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Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy

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Abstract

Purpose

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.

Experimental design

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.

Conclusion

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.

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Abbreviations

MMR:

DNA mismatch repair

MMR-D:

MMR-deficient

MMR-I:

MMR-intact

MSI:

The microsatellite instability

MSI-H:

High levels of MSI

MSI-L:

MSI-low

MSS or MSI-S:

MSI-stable

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Acknowledgments

This study was supported by the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (Grant No. 0412-CR01-0704-0001).

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Authors and Affiliations

  1. Divisions of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea

    Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang & Young Suk Park

  2. Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Jin Yong Kim, Young Ho Kim, Dong Kyung Chang & Poong-Lyul Rhee

  3. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Dae Shick Kim

  4. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea

    Haeran Yun, Yong Beom Cho, Hee Cheol Kim, Seong Hyeon Yun, Woo Yong Lee & Ho-Kyung Chun

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  1. Seung Tae Kim
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  2. Jeeyun Lee
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Correspondence to Ho-Kyung Chun or Young Suk Park.

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Kim, S.T., Lee, J., Park, S.H. et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol 66, 659–667 (2010). https://doi.org/10.1007/s00280-009-1206-3

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  • DOI: https://doi.org/10.1007/s00280-009-1206-3

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