NEW YORK (Reuters Health) – Two independent studies have shown that reduced-activity variants of the cytochrome P450 2D6 (CYP2D6) enzyme are not associated with poorer disease control in postmenopausal women with endocrine-responsive breast cancer receiving adjuvant tamoxifen.
The studies have been published online March 6 by the Journal of the National Cancer Institute.
In similar language, the authors of one study conclude, “The results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients”, while the authors of the other study comment, “Results suggest that CYP2D6 pharmacogenetic testing is not justified to determine whether tamoxifen should be given to postmenopausal women.”
The authors of a related editorial explain that a number of CYP2D6 polymorphisms lead to reduced enzyme activity and result in lower plasma concentrations of endoxifen, the active metabolite of tamoxifen.
“It was hypothesized that tamoxifen would be less effective in breast cancer patients with poor and intermediate metabolizer phenotypes and that these patients would experience fewer or less severe tamoxifen-induced hot flushes,” note Dr. Catherine M. Kelly at the Mater Misericordiae University Hospital in Dublin, Ireland, and Dr. Kathleen I. Pritchard at Sunnybrook Health Sciences Centre in Toronto, Canada.
“During the last 9 years, a great industry of CYP2D6 measurement has arisen,” they comment.
However, in practice the effect of the CYP2D6 phenotypes on outcomes has not been clearcut, prompting the two current studies.
In one, Dr. James M. Rae, at the University of Michigan Medical Center in Ann Arbor, and colleagues genotyped tumor specimens from a total of 1202 postmenopausal women with hormone receptor-positive early stage breast cancer who participated in a randomized trial of adjuvant tamoxifen and/or anastrozole.
Based on the CYP2D6 genotype, the patients were classified as poor, intermediate or extensive metabolizers. The investigators found no significant association between CYP2D6 genotype and breast cancer recurrence in tamoxifen-treated patients after a median follow-up of 10 years.
Specifically, comparing poor metabolizers to extensive metabolizers, the hazard ratio for any recurrence was 0.99 (p=0.99), the authors report.
In the second study involving a similar cohort of women, Dr. Meredith M. Regan, with the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues obtained tumor tissue from 4861 patients who were randomized to treatment with tamoxifen or letrozole. CYP2D6 genotyping was also used to classify metabolism phenotypes.
The team found that poor and intermediate metabolizers actually had a lower risk of breast cancer recurrence (HR 0.86), although this was not statistically significant.
“In the end, it is crucial to obtain data from randomized trials for clinical demonstration of associations between biomarkers and disease outcomes,” conclude Drs. Kelly and Pritchard in their editorial. “To advance breast cancer therapy, laboratory observations that raise hypotheses must be at the very core of what we do; however, it is only after independent validation that they can begin guide clinical practice.”
SOURCE:
CYP2D6 and UGT2B7 Genotype and Risk of Recurrence in Tamoxifen-Treated Breast Cancer Patients
