Angela Mislowsky

Functional subtyping with BluePrint 80-gene profile to identify distinct triple-positive subtypes with and without trastuzumab/chemosensitivity.

114 Background: Classification by molecular subtype can aid in the selection of therapy for patients with breast cancer. However at present, the methodology for molecular subtyping is not standardized. The aim of the prospective NBRST study is to compare chemosensitivity as defined by pathological Complete Response (pCR) using the 80-gene BluePrint (BP) functional subtype profile vs. conventional IHC/FISH subtyping. METHODS The study includes women aged 18-90 with histologically proven breast cancer, written informed consent, no excision biopsy or axillary dissection, and no prior therapy for breast cancer. Neo-adjuvant Chemotherapy (NCT) was at the discretion of the physician adhering to NCCN approved or other peer-reviewed regimens. BP in combination with MammaPrint classifies patients into 4 molecular subgroups: Luminal A, Luminal B, HER2 and Basal. RESULTS 721 patients had definitive surgery. 58/335 (17%) IHC/FISH HR+/HER2- patients were re-classified by BP as Basal (57) or HER2 (1). 92/222 (41%) IHC/FISH HER2+ patients were re-classified as BP Luminal (67) or BP Basal (25). 7/164 (4%) IHC/FISH triple negative (TN) patients were re-classified as BP Luminal (5) or BP HER2 (2). NCT pCR rates were 3% in Luminal A and 9% in Luminal B patients versus 10% pCR in IHC/FISH luminal patients. The NCT pCR rate was 54% in BP HER2 patients. This is significantly superior (p = 0.02) to the pCR rate in IHC/FISH HER2+ patients (40%). BP Basal and IHC/FISH TN had a pCR rate of 35%. Functional BP subtyping divided the 137 IHC/FISH triple positive patients into two major subgroups: BP Luminal (n = 66, pCR = 11%) and BP HER2 (n = 60, pCR = 45%).11 patients were re-classified as BP Basal with pCR = 45%. CONCLUSIONS Molecular subtyping using BP leads to a reclassification of 23% of tumors. The re-classification is most prominent in classically assessed triple positive patients where 48% of patients are re-assigned to the less responsive BP Luminal-type group vs. 44% of patients assigned to the responsive BP HER2-type group. These findings confirm the more accurate identification of molecular subgroups for treatment decision by BluePrint functional subtype classifier. CLINICAL TRIAL INFORMATION NCT01479101.

Abstract P4-14-10: Pertuzumab overcomes chemotherapy/trastuzumab resistance in ER+/Her2+ tumors classified as luminal functional subtype by the 80-gene BluePrint assay in the prospective neo-adjuvant breast registry symphony trial (NBRST)

Background The prospective Neo-adjuvant Breast Registry Symphony Trial (NBRST) enrolled over 1000 US patients between June 2011 and December 2014. The aim of NBRST study is to compare chemosensitivity as defined by pathological Complete Response (pCR) using the 80-gene BluePrint 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 trastuzumab (H) vs trastuzumab and pertuzumab (H + P) by conventional and BluePrint functional subtype. Methods The current analysis includes women from the NBRST study, with histologically proven breast cancer, who received neo-adjuvant chemotherapy plus H or H + P and who provided written informed consent. Pathological assessment of Her2 was done according to ASCO CAP guidelines at the time of diagnosis. 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. Fisher9s exact test was used to compare pCR rates within different subgroups. Results 252 IHC/FISH Her2+ patients received H (166) or H + P (86). The median age was 53 (range 23-81). 8% was stage I, 68% stage II and 24% stage III. 65% were ER positive. BP classified 55% of patients as HER2, 32% as Luminal, and 14% as Basal-type. The pCR rates and p-values within different subgroups of clinical Her2+ patients are provided in the table below. Conclusions Addition of pertuzumab to trastuzumab significantly increased response rate in ER+/Her2+, BP HER2 and BP Luminal patients but not in ER-negative and BP Basal patients. Pertuzumab overcame resistance to NCT/trastuzumab in a substantial proportion of the IHC/FISH Her2+/BP Luminal subgroup; indicated by a significantly increased pCR rate. Citation Format: Peter B, Pat W, Paul B, Jennifer B, Pellicane JV, Murray MK, Dul CL, Mislowsky AM, Nash CH, Richards PD, Lee LL, Stork-Sloots L, de Snoo F, Untch S, Gittleman M, Akbari S, Rotkis MC. Pertuzumab overcomes chemotherapy/trastuzumab resistance in ER+/Her2+ tumors classified as luminal functional subtype by the 80-gene BluePrint assay in the prospective neo-adjuvant breast registry symphony trial (NBRST). [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 P4-14-10.