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Novel mutations in neuroendocrine carcinoma of the breast: possible therapeutic targets
Daphne Ang1, Morgan Ballard, Carol Beadling
1*Department of Pathology ‡Knight Cancer Institute, Oregon Health & Science University, Portland, OR †Department of Pathology, Stanford University, Stanford, CA.
Abstract:
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.
Insights
Neuroendocrine breast cancer, a rare and aggressive type, was analyzed for mutations. Researchers identified actionable mutations in PIK3CA, FGFR, RAS, and KDR genes, suggesting new therapeutic targets for this cancer.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Primary neuroendocrine carcinoma of the breast is a rare breast cancer subtype (2-5% of cases) with potentially aggressive behavior.
- Previous mutational profiling studies of breast cancer have largely excluded neuroendocrine carcinomas, limiting targeted therapy development for this group.
- A tissue microarray screen revealed a prevalence of 2.4% for neuroendocrine breast carcinoma, with some cases exhibiting lobular morphology.
Purpose of the Study:
- To investigate the mutational landscape of primary or metastatic neuroendocrine breast carcinomas.
- To identify potential therapeutic targets by screening for mutations in common cancer genes.
- To assess the utility of broad-based genotyping in studying rare tumor types like neuroendocrine breast cancer.
Main Methods:
- Screening of 372 breast tissues identified a 2.4% prevalence of neuroendocrine breast carcinoma.
- Genomic analysis of 15 primary or metastatic neuroendocrine breast carcinomas (excluding papillary and mucinous types) was performed.
- Mutations were detected using polymerase chain reaction-mass spectroscopy (targeting 643 hotspot mutations across 53 genes) and semiconductor-based next-generation sequencing (37 genes).
Main Results:
- Mutations were identified in 5 out of 15 (33.3%) neuroendocrine breast carcinoma tumors.
- Three tumors harbored PIK3CA exon 9 E542K mutations; two of these also had mutations in FGFR family members (FGFR1 P126S, FGFR4 V550M).
- Single mutations were found in KDR (A1065T) and HRAS (G12A). FGFR, RAS, and KDR mutations are rare in breast cancer literature.
Conclusions:
- The study identified actionable mutations in PIK3CA, FGFR, RAS, and KDR genes within neuroendocrine breast carcinomas.
- These findings highlight the potential for targeted therapies, including VEGFR and fibroblast growth factor receptor inhibitors, for this rare cancer.
- Broad-based genotyping is a valuable approach for uncovering therapeutic targets in rare malignancies like neuroendocrine breast cancer.
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