| Part I:Genetic Biomarkers Predicting Efficacy or Toxicity in Metastatic Breast Cancer Patients treated with CapecitabineObjective:Capceitabine is a kind of cytotoxic agents and is absorbed in the small intestinal. It is converted to5-fluorouracil in a three-step enzymatic process, the final stage is mediated by the thymidine phosphorylase. However, there was no specific biomarker to predict the efficacy or toxicity of capecitabine till now. The aim of this study is to investigate the association of polymorphisms and the efficacy or toxicity of capecitabine-based chemotherapy among patients with metastatic breast cancer (MBC). Analyzing the genetic variation of metabolism related genes of capecitabine, we hope to find some genetic biomarkers predicting the efficacy or toxicity of capecitabine based chemotherapy in the MBC patients.Methods:A cohort of342patients with metastatic breast cancer treated in Cancer Hospital and Institute, Chinese Academy of Medical Sciences were retrospectively collected if archival DNA datas and clinical datas were available, from Jan2010to Sep2012. All patients received the regiments containing the capecitabine. We screened genetic variants in the target genes according to the metabolism pathway of capecitabine, which list in the public database (http://hapmap.ncbi.nlm.nih.gov/) and one thousand-genome project database. A total of twenty-six common tagging single nucleotide polymorphisms in4key genes in ethnic Han Chinese people with Hardy-Weinberg Equilibrium minor greater than0.1and minor allele frequency greater than0.05were genotyped. In the last, all the participant were genotyped for26SNPs in4candidate genes enrolled in the study and analysed in cohorts for the association between the genetic variations and the toxicity or efficacy of capecitabine based chemotherapy in the MBC patients.Results:The cohort of342patients are all women. The median age was51(26-81). The median follow up time was27.5months. All the patients received the regimens containing the capecitabine. There were several toxicities including leukopenia (141patients/41.2%), neuropenia (109patients/31.8%), aminotransferase increased(101patients/29.5%), hand-foot syndrome(193patients/56.4%), nausea and vomiting(204patients/59.6%),elevated bilirubin(72patients121.1%). All patients were evaluated according to RECIST1.0. There were7CR (2%),194PR (56.7%),90SD (26.3%) and12PD (3.5%). The median progression free survival was10months and the median overall survival was56months till Feb25,2014. There was no difference of genotype distribution with the survival and efficacy of capecitabine. However, only the toxicity of hand-foot syndrome(HFS), which was specific with capecitabine, had associated with4SNPs, such as rs4846048, rs3737964, rs2606241and rs2853741(P<0.05). A/G genotype of rs3737964and rs4846048in the MTHFR were protective factors for the incidence of HFS (OR=0.54,95%CI=0.31-0.97,P=0.038and OR=0.54,95%CI=0.30-0.98,P=0.042). G/T genotype of rs2606241and C/T genotype of rs2853741in the TYMS were risk factors for the HFS. Haplotype frequencies between the case group and the control group were no significant difference in the five genes.Conclusions:MTHFR and TYSM were associated with HFS. A/G genotype of rs3737964and A/G genotype of rs4846048are protective factors for HFS; G/T genotype of rs2606241and C/T genotype of rs2853741in the TYMS were related with the incidence of HFS.Part2:Study on primary Liver Metastasis from Luminal Subtype of Breast CancerObjective:The aim of this study is to investigate the efficacy of treatment, prognosis and their influencing factors of luminal subtype breast cancer patients with liver metastasis.Methods:182Female luminal subtype of breast cancer patients with primary liver metastasis were treated in Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences between Jan1,2000and Dec31,2011were taken into the study. The clinical, pathological and survival data of them were collected for prognostic analysis. Results:The median age of patients was47and there were118patients younger than50year-old. The median disease free survival (DFS) after primary operation of breast cancer was19.5months. All patients received chemotherapy as the first line treatment for liver metastases. Response (CR+PR) rate was60.4%. Progression free survival (PFS) and overall survival (OS) were8month and23months, respectively. The median OS was significantly longer in younger patients (≤50) than in older patients (>50)(P<0.05). In addition, PFS and OS were also significantly longer in patients who had complete response or partial response than those who had stable disease or progression disease(P<0.05).There was no difference on PFS and OS with different regimens.Conclusion:The age and response to the treatment were independent prognosticfactors for ER and/or PR positive breast cancer patients with liver metastasis... |
PDF Full Text Request