Breast cancer update: will genotyping help select best patients?

Previously, pharmacogenetic studies have demonstrated that women with a certain genotype have a better response to tamoxifen. Now, a modeling study has shown that for postmenopausal breast cancer patients with this genotype, tamoxifen is as good or better at reducing the risk for relapse as aromatase inhibitors. This finding does have clinical implications, but routine genotyping for all women considering tamoxifen is not yet recommended until the results have been validated with further studies.

Mathematical models to explore how genotype information affects therapy recommendations have been employed to analyze clinical data collected in the Breast International Group Trial 1-98 (BIG 1-98). This trial, published last year (J Clin Oncol. 2007;25:486-492), compared an aromatase inhibitor with tamoxifen in the adjuvant setting in postmenopausal women with estrogen-receptor-positive breast cancer.

The gene, CYP2D6, codes for a cytochrome P450 enzyme involved in tamoxifen's metabolism. About 60% of individuals of European descent are homozygous for the active alleles of this gene, known as "wild type," and it is this group that shows the best response to tamoxifen.

The model showed that women with this genotype had an outcome with tamoxifen that was similar or superior to the outcome seen with aromatase inhibitors. This finding differs from the results in unselected populations, in which aromatase inhibitors have demonstrated statistically significant improvements in disease-free survival over tamoxifen. It is possible that women who are concerned about the relative toxicity or cost of an aromatase inhibitor could consider undergoing genetic testing; if they are found to be wild type for CYP2D6, they could then pursue treatment with tamoxifen instead.

Several studies have shown that in postmenopausal women, aromatase inhibitors are generally more effective than tamoxifen. This model suggests, however, that the majority of women with the wild-type genotype have better outcomes with tamoxifen than with an aromatase inhibitor and, therefore, tamoxifen would be a better choice for them. The model also suggests that women who are heterozygous for this gene respond less well to tamoxifen, and so they should be treated with an aromatase inhibitor.