Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab

Disclosures

Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article

CYP19A1 Genetics

The drug target of AIs is the enzyme aromatase, which belongs to the superfamily of CYP450 enzymes. Aromatase converts androgens (testosterone, androstenedione) to estrogens and its inhibition results in estrogen depletion, which prevents growth of estrogen-dependent breast tumor cells. This is the therapeutic principle used in the antihormonal AI treatment of ER-positive postmenopausal breast cancer.

Aromatase is encoded by the CYP19A1 gene, which is located on chromosome 15q21.2, spanning 123 kb. The gene contains nine protein-coding exons and ten noncoding upstream exons controlled by tissue-specific promoters.[105]CYP19A1 is polymorphic and therefore genetic variants may influence gene expression or enzyme activity, which might alter AI efficacy.[106,107] The impact of CYP19A1 variants on AI outcome has been thoroughly reviewed by Del Re et al..[108]

Using a CYP19A1 resequencing approach, Ma et al. identified 88 polymorphisms resulting in 44 haplotypes and four nonsynonymous coding SNPs associated with aromatase activity.[106] A study investigating the prognosis of invasive primary breast cancer linked a 3'-UTR polymorphism, rs10046 (C>T), with a favorable 5-year disease-free survival in premenopausal women.[109] Prolonged time to progression in letrozole-treated patients has been linked with the 3'-UTR polymorphism rs4646 (C>A);[110] however, another study reported an association with reduced time to progression.[111] Wang et al. investigated the changes of aromatase activity in AI-treated postmenopausal breast cancer patients in relation to two tightly linked SNPs located in the 5'-flanking region of exon 1.1 (rs6493497 and rs7176005). Notably, both SNPs resulted in greater change in aromatase activity before and after AI treatment in tumor samples, indicating that patients carrying these two SNPs had greater inhibition of aromatase activity. Moreover, a moderate association of these two SNPs with baseline aromatase activity and their association with higher estradiol levels in tumor samples was found.[107] Women carrying the eight-repeat allele (TTTA8) of the tetranucleotide repeat polymorphism in intron 4 (rs60271534) suffered less frequently from AI-associated arthralgia.[112] In healthy individuals, the homozygous CC genotype of a SNP in exon 1.2 (rs1062033) was linked to lower spine and hip bone density.[113] Although the CYP19A1 polymorphisms rs10046 C>T, rs4646 G>T, rs749292 C>T and rs727479 T>G have been suggested to be related to circulating estrogen levels, no association with plasma estrone sulfate levels was reported in a recent study.[114] Despite numerous studies, as of yet there is questionable evidence whether CYP19A1 polymorphisms may impact AI drug response, currently not justifying any genetic testing in breast cancer patients and therefore further comprehensive studies are warranted.

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