background HER2-positive breast cancer consists of four intrinsic molecular subtypes—luminal A, luminal B, HER2- enriched, and basal-like—and a normal-like subtype, with the HER2-enriched subtype having the highest activation of the EGFR–HER2 pathway. We aimed to test the hypothesis that patients with the HER2-enriched subtype benefit the most from dual HER2 blockade. Methods PAMELA is an open-label, single-group, phase 2 trial done in 19 hospitals in Spain. We recruited female patients aged at least 18 years with previously untreated, centrally confirmed HER2-positive, stage I–IIIA invasive breast cancer regardless of hormone receptor status. Patients were given lapatinib (1000 mg per day orally) and trastuzumab (loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks intravenously) for 18 weeks; hormone receptor-positive patients were additionally given letrozole (2·5 mg per day orally; if menopausal) or tamoxifen (20 mg per day orally; if premenopausal). Surgery was done 1–3 weeks after the last dose of study treatment. Intrinsic molecular subtypes of tumour biopsy samples taken at baseline (day 0) and day 14 were determined with the PAM50 predictor. The primary outcome was the ability of the HER2-enriched subtype to predict pathological complete response at the time of surgery. The primary outcome was assessed in the evaluable population (ie, all patients who had initial tumour biopsy samples available and who underwent definitive surgery) and safety was assessed in all patients who received at least one part of study treatment. This study is registered with ClinicalTrials.gov, number NCT01973660, and is completed. Findings Between Oct 28, 2013, and Nov 26, 2015, we recruited 151 patients, of whom 14 (9%) discontinued treatment and 137 (91%) completed treatment as planned. At baseline, most patients had the HER2-enriched subtype (101 [67%]), followed by luminal A (22 [15%]), luminal B (16 [11%]), basal-like (nine [6%]), and normal-like (three [2%]) subtypes. At the time of surgery, 46 (30%, 95% CI 23–39) of 151 patients had pathological complete response in the breast. 41 (41%, 31–51) of 101 patients with the HER2-enriched subtype and five (10%, 4–23) of 50 patients with non-HER2- enriched subtypes achieved pathological complete response at the time of surgery (odds ratio 6·2, 95% CI 2·3–16·8; p=0·0004). Interpretation The HER2-enriched subtype can identify patients with HER2-positive breast cancer who are likely to benefit from dual HER2 blockade therapies. Funding GlaxoSmithKline, Susan Komen Foundation, CERCA Programme—Generalitat de Catalunya, Banco Bilbao Vizcaya Argentaria Foundation, Pas a Pas, and the Breast Cancer Research Foundation. Introduction Blockade of the HER2 signalling pathway by combining two inhibitors with non-overlapping mechanisms of action enhances cell death in HER2-overexpressed models of breast cancer. 1,2 In the clinical setting, dual HER2 blockade with trastuzumab plus either lapatinib or pertuzumab, in addition to chemotherapy, greatly improves overall survival by 4·5–6·3 months, compared with single HER2 blockade plus chemotherapy, in patients with metastatic HER2-positive breast cancer. 3–5 In patients with locally advanced HER2-positive breast cancer, the addition of lapatinib or pertuzumab to trastuzumab-based neoadjuvant chemotherapy increases the proportion of patients who achieve a pathological complete response. 6–8 Dual HER2 blockade with lapatinib and trastuzumab in combination with chemotherapy has been explored in early-stage breast cancer with little success until recently. 9 In the ALTTO trial published in 2016, 9 1 year of adjuvant lapatinib added to standard chemotherapy plus trastuzumab resulted in a 16% relative risk reduction in disease-free survival compared with chemotherapy plus trastuzumab. Moreover, pertuzumab Lancet Oncol 2017 Published Online February 23, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30021-9 See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(17)30150-X Hospital Arnau de Vilanova, Valencia, Spain (A Llombart-Cussac MD); Hospital Universitario Ramón y Cajal, Madrid, Spain (J Cortés MD, N Martínez MD); Molecular Oncology Laboratory (P Nuciforo MD), Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain (J Cortés, P Galván BS, A Prat MD); Hospital Clinic of Barcelona (L Paré PhD, P Galván, M Vidal MD*, M Muñoz MD, A Prat) and Translational Genomics and Targeted Therapeutics in Solid Tumors (L Paré, P Galván, A Prat), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Hospital Clínico de Valencia, Valencia, Spain (B Bermejo MD); Hospital Universitari Vall d’ Hebron, Barcelona, Spain (M Vidal, M Oliveira MD); Instituto Catalán de Oncología, Hospitalet, Barcelona, Spain (S Pernas MD); Complejo Universitario de Santiago de Compostela, Santiago de Compostela, Spain (R López MD); Hospital Universitari Arnau Vilanova, Lleida, Spain (S Morales MD); and SOLTI Breast Cancer Research Group, Barcelona, Spain (L de la Peña PhD, A Peláez MD) *Current address Correspondence to: Dr Aleix Prat, Hospital Clinic of Barcelona, Translational Genomics and Targeted