Abstract P1-14-05: Three distinct HER2 subtypes identified by BluePrint 80-gene functional subtyping predict treatment-specific response in the prospective neo-adjuvant NBRST registry
Authors: P Whitworth, P Beitsch, P Baron, J Beatty, JV Pellicane, MK Murray, CL Dul, AM Mislowsky, CH Nash, PD Richards, LA Lee, L Stork-Sloots, F de Snoo, S Untch, M Gittleman, S Akbari, MC Rotkis
Journal: Cancer Research (2016)

Abstract Background Ideally classification by subtype predicts treatment response and overall outcome. BluePrint 80-gene functional molecular subtype is based on mRNA expression (as is intrinsic subtype) associated with intact translation to protein (unlike intrinsic subtype). BluePrint (BP) classifies patients into Luminal, Her2 or Basal-type. Presently subtype is approximated using conventional immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) ("conventional subtype") or assigned by gene expression profiling. The main objective of the prospective neo-adjuvant NBRST study is to compare drug sensitivity as defined by pathological Complete Response (pCR), using 80-gene functional subtype vs. conventional IHC/FISH subtyping. NBRST enrolled over 1,000 US patients between June 2011 and December 2014. In this analysis we present the results for IHC/FISH Her2-positive patients. Methods Here we report findings in the 260 NBRST patients who had IHC/FISH Her2+ breast cancer, according to ASCO CAP guidelines at the time of diagnosis. Treatment, including chemotherapy and HER2-targeted agents, was at the discretion of the physician adhering to NCCN approved or other peer-reviewed, established regimens over the course of the study. pCR was defined as T0/isN0. Fisher's exact test was used to compare pCR rates among IHC/FISH and functional subtypes and treatment groups. Results The 260 IHC/FISH Her2+ patients had median age 53 (range 23-81) and included T1-4, N0-3 tumors. Of 169 ER+/Her2+ tumors 49% were re-classified as BP Luminal, 43% as BP HER2, and 8% as BP Basal. The median ER% of ER+/Her2+/BP Luminal tumors was 93% (range 3-100), compared to 79% in ER+/Her2+/BP HER2 (range 1-91) and 8% in ER+/Her2+/BP Basal-type (range 2-99).The overall pCR rate in ER+/Her2+/BP Luminal was 17% (4% with chemo/trastuzumab; 39% chemo/trastuzumab/pertuzumab, p&amp;lt;0.0001) and statistically inferior (p&amp;lt;0.0001) to the 59% pCR rate in ER+/Her2+/BP HER2. Of 91 ER-/Her2+ tumors 74% were classified as BP HER2, 25% were re-classified BP Basal and &amp;lt;1% was BP Luminal. NCT pCR rates for ER-/Her2+/BP HER2 was 67% (64% with chemo/trastuzumab; 77% chemo/trastuzumab/pertuzumab, p=0.40) and significantly superior (p=0.026) to the 39% pCR rate in ER-/Her2+/BP Basal (p=0.026). Conclusions In the NBRST study, BP 80-gene functional subtype (based on mRNA expression and translation): 1. Re-classifies over half of all IHC/FISH ER+/Her2+ patients; 2. Predicts treatment response or resistance in Her2+ patients not segregated by conventional IHC/FISH classification and 3. Identifies ER+/Her2+ tumors that are sensitive to chemo/trastuzumab/pertuzumab but resistant to chemo/trastuzumab. Citation Format: Whitworth P, Beitsch P, Baron P, Beatty J, Pellicane JV, Murray MK, Dul CL, Mislowsky AM, Nash CH, Richards PD, Lee LA, Stork-Sloots L, de Snoo F, Untch S, Gittleman M, Akbari S, Rotkis MC. Three distinct HER2 subtypes identified by BluePrint 80-gene functional subtyping predict treatment-specific response in the prospective neo-adjuvant NBRST registry. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-05.