title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  The HER2-enriched subtype can identify patients with HER2-positive breast cancer who are likely to benefit from dual HER2 blockade therapies.
  
  
  
  GlaxoSmithKline, Susan Komen Foundation, CERCA Programme-Generalitat de Catalunya, Banco Bilbao Vizcaya Argentaria Foundation, Pas a Pas, and the Breast Cancer Research Foundation.
authors.affiliation: Hospital Arnau de Vilanova, Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Llombart-Cussac
authors.affiliation: Hospital Universitario Ramón y Cajal, Madrid, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Paré
authors.affiliation: Vall d'Hebron Institute of Oncology, Barcelona, Spain; Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Galván
authors.affiliation: Hospital Clínico de Valencia, Valencia, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Bermejo
authors.affiliation: Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez
authors.affiliation: Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Hospital Universitari Vall d' Hebron, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Instituto Catalán de Oncología, Hospitalet, Barcelona, Spain.
authors.forename: Sònia
authors.initials: S
authors.lastname: Pernas
authors.affiliation: Complejo Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: López
authors.affiliation: Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: Molecular Oncology Laboratory, Barcelona, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.affiliation: Hospital Universitari Arnau Vilanova, Lleida, Spain.
authors.forename: Serafín
authors.initials: S
authors.lastname: Morales
authors.affiliation: Hospital Universitari Vall d' Hebron, Barcelona, Spain.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Oliveira
authors.affiliation: SOLTI Breast Cancer Research Group, Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: de la Peña
authors.affiliation: SOLTI Breast Cancer Research Group, Barcelona, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Peláez
authors.affiliation: Vall d'Hebron Institute of Oncology, Barcelona, Spain; Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Electronic address: alprat@clinic.cat.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012074:Remission Induction; D015996:Survival Rate; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab