Endocrine Therapy in 2009: Consideration of the Tumor and the Host

Breast cancer is the most common female malignancy in the Western world. Two-thirds of all breast cancers are estrogen receptor (ER)-positive, a phenotypic characteristic that is prognostic of disease-free survival and predictive of response to endocrine therapy.

Through its binding to either ER-alpha or -beta, estrogen is known to regulate a wide variety of cellular effects and physiologic conditions including breast cancer cell proliferation. Upon ligand binding, ERs dimerize to form an activated receptor and subsequently bind to specific DNA sequences (estrogen response elements), or interact with other protein/DNA complexes, to regulate target gene expression. Selective estrogen receptor modulators (SERMs) such as tamoxifen disrupt ER activity in cells by blocking estrogen binding to the receptors. In the case of tamoxifen, administration for 5 years following breast cancer surgery almost halves the annual recurrence rate and reduces the breast cancer mortality rate by one-third in both pre- and postmenopausal women.

‘Jekyll and Hyde’ Phenomenon

Unfortunately, there are unpredictable aspects of tamoxifen therapy. In the clinical setting, oncologists sometimes observed “tumor flare” following administration of tamoxifen to women with metastatic breast cancer. Furthermore, in the adjuvant setting, a peak in the hazard rates for recurrence was consistently observed within the first 2 to 3 years in the adjuvant tamoxifen trials.[1] While the reasons for these clinical observations were not entirely clear, preclinical evidence suggested that tamoxifen could stimulate nongenomic growth-factor pathways and that in vivo administration of tamoxifen to mice bearing HER2-transfected ER-positive xenografts stimulated tumor growth.[2] However, the mystery surrounding this “Dr. Jekyll and Mr. Hyde” phenomenon with tamoxifen has continued to baffle most researchers, as the large randomized trials comparing tamoxifen and the aromatase inhibitiors (AIs) have yet to identify a tumor-specific biomarker (such as HER2) or gene profile predictive for response to tamoxifen.[3,4]

Aromatase Inhibitor Strategy

Aromatase inhibitors were developed based on the premise that reduction of the ligand responsible for stimulation of breast cancer growth would be a superior way to treat breast cancer. Randomized trials comparing tamoxifen with the third-generation AIs in the metastatic setting demonstrated that AIs had superior response rates in most[5-7] but not all studies.[8] This led to large “head to head” studies comparing tamoxifen and aromatase inhibitors in the adjuvant treatment of breast cancer, which demonstrated a small but statistically significant improvement in disease-free survival in favor of anastrozole (Arimidex) and letrozole (Femara).[9,10] However, the small difference in disease-free survival comparing tamoxifen to AIs did not translate into a survival advantage. A recent meta-analysis representing data from over 20,000 women confirmed that the aromatase inhibitors offer no survival advantage.[11] This has left the oncology community in the strange position of trying to move from the pre-genomics era of “evidence based” science-in which thousands of patients are enrolled in clinical trials in order to proclaim a “winner” for the “average patient”-to 2009, when personalized medicine is a buzzword but not yet integrated into standard clinical practice in regard to the selection of hormonal therapy.

Genomics Revolution

While studies comparing tamoxifen and aromatase inhibitors were ongoing, a revolution was underway-the genomics revolution. Technologic advances allowed the rapid and accurate assessment of tumor gene expression and function, both at the level of individual genes and by global gene analysis. In the latter example, the expression patterns of thousands of tumor genes could be determined at one time through the use of tissue microarrays, which were critical in identifying specific biologic subsets of cancer more likely to relapse (prognostic) as well as the identification of genes or gene patterns associated with response (prediction).

In the well written paper by Ma et al, the authors summarize findings regarding multiple gene-expression profiles as well as prognostic factors associated with endocrine therapy outcome, mainly related to aromatase inhibitors. However, as of 2009, the study of the tumor genome has yet to identify a predictive marker that allows clinicians to discriminate which endocrine therapy, tamoxifen or AI, should be delivered to a specific patient.

In the specialty of oncology, it is becoming increasingly clear that clinicians must take into account all sources of genetic variation that influence drug effect. This includes both tumor (somatic) as well as host (germline) genetic variation. It should be noted that while the common final pathway of both tamoxifen and the AIs is to disrupt estrogen signaling, both classes of drugs undergo vastly different metabolic routes of elimination and/or activation, and each of these metabolic steps is under genetic control. Therefore, common genetic variations that alter the proteins involved in the metabolism, uptake, or distribution unique to each drug would be a leading candidate for a predictive factor. An obvious example is tamoxifen and the enzyme CYP2D6.

Tamoxifen (Mr. Hyde), Endoxifen (Dr. Jekyll)?

