CYP2D6 Genotype Not Predictive of Tamoxifen Effectiveness
March 9, 2012 — There has been considerable controversy about whether breast cancer patients planning to receive tamoxifen should undergo CYP2D6 genotyping. The results of 2 very large trials have now found that CYP2D6 does not predict tamoxifen effectiveness.
In addition, one of the studies showed that CYP2D6 genotypes with reduced enzyme activity are not linked to fewer tamoxifen-induced hot flushes.
The results of both studies — the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and the Breast International Group (BIG) 1-98 trial — initially presented in December 2010 at the Annual San Antonio Breast Cancer Symposium, as reported at that time by Medscape Medical News, were published online March 6 in the Journal of the National Cancer Institute.
ATAC and BIG 1-98 "strongly argue against pharmacogenetic testing of CYP2D6 to predict the efficacy of tamoxifen in early-stage hormone-receptor-positive breast cancer patients in postmenopausal women," said James Rae, PhD, assistant professor of medicine at the University of Michigan in Ann Arbor, and lead author of the ATAC trial.
But in both studies, only postmenopausal women were analyzed. "From these data, we cannot draw conclusions regarding CYP2D6 in premenopausal women or in women with advanced disease," he told Medscape Medical News.
It has been suggested that because cytochrome P450 2D6 (CYP2D6) metabolizes tamoxifen into clinically active metabolites, pharmacogenetic testing of CYP2D6 polymorphisms will help identify patients with reduced tamoxifen metabolism phenotypes, which can in turn predict poorer responsiveness to tamoxifen. However, research has produced contradictory and inconsistent results.
Lesson to Be Learned
It has been hypothesized that tamoxifen is less effective in breast cancer patients with poor- and intermediate-metabolizer phenotypes, and that these patients will experience fewer or less severe tamoxifen-induced hot flushes, note Kathleen I. Pritchard, MD, from Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, and Catherine M. Kelly, MD, MSc, from Mater Misericordiae University Hospital, Dublin, Ireland, in an accompanying editorial.
ATAC and BIG 1-98 confirm each other, and suggest that the matter has likely been laid to rest, they write. However, they note that in the past 9 years, "a great industry of CYP2D6 measurement has arisen. In fact, the US Food and Drug Administration Clinical Pharmacology Subcommittee suggested that tamoxifen be labeled to include information about increased risk for breast cancer recurrence in poor metabolizers of CYP2D6.
Even though no consensus has been reached on routine CYP2D6 genotype testing, many laboratories test for CYP2D6 allelic variants. Drs. Pritchard and Kelly explain that this means that "additional tests and charges were administered to patients, and therapies were presumably adjusted accordingly, all prematurely."
There are lessons to be learned from this, the editorialists write. One is that "randomized trials prospectively designed and retrospectively analyzed [are] critical to assess the role of biomarkers such as CYP2D6." Another is that "large confirmatory studies are required for decisions regarding the use of therapeutic agents." The editorialists emphasize that the "validation of predictive biomarkers is a complicated process."
"In the end, it is crucial to obtain data from randomized trials for clinical demonstration of associations between biomarkers and disease outcomes," they conclude. "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."
The ATAC clinical trial is a prospective randomized trial designed to compare the effectiveness and safety of the aromatase inhibitor anastrozole (Arimidex) with tamoxifen in postmenopausal women with hormone-receptor-positive early-stage breast cancer.
Dr. Rae and colleagues genotyped tumor samples for variants in the CYP2D6 gene from 1203 patients (615 in the anastrozole group and 588 in the tamoxifen group) and for variants in the UGT2B7 gene from 1209 patients (606 in the anastrozole group and 603 in the tamoxifen group), the product of which inactivates endoxifen.
The primary end point was an association between the CYP2D6 and UGT2B7 genotypes and distant recurrence; the secondary end point was an association between these genotypes and any recurrence.
At a median follow-up of 10 years, there were no statistically significant associations in the tamoxifen group between the CYP2D6 genotype in poor metabolizers, compared with extensive metabolizers, for distant recurrence (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.55 to 3.15; P = .64) or for any recurrence (HR, 0.99; 95% CI, 0.48 to 2.08; P = 0.99).
There was also a near-null association between the UGT2B7 genotype and recurrence in tamoxifen-treated patients. In addition, there were no associations between the CYP2D6 and UGT2B7 genotypes and recurrence in anastrozole-treated patients.
The BIG 1-98 trial, an international randomized phase 3 trial that compared 5 years of tamoxifen monotherapy 20 mg/day with letrozole (Femara) monotherapy 2.5 mg/day in postmenopausal women with estrogen-receptor-positive and/or progesterone-receptor-positive operable invasive breast cancer.
Meredith M. Regan, ScD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues obtained tumor tissue and isolated DNA from 4861 postmenopausal women with hormone-receptor-positive breast cancer who were enrolled in the BIG 1-98 trial. The DNA was used to genotype 9 CYP2D6 single-nucleotide polymorphisms; genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive.
No association between CYP2D6 metabolism phenotypes and breast-cancer-free interval was observed in chemotherapy-naïve women receiving tamoxifen monotherapy (P = .35). Poor and intermediate metabolizers had a nonstatistically significantly reduced risk for breast cancer recurrence, compared with extensive metabolizers (HR, 0.86; 95% CI, 0.60 to 1.24).
The BIG 1-98 researchers also investigated new-onset or worsening hot flushes during the first 2 years of therapy. In the 1706 chemotherapy-naïve patients treated with tamoxifen, an association was found between CYP2D6 metabolism phenotype and hot flushes (P = .020).
In addition, compared with extensive metabolizers, poor metabolizers had an increased rate of tamoxifen-induced hot flushes (HR, 1.24); the same was true for intermediate metabolizers (HR, 1.23). This finding is contrary to the initial hypothesis — that phenotypes with reduced CYP2D6 enzyme activity would be associated with fewer tamoxifen-induced hot flushes.
The results of BIG 1-98 "suggest that CYP2D6 pharmacogenetic testing is not justified to determine whether tamoxifen should be given to postmenopausal women, nor to withhold treatment with an aromatase inhibitor," they conclude. "The presence or absence of hot flushes should not be used in the clinical setting to estimate tamoxifen efficacy."
However, they add that these results apply only to postmenopausal women, and that the role of CYP2D6 in premenopausal women is not known.
The ATAC study was funded in part by the Breast Cancer Research Foundation, the Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale, Breakthrough Breast Cancer, the National Institute of Health Research Royal Marsden Biomedical Research Centre, and Cancer Research UK program grants. Dr. Rae reports being a scientific advisor for Olema Pharmaceuticals; receiving speaking honoraria from GTx Pharmaceuticals; and receiving research funding from Pfizer. Several of his coauthors report financial relationships with industry, as noted in the paper.
The BIG 1-98 trial was funded by Novartis and coordinated by the International Breast Cancer Study Group (IBCSG). Support for the IBCSG comes from the Swedish Cancer Society, Cancer Council Australia, the Australian New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, the National Institutes of Health at the National Cancer Institute, Cancer Research Switzerland/Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland. Several of the study authors have disclosed financial relationships, as noted in the paper.
J Natl Cancer Inst. Published online March 6, 2012. ATAC Abstract, BIG 1-98 Abstract, Editorial