Complexities of Adjuvant Endocrine Therapy in Young Premenopausal Women
Complexities of Adjuvant Endocrine Therapy in Young Premenopausal Women
This article is a review of Breast Cancer in Women Under 40
Younger women with breast cancer present important management challenges due in part to differences in both tumor biology and individual patient factors. In his article, Peppercorn provides a comprehensive overview of these issues with a particular focus on questions surrounding systemic therapy options.
Adjuvant Endocrine Therapy Choices
Younger age at diagnosis is typically associated with an increased likelihood of estrogen receptor (ER)-negative breast cancer compared to the cancers in older women, yet the majority of women under 40 are diagnosed with ER-positive cancer. Therefore, decision-making about adjuvant endocrine therapy in premenopausal women with breast cancer is important. Selection of endocrine therapy is complicated, however, by uncertainties associated with a lack of data regarding optimal antiestrogen treatment for premenopausal women, as well as difficulties in assessment of ovarian function in amenorrheic women.
The Early Breast Cancer Trialists’ Collaborative Group has shown that adjuvant tamoxifen is equally effective in both premenopausal and postmenopausal women and results in statistically significant improvements in disease recurrence and breast cancer mortality compared to no adjuvant endocrine therapy. Because aromatase inhibitor (AI) therapy is ineffective in women whose ovaries are functional and produce estrogen, tamoxifen is considered the standard of care for premenopausal women with ER-positive breast cancer in the United States. As outlined in the review article, there are a number of outstanding questions about choice of adjuvant endocrine therapy in young women that are currently being addressed by ongoing clinical trials.
Although the standard of care for premenopausal women is tamoxifen, some patients are being offered treatment with ovarian suppression in conjunction with AI therapy, either because they have a contraindication or intolerance to tamoxifen or because their physician believes that the AIs are superior based on data in postmenopausal women.
One concern with this approach is treatment with luteinizing hormone–releasing hormone agonists may result in incomplete ovarian suppression, either initially or over time. Therefore, women treated with ovarian suppression should have their ovarian function monitored serially. Serum estradiol assessment is challenging in this patient population because standard immunoassays for estradiol are inaccurate at low serum concentrations. In addition, immunoassays can result in falsely elevated estradiol levels in women treated with the steroidal AI exemestane (Aromasin) because of metabolite interactions in the assay. More accurate mass spectroscopy–based estradiol assays are available commercially, but these assays are more expensive, have a longer turnaround time, and can be less sensitive at very low estradiol levels.[7,8]
Choosing an adjuvant endocrine therapy for premenopausal women who develop chemotherapy-induced amenorrhea is also challenging. Although these women may be thought to be menopausal, and therefore candidates for AI therapy, ovarian estrogen production may persist even in the setting of prolonged amenorrhea. That is, chemotherapy-induced ovarian failure following chemotherapy is not necessarily permanent as patients may later regain ovarian function and even fertility.
In a retrospective study of 45 breast cancer patients with chemotherapy-induced amenorrhea age 40 and older, about one-quarter of women with chemotherapy-induced amenorrhea developed recurrent ovarian function when treated with an AI. The authors of that study recommended that women under the age of 40 not be treated with an AI alone, regardless of apparent ovarian failure following chemotherapy, and that older women who are postmenopausal based on biochemical assessment be monitored serially for at least the first 6 months of AI therapy. As mentioned above, however, there remain substantial technical limitations with currently available commercial estradiol assays, which make monitoring more challenging.
Assessment of CYP2D6 Metabolizer Status
For those women treated with tamoxifen, the question of whether or not to assess CYP2D6 metabolizer status is timely and controversial. Tamoxifen, a relatively weak selective estrogen receptor modulator, is a prodrug that is metabolized in the liver to a number of active metabolites, including 4-hydroxytamoxifen and endoxifen (4-hydroxy-N-desmethyltamoxifen). Although these two equipotent metabolites are more active antiestrogens than tamoxifen, endoxifen is present at higher concentrations in most women taking tamoxifen.
CYP2D6 is a noninducible, highly polymorphic P450 enzyme that converts tamoxifen to endoxifen. Of the 80 different major alleles of CYP2D6 that have been identified to date, many cause decreased or absent CYP2D6 activity. Patients can be divided into poor, intermediate, extensive, and ultrarapid metabolizer cohorts based on their CYP2D6 genotype. Approximately 7% of Caucasians are homozygous for an inactive, variant allele designated *4; in a prospective observational study of breast cancer patients treated with tamoxifen, those who were homozygous for this poor-metabolizer genotype (*4/*4) had lower levels of endoxifen than those with wild-type (extensive metabolizer) (*1/*1) genotypes.
