Genetic Variations Are Associated With The Response Or Prognosis To Chemotherapy In Breast Cancer And Small Cell Lung Cancer Patients

Objective:Chemotherapy is one of common treatments for most cancers,including breast cancer and SCLC.However,the efficacy of chemotherapy differs significantly from individual to individual and the reason remains to be clarified.The ability to predict tumor response in routine clinical practice is difficult.Genetic variations of individual might affect clinical response,toxicity and overall survival in cancer patients receiving chemotherapy.This study explored the associations between genetic variants in genes involved in apoptosis pathway and response or acute adverse events or survival in breast cancer patients receiving neoadjuvant chemotherapy.The associations between genetic variants in genes involved in GSS and response or survival in SCLC patients receiving platinum-based chemotherapy were also explored.Methods:Sixty-five haplotype-tagging single nucleotide polymorphisms(htSNPs)in 17 genes involved in apoptosis pathway were genotyped in 509 breast cancer patients receiving neoadjuvant chemotherapy.Four htSNPs in GSS gene were genotyped in 903 SCLC patients receiving platinum-based chemotherapy.The associations between genotypes and risk of clinical response or risk of acute adverse events were measured by odds ratios(ORs)and 95%confidence intervals(Cls),adjusted for some clinical pathological parameters.Kaplan-Meier survival curve was applied to evaluate the differences of survival time among genotypes.The hazard ratios(HRs)were estimated using multivariate Cox proportional hazard regression model while the multivariate Cox proportional hazards regression model was used to analyze the association between the clinical pathological parameters and prognosis.We also conducted biochemical assays to investigate the function of TRAILR2 rs 1047275 G>C SNP which was associated with response and survival of breast cancer patients.Results:Among 509 breast cancer patients,116(22.8%)had died until the last date of follow-up(5 May,2016).Four hundred and thirty patients were chemotherapy responders in the study with a response rate of 84.5%.We found that rs1047275 in TRAILR2 was associated with the risk of non-response,with the ORs being 1.54(95%CI=1.05-2.26).Among 509 patients,347(68.2%)suffered from medium or severe adverse events.Rs 11296996 and rs 12581708 in APAF1 were associated with the protection of myelosuppression,with the ORs being 0.71(95%CI = 0.54-0.93)and 0.72(95%CI = 0.54-0.96),respectively.We found that patients carrying more protective alleles tended to have lower risk of myelosuppression.Compared with patients without the rs11296996-and rs12581708Gprotective allele,ORs for patients carrying 1-2 protective alleles or 3-4 protective alleles was 0.62(95%CI=0.42-0.92)or 0.55(95%CI= 0.30-0.99),with P= 0.012 for trend test.Rs4934431 in FAS was associated with the risk of gastrointestinal adverse reactions,with the OR being 1.31(95%CI = 1.00-1.71).The clinical stage and chemotherapy response had significantly impact on overall survival time,with the adjustedHRs of 2.52(95%CI =1.65-3.84,P<0.001)and 1.68(95%CI = 1.07-2.65,P = 0.025).For the genetic factors,six SNPs including rs8190256 in BID,rs5745568 in BAK,rs7660005 in CASP6,rs1052576 in CASP9,rs1047275 and rs2889 in TRAILR2 were associated with overall survival(OS),with the HRs being 0.57(95%CI = 0.34-0.97,P = 0.039),1.41(95%CI= 1.05-1,89,P = 0.024),0.72(95%CI = 0.52-0.99,P = 0.041),0.66(95%CI= 0.48-0.91,P= 0.012),1.40(95%CI= 1.04-1.89,P= 0.026)and 1.40(95%CI = 1.03-1.90,P = 0.032),calculated using multivariable-adjusted Cox additive model.The rest 59 SNPs were not associated with OS of breast cancer patients treated with neoadjuvant chemotherapy.Biochemical assays showed that rs1047275 G>C change result in altered regulation of TRAILR2.Among 903 SCLC cases,462(51.2%)cases received cis-platinum and etoposide treatment while others treated with carboplatin and etoposide.Six hundred and fifty six patients were chemotherapy responders in the study with a response rate of 72.6%.Patients were followed up to get their survival information.The median survival time(MST)of these patients was 25.0 months.We found that rs725521 which located in the 3' near gene region of GSS was significantly associated with chemotherapy response.Compared with the T allele,patients with C allele had a worse chemotherapy response and increased the risk of no-responders(OR = 1.28,95%CI=1.03-1.59,P = 0.027).Rs7265992 and rs725521 of GSS were associated with the OS and progression free survival(PFS)of SCLC patients who received platinum-based chemotherapy(for OS:HR = 1.16,95%CI = 1.02-1.33,P = 0.027;HR=1.17 95%CI= 1.05-1.31,P = 0.006;for PFS:HR=1.14,95%CI=1.04-1.29,P = 0.047;HR =1.16,95%C7 = 1.04-1.29,P = 0.010,respectively).The patients carrying 1-2 risk alleles and the patients carrying 3-4 risk alleles had worse MST than the patients without the rs7265992 A and rs725521 C risk alleles(24.0 and 22.0 versus 30.0 months),with the HR for death being 1.26(95%CI = 1.04-1.54)and with the HR of 1.52(95%CI = 1.18-1.97)(Ptrend = 0.001).Rs2025096 and rs2273684 were not associated with the OS of SCLC patients who received platinum-based chemotherapy.Age ? 56,KPS>80,limited-stage,chemotherapy response and radiation therapy can remarkably prolong OS(all P<0.05).Conclusions:These results show that several genetic variants in genes involved in apoptosis pathway are associated with response or acute adverse events or prognosis in breast cancer patients receiving neoadjuvant chemotherapy.GSS genetic polymorphisms rs725521 and rs7265992 play important role on the response and prognosis to platinum-based chemotherapy in SCLC patients.Together,these findings suggest that genetic variations might serve as biomarkers for predicting clinical response,acute adverse events and prognosis of chemotherapy in breast cancer or SCLC patients.