Molecular Predictors of Survival After Adjuvant Chemotherapy for Colon Cancer
Molecular Predictors of Survival After Adjuvant Chemotherapy for Colon Cancer
Abstract & Commentary
Synopsis: Chromosomal analysis on tumor tissue was performed on 460 patients subjected to fluorouracil-based chemotherapy for stage II and III colon cancer. Two chromosomal abnormalities were associated with favorable outcomes after adjuvant chemotherapy. It was postulated that this may be a first step toward individualized cancer treatment based on chromosomal markers.
Source: Watanabe T, et al. N Engl J Med. 2001;344: 1196-1206.
Molecular predictors of outcome in colon cancer may guide delivery of appropriate chemotherapy regimens but remain largely undefined. Watanabe and colleagues tested colon cancer specimens, removed from patients in 2 National Cancer Institute (NCI) Gastrointestinal Intergroup trials, for such prognostic markers.
Specimens were resected from 460 patients undergoing 1 of 5 fluorouracil-based chemotherapy regimens for stage III or high-risk stage II colon cancer. A panel of molecular markers with previously established prognostic value was defined and included in an accompanying glossary. The presence of microsatellite instability (MSI: insertions or deletions of nucleotides within repeated sequences of DNA) was assessed using 1 of 2 general processing methods, dependent upon control tissue availability. Loss of heterozygosity (LOH: deletion of part or all of an allele) was determined by polymerase chain reaction (PCR) amplification, and PCR interpretability ranged from 67-94%. Immunohistochemical analysis was used to identify p53 and p21 abnormalities.
After completion of the molecular analysis, these findings were related to patient data from the Eastern Cooperative Oncology Group Statistical Center.
Survival analysis for patients with stage II disease was performed separately and lacked statistical power to draw conclusions.
Among patients with stage III disease, LOH at 18q (the Deleted in Colon Cancer [DCC] gene) was a significant indicator of recurrence and death and remained a significantly poor prognostic factor after adjustment for multiple markers. Retention of 18q was associated with 69% 5-year survival, while allelic loss at this site was associated with 50% 5-year survival (P = .005).
Those patients whose tumors had high levels of MSI, traditionally a favorable prognostic marker, experienced a 5-year disease-free survival rate of 68%, compared to 56% in the microsatellite stable group (P = .02). However, a significant overall 5-year survival difference between these groups was not realized.
Mutation in the gene for type II receptor for TGF-b1 (TGF-b1 RII), 1 marker of MSI, had a greater association with favorable prognosis. Mutation at this site was associated with 79% disease-free 5-year survival, while no mutation was associated with 59% disease-free 5-year survival (P = .002). Overall 5-year survival rates were 74% and 50% for patients whose tumors had a TGF-b1 RII mutation compared to those whose tumors did not, respectively (P = .06).
Lastly, among those patients with high levels of MSI, mutation of TGF-b1 RII conferred additional favorable prognosis, with 5-year survival rate of 74% compared to 46% in those patients with high levels of MSI and no mutation of TGF-b1 RII (P = .04).
Watanabe et al concluded that the specific molecular markers listed above could be used to predict survival in patients with stage III resected colon cancer after adjuvant fluorouracil-based chemotherapy regimens. They postulated that prospective molecular marker investigation may eventually assist in developing alternative regimens for patients whose tumors do not respond to fluorouracil.
Comment by Arden Morris, MD
If the recent American Society of Clinical Oncology annual meeting was any indication, molecular markers in cancer treatment are capturing the imagination of not only researchers but clinical practitioners as well.1 Understanding molecular markers can improve efficacy of treatment in 3 ways: 1) development of marker-specific therapies, such as tamoxifen for ER+ tumors or cetuximab, which prevents the stimulation of ongoing cell division by blocking the epidermal growth factor receptor on colon and other tumors; 2) enhancement of cell-mediated immunity by vaccines targeted against specific tumor markers; and 3) characterization of markers on tumors that may be susceptible or resistant to specific therapies, in order to better identify efficacious treatment strategies for individual tumors.
Watanabe et al have addressed this last method of using markers to identify patients likely to have a favorable outcome after adjuvant fluorouracil-based treatment for colon cancer. Their results point to 2 favorable prognostic markers for stage III disease: retention of 18q, and mutation of TGF-b1 RII in tumors with MSI. 18q is the site of a tumor suppressor gene, DCC, which behaves similarly to p53. When mutated or deleted, these gene products no longer provide regulation of cell growth.2 MSI, for which TGF-b1 RII is one marker, is associated with decreased metastasis and better overall prognosis.3
Although NIH consensus recommendations for adjuvant treatment of stage III colon cancer have been established, some stage III tumors have demonstrated resistance to fluorouracil-based regimens.4,5 Moreover, adjuvant treatment for stage II disease remains controversial. Identification of tumor markers that could predict the benefit of specific adjuvant regimens would have a clear value in current colon cancer treatment. Watanabe et al have provided a first step toward more individualized and, therefore, more efficacious treatment. Further steps within this current investigation might include examining tumor tissue from those ECOG-enrolled patients who did not receive fluorouracil, to identify whether these same markers are present and whether any association with survival can be documented.
Dr. Morris is Robert Wood Johnson Clinical Scholar, University of Washington, Seattle, Wash.
References
1. McCarty M. Lancet. 2001;357:1593.
2. Gryfe R, et al. Curr Probl Cancer. 1997;21(5):233-300.
3. Jernvall P, et al. Eur J Cancer. 1999;35(2):197-201.
4. NIH consensus conference. JAMA. 1990;264(11): 1444-1450.
5. Tokunaga E, et al. Eur J Cancer. 2000;36(15): 1998-2006.
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