Abstract P4-14-29: One-third of HER2 positive patients have 80-gene luminal subtype that is resistant to chemo-trastuzumab but sensitive to chemo-trastuzumab-pertuzumab: Critical implications for the adjuvant setting from the NBRST phase 4 neoadjuvant study
Authors: Beitsch P , Whitworth P , Baron P , Beatty J , Pellicane JV , Murray MK , Dul C , Mislowsky AM , Nash CH , Richards PD , Lee LA , Stork-Sloots L , de Snoo F , Untch S , Gittleman M , Akbari S , Rotkis MC 
Published: May 2016

Abstract
Background
The phase 4 Neo-adjuvant Breast Registry Symphony Trial (NBRST) enrolled over 1,000 US patients between June 2011 and December 2014. The aim of NBRST study is to compare chemo-sensitivity as defined by pathological Complete Response (pCR) using the 80-gene BluePrint (BP) functional subtype profile vs. conventional IHC/FISH subtyping. Treatment was at the discretion of the physician utilizing standard NCCN regimens. Pertuzumab, a monoclonal antibody, inhibits the dimerization of HER2 with other HER receptors. Pertuzumab received US FDA approval for the neo-adjuvant treatment of HER2-positive breast cancer in September 2013. Essentially all patients with HER2 positive cancers were treated with chemotherapy + trastuzumab and after this date pertuzumab was added, creating 2 distinct groups of Her2-treated patients.
The aim of the current analysis is to compare the pCR rate of chemo-trastuzumab (c-t) vs chemo-trastuzumab plus pertuzumab (c-t-p) by conventional and 80-gene BP functional subtype. 80-gene BP functional subtype was derived by supervised cluster analysis for concordant mRNA and protein expression.
Methods
The current analysis includes women from the NBRST study, with histologically proven breast cancer, who received neo-adjuvant treatment, had 80-gene subtyping and provided written informed consent. Pathological assessment of HER2 was performed according to ASCO CAP guidelines at the time of diagnosis. 80-gene BluePrint (BP) classifies patients into Luminal, HER2 or Basal-type. pCR is defined as T0/isN0. All pCRs were verified with a de-identified copy of the surgical pathology report. Fisher's exact test was used to compare pCR rates within different subgroups.
Results
286 IHC/FISH HER2+ patients received c-t (175) or c-t-p (111). Of these 80-gene BP subtype classified 53% as HER2-type, 33% as Luminal-type and 14% as Basal-type. 64% were ER positive.
The pCR rates and p-values within different subgroups of clinical HER2+ patients are provided in the table below.
c-tc-t-p (n)pCR ratep-valueTotal (n=286)41%57%0.01BP HER2 (153)58%73%0.06 BP Luminal (93) 6% 39% 0.0002BP Basal (40)45%1.0IHC/FISH HER2+/ER+ (183)31%53%0.003IHC/FISH HER2+/ER- (103)59%64%0.68
Conclusions
One-third of ASCO/CAP Her2+ patients had 80-gene BP Luminal subtype and demonstrated resistance to c-t (pCR 6%). Addition of Pertuzumab overcame resistance in this group (pCR 39%). This finding in the neoadjuvant setting suggests a substantial potential benefit in the adjuvant setting and thus an urgent need to consider treatment in at-risk patients as well as confirmatory tissue analysis from independently reported trials.
Citation Format: Beitsch P, Whitworth P, Baron P, Beatty J, Pellicane JV, Murray MK, Dul C, Mislowsky AM, Nash CH, Richards PD, Lee LA, Stork-Sloots L, de Snoo F, Untch S, Gittleman M, Akbari S, Rotkis MC. One-third of HER2 positive patients have 80-gene luminal subtype that is resistant to chemo-trastuzumab but sensitive to chemo-trastuzumab-pertuzumab: Critical implications for the adjuvant setting from the NBRST phase 4 neoadjuvant study. [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 P4-14-29.