Abstract PD3-01: BluePrint performance in predicting pertuzumab benefit in genomically HER2-positive patients: A biomarker analysis of the APHINITY trial
Authors: Krop Ian , Mittempergher Lorenza , Paulson Joseph , Andre Fabrice , Bonnefoi Hervé , Loi Sherene , Loibl Sibylle , Gelber Richard D , Caballero Carmela , Fumagalli Debora , Dreezen Christa , Bernards Rene , van ‘t Veer Laura , Piccart Martine 
Published: February 2021

Abstract
BACKGROUND:APHINITY is a phase III study (NCT01358877) which included 4805 patients (pts) with histologically centrally confirmed HER2+ early breast cancer (EBC) randomized to standard adjuvant chemotherapy (C) plus trastuzumab (T), plus either pertuzumab (P) or placebo1 for 1 year. With median follow up of 45 months, the primary analysis showed significant invasive disease-free survival (iDFS) benefit at 3 years with a hazard ratio (HR) of 0.81 (95% CI: 0.66-1.00; P = 0.045) for the addition of P to C/T1. BluePrint (BP) is an 80-gene molecular subtyping test that classifies EBC into functional basal, luminal and HER2 BP-subtypes3 according to gene expression. Previous studies showed that this genomic test can reclassify HER2+ EBC (as determined by IHC/FISH) into basal, luminal or HER2 BP-subtypes4. Recently, it was revealed that a smaller proportion of breast tumours may display two functionally activated BP pathways (BP dual activated subtypes, of which one is usually less pronounced), whereas the majority has clearly only one activated functional BP pathway (BP single activated subtypes)5. We hypothesized that BluePrint could identify a subgroup of patients within the APHINITY population who derived additional benefit from the addition of P to C/T.METHODS:Genomic results were obtained using RNA sequencing (RNAseq) data6 from a subset of APHINITY pts (N=970) derived from a 1023 unique patients nested case-control (NCC) set where event and matched controls were selected (1 iDFS event matched to 3 controls from the primary analysis database with 45 months median follow-up). Raw read counts were log2 transformed followed by quantile normalization prior to genomic assessment. BP subtype scores were calculated equally to the standard microarray diagnostic testing and calibrated based on a bridge analysis with matched microarray and RNAseq data. IDFS outcome based on genomic subtype and the treatment arm (P+C/T vs placebo + C/T) was analysed. Results are reported descriptively with 95% CIs.RESULTS:From the patients within the NCC subset, BP subtype testing classified the 970 pts as basal, n=210 (22%); luminal, n=485 (50%) and HER2, 275 (28%) subtypes, an expected finding since the majority were hormone receptor positive (N=598/970, 62%). Further dissection of the BP results showed single activated subtype in 123 of 210 (59%) basal, 413 of 485 (85%) luminal and 139 of 275 (51%) of HER2 subtype cancers.
After NCC-inverse probability weighted corrected multivariate Cox regression analysis, no significant differences in iDFS were observed among the different genomic subtypes. A greater benefit with the addition of P to T/C was suggested in the ‘single activated’ HER2 BP-subtype compared with other groups (single HER2 HR=0.56, 95% CI 0.27-1.15, single basal HR=0.89, 95% CI 0.44-1.79 and single luminal HR=0.93, 95% CI 0.61-1.41).
CONCLUSIONS:In this exploratory analysis, HER2+ tumors with a single transcriptional HER2 activated pathway showed a trend for greater benefit from pertuzumab than tumors in which multiple mitogenic pathways are activated. Further research is ongoing to confirm these findings.
References1.von Minckwitz G et al, NEMJ, 20172.Piccart M et al, SABCS, 20193.Krijgsman O et al, BCRT, 20114.Whitworth P et al, ASO, 20145.Kuilman M et al, EBCC12, 20206.Krop IE et al, ASCO, 2020
Citation Format: Ian Krop, Lorenza Mittempergher, Joseph Paulson, Fabrice Andre, Hervé Bonnefoi, Sherene Loi, Sibylle Loibl, Richard D Gelber, Carmela Caballero, Debora Fumagalli, Christa Dreezen, Rene Bernards, Laura van ‘t Veer, Martine Piccart. BluePrint performance in predicting pertuzumab benefit in genomically HER2-positive patients: A biomarker analysis of the APHINITY trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-01.