Abstract P2-09-11: PAM50 intrinsic subtyping as a predictor of pathological complete response to neoadjuvant trastuzumab-based chemotherapy in early HER2-positive breast cancer
Authors: Pernas S , Petit A , Climent F , Pare L , Perez-Martin J , Ventura L , Galvan P , Falo C , Morilla I , Fernandez-Ortega A , Stradella A , Pascual T , Gil-Gil M , Prat A 
Published: February 2018

Background: HER2-positive breast cancer (BC) is a heterogeneous disease from a clinical and biological perspective. Intrinsic subtype defined by gene expression has an important role in determining response to treatment, as seen in several neoadjuvant trials (e.g. CALGB40601, CherLOB, NeoALTTO and PAMELA). However, limited data exist in an off-trial setting. The objective of this study was to evaluate the association of intrinsic subtypes with pathological completed response (pCR) and survival outcomes of a series of HER2-positive patients (pts) homogeneously treated with trastuzumab-based primary chemotherapy (PC) in a single comprehensive cancer center.

Methods: Clinical-pathological data were evaluated in a series of 150 consecutive stage II-IIIC (T4d included) HER2-positive BC pts treated in ICO-Hospitalet (Spain) from August-2009 to December-2012 with weekly paclitaxel x12 followed by FEC/3w x 4 and concurrent trastuzumab for a total of 24w. HER2-positivity was considered according to ASCO-CAP 2007 guidelines. pCR was defined as ypT0/isypN0. The expression of 105 BC-related genes, including the PAM50 genes, was determined in baseline and residual formalin-fixed paraffin-embedded tumor samples using the nCounter platform. Intrinsic subtypes were determined by the research-based PAM50 gene expression predictor. Association of variables with pCR or disease-free survival (DFS) was evaluated using logistic regression analyses and cox proportional hazard models.All statistical tests were two-sided and considered significant when p≤0.05.

Results: Most pts had T2 (64%) and T4 (20%) tumors and clinically node-positive disease (77%). 53% had hormonal receptor (HR)+ disease. 84 of the 150pts (56%) achieved a pCR; HR-neg was associated with higher pCR rates (72.5%vs 42% in HR+ P&lt;0.001). 90 of the 150 (60%) baseline samples were evaluated. Baseline subtype distribution: HER2-enriched (HER2-E) 63%, Luminal A 11%, Basal-like 8.9%, Normal-like 8.9% and Luminal B 7.8%. Although HER2-E predominated in HR-neg tumors (74%), 53% of HR+ tumors were HER2-E. pCR rates varied according to intrinsic subtype (P&lt;0.001). HER2-E tumors were associated with higher pCR rates compared to non-HER2-E (68.4% vs 33.3%, P&lt;0.001) regardless HR-status. Five of the 8 PAM50 signatures (HER2E, ROR-S, ROR-P, Basal-like and Proliferation score) were associated with pCR, whereas Luminal A was associated with no-pCR (P&lt;0.001). With a median follow-up of 6.6 years, HER2-E subtype was associated with a better DFS compared to non-HER2-E (5-year DFS 92.4% vs 75.9%; HR= 0.27; 95% CI 0.08-0.91; P=0.034). Finally, 28 of the 66 (42.4%) surgical specimens with residual disease were studied. Residual subtype distribution was: Normal-like (50.0%), Luminal A (32.1%), HER2-E (14.3%) and Luminal B (3.5%).

Conclusions: In this consecutive series of HER2-positive BCtreated homogeneously with neoadjuvant trastuzumab-based PC, all of the main intrinsic molecular subtypes were identified with a predominance of HER2-E. HER2-E was significantly associated with pCR and survival outcome. Distribution of the intrinsic subtypes in residual disease differed from untreated tumors.

Citation Format: Pernas S, Petit A, Climent F, Pare L, Perez-Martin J, Ventura L, Galvan P, Falo C, Morilla I, Fernandez-Ortega A, Stradella A, Pascual T, Gil-Gil M, Prat A. PAM50 intrinsic subtyping as a predictor of pathological complete response to neoadjuvant trastuzumab-based chemotherapy in early HER2-positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-11.