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TMB is linked with prognosis

Limited molecular markers are available to guide therapeutic decisions for patients with advanced-stage colorectal cancer (CRC). Now, a comprehensive mutational analysis of CRC samples indicates that several genetic features provide prognostic information in this setting.

This analysis was performed on a subset of tumour specimens from 2,326 patients with newly diagnosed, advanced-stage CRC collected before treatment in the CALGB/SWOG 80405 trial. In this trial, patients received chemotherapy plus bevacizumab and/or cetuximab; no significant difference in overall survival (OS) was reported between arms. Mutational analysis of 11 genes was performed in 843 patients, 827 of which were profiled for microsatellite instability (MSI) status. Tumour mutational burden (TMB) was assessed in samples from 1,300 patients.

Longer OS durations were reported in patients with wild-type BRAF versus mutated BRAF (30.6 months versus 13.5 months; P < 0.001) or wild-type RAS versus mutated RAS (32.1 months versus 25.0 months; P < 0.001). No significant differences in OS were observed between treatment arms.

Patients with MSI-high (MSI-H) tumours receiving bevacizumab had longer median OS than those receiving cetuximab: 30.0 months versus 11.9 months (P < 0.001). “This finding has important implications for the treatment of this patient subgroup, for which immunotherapy is not approved yet in the first-line setting,” says lead author Federico Innocenti.

Among tumours evaluated for both TMB and microsatellite status, 89% had microsatellite stability (MSS) and a median TMB of 6 mutations per Mb, 6% had MSI-H (median TMB: 52 mutations per Mb) and the remainder were classified as MSI-low (no TMB results available). In patients with tumours with MSS and high TMB (>8 mutations per Mb), median OS was longer than in those with tumours with MSS and low TMB (33.8 months versus 28.1 months; P = 0.02). No significant differences in OS were observed between treatment arms. “We will now investigate if patients with high TMB are more responsive to immune-checkpoint inhibition in this setting,” comments Innocenti.

The results … could provide a new classification for precision medicine in CRC

“The results of these analyses and their future clinical testing could provide a new classification for precision medicine in CRC, improving the survival of patients with this disease,” he concludes.


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Correspondence to Diana Romero.

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Romero, D. TMB is linked with prognosis. Nat Rev Clin Oncol 16, 336 (2019).

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