Study on association of polymorphism of CYP450 2D6 with head and neck cancer and treatment response in patients receiving neoadjuvant chemotherapy paclitaxel, cisplatin, 5fu (TPF) followed by chemoradiation.

Background: Aims of this study were to study the association of genetic polymorphism in CYP450 2D6 in patients of locally advanced head and neck cancer, and try to assess a correlation between this polymorphism & response to treatment. Need of the study was to find out a possible genetic level explanation for the different response achieved in patients with similar histopathology, stage, exposure to carcinogen & ethnicity undergoing similar treatment. Methods: A study comprising of 150 patients & 150 controls was done to analyze the association between polymorphs of CYP450 2D6 with head & neck cancer and treatment response (TPFCTRT). Two cycles of TPF (paclitaxel-175mg/m2 D1, cisplatin 35mg/m2 D2-D3 and 5Fu 1gm/m2 D1-D3) were given followed by radiotherapy with concurrent cisplatin (40 mg/m2).The response to the treatment was assessed clinically, radiologically & by laryngoscopy-post treatment. Genotyping of the blood samples was done. Analysis of the association between genetic polymorphisms and risk of HNSCC was estimated by calculating crude odds ratio (OR). A P value of <0.05 was considered statistically significant. The statistical analysis was performed with the SPSS software package (version 11.0 for Windows; SPSS Chicago, IL). Results: Patients with CYP 2D6*1 showed good response to the therapy given, while CYP 2D6*4 and *10 were poor responders. Conclusion: There is a strong association of polymorphs of CYP 2D6 with occurrence of head and neck cancer. Response to treatment (TPFCT-RT) is polymorph graded. Our study thus provides an insight in to the concept of “Right therapy to the right patient”.

Association of functionally important polymorphisms in cytochrome P450s with squamous cell carcinoma of head and neck.

Head and neck squamous cell carcinoma (HNSCC), a common malignancy that possibly involves a combination of exposure to the carcinogens and inherited genetic differences in the enzymes catalyzing their metabolism. Alcohol and tobacco consumption are the primary environmental risk factors, while polymorphism in various biotransformation enzymes such as cytochrome P450s (CYPs) and glutathione S-transferases, (GSTs) has been implicated as the major genetic risk factors for the development of HNSCC. The functionally important polymorphisms in these CYPs (1A1*2A, 1A1*2C, 1B1*2, 2E1*5B, 2E1*6, 2C19*2, 2D6*4, 2D6*10) and GSTs (GSTM1-null or GSTT1-null) were found to be significantly associated with HNSCC risk. Significant differences in the distribution of certain haplotypes of CYPs have also been reported and prevalence of certain genotype combinations of CYPs and GSTS in cases has indicated the importance of gene-gene interactions in HNSCC risk. Alcohol or tobacco use (smoking and chewing) were also found to interact synergistically with variant genotypes of these CYPs and GSTS in significantly enhancing HNSCC risk. This increase in risk associated with the variant genotypes with tobacco or alcohol use have further demonstrated the importance of gene–environment interactions in determining the susceptibility to HNSCC.