Abstract P3-06-24: Brief exposure to trastuzumab prior to preoperative chemotherapy confirms predictors of response to treatment
Authors: Vadodkar Aditi Shirish , Varadan Vinay , Miskimen Kristy , Bossuyt VV , Abu-khalaf MM , Krop I , Winer E , Harris LN 
Published: May 2015

Background: HER2-positive (HER2+) breast cancer is biologically heterogeneous; no consistent biomarkers of response to trastuzumab (T) have been identified. Recent data suggest intrinsic subtypes applied to HER2 cohorts are able to predict response to T-based therapy. We designed a multicenter trial (DFCI 03-311) to determine if exposure to T-alone prior to combination T-based chemotherapy (C) could produce predictors of pathologic complete response (pCR). We previously reported that change in AKT and IGF signatures by gene expression could predict pCR. New gene expression pathways (immune and HER2 subtypes) were evaluated.

Design : Fresh tumor core biopsies were taken at baseline and 2 weeks after a single dose of T (8mg/m2) from 80 HER2-overexpressing, stage II/III breast cancer patients enrolled on a clinical trial of T&gt;T+C. A total of 122 samples (50 matched pairs and 22 single timepoints) produced useable gene expression data. Nucleic acids were extracted using Qiagen AllPrep and were analyzed with Illumina HT12v3. Data generated was normalized and median subtracted using Illumina's Genome Studio software; intrinsic subtyping was performed using median-subtracted PAM50 genes; ‘Estimation of STromal and Immune cells in Malignant Tumors using Expression data’ (ESTIMATE) algorithm was used to infer the fraction of stromal and immune cells in tumor samples.

Results: ESTIMATE Immune score predicts pCR after one dose of treatment of T compared with patients with stable disease or progression as best response ,(NOR;p=0.01) PAM50 subtyping of baseline samples showed increase in pCR in the HER2-enriched cluster (7/17; 41%) versus the Luminal B (2/14; 14%) and HER2 basal clusters (1/8; 12.5% ; P=0.04). ). Change in subtype between baseline and 2 weeks appeared less common in HER2-Luminal B (4/13; 31%) compared with HER2 enriched (9/16; 56%) or HER2 Basal (5/9; 55%). Of note, HER2-Basal had the highest frequency of NOR (4/13; 31%; P=0.06), despite having greater subtype change than HER2-luminal tumors.

Conclusions:

Biomarkers of response to T-based regimens are greatly needed as no consistent predictors beyond HER2 are available. This data confirms (Carey et al, ASCO 2014) that the HER2 enriched subtype predicts pCR and (Harris et al, CCR 2007) that HER2 basal tumors are more likely to be non-responders. In this study, one dose of T is necessary to predict pCR using ESTIMATE immune signature. Validation of these findings a large cohort is needed.

Citation Format: Aditi Shirish Vadodkar, Vinay Varadan, Kristy Miskimen, VV Bossuyt, MM Abu-khalaf, I Krop, E Winer, LN Harris. Brief exposure to trastuzumab prior to preoperative chemotherapy confirms predictors of response to treatment [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-24.