Abstract S3-03: PAM50 intrinsic subtype as a predictor of pathological complete response following neoadjuvant dual HER2 blockade without chemotherapy in HER2-positive breast cancer: First results of the PAMELA clinical trial
Authors: Prat Aparicio A , Cortes Castan J , Pare L , Galvan P , Bermejo B , Martínez N , Vidal M , Pernas S , López R , Muñoz M , Nuciforo P , Fasani R , Morales S , Oliveira M , de La Peña L , Peláez A , Llombart A 
Published: March 2017

Abstract
Background: Prior neoadjuvant studies in HER2+ breast cancer have shown that dual HER2 blockade without chemotherapy achieves pathological complete responses (pCR) rates of 6-36% (TBCRC006/TBCRC023/NeoSphere). However, a major challenge today is how to select prospectively patients who will derive the maximum benefit from dual anti-HER2 therapies without chemotherapy. In this context, we and others have previously shown that HER2+ disease is biologically heterogeneous and composed of all the intrinsic molecular subtypes (Luminal A, Luminal B, HER2-enriched [HER2-E] and Basal-like). Among them, the HER2-E subtype shows the highest activation of the EGFR/HER2 pathway.
Methods: PAMELA (NCT01973660) is a non-randomized, open-label, multicentric, prospective translational research study in stage I-IIIA HER2+ breast cancer designed to evaluate the ability of the PAM50 intrinsic subtypes to predict pCR in the breast (pCRB; in situ allowed) following 18 weeks of neoadjuvant lapatinib and trastuzumab). Patients with HR+ disease received letrozole (if postmenopausal) or tamoxifen (if pre-menopausal). The primary objective was to compare the pCRB rates of the HER2-E versus the non-HER2-E subtypes in the intent-to-treat population. The study was planned with a power of 95% at a significance level of 0.05 to detect an absolute relative difference in pCRB rates between the two groups of 27% (i.e. 35% in HER2E and 8% in non-HER2-E). Day-15 formalin-fixed, paraffin-embedded tissue samples were prospectively collected and gene expression profiled using the nCounter platform. The intrinsic subtypes were identified using the research-based PAM50 predictor (Parker JCO 2009).
Results: A total of 151 patients were recruited (n=77 HR+ and n=74 HR-). Patient characteristics were: mean age (55 years), mean tumor size (2.84 cm), negative axilla (63.5%) and postmenopausal (60.2%). At baseline, intrinsic subtype distribution was: HER2-E (n=101, 66.9%), Luminal A (n=22; 14.6%), Luminal B (n=16; 10.6%), Basal-like (n=9; 6%) and Normal-Like (n=3; 2%). The overall pCRB was 30.5% (46/151), 18.2% in HR+ disease and 43.2% in HR- disease. Five patients (3.3%) presented progressive disease. Rates of pCRB in HER2-E and non-HER2-E subtypes were 40.6% and 10.0% (p&lt;0.0001), respectively. HER2-E subtype predicted pCRB independently of HR status. Within HR+ disease, pCRB rates were 31.6% in HER2-E subtype and 5.3% in non-HER2-E subtype (p=0.006). Within HR- disease, pCRB rates were 46.0% in HER2-E subtype and 27.3% in non-HER2-E subtypes (p=0.331). At Day-15, the majority of tumors became Normal-like (48.9%) or Luminal A (27.5%). Rates of pCRB were 46.9% in Normal-like tumors and 11.9% in non-Normal-like tumors when evaluated at day-15 (p&lt;0.0001).
Conclusions: The PAMELA trial met its primary endpoint. PAM50 HER2-E subtype identifies patients with HER2+ disease likely to derive a large benefit from dual anti-HER2 therapies +/- endocrine therapy, especially in HER2+/HR+ disease. In addition, early changes in gene expression indicative of a reduction of tumor cellularity are predictive of pathological complete response at surgery.
Citation Format: Prat Aparicio A, Cortes Castan J, Pare L, Galvan P, Bermejo B, Martínez N, Vidal M, Pernas S, López R, Muñoz M, Nuciforo P, Fasani R, Morales S, Oliveira M, de La Peña L, Peláez A, Llombart A. PAM50 intrinsic subtype as a predictor of pathological complete response following neoadjuvant dual HER2 blockade without chemotherapy in HER2-positive breast cancer: First results of the PAMELA clinical trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S3-03.