Abstract P6-07-06: Clinicopathologic characterization and comprehensive genomic profiling (CGP) of advanced breast cancer patients with fibroblast growth factor receptor (FGFR) alterations
Authors: Alvarez RH , Thomas JW , Kramer K , Niu J , Ahn E , McKnight JE , Dhillon N , Pabbathi H , Johnson AT , Wang K , Ross JS , Miller VA , Stephens PJ , Daneker GW , Ali S , Markman M 
Published: May 2016

Abstract
BACKGROUND: FGFR family members are infrequently mutated but are frequently overexpressed in breast cancer and often accompanied by increased, or altered, expression of FGF ligands. In this retrospective study, we reviewed a large series of FGFR altered breast cancer cases that received comprehensive genomic profiling (CGP) in the course of clinical care.
MATERIAL AND METHODS: CGP was performed on hybridization-captures, adaptor ligation-based libraries using DNA extracted from 40 μm formalin-fixed paraffin-embedded (FFPE) section cut at 10 μm performed in a CLIA-certified lab (Foundation Medicine, Inc.). The pathologic diagnosis of each case was confirmed on routine hematoxylin and eosin-stained slides, and all samples forwarded for DNA extraction contained a minimum of 20% of DNA derived from tumor cells. The FoundationOne test sequences the full coding regions of up to 315 cancer-related genes, and up to 28 genes that are frequently altered in cancer to detect all classes of genomic alterations including base substitutions, indels, copy-number alterations (CNA), and fusions/rearrangements. The average depth of coverage is greater than 600X. The genomic profiles of 2,617 patients with diverse advanced malignancies who were evaluated at Cancer Treatment Centers of America between 12/24/12 and 03/11/15 were reviewed. 176 FGFR alterations (7.8%) were detected, of which 76 (43.5%) were found in breast cancer cases out of 434 (16.5%). The study was carried out in accordance with WIRB Institutional Review Board.
RESULTS: A total of 76 female breast cancer patients, having a median age 50 (range, 28-69), with FGFR alterations were reviewed. All patients had metastatic/relapsed advanced breast cancer. 54 patients were Estrogen Receptor-positive (70%), and 15 were HER2+ (20%). 6 patients had gBRCA deleterious mutations. 84% of the samples (n=67) tissue block were analyzed, and the anatomic sites represented by the samples were 24 breast primary tumor (31%), 15 liver (19%), 10 lymph nodes (13%), and other sites (37%). The median number of chemotherapies cycles was 4 (range, 1-12), and the median time to metastasis was 31 months (range, 0-175). At the time of this report, 31 patients (40%) were deceased. 79 FGFR gene alterations were identified in 76 patients, including FGFR1 (65), FGFR2 (6), FGFR3 (2), and FGFR4 (4), with all but 7 of these being amplifications. The most co-existent altered gene was TP53 (66%), and other altered genes included PIK3CA (37%), MYC (28%), FGF3/4/19 (17%), CCND1 (17%), and CCNE1 (16%). The subset of co-amplified FGF3/4/19 and FGFR amplified patients were all (7) ER+ except for 1 patient.
CONCLUSIONS: FGFR genomic alterations in breast cancer patients are predominantly amplifications and are most commonly observed in ER+ patients. Further review of treatment history will be performed to evaluate the hypothesis that alterations of FGFR is a modifier of response to endocrine therapy, and co-amplified FGF3/4/19 and FGFR breast cancer cases may be a distinct clinic-pathologic entity. Any patients in this series initiated on anti-FGFR targeted therapy will also be reported.
Citation Format: Alvarez RH, Thomas JW, Kramer K, Niu J, Ahn E, McKnight JE, Dhillon N, Pabbathi H, Johnson AT, Wang K, Ross JS, Miller VA, Stephens PJ, Daneker GW, Ali S, Markman M. Clinicopathologic characterization and comprehensive genomic profiling (CGP) of advanced breast cancer patients with fibroblast growth factor receptor (FGFR) alterations. [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 P6-07-06.