gms | German Medical Science

Background: Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-flourouracil. Especially in colorectal cancer gender differences exist in respect of toxicity, response and prognosis. For females higher toxicity and lower sensitivity for fluoropyrimidines were reported. Aim of this retrospective exploratory study is the gender specific analysis of two functional relevant MTHFR polymorphisms in respect of response and prognosis.

Materials and methods: 569 patients from two centers were analyzed (gastric cancer n=218, carcinomas of the esophagogastric junction type II/III (AEG II/III) n=208 and AEG I n=142). 369 patients had neoadjuvant chemotherapy followed by surgery, 200 had primary resection. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with gender, clinical and histopathological response and prognosis were analyzed retrospectively within a prospective database (chi-square, log rank, cox regression).

Results: 431 patients were male, 128 female. Of the MTHFR C677T polymorphism n=254 had the CC genotype, n=262 the CT genotype and n=53 the TTgenotype. Of the MTHFR A1298C polymorphim n=244 had the AA genotype, n=268 the AC genotype and n=54 the CC genotype. There was no association of gender and the respective MTHFR genotypes (MTHFR C677T p=0,78 and MTHFR A1298C p=0,90) or any genotype combination (all p>0,05). Also we found no association of the application of neoadjuvant treatment and the MTHFR C677T polymorphism (p=0,14) or the MTHFR A1298C polymorphism (p=0,4). Men had significant more often intestinal Lauren classification (p<0,001), more frequently AEG (p<0,001), less advanced tumor categories (p=0,013), but female underwent significantly more frequent neoadjuvant chemotherapy (p<0,001).

105 patients were clinical responder and 104 histopathological responder resulting in a significant improved prognosis (each p<0,001). There was a trend towards improved clinical reponse within male patients (p=0,056). Histopathological response was not gender dependent (p=0,27). No association of any MTHFR genotype and clinical or histopathological response could be found (all p>0,05).

The median survival of all patients was 66 months. The survival of male and female patients was nearly identically (median 66 months each, p=0,64). The application of neoadjuvant treatment was not different(p=0,157). Within the neoadjuvantly treated patients male patients had a significantly improved prognosis (p=0,05). In the whole patient population only the AC genotype of the MTHFR A1298C polymorphism was significantly associated with worse prognosis (p=0,02). Male with the AC genotype had a significant worse prognosis (p=0,03), whereas female did not (p=0,32). The worse prognosis for males with the AC genotype remains significant within the neoadjuvantly treated group (p=0,05), again not for the females (p=0,32). In the primary resected group the AC genotype was not statistically relevant (male: p=0,31, female p=0,72).

Conclusion: Male patients show higher clinical response rates and better prognosis within the neoadjuvantly treated patients. The subgroup of male patients with the AC genotype have a worse prognosis within the neoadjuvantly treated patients. After primary resection the AC genotype is not prognostic relevant, neither for men or women. Therefore the MTHFR a1298C polymorphism might play a gender specific role in 5-FU based chemotherapy in upper GI cancer.