Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded and immunohistochemically stained tumor samples

Abstract

Accurate genetic testing for polymorphisms in several genes of pharmacogenetic importance can be obtained from archival paraffin-embedded tumor samples. Thus, pharmacogenetic analysis can be applied to existing cancer therapy trials to test associations between these polymorphisms and treatment response.

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

“…Despite these differences, investigators in all 6 studies agreed that DNA extracted from tumor-infiltrated tissue is a suitable alternative to DNA extracted from nonneoplastic tissue as a source for pharmacogenetic studies of CYP2D6 activity. This could be explained by negligible LOH at the CYP2D6 locus or by contribution of germline genotype information by stromal and immune cells (44). These CYP2D6-specific concordance findings comport with similar work on different chromosomal loci with high LOH in breast cancer (48,49).…”

“…We defined the specificity of genotype classification as the probability that a germline CYP2D6 wild-type homozygote was correctly classified as such by genotyping DNA from tumor-infiltrated tissue. We specified beta distributions for sensitivity and specificity using direct evidence from the 3 genotype concordance studies that published contingency tables (33,43,44) (see Web Figure 1). For each study based on tumor-infiltrated tissue, we randomly selected values of sensitivity and specificity from their respective beta distributions and used these to estimate frequencies of cases and persons-at-risk (or controls, for case-control designs) that would have been observed had nonneoplastic tissue been used instead.…”

“…Five of these studies found near-perfect genotype concordance between tissue sources (39,(43)(44)(45)(46). Most recently, Goetz et al (33) studied CYP2D6 genotype concordance in a series of 190 breast cancer patients enrolled in the North Central Cancer Treatment Group adjuvant breast cancer trial.…”

“…As is reviewed in detail below, 6 validation studies (578 patients) have compared CYP2D6 genotype in DNA extracted from tumorinfiltrated tissues with CYP2D6 genotype in DNA extracted from nonneoplastic tissues (33,39,(43)(44)(45)(46). While in 5 of these 6 validation studies (388 patients) investigators reported near-perfect concordance (37), another study (190 patients) found only 88% agreement (33).…”

Pharmacogenetics in the treatment of breast cancer

“…Genetic variants that might predict the composite results of treatment represented by tumor response and side effects may reside in the germline, since most tumor DNA remains the germline DNA of the patient. 10 Indeed, a woman's primary breast cancer is more likely to genetically resemble her metastatic foci than another woman's primary tumor with similar histological characteristics. 6 Pharmacogenomics of drug response may also be related to the genetic inheritance of single-nucleotide polymorphism (SNPs) or other changes such as insertions or deletions in important genes relevant to drug disposition and effect, including drug metabolizing enzymes, transporters, or drug targets.…”