Glutathione-S-transferase P1 isoenzyme polymorphisms, platinum-based chemotherapy, and non-small cell lung cancer.
BACKGROUND
Polymorphisms within the P1 isoenzyme of GST (GSTP1) are associated with alterations in enzyme activity and may change sensitivity to platinum-based chemotherapy. We investigated the relationship between exon 5 and exon 6 GSTP1 gene polymorphisms and treatment response, hematological, and nonhematological toxicity and overall survival for patients receiving platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC).


METHODS
Between 2001 and 2002, 108 patients with chemotherapy-naïve advanced NSCLC were recruited. Associations between the GSTP1 polymorphisms (Ile105Val, Thr110Ser, Ala114Val, and Asp 147Tyr) and GSTP1*A, *B, and *C haplotypes and treatment response and toxicity were evaluated using the Pearson chi and Kruskal-Wallis tests, respectively. Associations with survival were compared using Kaplan-Meier survival curves and Cox proportional hazard ratios.


RESULTS
No significant associations were noted between GSTP1 polymorphisms and treatment response or survival. Significantly less neutropenic toxicity was demonstrated for patients possessing the 105Val allele (p = 0.020) or the GSTP1*B haplotype (p = 0.038). However, the variant allele GSTP1 105Val, and patients possessing a GSTP1*B allele demonstrated notable trends toward inferior response and survival.


CONCLUSIONS
GSTP1 haplotype can be used to stratify hematological toxicity after platinum-based chemotherapy, but the lack of significant associations with response or survival suggests that GSTP1 polymorphisms may not be strong pharmacogenomic markers in this population. Additional large prospective studies incorporating the GSTP1 haplotype may clarify the reported discrepancies.
Booton
Richard
R
Christie Hospital NHS Trust, Manchester, United Kingdom. r.booten@btopenworld.com
Booten
Richard
R
Ward
Tim
T
Heighway
Jim
J
Ashcroft
Linda
L
Morris
Julie
J
Thatcher
Nicholas
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000009:adverse effects / Q000627:therapeutic use; D008937:Mitomycins / Q000009:adverse effects / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D015996:Survival Rate; D014747:Vinblastine / Q000009:adverse effects / Q000627:therapeutic use
D008937:Mitomycins; D016685:Mitomycin; D014747:Vinblastine; D051549:Glutathione S-Transferase pi; D002945:Cisplatin; D007069:Ifosfamide