Tamoxifen is a weak antiestrogen (with the ability to stimulate breast cancer growth in some model systems), but metabolism leads to the activation of the drug. Although the tamoxifen metabolite endoxifen was first identified in 1989,[12] it was not until 2003 that its effects on breast cancer proliferation and the enzymes involved in its formation were characterized. Endoxifen is approximately 100-fold more potent than its parent drug (tamoxifen) as an antagonist of the estrogen receptor and is formed by the CYP2D6-mediated oxidation of N-desmethyl tamoxifen.[13,14] Common CYP2D6 genetic variation and/or drug-induced inhibition of CYP2D6 enzyme activity significantly reduces endoxifen plasma concentrations in humans.[15] Seven studies from different cohorts of tamoxifen-treated women in the adjuvant setting have established that patients with decreased CYP2D6 metabolism are at significantly increased risk of breast cancer recurrence compared to those with substantial 2D6 activity.[16-23]

Perhaps the most intriguing part of this story, however, is the recent “bedside-to-bench” discovery demonstrating that the mechanism of action of endoxifen differs substantially from that of either tamoxifen or 4-hydroxy tamoxifen. Endoxifen is a potent antiestrogen that mimics the actions of fulvestrant (Faslodex) with regard to its ability to target ER-alpha for degradation by the proteasome, to block ER-alpha–mediated transcriptional activation, and to inhibit estrogen-induced breast cancer cell proliferation.[24] Importantly, the mechanism by which endoxifen blocks ER signaling and its effect on proliferation is dose-dependent and is maintained even when cells are pretreated with the same concentrations of tamoxifen and 4-hydroxy tamoxifen seen in humans.[24] These findings for the first time identify the reason why metabolic activation by CYP2D6 is key to understanding tamoxifen drug effect, and are likely to unlock the “Dr. Jekyll and Mr. Hyde” mystery surrounding some of the unpredictable aspects of tamoxifen therapy.

In the case of AIs (and in contrast to tamoxifen), the parent drug is considered active, and metabolism inactivates the parent drug. Also in contrast to tamoxifen, CYP2D6 is not known to be involved in the metabolism of any of the three aromatase inhibitors. Large ongoing investigations, including genome-wide association studies, are testing the hypothesis that genetic variation in genes that encode proteins involved in the metabolism, uptake, and distribution of these drugs might be associated with clinical outcome and side effects. Like tamoxifen, this hypothesis is based on the knowledge that there are substantial differences in the frequency of these genetic changes across different populations.

Conclusions

Although the promise of pharmacogenetics and pharmacogenomics has yet to be fully achieved, health-care professionals increasingly have access to gene sequence information. When applied properly, this information has the potential to improve our ability to select the optimal drug at the optimal dose for each patient. We must be clear that the future of individualized medicine in oncology will require consideration of all sources of genetic variation-the tumor and the host. As a result, pharmacogenetics and pharmacogenomics promise to fundamentally alter rational drug therapy.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Buzdar AU, Cuzick J: Anastrozole as an adjuvant endocrine treatment for postmenopausal patients with breast cancer: Emerging data. Clin Cancer Res 12:1037s-1048s, 2006.
2. Shou J, Massarweh S, Osborne CK, et al: Mechanisms of tamoxifen resistance: Increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96:926-935, 2004.
3. Dowsett M, Allred C, on behalf of the TransATAC Investigators: Relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial (abstract 48). Breast Cancer Res Treat 100(suppl 1), 2006.
4. Viale G, Regan M, Dell’Orto P, et al: Central review of ER, PgR and HER-2 in BIG 1-98 evaluating letrozole vs. tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer (abstract 44). Breast Cancer Res Treat 94(suppl 1):S13, 2005.
5. Mouridsen H, Gershanovich M, Sun Y, et al: Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: Analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21:2101-2109, 2003.
6. Nabholtz JM, Buzdar A, Pollak M, et al: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18:3758-3767, 2000.
7. Paridaens RJ, Dirix LY, Beex LV, et al: Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: The European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol 26:4883-4890, 2008.
8. Bonneterre J, Thurlimann B, Robertson JF, et al: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18:3748-3757, 2000.
9. Forbes JF, Cuzick J, Buzdar A, et al: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9:45-53, 2008.
10. Coates AS, Keshaviah A, Thurlimann B, et al: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: Update of study BIG 1-98. J Clin Oncol 25:486-492, 2007.
11. Ingle J, Dowsett M, Cuzick J, et al: Aromatase inhibitors versus tamoxifen as adjuvant therapy for postmenopausal women with estrogen receptor positive breast cancer: Meta-analyses of randomized trials of monotherapy, and switching strategies (abstract 12). Cancer Res 69(suppl):66s, 2008.
12. Lien EA, Solheim E, Lea OA, et al: Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 49:2175-2183, 1989.
13. Desta Z, Ward BA, Soukhova NV, et al: Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 310:1062-1075, 2004.
14. Stearns V, Johnson MD, Rae JM, et al: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758-1764, 2003.
15. Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30-39, 2005.
16. Goetz MP, Ames MM, Gnant M, et al: Pharmacogenetic (CYP2D6) and gene expression profiles (molecular grade index and HOXB13/IL17BR) for prediction of adjuvant endocrine therapy benefit in the ABCSG 8 trial (abstract 57). Cancer Res 69(suppl):76s, 2008.
17. Goetz MP, Knox SK, Suman VJ, et al: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113-121, 2007.
18. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005.
19. Gonzalez-Santiago S, Zárate R, Haba-Rodríguez J: CYP2D6*4 polymorphism as blood predictive biomarker of breast cancer relapse in patients receiving adjuvant tamoxifen (abstract 590). J Clin Oncol 25(18S):25s, 2007.
20. Kiyotani K, Mushiroda T, Sasa M, et al: Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci 99:995-999, 2008.
21. Newman WG, Hadfield KD, Latif A, et al: Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res 14:5913-5918, 2008.
22. Schroth W, Antoniadou L, Fritz P, et al: Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187-5193, 2007.
23. Xu Y, Sun Y, Yao L, et al: Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 19:1423-1429, 2008.
24. Wu X, Hawse J, Subramaniam M, et al: The tamoxifen metabolite, endoxifen, is a potent anti-estrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res. In press.