Single Nucleotide Polymorphisms And Risk Of Breast Cancer And Neoadjuvant Chemotherapy Sensitivity

The FAS-FASL system plays crucial role in counterattack of cancer cell against immune system and polymorphisms in this system contribute to cancer susceptibility. This study examined the effects ofFAS (-1377G/A and -670A/G) and FASL (-844T/C and 7896G/C) polymorphisms on breast cancer risk and apoptosis of T lymphocytes. The effect on breast cancer risk was determined by case-control analysis of 840 patients and 840 controls. The effects on T lymphocyte apoptosis were determined by activation-induced cell death (AICD) of T cells ex vivo and by analyzing apoptotic tumor-infiltrating lymphocytes (TILs) in breast cancer tissue. We found moderately increased breast cancer risk associated with FAS-1377AG (OR, 1.29; 95% CI, 1.05-1.59; P = 0.017), FAS -1377AA (OR, 1.36; 95% CI, 1.01-1.82; P = 0.045), or FASL -844CC (OR, 1.53; 95% CI, 1.01-2.31; P = 0.045) genotype. T lymphocytes with the FASL -844CC genotype had heightened FASL expression, which is associated with increased AICD of the T cells stimulated by MCF-7 cells or phytohemagglutinin compared with the FASL -844TT genotype (10.38±4.09% and 24.29±1.50% versus 6.03±0.41% and 17.96±3.66％; P＜0.05 and 0.001). Breast cancer patients with the FASL -844CC genotype had higher apoptotic TILs in their cancer tissues than those with the FASL -844TT genotype (33.7±1.2% versus 19.1±2.0%; P = 0.007). These findings indicate that genetic polymorphisms in the FAS-FASL system may confer host susceptibility to breast cancer, which could be mediated by depletion of TILs. Although chemotherapy is one of the most important treatments of breast cancer, it is limited by significant inter-individuval variations in response and toxicity. The metabolism of epirubicin and cyclophosphamide is mainly mediated by cytochrome P450s (CYPs) and glutathione S-transferases (GSTs). It has been well-known that the activities of these enzymes are polymorphic in population due to their genetic polymorphisms. This study examined the effects of genetic polymorphisms in CYP3A4 and GSTPI on response and side-effects of breast cancer patients to epirubicin/ cyclophosphamide chemotherapy. One hundred twenty one patients with stageⅡorⅢinvasive breast cancer were recruited and treated with three to six cycles of epirubicin 80 mg/m~2 and cyclophosphamide 600 mg/m~2 every two weeks. The Miller and Panye grading system were used to evaluate the pathological response of primary tumor and axillary lymph nodes. The genotypes of CYP3A4~*1G (C/T) and GSTP1 (Ile/Val) polymorphisms were determined using PCR-restriction fragment length polymorphism methods. We found that patients with the CYP3A4~*1G CT or TT genotype had a significantly higher response rate to the treatment compared with those with the CC genotype (OR, 0.26; 95% CI, 0.10-0.65; P = 0.001). For side-effects, patients with the GSTP1 Ile/Val or Ile/Ile genotype were less likely to suffer 3-4 grade toxicity effects compared with those with the Val/Val genotype (OR, 0.35; 95% CI, 0.14-084; P = 0.009). The distributions of age, tumor staging, menopause status and mean dosage intensity of patients were not significantly different between well and poor response groups. The response to the treatment was not correlated with ER, PR and Her2/neu status of tumors. No correlation was found between toxicity effect and patient's age, tumor staging, menopause status, and dose intensity of the drugs. These results suggest that patients with CYP3A4~*1G CC genotype and GSTP1 Val genotype trend to have a poor response to chemotherapy of epirubicin and cyclophosphamide regimens and severe adverse effects.