Abstract P1-05-07: Comprehensive genomic profiling of clinically malignant phyllodes tumors of the breast reveals frequent mutation of NF1 and other genes associated with PI3K and RAS pathway activation

Abstract

Abstract Background: Malignant or metastatic breast phyllodes tumors (MPT) are exceptionally rare, and the underlying genomic drivers are still being elucidated. Recent studies report frequent mutations in the RAS and PI3K pathways but have not commonly reported mutations in NF1. Comprehensive genomic profiling (CGP) can measure mutation load (TMB) and identifies all four classes of oncogenic alterations, including rearrangements and copy number loss that commonly affect tumor suppressors such as NF1, and can direct personalized treatment strategies. Methods: CGP using hybridization capture of 3,769 exons from up to 315 cancer-related genes and select introns of 28 genes commonly rearranged in cancer was applied to ≥50ng of DNA extracted from 21 consecutive MPT and sequenced to high, uniform median coverage (>400X). TMB was determined as mutations/Mb on 1.1 Mb of sequenced DNA. Results: The 21 MPT featured a median age of 51 yrs (range 14-70 yrs). CGP was performed on the primary MPT in 15 cases and on metastasis biopsies in 6 cases. TMB for all MPT was low (<10 mut/Mb), and all evaluable tumors (17/21) were microsatellite stable (MSS). The most commonly mutated genes were TP53 (57.1%), TERT (56.3%), NF1 (52.4%), MED12 (38.1%), CDKN2A/B (33.3%), and MLL2 (33.3%). 19/21 (90.5%) MPT harbored clinically relevant genomic alterations (CRGA) associated with therapies available on the market or under investigation in late stage clinical trials. Additional alterations in the PI3K/AKT/MTOR, RAS/RAF/MEK, and FGFR pathways were identified (see table); the PI3K/ATK/MTOR pathway was mutated in 10/21 (47.6%) of samples. Although CDKN2A/B loss was found in 6/11 tumors with NF1 mutation and only 1/10 NF1 wild-type samples, the co-occurrence was not significant (p<0.07). No significant correlation exists between the occurrence of NF1 mutations and mutation of MED12, TERT, the PI3K pathway, or other genes in the RAS/RAF pathway (NRAS, BRAF, EGFR). Targetable KIAA1549-BRAF or FGFR3-TACC3 fusions were identified in 2/21 (9.5%) tumors. Responses to targeted treatments will be presented. Conclusions: More than 90% of MPT feature CRGA, including alteration of NF1, which was by far the most common targetable GA in this study. 52.4% of MPT had alterations predicted to result in loss of NF1 activity. NF1 mutation does not significantly co-occur with mutations in any other gene or pathway commonly altered in MPT. Other tumors with underlying NF1 mutations have responded to the MEK inhibitor selumetinib, suggesting MEK inhibitors may be relevant for the treatment of MPT. Other targetable alterations, including known gene fusions, are common in MPT. Thus, MPT may benefit from combination targeted therapy, warranting further investigation in the clinical trial setting. Total Mutation NumberPathwayTotal Cases (n=21)Short VariantsCopy NumberRearrangementsRAS/RAF/MEK NF111 (52.4%)722BRAF3 (14.3%)301NRAS2 (9.5%)300PI3K/AKT/MTOR PIK3CA4 (19%)310PTEN4 (19%)130STK112 (9.5%)110AKT11 (4.8%)100FBXW71 (4.8%)001TSC21 (4.8%)010PIK3R11 (4.8%)100FGFR FGFR11 (4.8%)100FGFR31 (4.8%)001Other EGFR2 (9.5%)020BRCA21 (4.8%)100PDGFRA1 (4.8%)010KIT1 (4.8%)010 Citation Format: Gay LM, Elvin JA, Vergilio J-A, Suh J, Ramkissoon S, Ali S, Schrock A, Hirshfield K, Ganesan S, Miller VA, Stephens PJ, Ross JS. Comprehensive genomic profiling of clinically malignant phyllodes tumors of the breast reveals frequent mutation of NF1 and other genes associated with PI3K and RAS pathway activation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-07.