Abstract P2-12-01: Comprehensive genomic profiling of 34 cases of breast angiosarcoma
Authors: Ravi V , Madison R , Schrock AB , Cote G , Millis S , Alvarez R , Choy E , Katz D , Chung J , Gay L , Miller VA , Ross JS , Ali SM , Schnitt S 
Published: March 2017

Background: Angiosarcoma of the breast (BAS) is a rare but lethal neoplasia, either arising de novo or secondary to radiation therapy, with incidence of the latter disease increasing. We queried a database of more than 70,000 advanced cancer patients assayed with comprehensive genomic profiling (CGP) in the course of clinical care to uncover the frequency, type and associated genomic alterations (GA) in BAS and to highlight possible routes to benefit from targeted therapy.

Methods: CGP was performed for 34 BAS cases using a hybrid-capture, adaptor ligation based next generation sequencing assay of up to 315 genes to a mean coverage depth of &gt;500X. The results were analyzed for base substitutions, short insertions and deletions, selected rearrangements, and copy number changes. RNA sequencing for 265 genes was also performed for 24 cases. Limited clinical histories from submitted pathology reports were reviewed under IRB permission.

Results: Clinical specimens from 34 BAS patients, all females, were assayed. The cases harbored 87 total GA for a mean of 2.59 per case, 25% of which were copy number amplifications. The most commonly altered genes were MYC (41%, 14/34), PIK3CA (26%, 9/34), and KDR (26%, 9/34). All MYC alterations were amplifications with a mean copy number of 39, and alterations in other MYC family members (MYCN and MYCL1) were not observed. KDR was recurrently altered as T771R (7/9) and T771K (1/9) and amplified in one case (1/9).

MYC and KDR alterations were mutually exclusive (p&lt;0.0001). 6/14 MYC amplified cases had prior histories of breast carcinoma, with 3/6 noted as being treated with radiation therapy. For the remainder of MYC amplified cases (8/14), no relevant clinical history was available.

Two cases harboring gene fusions were identified including CIC-MEGF8 and NTRK1-PEAR1. Two rearrangements of potential functional significance including CIC-DEDD2 and HT-ALK (exon1 HT - exon5-29 ALK including kinase domain) were also observed. The case harboring HT-ALK also had MYC amplification and known prior radiation therapy. Two other MYC amplified cases also harbored targetable kinase alterations, including FLT4 amplification (described as targetable in Ravi et al JNCCN 2016) and FGFR3 S249C, a known activating mutation.

Conclusions: MYC amplification defines over 40% (14/34) of advanced BAS cases. Of MYC amplified cases, 28% (4/14) harbored targetable alterations of tyrosine kinases including a potential novel ALK fusion. FLT4 amplification only co-occurred with MYC amplification, but this result was not statistically significant in this small series. KDR and MYC alteration were mutually exclusive, and 45% of non-MYC altered cases (9/20) harbored KDR alterations, which were predominantly mutations of T771. Further clinico-pathologic correlation, particularly history of radiation therapy, will be explored in this series, as well defining BAS that harbor neither MYC nor KDR alterations.

Citation Format: Ravi V, Madison R, Schrock AB, Cote G, Millis S, Alvarez R, Choy E, Katz D, Chung J, Gay L, Miller VA, Ross JS, Ali SM, Schnitt S. Comprehensive genomic profiling of 34 cases of breast angiosarcoma [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 P2-12-01.