CYP2D6 Genotype: What Are the Clinical Implications?
Multiple retrospective studies have been conducted evaluating the effect of CYP2D6 genotype on breast cancer outcomes. In the first, tamoxifen-treated ER-positive breast cancer patients homozygous for the poor-metabolizer genotype were more likely to experience breast cancer recurrence than those patients homozygous for wild-type enzyme.[14,15] The authors hypothesized that patients who were poor metabolizers did not activate tamoxifen to endoxifen and therefore received less or no benefit from tamoxifen. Results from some subsequent studies have confirmed this finding.[16,17] Two studies, however, demonstrated that CYP2D6 *4/*4 patients had better outcomes when treated with tamoxifen compared to those with wild-type CYP2D6 genotype, which is the opposite of the initial findings.[18,19]
These investigations suggest an important role for CYP2D6 activity in tamoxifen metabolism, although further studies are required. Until these contradictory results have been resolved, however, it remains unclear how the results of CYP2D6 testing should be applied clinically—especially in the premenopausal population for whom there are limited available alternative therapies.
As mentioned by Peppercorn, multiple antidepressants, including paroxetine, fluoxetine, duloxetine (Cymbalta), bupropion, and possibly sertraline are known to be moderate or potent inhibitors of CYP2D6. Studies have demonstrated lower levels of endoxifen in women treated concomitantly with several of these antidepressants and tamoxifen.[13,20] Since alternative treatments for depression or hot flashes that do not affect CYP2D6 activity are indeed available—including venlafaxine (Effexor), citalopram, and gabapentin—known CYP2D6 inhibitors can generally be avoided in tamoxifen-treated patients.
Overall, this excellent overview of management issues for breast cancer patients under 40 years of age highlights the major questions surrounding choices of adjuvant systemic therapy. Treatment choices are dependent on breast cancer biology (receptor status) as well as patient factors (ovarian function and desire for future fertility). As many unanswered questions remain, it is important to continue to enroll subjects in clinical trials focused on this important patient population.
Financial Disclosure: Dr. Henry has received research funding from AstraZeneca.
2. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005.
3. Dowsett M, Haynes BP: Hormonal effects of aromatase inhibitors: Focus on premenopausal effects and interaction with tamoxifen. J Steroid Biochem Mol Biol 86:255-263, 2003.
4. Carlson RW, Schurman CM, Rivera E, et al: Goserelin plus anastrozole for the treatment of premenopausal women with hormone receptor positive, recurrent/metastatic breast cancer (abstract 6052). Breast Cancer Res Treat 88(suppl 1):S237, 2004.
5. Dowsett M, Folkerd E: Deficits in plasma oestradiol measurement in studies and management of breast cancer. Breast Cancer Res 7:1-4, 2005.
6. Johannessen DC, Engan T, Di Salle E, et al: Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: A phase I study. Clin Cancer Res 3:1101-1108, 1997.
7. Nelson RE, Grebe SK, DJ OK, et al: Liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of estradiol and estrone in human plasma. Clin Chem 50:373-384, 2004.
8. Kushnir MM, Rockwood AL, Bergquist J, et al: High-sensitivity tandem mass spectrometry assay for serum estrone and estradiol. Am J Clin Pathol 129:530-539, 2008.
9. Braverman AS, Sawhney H, Tendler A, et al: Pre-menopausal serum estradiol (E2) levels may persist after chemotherapy (CT)-induced amenorrhea in breast cancer (BC) (abstract 164). Proc Am Soc Clin Oncol 21, 2002.
10. Smith IE, Dowsett M, Yap Y-S, et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: Caution and suggested guidelines. J Clin Oncol 24:2444-2447, 2006.
11. 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.
12. Johnson MD, Zuo H, Lee KH, et al: Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85:151-159, 2004.
13. 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.
14. 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.
15. Goetz MP, Suman V, Ames M, et al: Tamoxifen pharmacogenetics of CYP2D6, CYP2C19, and SULT1A1: Long term follow-up of the North Central Cancer Treatment Group 89-30-52 adjuvant trial (abstract 6037). Cancer Res 69(suppl), 2009.
16. Lim HS, Ju Lee H, Seok Lee K, et al: Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25:3837-3845, 2007.
17. 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.
18. Wegman P, Elingarami S, Carstensen J, et al: Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9:R7, 2007.
19. Wegman P, Vainikka L, Stal O, et al: Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7:R284-R290, 2005.
20. Borges S, Desta Z, Li L, et al: Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80:61-74, 2006.