title: Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations.
abstract: Inflammatory breast cancer (IBC) is a distinct clinicopathologic entity that carries a worse prognosis relative to non-IBC breast cancer even when matched for standard biomarkers (ER/PR/HER2). The objective of this study was to identify opportunities for benefit from targeted therapy, which are not currently identifiable in the standard workup for advanced breast cancer. Comprehensive genomic profiling on 53 IBC formalin-fixed paraffin-embedded specimens (mean, 800× + coverage) using the hybrid capture-based FoundationOne assay. Academic and community oncology clinics. From a series of 2208 clinical cases of advanced/refractory invasive breast cancers, 53 cases with IBC were identified. The presence of clinically relevant genomic alterations (CRGA) in IBC and responses to targeted therapies. CRGA were defined as genomic alterations (GA) associated with on label targeted therapies and targeted therapies in mechanism-driven clinical trials. For the 44 IBCs with available biomarker data, 19 (39 %) were ER-/PR-/HER2- (triple-negative breast cancer, TNBC). For patients in which the clinical HER2 status was known, 11 (25 %) were HER2+ with complete (100 %) concordance with ERBB2 (HER2) amplification detected by the CGP assay. The 53 sequenced IBC cases harbored a total of 266 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 51/53 (96 %) of cases with an average of 2.6 CRGA/case. The most frequently altered genes were TP53 (62 %), MYC (32 %), PIK3CA (28 %), ERBB2 (26 %), FGFR1 (17 %), BRCA2 (15 %), and PTEN (15 %). In the TNBC subset of IBC, 8/19 (42 %) showed MYC amplification (median copy number 8X, range 7-20) as compared to 9/32 (28 %) in non-TNBC IBC (median copy number 7X, range 6-21). Comprehensive genomic profiling uncovered a high frequency of GA in IBC with 96 % of cases harboring at least 1 CRGA. The clinical benefit of selected targeted therapies in individual IBC cases suggests that a further study of CGP in IBC is warranted.
authors.affiliation: Foundation Medicine, Cambridge, MA, USA. rossj@mail.amc.edu.|Department of Pathology, Albany Medical College, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA. rossj@mail.amc.edu.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Cambridge, MA, USA. sali@foundationmedicine.com.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Depinder
authors.initials: D
authors.lastname: Khaira
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Norma A
authors.initials: NA
authors.lastname: Palma
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Palmer
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Thomas Jefferson University Cancer Center, Philadelphia, PA, USA.
authors.forename: Sandra V
authors.initials: SV
authors.lastname: Fernandez
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Thomas Jefferson University Cancer Center, Philadelphia, PA, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
mesh_terms: D005091:Exons; D005260:Female; D015894:Genome, Human; D042822:Genomic Instability / Q000235:genetics; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins
keywords: Comprehensive genomic profiling; EGFR; ERBB2; Inflammatory breast cancer; MYC; NGS