Prognostic value of Lynch syndrome, BRAF V600E, and RAS mutational status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts.

Koen Zwart, Frederieke H van der Baan, Romain Cohen, Thomas Aparicio, Christelle de la Fouchardiére, Thierry Lecomte, Cornelis J A Punt, David Sefrioui, Rik J Verheijden, Geraldine R Vink, G Emerens Wensink, Aziz Zaanan, Miriam Koopman, David Tougeron, Jeanine M L Roodhart

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Abstract

BACKGROUND: Current knowledge on prognostic biomarkers (especially BRAF V600E /RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors.

METHODS: This observational cohort study combined a population-based Dutch cohort (2014-2019) and a large French multicenter cohort (2007-2017). All mCRC patients with a histologically proven dMMR tumor were included.

RESULTS: In our real-world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line palliative systemic chemotherapy. Mean age of first-line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAF V600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66-1.72), BRAF V600E mutational status (HR: 1.02, 95% CI: 0.67-1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64-1.59), with similar results for PFS.

CONCLUSION: BRAF V600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision-making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.

Original languageEnglish
Pages (from-to)15841-15853
Number of pages13
JournalCancer Medicine
Volume12
Issue number15
Early online date16 Jun 2023
DOIs
Publication statusPublished - Aug 2023

Keywords

  • deficient mismatch repair
  • Lynch syndrome
  • metastatic colorectal cancer
  • microsatellite instability
  • molecular biology

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