Gleeson Elizabeth M, Feldman Rebecca, Mapow Beth L, Mackovick Lynn T, Ward Kristine M, Morano William F, Rubin Rene R, Bowne Wilbur B
Drexel University College of Medicine, Philadelphia, PA.
Carolinas HealthCare System, Charlotte, NC.
Am J Clin Oncol. 2018 Aug;41(8):777-783. doi: 10.1097/COC.0000000000000376.
Pseudomyxoma peritonei (PMP) is a rare malignancy originating from the appendix, characterized by disseminated mucinous tumor implants on peritoneal surfaces. We examined the role of multiplatform molecular profiling to study biomarker-guided treatment strategies for this rare malignancy.
A total of 54 patients with appendix-derived PMP were included in the study. Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing), protein expression (immunohistochemistry), and gene amplification (C/fluorescent in situ hybridization).
Targeted sequencing of 47 genes detected variants in KRAS (81%), GNAS (74%), SMAD4 (16%), and ATM (16%). Mutations were found at low frequencies (n=1 to 2) in APC, BRAF, PIK3CA, MLH1, and TP53. GNAS and KRAS co-occurrence was found in 87%. Protein overexpression was found in epidermal growth factor receptor (83%), cyclooxygenase-2 (73%), cMET (63%), cKIT (58%), and platelet-derived growth factor receptor alpha (58%). Immune checkpoint expression was found in 36% (programmed cell death protein 1) and 18% (programmed death-ligand 1). Surrogate markers of cell proliferation were found at low rates (TLE3 23%, TOP2A 22%), consistent with the slow-growing biology of PMP. Phosophatase and tensin homolog was intact (wild type [100%]) and positive (immunohistochemistry [80%]). Patients exhibited stable microsatellite status and mismatch repair proficiency (93%). Importantly, multidrug resistance protein expression was elevated (100% BCRP, 94% MRP1, 88% PGP). Markers for gemcitabine (RRM1), fluorouracil (TS), oxaliplatin (ERCC1), and irinotecan (TOPO1) chemosensitivities were detected at favorable rates: 93%, 87%, 77% and 65%, respectively.
Molecular profiling by multiple platforms identified potential therapies for the nontargetable KRAS-mutated population. The role of cMET-targeted therapeutics and immune checkpoint inhibitors merits further investigation. Biomarker-guided selection of cytotoxic chemotherapies may facilitate efficacy to systemic treatment.
腹膜假黏液瘤（PMP）是一种起源于阑尾的罕见恶性肿瘤，其特征是腹膜表面有弥漫性黏液性肿瘤种植。我们研究了多平台分子分析在研究这种罕见恶性肿瘤的生物标志物导向治疗策略中的作用。
本研究共纳入54例阑尾来源的PMP患者。检测包括以下一项或多项：基因测序（桑格测序或新一代测序）、蛋白表达（免疫组织化学）和基因扩增（C/荧光原位杂交）。
对47个基因进行靶向测序，检测到KRAS（81%）、GNAS（74%）、SMAD4（16%）和ATM（16%）存在变异。在APC、BRAF、PIK3CA、MLH1和TP53中发现低频突变（n = 1至2）。发现87%的患者存在GNAS和KRAS共现。在表皮生长因子受体（83%）、环氧化酶-2（73%）、cMET（63%）、cKIT（58%）和血小板衍生生长因子受体α（58%）中发现蛋白过表达。在36%（程序性细胞死亡蛋白1）和18%（程序性死亡配体1）中发现免疫检查点表达。细胞增殖的替代标志物发生率较低（TLE3为23%，TOP2A为22%），这与PMP生长缓慢的生物学特性一致。磷酸酶和张力蛋白同源物完整（野生型[100%]）且呈阳性（免疫组织化学[80%]）。患者表现出稳定的微卫星状态和错配修复能力（93%）。重要的是，多药耐药蛋白表达升高（BCRP为100%，MRP1为94%，PGP为88%）。吉西他滨（RRM1）、氟尿嘧啶（TS）、奥沙利铂（ERCC1）和伊立替康（TOPO1）化疗敏感性标志物的检测率良好，分别为93%、87%、77%和65%。
多平台分子分析为不可靶向的KRAS突变人群确定了潜在的治疗方法。cMET靶向治疗和免疫检查点抑制剂的作用值得进一步研究。生物标志物导向的细胞毒性化疗药物选择可能会提高全身治疗的疗效。
