CYP2D6 Hot Flashes and Tamoxifen
For those of you who missed it, back in March of 2012, researchers laid to rest the common belief that patients who experience hot flashes were BETTER at metabolizing Tamoxifen. Furthermore, CONTRARY to that belief, it was discovered that POORER metabolizers of TAmoxifen experienced MORE hot flashes. In the same study, they found that using the CYP2D6 genetic test was of no significance either in determining how well patients' bodies metabolized Tamoxifen. And, for those of you who were concerned because you were either a "poor" or "intermediate" metabolizer, based on the CYP2D6 test, THERE WAS NO STATISTICALLY SIGNIFICANT DATA TO SUPPORT THAT CONCLUSION, either!
Comments
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Here is The National Insititue of Cancer's Editorial on the subject:
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CYP2D6 Genotype as a Marker for Benefit of Adjuvant Tamoxifen in Postmenopausal Women: Lessons Learned
Catherine M. Kelly and Kathleen I. Pritchard+ Author Affiliations
- <address>Affiliations of authors: Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland (CMK); Department of Medical Oncology, Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, ON, Canada (KIP) </address>
- Correspondence to:
Kathleen I. Pritchard, MD, FRCPC, Department of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada (e-mail: kathy.pritchard@sunnybrook.ca) and Catherine M. Kelly, MD, MSc, Department of Medical Oncology, Mater Misericordiae University Hospital, 36 Eccles St, Dublin 7, Ireland (e-mail: Catherine.kelly@ucd.ie).
He who does not know history is doomed to repeat it.
Since 2003, there has been considerable interest and a good degree of credence given to the role of cytochrome P450 2D6 (CYP2D6) genotyping to predict tamoxifen benefit in adjuvant therapy (1-5). This construct was based on the fact that a variety of CYP2D6 polymorphisms lead to reduced CYP2D6 enzyme activity and hence result in lower plasma concentrations of endoxifen, a clinically active metabolite of tamoxifen. Tamoxifen itself is known to have a relatively weak affinity for the estrogen receptor (ER) and to undergo extensive primary and secondary metabolism mainly by the CYP2D6 enzyme, forming clinically active metabolites, which include 4-hydroxytamoxifen and endoxifen (4-hydroxytamoxifen and N-desmethyltamoxifen). These latter two metabolites have 30- to 100-fold greater affinity for ER compared with tamoxifen, and endoxifen has been assumed to be the most clinically important metabolite based on its high level in the plasma and high affinity for ER. Patients homozygous for functional CYP2D6 alleles, or heterozygous or homozygous for loss of functional CYP2D6 alleles, have been phenotypically classified as extensive, intermediate, or poor metabolizers, respectively, reflecting plasma concentrations of endoxifen (1,2,6). 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 (4,7,8).
This theory that certain CYP2D6 genotypes and phenotypes were associated with lower endoxifen concentrations and worse breast cancer outcome was supported by laboratory (1,6,9), cohort (9-11), and case-control (12) studies, as well as the prototype retrospective analysis of prospectively collected samples from a North Central Cancer Treatment Group adjuvant breast cancer trial by Goetz et al. (4,13). A variety of subsequent articles both supported and refuted these observations (14).
In this issue of the Journal, two articles by Regan et al. (15) and Rae et al. (16) appear to refute the utility of CYP2D6 genotyping for predicting either tamoxifen benefit in the adjuvant setting or producing hot flushes. In these two large randomized studies comparing tamoxifen to an aromatase inhibitor, relatively large subsets were analyzed. In the study by Rae et al. (16), UK-only patients from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial were included, and in the study by Regan et al. (15), more than half of the patients in the Breast International Group (BIG) 1-98 Trial, for whom tumor tissues could be obtained were analyzed. Extracted DNA was used for genotyping and compared in multivariable analysis with endpoints of breast cancer recurrence (15,16) or occurrence of hot flushes (15). In neither study, was there a statistically significant association between the presence of poor or intermediate metabolizer phenotype and breast cancer outcome. In the study by Rae et al. (16), measurements of UDP-glucuronosyltransferase-2B7 (UGT2B7), whose gene product inactivates endoxifen, were also examined in relation to breast cancer outcome, and no association was observed. Although each of these studies has their weaknesses, the randomized design of the original trials, the examination of 4861 of 8010 patients randomized to receive tamoxifen or letrozole from BIG 1-98 (15), and 1203 of the 2145 patients randomly assigned to receive tamoxifen or anastrozole in the United Kingdom as part of the ATAC study (20% of the total trial) (16) provided large sample sizes, which were basically selected in an unbiased fashion. The blinded genotyping and the statistical analysis were also strong methodological features. The statistical power may still be insufficient to show a positive association between CYP2D6 activity and outcome in patients taking tamoxifen, but possibly further data from other large randomized controlled trials will become available.
However, the fact that these two studies confirm each other suggests that this matter has likely been laid to rest. Why has such a good hypothesis gone wrong? First, it is clear from the discussion in the study by Regan et al. (15) that endoxifen may not be the important metabolite in this setting. It seems that one of the reasons for considerable efficacy of tamoxifen is that several of its active metabolites actually totally saturate ER (17). Furthermore, endoxifen has a different mechanism of action than 4-hydroxytamoxifen by targeting ER-alpha for degradation as opposed to stabilizing it and inhibiting estradiol-mediated overexpression of amphiregulin, a ligand of epidermal growth factor (18). Thus, 4-hydroxytamoxifen may, in fact, be the important metabolite. Furthermore, plasma concentrations of tamoxifen and a primary metabolite N-desmethyltamoxifen are higher than concentrations of either endoxifen or 4-hydroxytamoxifen. Tamoxifen metabolites N-desmethyltamoxifen, di-desmethyltamoxifen, and 4-hydroxytamoxifen have been estimated to nearly saturate ER with 99.94% occupancy (17). Interestingly, the Women's Healthy Eating and Living Study (WHEL), although findings showed no relationship between endoxifen levels and outcome in 1370 women, did observe a poorer outcome in the 20% of women with a plasma endoxifen concentration in the lowest quintile compared with higher quintiles, an observation that may illustrate a minimum critical concentration threshold (19). This may suggest that endoxifen plays a role at low concentrations, but in general, tamoxifen is being dosed at a level that is more than sufficient for even poor metabolizers to derive full benefit from this drug.
