The oncologist · 2026
Prognostic and therapeutic roles of specific genotypes through target-gene sequencing on gastroenteropancreatic neuroendocrine carcinoma.
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Zhang Jianwei, Zhang Panpan, Zhang Yanyan, Hu Qiaomian, Li Jie, Zhang Xiaotian, Li Jian, Wang Xicheng, Zhou Jun, Lu Zhihao, Peng Zhi, Sun Yu, Wang Sha, Lu Ming, Shen Lin
Аннотация
PURPOSE: Despite emerging genomic discoveries, few have been translated into practical management strategies for people with gastroenteropancreatic neuroendocrine carcinoma (GEPNEC). This study aims to identify key genes and their potential clinical relevance to improve care for this patient group.
METHODS: In the analytical cohort, we reported high-frequency alteration genes, significantly mutated genes, and driver genes and defined their overlap as key genes. Genotypes were identified as Type I/II/III. For further validation, we prospectively recruited eligible patients to build a main cohort, through which we performed univariate/multivariate Cox regression analysis and sketched Kaplan-Meier survival plot. Targetable genes were defined by the OncoKB database.
RESULTS: The analytical cohort consisted of 124 patients. The genes most frequently altered were TP53 (78%), RB1 (35%), APC (27%), and KRAS (17%). Key genes were identified as TP53, RB1, APC, and KRAS. The main cohort included 171 patients. We defined the genotype "Type I" (defined as TP53/RB1 co-alterations) as a reference. In midgut/hindgut NEC, we identified a "Type II" subtype characterized by mutations in either APC or KRAS alterations without TP53/RB1 co-alterations. Type II of midgut/hindgut NEC patients had elevated carcinoembryonic antigen (CEA) levels and longer median overall survival (mOS) than others (not reached vs 11.4 months, HR = 0.19[0.08, 0.44], P = .0028). In foregut NEC, we identified "Type III" (either APC/KRAS alterations or TP53/RB1 co-alterations). Type III of foregut NEC patients showed shorter mOS than others (11.6 vs 19.0 months, HR = 1.93[1.13, 3.25], P = .01). Type II patients who received non-platinum/etoposide (EP) chemotherapy had longer first-line progression-free survival (PFS) compared to EP regimen. They also benefited from second-line immunotherapy. Targeted therapy as second-line was also suitable for targetable patients (longer PFS than others: 12.5 vs 3.0 months, HR = 0.40[0.21-0.75], P = .0017).
CONCLUSIONS: Our study identified key gene-based genotypes (Type II/III) of distinct GEPNEC patients and yielded their prognosis and therapeutic utility.
METHODS: In the analytical cohort, we reported high-frequency alteration genes, significantly mutated genes, and driver genes and defined their overlap as key genes. Genotypes were identified as Type I/II/III. For further validation, we prospectively recruited eligible patients to build a main cohort, through which we performed univariate/multivariate Cox regression analysis and sketched Kaplan-Meier survival plot. Targetable genes were defined by the OncoKB database.
RESULTS: The analytical cohort consisted of 124 patients. The genes most frequently altered were TP53 (78%), RB1 (35%), APC (27%), and KRAS (17%). Key genes were identified as TP53, RB1, APC, and KRAS. The main cohort included 171 patients. We defined the genotype "Type I" (defined as TP53/RB1 co-alterations) as a reference. In midgut/hindgut NEC, we identified a "Type II" subtype characterized by mutations in either APC or KRAS alterations without TP53/RB1 co-alterations. Type II of midgut/hindgut NEC patients had elevated carcinoembryonic antigen (CEA) levels and longer median overall survival (mOS) than others (not reached vs 11.4 months, HR = 0.19[0.08, 0.44], P = .0028). In foregut NEC, we identified "Type III" (either APC/KRAS alterations or TP53/RB1 co-alterations). Type III of foregut NEC patients showed shorter mOS than others (11.6 vs 19.0 months, HR = 1.93[1.13, 3.25], P = .01). Type II patients who received non-platinum/etoposide (EP) chemotherapy had longer first-line progression-free survival (PFS) compared to EP regimen. They also benefited from second-line immunotherapy. Targeted therapy as second-line was also suitable for targetable patients (longer PFS than others: 12.5 vs 3.0 months, HR = 0.40[0.21-0.75], P = .0017).
CONCLUSIONS: Our study identified key gene-based genotypes (Type II/III) of distinct GEPNEC patients and yielded their prognosis and therapeutic utility.