Ang Daphne, Ballard Morgan, Beadling Carol, Warrick Andrea, Schilling Amy, O'Gara Rebecca, Pukay Marina, Neff Tanaya L, West Robert B, Corless Christopher L, Troxell Megan L
*Department of Pathology ‡Knight Cancer Institute, Oregon Health & Science University, Portland, OR †Department of Pathology, Stanford University, Stanford, CA.
Appl Immunohistochem Mol Morphol. 2015 Feb;23(2):97-103. doi: 10.1097/PDM.0b013e3182a40fd1.
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.
乳腺原发性神经内分泌癌是一种罕见的变体，仅占确诊乳腺癌的2%至5%，且可能具有相对侵袭性的行为。浸润性导管癌的突变谱分析已产生了定向癌症治疗的潜在靶点，但大多数研究并未纳入神经内分泌癌。在一项组织微阵列筛查中，我们发现神经内分泌乳腺癌的患病率为2.4%（9/372），包括几例具有小叶形态的病例。然后，我们使用聚合酶链反应 - 质谱法（对53个基因的643个热点突变）或基于半导体的下一代测序分析（37个基因），对原发性或转移性神经内分泌乳腺癌（不包括乳头状和黏液性）进行常见癌症基因的突变筛查。在15个肿瘤中的5个中发现了突变，其中3个具有PIK3CA外显子9 E542K突变，其中2个在FGFR家族成员中也存在点突变（FGFR1 P126S、FGFR4 V550M）。在KDR（A1065T）和HRAS（G12A）中各发现了单个突变。PIK3CA突变在其他类型的乳腺癌中很常见。然而，FGFR和RAS家族突变在乳腺癌文献中极为罕见。同样，受体酪氨酸激酶KDR（VEGFR2）的激活突变已在血管肉瘤和非小细胞肺癌中报道；据报道，KDR A1065T突变对VEGFR激酶抑制剂敏感，而成纤维细胞生长因子受体抑制剂正在进行试验。我们的研究结果证明了广泛基因分型在神经内分泌乳腺癌等罕见肿瘤研究中的实用性。