During the last 9 years, a great industry of CYP2D6 measurement has arisen. The Food and Drug Administration (FDA) Clinical Pharmacology Subcommittee suggested that the tamoxifen label should be updated to include information about increased risk of breast cancer recurrence in CYP2D6 poor metabolizers taking tamoxifen. Although no consensus was reached regarding routine CYP2D6 genotype testing, many laboratories began testing for CYP2D6 allelic variants. Additional tests and charges were administered to patients, and therapies were presumably adjusted accordingly, all prematurely.
What lessons can we learn?
1. We must avoid bias. The use of randomized trials prospectively designed and retrospectively analyzed is critical to assess the role of biomarkers such as CYP2D6.
2. Large confirmatory studies are required for decisions regarding the use of therapeutic agents. Such studies should be required for the adoption of biomarkers as well.
3. Validation of predictive biomarkers is a complicated process. The clinical importance of valid laboratory observations can be obscured by multiple factors. For example, when the baseline risk of recurrence is low, sometimes surgery alone is adequate without tamoxifen. Second, CYP2D6 phenotype would have little impact on tamoxifen benefit when the breast cancer is already de novo resistant to endocrine therapy. Finally, it is likely that there are many undefined drug interactions between tamoxifen and other medications that affect production of endoxifen and its metabolites, and ultimately treatment response.
In the end, it is crucial to obtain data from randomized trials for clinical demonstration of associations between biomarkers and disease outcomes. 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.
Next SectionFunding
None.
Previous SectionNext SectionFootnotes
The authors declare no conflict of interest. We would like to thank Prof. Lajos Pusztai, Division of Medical Oncology, University of Texas, MD Anderson Cancer Center (Houston, TX) for thoughtful comments regarding the complexities of biomarker validation.
- © The Author 2012. Published by Oxford University Press.
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Here's one of the studies:
__________________________________________________________________________________________________________
J Natl Cancer Inst. 2012 Mar 21;104(6):441-51. Epub 2012 Mar 6.
CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial.
Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R, Dell'orto P, Biasi MO, Thürlimann B, Lyng MB, Ditzel HJ, Neven P, Debled M, Maibach R, Price KN, Gelber RD, Coates AS, Goldhirsch A, Rae JM, Viale G; Breast International Group (BIG) 1-98 Collaborative Group.Source
IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. mregan@jimmy.harvard.edu
Abstract
BACKGROUND:
Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms.
METHODS:
We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor-positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction-based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
RESULTS:
No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43).
CONCLUSIONS:
CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen.
Comment in
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Sounds like this applies to Post Meno women....but these patients typically get an AI now.
I did not link to all of your abstracts but at cursory look, no pre-meno were mentioned....??
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Wallycat...the researchers were specifically looking for those patients who were taking Tamoxifen. And yes, this data specifically looked at post menopausal women. The important news from this study suggests the CYP2D6 test is of no relevance to ascertaining whether or not Tamoxifen is working and that basing whether or not Tamoxifen was effective based on hot flashes did not prove to be a good predictor either.
No PRE menopausal women were included. -
Great thread:
This paper on tamoxifen and endoxifen seems to indicate that only the lowest 20% percentile metabolizers may have somewhat higher risk:
http://www.nature.com/clpt/journal/v89/n5/abs/clpt201132a.html
Tamoxifen has been discovered 40+ years ago. Yet we still aren't sure how it works and why it doesn't work for certain women and fails to work long term for others. This state of ignorance is not blissful!
Clinical trials on endoxifen:
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The link doesn't work. I am assuming, Jenrio, that you are referring to the Barginear study that is looking at increasing the Tamoxifen dose for poor metabolizers based on CYP2D6 results. But like you said... I think the operative word is "may."And after decades of researching and prescribing Tamoxifen and first now realizing hot flashes are NOT indicative of how well it is being metabolized, but more likely how BADLY... Hmmmmm! I am dumbstruck by this new information and ever more dumbstruck by the fact that it is not well known.
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Frankly, I do not think you can extrapolate pre-meno and post meno with metabolizing. It may be that post meno women have enough low estrogen circulating naturally, that the tamoxifen does not impact as much---which would not be the case in premenopause.
It is a leap to presume (in my humble opinion) that pre/post meno is insignificant. The cyp2d6 metabolization may not be an issue but it may be irrespective (or not) of the menopause status.
I am done with my 5year antihormonals, so it is a moot point to me at this time, but if I were taking them, I would certainly care and base my decision accordingly (I was intermediate metabolizer and felt OK with the tamoxifen).
As with every treatment we gals must endure, we make the best choice with the info we have at the time and then try not to look back and second guess ourselves.
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Wally... I was premenopausal when I began this journey. On Tamoxifen and ovarian suppression. Did the CYP2D6 test and found out I was an Ultra metabolizer. Never had a single hot flash.
I agree we make our decisions based on the best available evidence. Perhaps they will do a study of premenopausal women. Stay tuned. -
Sorry the link above doesn't work. let me try again:
http://www.ncbi.nlm.nih.gov/pubmed/21430657
Another article on MBC patients:
http://www.nature.com/bjc/journal/v103/n6/full/6605800a.html
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