Abstract P6-14-02: Genomic profiling by FoundationOne® analysis of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations (GA)
Authors: Palma Norma A , Ali Siraj M , Wang Kai , Chmeleiki Juliann , Palmer Gary , Morosini Deborah , Ross Jeffrey S , Miller Vincent A , Stephens Phil J , Cristofannilli Massimo 
Published: May 2015

Abstract
Background: Inflammatory breast cancer (IBC) is a distinct clinicopathologic entity that carries a worse prognosis relative to non-IBC breast cancer even when matched for biomarkers (ER/PR/HER2). Genomic profiling of IBC cases may identify alterations that suggest response to targeted therapies, but is best implemented by an integrated NGS assay capable of detecting all classes of genomic alterations (GA).
Methods: Hybridization capture of 3769 exons of 236 cancer-related genes and 47 introns from 19 genes that are frequently rearranged in cancer were fully sequenced to high, uniform coverage from a commercial CLIA-certified laboratory (Foundation Medicine).
Results: Of 2,208 clinical breast cancer cases assayed, 55 IBC cases were identified, and of the 50 cases for which hormone receptor and HER2/neu status were know, 34% were ER-/PR-/HER2- (TNBC). IBC cases harbored 274 GA with an average of 5.0 GA/tumor (range 1-15). At least one alteration associated with an FDA approved therapy or clinical trial was identified in 53/55 (96%) of cases, yielding an average of 2.6 clinically relevant GA/case. Genes most frequently altered were TP53 (60%), MYC (31%), PIK3CA (25%), ERBB2 (20%), FGFR1 (18%) and PTEN (16%). MYC amplifications were present in 24% of the 2,208 clinical breast carcinoma cases. In the TNBC subset of IBC, 8/19 (42%) pt samples showed MYC amplification (median copy number 8X, range 7-20) as compared to 9/36 (25%) in non-TNBC pt samples (median copy number 7X, range 6-21).
Within this prospective series, treatment decisions were made based on FoundationOne results. A58-year old pt with likely secondary IBC harbored two ERBB2 activating base substitutions (V777L and S310F), but without amplification of ERBB2), and had durable response to lapatinib (Ali et al. JCO 2014). In another case, a 53 year old pt presented with ERBB2-amplified IBC now refractory to HER2-targeted therapy. FoundationOne testing revealed an activating EGFR mutation (L858R) as well as the previously described ERBB2 amplification, suggesting that the EGFR alteration may underlie the acquired resistance. The pt responded to erlotinib monotherapy for 8 months. (Ali et al. Clin Br Ca, 2013). Clinical follow-up for additional patients is ongoing.
Conclusions: 96% of IBC cases harbored at least one alteration that suggests responsiveness to agents that are FDA approved or being studied in clinical trials. IBC cases also frequently had MYC amplifications (31%), but this may reflect a high percentage of TNBC-IBC cases with MYC amplifications (42%) in this series. Given the limited treatment options and poor prognosis of patients with metastatic IBC, the FoundationOne assay with comprehensive NGS-based genomic profiling has the potential to identify new treatment paradigms and address an unmet clinical need for this disease.
Citation Format: Norma A Palma, Siraj M Ali, Kai Wang, Juliann Chmeleiki, Gary Palmer, Deborah Morosini, Jeffrey S Ross, Vincent A Miller, Phil J Stephens, Massimo Cristofannilli. Genomic profiling by FoundationOne® analysis of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations (GA) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-14-02.