Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy.
OBJECTIVE
Colon cancer with DNA mismatch repair (MMR) defects reveals indistinguishable clinical and pathologic aspects, including better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. There has been no consensus for p53 as a prognostic marker in colorectal cancer. This study investigated the clinical implication of MSI-H/MMR-D and p53 expression in R0-resected colon cancer patients who received adjuvant oxaliplatin/5-FU/leucovorin (FOLFOX) therapy.


METHODS
We analyzed 135 patients, who had been treated by adjuvant chemotherapy containing 5-FU and oxaliplatin (FOLFOX) after curative resection (R0) for colon adenocarcinoma between May 2004 and November 2007. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. MSI was analyzed by polymerase chain reaction (PCR) amplification using fluorescent dye-labeled primers specific for microsatellite loci. Tumors with MMR defects were defined as those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Expression patterns of p53 were determined in a semiquantitative manner by light microscopy.


RESULTS
There were 13 (9.6%) patients with stage II, 108 (80%) with stage III, and 14 (10.4%) with stage IV. Fourteen patients with stage IV (10.3%) had metastases to liver only, all of whom underwent complete metastasectomy for liver metastases. In total, 134 tumor specimens were genotyped, 115 specimens were tested by IHC and 113 cases had both genotyping and IHC results available for analysis. Genotyping results demonstrated that 12 (9.0%) cases were MSI-H and 122 (91.0%) were MSI-L/S. By IHC, 11 (9.6%) patients were MMR-D and 104 (90.4%) were MMR-I. The methods were in agreement in 108 patients (94.7%). We assessed 114 patients for p53 expression by immunostaining. MMR status was not significantly associated with DFS (P = 0.56) or OS (P = 0.61) in patients with colon cancer (n = 135) receiving adjuvant FOLFOX. According to p53 status, there was also no significant difference for DFS (P = 0.11) and OS (P = 0.94). For patients with genotyping/IHC agreement (n = 108), there was no difference in DFS (P = 0.57) and OS (P = 0.98) between patients with MSI-H/MMR-D and MSI-L/S/MMR-I tumors.


CONCLUSIONS
The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D.
Kim
Seung Tae
ST
Divisions of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, South Korea.
Lee
Jeeyun
J
Park
Se Hoon
SH
Park
Joon Oh
JO
Lim
Ho Yeong
HY
Kang
Won Ki
WK
Kim
Jin Yong
JY
Kim
Young Ho
YH
Chang
Dong Kyung
DK
Rhee
Poong-Lyul
PL
Kim
Dae Shick
DS
Yun
Haeran
H
Cho
Yong Beom
YB
Kim
Hee Cheol
HC
Yun
Seong Hyeon
SH
Lee
Woo Yong
WY
Chun
Ho-Kyung
HK
Park
Young Suk
YS
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D003131:Combined Modality Therapy; D053843:DNA Mismatch Repair; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D053842:Microsatellite Instability / Q000187:drug effects*; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D005819:Genetic Markers; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D002955:Leucovorin; D005472:Fluorouracil