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Novel Mutations in Neuroendocrine Carcinoma of the Breast

Possible Therapeutic Targets

Ang, Daphne MD*; Ballard, Morgan MD*,†; Beadling, Carol PhD; Warrick, Andrea BS; Schilling, Amy BS; O’Gara, Rebecca AAAS; Pukay, Marina BS; Neff, Tanaya L. MS; West, Robert B. MD, PhD; Corless, Christopher L. MD, PhD*,‡; Troxell, Megan L. MD, PhD*,‡

Applied Immunohistochemistry & Molecular Morphology: February 2015 - Volume 23 - Issue 2 - p 97–103
doi: 10.1097/PDM.0b013e3182a40fd1
Research Articles
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Primary neuroendocrine carcinoma of the breast is a rare variant, accounting for only 2% to 5% of diagnosed breast cancers, and may have relatively aggressive behavior. Mutational profiling of invasive ductal breast cancers has yielded potential targets for directed cancer therapy, yet most studies have not included neuroendocrine carcinomas. In a tissue microarray screen, we found a 2.4% prevalence (9/372) of neuroendocrine breast carcinoma, including several with lobular morphology. We then screened primary or metastatic neuroendocrine breast carcinomas (excluding papillary and mucinous) for mutations in common cancer genes using polymerase chain reaction-mass spectroscopy (643 hotspot mutations across 53 genes), or semiconductor-based next-generation sequencing analysis (37 genes). Mutations were identified in 5 of 15 tumors, including 3 with PIK3CA exon 9 E542K mutations, 2 of which also harbored point mutations in FGFR family members (FGFR1 P126S, FGFR4 V550M). Single mutations were found in each of KDR (A1065T) and HRAS (G12A). PIK3CA mutations are common in other types of breast carcinoma. However, FGFR and RAS family mutations are exceedingly rare in the breast cancer literature. Likewise, activating mutations in the receptor tyrosine kinase KDR (VEGFR2) have been reported in angiosarcomas and non–small cell lung cancers; the KDR A1065T mutation is reported to be sensitive to VEGFR kinase inhibitors, and fibroblast growth factor receptor inhibitors are in trials. Our findings demonstrate the utility of broad-based genotyping in the study of rare tumors such as neuroendocrine breast cancer.

*Department of Pathology

Knight Cancer Institute, Oregon Health & Science University, Portland, OR

Department of Pathology, Stanford University, Stanford, CA

D.A. and M.B. contributed equally.

A portion of these data were presented in abstract form at the USCAP 2013 annual meeting, March 5, 2013, Baltimore, MD.

Supported by a grant from Susan G. Komen for the Cure (M.L.T.).

The authors declare no conflict of interest.

Reprints: Megan L. Troxell, MD, PhD, Department of Pathology, Oregon Health & Science University, L471, 3181 SW Sam Jackson Park Rd, Portland, OR 97239 (e-mail: troxellm@ohsu.edu).

Received June 29, 2013

Accepted July 8, 2013

© 2015 Lippincott Williams & Wilkins, Inc.