Prognostic value of circulating mutant DNA in unresectable metastatic colorectal cancer.
OBJECTIVE
No validated biologic prognostic marker is presently available in metastatic colorectal cancer (MCRC). We prospectively evaluated the prognostic value of circulating mutant DNA in 31 patients presenting an unresectable MCRC treated by chemotherapy, and we used, as tumor markers, KRAS mutations and methylation of the RASSF2A promoter.


METHODS
Detection in the serum of KRAS mutation and RASSF2A methylation were performed using sensitive methods, respectively, real-time polymerase chain reaction (PCR) performed in the presence of a peptide nucleic acid specific of the wild-type sequence and methyl-specific PCR after bisulfite treatment.


RESULTS
Among 29 MCRC patients for whom DNA from the primary tumor was available, 23 (79%) presented at least one of the markers in their primary tumor, and 12 of them presented the same alteration in serum. For the 2 remaining patients, RASSF2A methylation was detected in serum indicating that this alteration was present in the primary tumor. These 14 patients with a detectable tumor marker in their serum were designed sDNA+ patients. After 6 months of follow-up, 11/14 (79%) sDNA+ and 1/11 (9%) sDNA- patients presented a progressive disease (P = 0.001). The median progression free survival was 5 months in sDNA+ patients versus 14 months in sDNA- patients (P = 0.004). After 1 year of follow-up, 2 of 14 (14%) sDNA+ and 8 of 11 (73%) sDNA- patients presented no signs of disease progression (P = 0.005).


CONCLUSIONS
This study suggests that the presence of circulating mutant DNA in unresectable MCRC patients, which can be detected using simple methods such as methylation-specific PCR or real-time PCR, is highly predictive of clinical outcome.
Lefebure
Benoit
B
Inserm U614, Institute for Medical Research, Rouen Northwest Canceropole, France. benoit.lefebure@chu-rouen.fr
Charbonnier
Françoise
F
Di Fiore
Frédéric
F
Tuech
Jean Jacques
JJ
Le Pessot
Florence
F
Michot
Françis
F
Michel
Pierre
P
Frebourg
Thierry
T
D000230:Adenocarcinoma / Q000097:blood* / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000097:blood* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000097:blood* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D025521:Tumor Suppressor Proteins / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C425300:RASSF2 protein, human; D025521:Tumor Suppressor Proteins; D004247:DNA; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins