KRAS and BRAF mutational status in primary colorectal tumors and related metastatic sites: biological and clinical implications.
BACKGROUND
KRAS and BRAF mutations in primary colorectal tumors (PT) are predictive of nonresponse to anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). The question of primary resistance to anti-EGFR treatment as a result of the presence of KRAS or BRAF mutations only in metastases has been raised but not resolved.


METHODS
We analyzed the mutational status of KRAS and BRAF in 64 new patients with mCRC and performed a systematic review of published data from 285 patients.


RESULTS
A total of 285 and 95 matched PT/metastases were available for the analysis of the KRAS and the BRAF status, respectively. An identical mutational pattern of KRAS in PT and the matching metastases were reported in all the cases but 14 (5%). In six cases (2%), KRAS was mutated in the PT and wild type in the metastatic site, whereas in eight cases (3%), KRAS was wild type in the PT and mutated in the metastatic site. An identical mutational pattern of BRAF in PT and the matching metastases was reported in all but two cases (3%). In one case (1.5%), BRAF was mutated in the PT and wild type in the metastatic site, whereas in one case (1.5%), BRAF was wild type in the PT and mutated in the metastatic site.


CONCLUSIONS
The acquisition by metastases of a KRAS or a BRAF mutation that was not present in the PT is a rare event, occurring in 5% of cases of mCRC. This is not a frequent mechanism of primary resistance to anti-EGFR treatments in mCRC.
Italiano
Antoine
A
Laboratory of Solid Tumors Genetics, Nice University Hospital, Nice, France. italiano@bergonie.org
Hostein
Isabelle
I
Soubeyran
Isabelle
I
Fabas
Thibault
T
Benchimol
Daniel
D
Evrard
Serge
S
Gugenheim
Jean
J
Becouarn
Yves
Y
Brunet
René
R
Fonck
Marianne
M
François
Eric
E
Saint-Paul
Marie-Christine
MC
Pedeutour
Florence
F
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins