McCullar Brennan, Pandey Manjari, Yaghmour George, Hare Felicia, Patel Kruti, Stein Matthew, Feldman Rebecca, Chandler Jason C, Martin Michael G
University of Tennessee Health Science Center, Memphis, TN, USA.
Breast Cancer Res Treat. 2016 Jul;158(1):195-202. doi: 10.1007/s10549-016-3867-z. Epub 2016 Jun 21.
Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes. 19 patients with small cell carcinoma of the breast were identified, median age was 58 years (range 37-79) and 42 % had metastatic disease at presentation; for comparison, 58 patients with small cell carcinoma of the lung were identified (66 [36-86], 65 % metastatic). By immunohistochemistry, 31 % of small cell carcinoma of the breast patients expressed ER, 13 % expressed PR, and 16 % expressed AR; small cell carcinoma of the lung patients expressed ER 0 %, PR 2 %, and AR 6 %. Small cell carcinoma of the breast and small cell carcinoma of the lung patients had similar patterns of other immunohistochemical expression (0 v 0 % PDL1, 50 v 42 % PD1, and 77 v 95 % TOP2A, respectively). All small carcinoma of the breast and small cell carcinoma of the lung patients were negative for HER2 and cMET amplification by in situ hybridization. Next generation sequencing revealed TP53 mutations in 75 % of patients both with small cell carcinoma of the breast and small cell carcinoma of the lung and PIK3CA mutations in 33 % of small cell carcinoma of the breast patients but no small cell carcinoma of the lung patients (Fisher's exact test p = 0.005, OR 0.02 [0.00-0.52]). No other mutations were found in small cell carcinoma of the breast patients and no other mutation occurred in over 10 % of small cell carcinoma of the lung patients except RB1 in 19 % (p = 0.31). Small cell carcinoma of the breast is an aggressive tumor with few therapeutic options. Molecular profiling suggests many similarities between small cell carcinoma of the breast and small cell carcinoma of the lung with the exception an increased incidence of PIK3CA mutations in small cell carcinoma of the breast, which may have therapeutic implications.
乳腺小细胞癌是一种罕见的侵袭性乳腺癌，其预后极差[1]。为了确定可能的治疗靶点，我们对乳腺小细胞癌进行了全面的基因组分析。根据机构审查委员会（IRB）批准的方案，我们确定了2007年至2015年间由Caris生命科学公司进行分析的乳腺小细胞癌和肺小细胞癌患者。对肿瘤进行了多达25种免疫组织化学染色、cMET、EGFR、HER2、PIK3CA和TOP2A的原位杂交、二代测序以及47个基因的桑格测序。确定了19例乳腺小细胞癌患者，中位年龄为58岁（范围37 - 79岁），42%的患者初诊时已有转移；作为对照，确定了58例肺小细胞癌患者（66岁[36 - 86岁]，65%有转移）。通过免疫组织化学分析，31%的乳腺小细胞癌患者表达雌激素受体（ER），13%表达孕激素受体（PR），16%表达雄激素受体（AR）；肺小细胞癌患者中ER表达率为0%，PR为2%，AR为6%。乳腺小细胞癌和肺小细胞癌患者的其他免疫组织化学表达模式相似（程序性死亡受体配体1[PDL1]均为0%，程序性死亡蛋白1[PD1]分别为50%和42%，拓扑异构酶2A[TOP2A]分别为77%和95%）。所有乳腺小细胞癌和肺小细胞癌患者的HER2和cMET扩增原位杂交结果均为阴性。二代测序显示，75%的乳腺小细胞癌患者和肺小细胞癌患者存在TP53突变，33%的乳腺小细胞癌患者存在PIK3CA突变，而肺小细胞癌患者未出现（Fisher精确检验p = 0.005，比值比[OR]0.02[0.00 - 0.52]）。乳腺小细胞癌患者未发现其他突变，肺小细胞癌患者除19%存在RB1突变外，超过10%的患者未出现其他突变（p = 0.31）。乳腺小细胞癌是一种侵袭性肿瘤，治疗选择有限。分子分析表明，乳腺小细胞癌和肺小细胞癌之间存在许多相似之处，但乳腺小细胞癌中PIK3CA突变的发生率增加，这可能具有治疗意义。
