Palisoul Marguerite L, Mullen Mary M, Feldman Rebecca, Thaker Premal H
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St Louis, MO, United States.
Department of Solid Tumor Oncology, Carolinas HealthCare System, Levine Cancer Institute, Charlotte, NC, United States.
Gynecol Oncol. 2017 Aug;146(2):305-313. doi: 10.1016/j.ygyno.2017.05.011. Epub 2017 May 20.
To identify molecular alterations that contribute to vulvar cancer pathogenesis with the intent of identifying molecular targets for treatment.
After retrospective analysis of a database of molecularly-profiled gynecologic cancer patients, 149 vulvar cancer patients were included and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (C/FISH). A Fisher's exact test was used when indicated with a p-value≤0.05 indicating significance.
Median age was 65. 85% had squamous cell carcinoma (SCC) and 15% adenocarcinoma (ADC) histologies. 46% had metastatic (Stage IV) disease. Targeted hot-spot sequencing identified variants in the following genes: TP53 (33%), PIK3CA/BRCA2 (8%, 10%, respectively), HRAS/FBXW7 (5%, 4%, respectively) and ERBB4/GNAS (3%, 3% respectively). Mutations in AKT1, ATM, FGFR2, KRAS, NRAS (n=1, respectively) and BRAF (n=2) also occurred. Specific protein changes for targetable genes included clinically pathogenic mutations commonly found in other cancers (e.g. PIK3CA: exon 9 [E545K], RAS: G13D, Q61L, BRCA2: S1667X, BRAF: R443T, FBXW7: E471fs, etc.). Drug targets identified by IHC and ISH methodologies include cMET (32% IHC, 2% ISH), PDL1 (18%), PTEN loss (56%), HER2 (4% IHC, 2% ISH) and hormone receptors (AR, 4%; ER, 11%; PR, 4%). Comparisons between SCC and ADC identified differential rates for AR, ER, HER2 and GNAS with an increased presence in ADC (p-values all <0.05).
Molecularly-guided precision medicine could provide vulvar cancer patients alternative, targeted treatment options.
识别导致外阴癌发病机制的分子改变，旨在确定治疗的分子靶点。
在对分子特征化的妇科癌症患者数据库进行回顾性分析后，纳入149例外阴癌患者，并在CLIA实验室（亚利桑那州凤凰城的Caris生命科学公司）进行集中检测。检测包括以下一项或多项：基因测序（桑格测序或二代测序[NGS]）、蛋白表达（免疫组织化学[IHC]）和基因扩增（C/FISH）。在p值≤0.05表示有统计学意义时使用Fisher精确检验。
中位年龄为65岁。85%为鳞状细胞癌（SCC）组织学类型，15%为腺癌（ADC）组织学类型。46%患有转移性（IV期）疾病。靶向热点测序在以下基因中发现了变异：TP53（33%）、PIK3CA/BRCA2（分别为8%、10%）、HRAS/FBXW7（分别为5%、4%）和ERBB4/GNAS（分别为3%、3%）。AKT1、ATM、FGFR2、KRAS、NRAS（各1例）和BRAF（2例）也发生了突变。可靶向基因的特定蛋白变化包括其他癌症中常见的临床致病突变（例如PIK3CA：外显子9 [E545K]、RAS：G13D、Q61L、BRCA2：S1667X、BRAF：R443T、FBXW7：E471fs等）。通过免疫组织化学和原位杂交方法确定的药物靶点包括cMET（免疫组织化学32%，原位杂交2%）、PDL1（18%）、PTEN缺失（56%）、HER2（免疫组织化学4%，原位杂交2%）和激素受体（AR，4%；ER，11%；PR，4%）。SCC和ADC之间的比较确定了AR、ER、HER2和GNAS的差异率，ADC中的发生率更高（所有p值均<0.05）。
分子导向的精准医学可为外阴癌患者提供替代的、靶向的治疗选择。
