Rossi Sabrina, Gasparotto Daniela, Miceli Rosalba, Toffolatti Luisa, Gallina Giovanna, Scaramel Enrico, Marzotto Alessandra, Boscato Elena, Messerini Luca, Bearzi Italo, Mazzoleni Guido, Capella Carlo, Arrigoni Gianluigi, Sonzogni Aurelio, Sidoni Angelo, Mariani Luigi, Amore Paola, Gronchi Alessandro, Casali Paolo G, Maestro Roberta, Dei Tos Angelo P
*Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso †Experimental Oncology I, CRO Aviano National Cancer Institute, Aviano ‡Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale Tumori **Department of Pathology, IRCCS San Raffaele Hospital, Milano §Department of Pathology, Firenze University School of Medicine, Firenze ∥Department of Pathology, University of Marche, Ancona School of Medicine, Ancona ¶Department of Pathology, General Hospital, Bolzano #Department of Pathology, Macchi Foundation, Varese ††Department of Pathology, General Hospital, Bergamo ‡‡Department of Pathology, Perugia University, School of Medicine, Perugia §§Novartis Farma, Origgio Departments of ∥∥Surgery ¶¶Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
Am J Surg Pathol. 2015 Jul;39(7):922-30. doi: 10.1097/PAS.0000000000000418.
The mutation status of KIT or PDGFRA notoriously affects the response of advanced gastrointestinal stromal tumors (GISTs) to tyrosine kinase inhibitors. Conversely, it is currently still unclear whether mutation status impinges on the prognosis of localized, untreated GISTs. Hence, at present, this variable is not included in decision making for adjuvant therapy. A series of 451 primary localized GISTs were analyzed for KIT, PDGFRA, and BRAF mutations. Univariable and multivariable analyses and a backward selection procedure were used to assess the impact of mutation status on overall survival and to identify prognostically homogenous groups. Mutation was a significant prognostic indicator of overall survival in naive, localized GISTs (P<0.001): KIT-mutated patients had a worse outcome than PDGFRA-mutated or triple-negative (KIT, PDGFRA, BRAF wild-type) cases. Multivariable Cox regression models allowed us to identify 3 molecular risk groups: group I exhibited the best outcome and included PDGFRA exon 12, BRAF, and KIT exon 13-mutated cases; group II, of intermediate clinical phenotype (HR=3.06), included triple-negative, KIT exon 17, PDGFRA exon 18 D842V, and PDGFRA exon 14-mutated cases; group III displayed the worst outcome (hazard ratio=4.52), and comprised KIT exon 9 and exon 11 and PDGFRA exon 18 mutations apart from D842V. This study highlights the prognostic impact of mutation status on the natural course of GIST and suggests that the molecular prognostic grouping may complement the conventional clinicopathologic risk stratification criteria in decision making for adjuvant therapy.
KIT或PDGFRA的突变状态显著影响晚期胃肠道间质瘤（GIST）对酪氨酸激酶抑制剂的反应。相反，目前尚不清楚突变状态是否会影响局限性、未经治疗的GIST的预后。因此，目前这一变量未被纳入辅助治疗的决策中。对451例原发性局限性GIST进行了KIT、PDGFRA和BRAF突变分析。采用单变量和多变量分析以及向后选择程序来评估突变状态对总生存期的影响，并确定预后同质组。在未经治疗的局限性GIST中，突变是总生存期的一个重要预后指标（P<0.001）：KIT突变患者的预后比PDGFRA突变或三阴性（KIT、PDGFRA、BRAF野生型）病例更差。多变量Cox回归模型使我们能够识别出3个分子风险组：第一组预后最佳，包括PDGFRA外显子12、BRAF和KIT外显子13突变病例；第二组具有中等临床表型（HR=3.06），包括三阴性、KIT外显子17、PDGFRA外显子18 D842V和PDGFRA外显子14突变病例；第三组预后最差（风险比=4.52），除D842V外，还包括KIT外显子9和外显子11以及PDGFRA外显子18突变。本研究强调了突变状态对GIST自然病程的预后影响，并表明分子预后分组在辅助治疗决策中可能补充传统的临床病理风险分层标准。
