Abstract 2836: A discovery and validation set of breast cancer preoperative clinical trials show an increase in immune score upon brief-exposure to trastuzumab (T) and the HER2-enriched subtype predict response to combination chemotherapy and T
Authors: Varadan Vinay , Miskimen Kristy L.S. , Parsai Shikha , Krop Ian E. , Winer Eric P. , Bossuyt Veerle , Abu-Khalaf Maysa , Sikov William , Harris Lyndsay N. 
Published: August 2015

Background: HER2-positive (HER2+) breast cancer is biologically heterogeneous; no consistent biomarkers of response to T have been identified. Recent data suggest intrinsic subtypes and immune infiltration estimates applied to HER2 cohorts are able to predict response to T-based therapy. Two multicenter trials (DFCI 03-311 and BrUOG 211B) were conducted to determine if exposure to T alone prior to combination T-based chemotherapy could provide predictors of pathologic complete response (pCR).

Design: In both trials, fresh tumor core biopsies were taken at baseline and a 2 week time point after a single dose of T. Eighty HER2+ early breast cancer (EBC) patients enrolled in the 03-311 trial of T&gt;T+C. A total of 122 samples (50 matched pairs and 22 single timepoints) produced useable gene expression data using the Illumina HT12v3 platform. Similarly, in the BrUOG 211B trial, 60 HER2+ EBC patients were enrolled and randomized to either a single dose of T or a single dose of nab-paclitaxel (N) followed by T+N+C. RNA from a total of 74 samples (33 matched pairs and 8 single timepoints) was profiled using a novel targeted RNA-sequencing platform that included a total of 950 genes, including the predefined PAM50 and Immune Score (ESTIMATE) signatures.

Results: PAM50 subtypes were largely stable after one dose of therapy in both the 03-311 and 211B trials. PAM50 subtypes evaluated at baseline in the 03-311 trial showed an increase in pCR in the HER2-enriched subtype (10/26; 38.4%) as compared to Luminal B (1/9; 11.11%) and HER2-basal (5/29; 17.2%). This was confirmed in 211B, with the HER2-enriched subtype exhibiting the highest pCR rate (4/8; 50%) as compared to Luminal B (4/15; 26.6%) or HER2-basal (2/9; 22.2%). After a single dose of T, a significant increase in a 140-gene expression-based index of immune infiltration (Immune Score) was observed only in the HER2-enriched subtype in both the 03-311 (p = 0.04) and the 211B (p = 0.016) trials. Interestingly, the Immune Score distinguished between responders and non-responders after a single dose of T in both the 03-311 (p = 0.03) and the 211B (p = 0.05) trials but not at baseline in either trial. In contrast, brief-exposure to nab-paclitaxel did not show either of the above associations.

Conclusions: The HER2-enriched subtype has the highest response rate to preoperative trastuzumab, confirmed by two brief-exposure preoperative clinical trials. Strikingly, both trials also revealed that the Immune Score was discriminative of response after a single dose of trastuzumab and not at baseline suggesting a unique role of immune infiltration within the HER-enriched subtype. The brief-exposure paradigm adopted in our study provides novel insights into tumor biology mediating response, while also allowing for the discovery of novel biomarkers predictive of pCR.

Citation Format: Vinay Varadan, Kristy L.S. Miskimen, Shikha Parsai, Ian E. Krop, Eric P. Winer, Veerle Bossuyt, Maysa Abu-Khalaf, William Sikov, Lyndsay N. Harris. A discovery and validation set of breast cancer preoperative clinical trials show an increase in immune score upon brief-exposure to trastuzumab (T) and the HER2-enriched subtype predict response to combination chemotherapy and T. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2836. doi:10.1158/1538-7445.AM2015-2836