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Journal of Clinical Oncology, Vol 26, No 20 (July 10), 2008: pp. 3468 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.6479
Methylenetetrahydrofolate Reductase Gene Polymorphisms: Genomic Predictors of Clinical Response to Fluoropyrimidine-Based Chemotherapy in FemalesGenetics Department, Hospital de Sant Pau, Barcelona, Spain
Hematology Department, Hospital de l'Esperit Sant, Santa Coloma de Gramenet, Barcelona, Spain
Medical Oncology, Hospital de Sant Pau, Barcelona, Spain To the Editor: The article by Zhang et al1 provides evidence that A1298C polymorphism in methylenetetrahydrofolate reductase (MTHFR) has a role as a prognostic marker in female patients with metastatic colon cancer treated with fluorouracil (FU) -based chemotherapy. The authors stated that further studies are needed to confirm these findings. Recently, we reported a study in 94 patients with metastatic colorectal cancer who received FU and oxaliplatin chemotherapy as first-line treatment.2 The aim of the study was to ascertain whether polymorphisms 677 C > T and 1298 A > C in the MTHFR gene could be used as genomic predictors of clinical outcome in this group of patients. Our results showed a lack of predictive value of these two MTHFR polymorphisms in this cohort. As we did not perform a stratified analysis by sex in our study, Zhang et al's results1 prompted us to replicate their sex-specific analysis in our series of patients. We analyzed the previously studied population enlarged with 93 additional patients who met the inclusion and exclusion criteria defined in our previous study. Our present cohort comprised a total of 187 patients, 67 women (36%) and 120 men (64%). There were no statistically significant differences between the two populations—males and females—regarding location of the primary tumor, number of metastatic sites, WBC at diagnosis, Eastern Cooperative Oncology Group performance status, phosphatase alkaline levels, or global clinical assessment risk according to Kohne et al's classification.3 Age was significantly different in the two groups (median age, 62 years for women and 67 years for men; P = .004). The MTHFR polymorphisms were tested as previously described.2 For MTHFR C677T polymorphism, 38% of patients had the C/C genotype (71 of 187 patients), 51% of patients had the C/T genotype (95 of 187 patients), and 11% of patients had the T/T genotype (21 of 187 patients). For MTHFR A1298C polymorphism, 46.5% of patients had the A/A genotype (87 of 187), 46.5% had the A/C genotype (87 of 187), and 7% had the homozygous C/C genotype (13 of 187 patients). We found no differences in overall survival (OS) related to the MTHFR C677T or MTHFR A1298C markers when the analysis was performed without taking into account the variable sex. When the statistical analysis was stratified by sex, we found no differences in OS in men or women groups according to the MTHFR C677T polymorphism. However, when the patient population was separated by sex, the MTHFR A1298C polymorphism was found to be significantly associated with OS (log-rank test, P = .03) in females. Among females, OS was lower for patients with the A/C genotype (n = 33; median OS, 16 months) than for patients with the A/A genotype (n = 28; median OS, 42 months) or the C/C genotype (n = 6; median OS, 32 months). The probability of death was 2.5 times higher for A/C patients (relative risk, 2.5; 95% CI, 1.2 to 5.3). However, there were no statistically significant differences between A1298C polymorphism and OS in male patients. Our results confirm Zhang et al's1 observation that the A1298C polymorphism in the MTHFR gene may play a pharmacogenetic role as a prognostic marker in female patients on FU-based chemotherapy. In both studies, OS was higher for C/C female patients than for A/C female patients. Although the number of patients with a C/C genotype was insufficient in either study (n = 10 in Zhang's study and n = 6 in our own) to allow a definitive conclusion, the OS in this group showed an intermediate value. The differences in OS between the two studies could be attributed to the fact that all the patients in our cohort received a similar regimen as first-line chemotherapy. The value of the present data is enhanced by this therapeutic homogeneity. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported by Fondo de Investigaciones Sanitarias 051218. REFERENCES
1. Zhang W, Press OA, Haiman CA, et al: Association of methylenetetrahydrofolate reductase gene polymorphisms and sex-specific survival in patients with metastatic colon cancer. J Clin Oncol 25:3726-3731, 2007 2. Menoyo A, Marcuello E, del Rio E, et al: Methylenetetrahydrofolate reductase gene polymorphisms: Genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 57:835-840, 2006 3. Köhne CH, Cunningham D, Di Costanzo F, et al: Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: Results of a multivariate analysis of 3825 patients. Ann Oncol 13:308-317, 2002 Related Reply Related Article |
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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