Novel Mutations in Neuroendocrine Carcinoma of the Breast: Possible Therapeutic Targets
Morgan Ballard, Daphne Ang, Carol Beadling, Andrea Warrick, Amy Schilling, Rebecca O'Gara, Marina Pukay, Robert West, Christopher Corless, Megan Troxell. Oregon Health & Science University, Portland, OR; Stanford, Stanford, CA
Background: Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2-5% of diagnosed breast cancers. Literature on pathogenesis, prognosis and treatment options is extremely limited. Recent data suggest that neuroendocrine breast cancer may have a relatively poor prognosis. Mutational profiling of invasive ductal breast cancers has yielded potential targets for directed cancer therapy, yet most studies have not included neuroendocrine carcinomas. In this study we sought to evaluate the mutational profile of this potentially aggressive breast cancer variant.
Design: Twelve cases of neuroendocrine breast carcinoma were identified from pathology archives, and also by screening a tissue microarray with synaptophysin and chromogranin. Stains were then confirmed on full tissue sections, and cases with > 50% neuroendocrine differentiation, as defined by WHO criteria, were included in the study; tumors with a mucinous component were excluded. In four cases metastases were tested. Using H&E stained slides as a guide, lesional tissue was punched from paraffin embedded tissue blocks; genomic DNA was extracted and screened for a panel of known hotspot mutations using PCR and mass spectroscopy analysis (SequenomMassARRAY). This mutation panel screens 643 point mutations in 53 genes, including PIK3CA, AKT1, FGFR1/2/3/4 and KDR. Mutations were confirmed by Sanger sequencing.
Results: Of the 12 cases, mutations were identified in 3 tumors, including 2 with PIK3CA exon 9 E542K mutations (both metastatic), and one with a KDR exon 24 A1065T mutation. One of the tumors with a PIK3CA mutation also harbored a FGFR4 exon 13 V550M mutation.
Conclusions: In this small study, 17% of neuroendocrine breast carcinomas had PIK3CA mutations, a mutation not uncommon in other breast carcinomas. Interestingly, both FGFR4 and KDR mutations were also identified. Mutations in fibroblast growth factor receptors such as FGFR4 are exceedingly rare in the breast cancer literature, but have been reported in a subset of pediatric rhabdomyosarcomas. KDR (VEGFR2) encodes a receptor tyrosine kinase involved in angiogenesis. Activating KDR mutations have been reported in angiosarcomas and non-small cell lung cancers; the A1065T mutation identified in this study has previously been shown to be sensitive to VEGFR kinase inhibitors. Our findings demonstrate the utility of broad-based genotyping in the study of rare tumors such as neuroendocrine breast cancer. Further studies are needed to investigate potential roles for PIK3CA, FGFR4 and KDR in driving growth of these cancers.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 63, Tuesday Afternoon