Highlights
- •Metastatic colorectal cancers with sporadic or inherited MMR deficiency display distinct natural histories.
- •A algorithm combining MMR protein expression, BRAF mutation and MLH1 methylation is mandatory to properly determine the mechanism of MMR deficiency.
- •A better characterisation of dMMR CRCs is needed to determine whether therapeutic agents efficacy differs depending on the origin of the MMR deficiency.
Abstract
Background
Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch
repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis.
We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome
(LS)-like mCRCs.
Patients and methods
MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour
samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2
loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.
Results
Among 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (37%) had sporadic
tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm
based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR,
BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall
survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were
associated with more frequent liver involvement, metastatic resection and better disease-free
survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar
between the two groups (4.2 and 4.2 months; P = 0.44).
Conclusions
LS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR
mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs
in these two populations.
Keywords
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Article info
Publication history
Published online: October 19, 2017
Accepted:
September 14,
2017
Received in revised form:
September 5,
2017
Received:
July 4,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
