Polymorphisms in genes involved in drug detoxification and clinical outcomes of anthracycline-based neoadjuvant chemotherapy in Chinese Han breast cancer patients.
BACKGROUND
The large individual variability for anticancer drugs in both outcome and toxicity risk makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect.


OBJECTIVE
This work aimed to evaluate the importance of genetic polymorphisms involved in drug detoxification to predict clinical outcomes of anthracycline-based neoadjuvant chemotherapy for breast cancer.


RESULTS
GSTP1 313 AA genotype was associated with a poor clinical response relative to G allele carrier (58.4% vs 80.8%; p = 0.006), and MDR1 3435 TT genotype had a worse response compared with C allele carrier (33.3% vs 71.2% p = 0.001). Patients with both the adverse genotypes of GSTP1 314AA and MDR 3435TT showed the worst therapy efficacy in all (14.3%; p = 0.000). Kaplan-Meier survival analysis showed that the patients with no adverse genotype were associated with decreased hazard of relapse (p = 0.002), compared with those with 1 or 2 adverse genotypes. Multivariate analysis demonstrated that clinical response and no adverse genotype was independent predictors of disease-free survival (DFS).


METHODS
Genotyping was performed by allele-specific oligonucleotide ligation reaction (MnSOD, CAT, GSTP1), multiplex PCR (GSTM1, GSTT1) or PCR-RFLP (MDR1). Based on 153 patients received anthracycline-based neoadjuvant chemotherapy, these genotypes or their combinations in relation to treatment-related response, hematologic toxicity and DFS were investigated.


CONCLUSIONS
These results suggest that polymorphisms in GSTP1 and MDR1 may help to predict clinical response and DFS of anthracycline-based chemotherapy, and a polygenic pathway approach should provide more useful information. The findings required independent prospective confirmation.
Department of Radiotherapy, Jiangsu Cancer Hospital, Nanjing, China.
Minghua
M
Ji
Jinhai
J
Tang
Jianhua
J
Zhao
Bin
B
Xu
Jianwei
J
Qin
Jianwei
J
Lu
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi