ESMO open · 2026
Distinct molecular and clinical aggressiveness in very early-onset metastatic colorectal cancer: survival and genomic divergence between patients aged 30-39 versus 40-49 years.
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Pretta A, Rebecchi G, Maddalena G, Marmorino F, Ziranu P, Manoni F, De Grandis M C, Carullo M, Ferrari P A, Donisi C, Randon G, Perissinotto E, Taravella A, Nasca V, Buggin F, Pretta G, Ciracì P, Bergamo F, Cremolini C, Lonardi S, Scartozzi M, Pietrantonio F
Аннотация
BACKGROUND: Early-onset colorectal cancer (EOCRC) is increasing worldwide and exhibits clinical heterogeneity. Patients younger than 40 years may constitute a biologically distinct subgroup within EOCRC. We investigated whether 'very early-onset' metastatic colorectal cancer (VEOCRC, ages 30-39) exhibits specific clinical and genomic features compared with EOCRC in patients aged 40-49 and whether these differences lead to variations in survival from the time of metastatic diagnosis.
MATERIALS AND METHODS: We analysed the data of metastatic EOCRC patients in a multi-institutional database, divided into two predefined age groups: 30-39 years and 40-49 years. Overall survival (OS) from metastatic diagnosis was estimated using Kaplan-Meier methods, and hazard ratios (HRs) were calculated with Cox regression. Comprehensive genomic profiling was carried out using the Foundation Medicine next-generation sequencing platform (FoundationOne®). Key molecular alterations were compared using odds ratios (ORs). Baseline clinicopathologic characteristics were assessed using χ2 or two-sided Fisher's exact tests.
RESULTS: A total of 264 patients were included (aged 30-39: n = 65; aged 40-49: n = 199). Median OS was shorter in patients aged 30-39 years than in those aged 40-49 years (30.0 versus 38.0 months; log-rank P = 0.0269; HR 0.67). A distinct genomic profile appeared in patients with VEOCRC, characterised by higher KRAS mutation rates (55.4% versus 42.0%; OR 1.71; one-sided P = 0.041) and fewer APC alterations (69.2% versus 82.0%; one-sided P = 0.024). NRAS, BRAF, PTEN, and POLE alterations were directionally consistent with a more aggressive biology, although event counts were limited. Clinically, overall Eastern Cooperative Oncology Group performance status (ECOG PS) distribution was similar (χ2P = 0.099), but ECOG PS 0 was more common in VEOCRC (89.1% versus 76.8%; P = 0.0468). Peritoneal metastases occurred significantly more frequently in patients aged 30-39 (32.3% versus 19.6%; P = 0.041). No differences were observed regarding liver, lung, or nodal involvement.
CONCLUSIONS: Patients aged 30-39 years constitute a biologically distinct subgroup within EOCRC, with shorter survival, KRAS mutation enrichment, fewer APC alterations, and increased peritoneal involvement. These findings support the emerging idea of an 'ultra-young', genomically driven CRC subtype, with implications for disease biology, risk assessment, and treatment development.
MATERIALS AND METHODS: We analysed the data of metastatic EOCRC patients in a multi-institutional database, divided into two predefined age groups: 30-39 years and 40-49 years. Overall survival (OS) from metastatic diagnosis was estimated using Kaplan-Meier methods, and hazard ratios (HRs) were calculated with Cox regression. Comprehensive genomic profiling was carried out using the Foundation Medicine next-generation sequencing platform (FoundationOne®). Key molecular alterations were compared using odds ratios (ORs). Baseline clinicopathologic characteristics were assessed using χ2 or two-sided Fisher's exact tests.
RESULTS: A total of 264 patients were included (aged 30-39: n = 65; aged 40-49: n = 199). Median OS was shorter in patients aged 30-39 years than in those aged 40-49 years (30.0 versus 38.0 months; log-rank P = 0.0269; HR 0.67). A distinct genomic profile appeared in patients with VEOCRC, characterised by higher KRAS mutation rates (55.4% versus 42.0%; OR 1.71; one-sided P = 0.041) and fewer APC alterations (69.2% versus 82.0%; one-sided P = 0.024). NRAS, BRAF, PTEN, and POLE alterations were directionally consistent with a more aggressive biology, although event counts were limited. Clinically, overall Eastern Cooperative Oncology Group performance status (ECOG PS) distribution was similar (χ2P = 0.099), but ECOG PS 0 was more common in VEOCRC (89.1% versus 76.8%; P = 0.0468). Peritoneal metastases occurred significantly more frequently in patients aged 30-39 (32.3% versus 19.6%; P = 0.041). No differences were observed regarding liver, lung, or nodal involvement.
CONCLUSIONS: Patients aged 30-39 years constitute a biologically distinct subgroup within EOCRC, with shorter survival, KRAS mutation enrichment, fewer APC alterations, and increased peritoneal involvement. These findings support the emerging idea of an 'ultra-young', genomically driven CRC subtype, with implications for disease biology, risk assessment, and treatment development.