Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide

Abstract

Background: Doxorubicin and cyclophosphamide (AC) therapy is an effective treatment for early-stage breast cancer. Doxorubicin is a substrate for ABCB1 and SLC22A16 transporters. Cyclophosphamide is a prodrug that requires oxidation to 4-hydroxycyclophosphamide, which yields a cytotoxic alkylating agent. The initial oxidation is catalysed by cytochrome P450 enzymes including CYP2B6, CYP2C9, CYP2C19 and CYP3A5. Polymorphic variants of the genes coding for these enzymes and transporters have been identified, which may influence the systemic pharmacology of the two drugs. It is not known whether this genetic variation has an impact on the efficacy or toxicity of AC therapy.

Methods: Germ line DNA samples from 230 patients with breast cancer on AC therapy were genotyped for the following SNPs: ABCB1 C1236T, G2677T/A and C3435T, SLC22A16 A146G, T312C, T755C and T1226C, CYP2B6*2, *8, *9, *3, *4 and *5, CYP2C9*2 and *3, CYP3A5*3 and CYP2C19*2. Clinical data on survival, toxicity, demographics and pathology were collated.

Results: A lower incidence of dose delay, indicative of less toxicity, was seen in carriers of the SLC22A16 A146G, T312C, T755C variants. In contrast, a higher incidence of dose delay was seen in carriers of the SLC22A16 1226C, CYP2B6*2 and CYP2B6*5 alleles. The ABCB1 2677A, CYP2B6*2, CYP 2B6*8, CYP 2B6*9, CYP 2B6*4 alleles were associated with a worse outcome.

Conclusion: Variant alleles in the ABCB1, SLC22A16 and CYP2B6 genes are associated with response to AC therapy in the treatment of breast cancer.

Figure 1

Kaplan–Meier plots illustrating impact of MDR1 genotype on progression-free survival (A) and OS (B) of breast cancer patients treated with adjuvant AC therapy with intention to cure. Curves are categorised according to MDR1 2677A allele carrier (dashed line) vs G2677 or 2677T allele carriers (solid line). Equality of survival distribution was tested by log rank.

Figure 2

Kaplan–Meier illustrating impact of CYP2B6^*2 genotype on progression-free survival (A) and OS (B) of breast cancer patients treated with adjuvant AC therapy with intention to cure. Curves are categorised by heterozygotes (dashed line) vs wild-type homozygotes (solid line). Equality of survival distribution was tested by log rank.

Figure 3

Kaplan–Meier plots illustrating impact of CYP2B6^*4 and ^*9 genotype on OS of breast cancer patients treated with adjuvant AC therapy with intention to cure. Curves are categorised by rare allele homozygotes for CYP2B6^*9 (A) and CYP2B6^*4 (B) (dashed lines) vs wild-type allele carriers (solid lines). Equality of survival distribution was tested by log rank.