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Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. 2444-2447 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.3694 Adjuvant Aromatase Inhibitors for Early Breast Cancer After Chemotherapy-Induced Amenorrhoea: Caution and Suggested Guidelines
From the Royal Marsden Hospital Institute of Cancer Research, London, United Kingdom; Section of Oncology, Department of Medicine, Haukeland University Hospital, Bergen, Norway; University of Virginia Health Sciences Center, Charlottesville, VA; and the University of Michigan Comprehensive Cancer Center, Ann Arbor, MI Address reprint requests to Ian Smith, MD, Breast Unit, the Royal Marsden Hospital, Fulham Rd, London, SW3 6JJ United Kingdom; e-mail: ian.smith{at}rmh.nhs.uk
PURPOSE: Aromatase inhibitors (AIs) are now established as adjuvant therapy for early hormone receptor–positive breast cancer in postmenopausal women. Their use is sometimes extended to younger women after chemotherapy-induced amenorrhoea; we have audited this in one institution's breast unit, and we propose guidelines for use in such circumstances.
PATIENTS AND METHODS: The use of aromatase inhibitors as adjuvant therapy in younger women age RESULTS: A total of 45 such women were identified in the audit, with a median age of 47 years (range, 39 to 52 years). Twelve women (27%) showed a return of ovarian function (10 renewed menses, one pregnancy, one biochemically premenopausal) after starting an AI. Median age at restart of ovarian function was 44 years (range, 40 to 50 years). CONCLUSION: AIs may promote recovery of ovarian function in some women with chemotherapy-induced amenorrhea and should be used with caution. Biochemical monitoring of ovarian function requires highly sensitive immunoassays. Guidelines for the selection and delivery of adjuvant endocrine therapy in such patients are proposed.
We wish to draw urgent attention to a clinically important pitfall in the use of adjuvant aromatase inhibitors (AIs) in early breast cancer. These agents are increasingly used for the treatment of postmenopausal women with hormone receptor–positive early breast cancer, based on evidence of superiority to tamoxifen.1-4 AIs are contraindicated in women with functioning ovaries5 because the reduced feedback of estrogen to the hypothalamus and pituitary leads to an increase in secretion of gonadotrophins. Many premenopausal women with early breast cancer develop amenorrhoea after chemotherapy, however, and in the majority of those older than age 40, this is permanent.6 Some oncologists have therefore started extending the use of AIs to selected women older than age 40 with chemotherapy-induced ovarian failure, on the premise that these patients should benefit just as much as women who are biologically postmenopausal. However, it has recently become apparent to one of us using this practice (I.S.) that some of these women may regain ovarian function while receiving AI therapy and even become pregnant. An audit has therefore been carried out at the Royal Marsden Hospital (London, United Kingdom) and the results discussed with other experts in the field. We present our results here along with proposed consensus guidelines, which we have drawn up jointly for this important clinical issue.
From 2004, the Royal Marsden Breast Unit began to offer AIs as adjuvant therapy to younger women older than age 40 with high-risk breast cancer who had developed chemotherapy-induced amenorrhea that had persisted for at least 6 months, with confirmatory biochemical evidence of ovarian suppression. Previous data have suggested a low chance of recovery of ovarian function in this age group.7 For the audit, we identified all such patients from a prospectively maintained database. Some patients who were receiving AIs and had recovered ovarian function had already been detected on routine clinical follow-up. These patients were recalled, their menstrual history and menopausal symptoms reviewed, and their plasma estradiol levels measured while receiving AI therapy using a high-sensitivity assay (detection limit 3 pmol/L; postmenopausal reference range < 60 pmol/L).
A total of 45 women with early breast cancer who had been treated with an adjuvant AI after chemotherapy-induced amenorrhoea at the Royal Marsden Hospital Breast Unit from April 2004 to September 2005 were identified for the audit. Sixteen patients received first-line treatment (11 anastrozole and five letrozole), 20 received AI treatment after 1 to 3 years of tamoxifen (15 anastrozole, three exemestane, and two letrozole), and nine patients received AI treatment as extended adjuvant therapy after 5 years of tamoxifen. Their median age was 47 years (range, 39 to 52 years), and 33 had biochemically confirmed ovarian suppression before starting treatment. Ten women restarted menstruation while receiving AI therapy, one became pregnant without prior menstruation, and another had a biochemical recovery with a plasma estradiol of more than 1,500 pmol/L and improvement in hot flashes, but without recurrence of menstruation. Overall, 12 of the 45 women, therefore, had recovery of ovarian function (27%). Eight of these had biochemically confirmed suppression of ovarian function with postmenopausal plasma estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels. Eight had recovery of ovarian function confirmed biochemically, with a median plasma estradiol of 252 pmol/L (range, 47 to 461 pmol/L), whereas the expected value while receiving an aromatase inhibitor would be less than 5 pmol/L. Their median age at restart of ovarian function was 44 years (40, 40, 40, 41, 42, 44, 44, 46, 48, 48, 49, and 50 years). Twenty-four (73%) of the remaining 33 patients who remained clinically postmenopausal also had ovarian function checked biochemically and all had postmenopausal plasma estradiol levels. The median duration of amenorrhea before recovery of ovarian function in these 12 patients was 12 months (range, 4 to 59 months). The median duration of AI therapy before ovarian recovery was identified was 6 months (range, 3 to 18 months). Nine of the 12 patients developing recovery of ovarian function had received prior tamoxifen. In the entire series, 29 of the 45 women had been treated with prior tamoxifen.
Most women older than age 40 treated with chemotherapy will develop permanent amenorrhoea.6,7 However, in a small minority, reported as 0% to 11%, ovarian suppression may be temporary, and they may renew menses over time.6,8 Our clinical observations suggest that the incidence of recovery is probably increased by the use of AIs (27% in our audit, compared with 0% to 11% spontaneously in women older than age 40).6 Indeed, AIs are being developed to induce ovulation in premenopausal women, and they may be even more efficacious than the selective estrogen receptor modulator, clomiphene citrate, which currently is standard therapy.9,10 Recovery of ovarian function in women with chemotherapy-induced menopause receiving an AI raises two major concerns: first, the associated return of premenopausal estradiol levels would be expected to diminish or abolish the anticipated anticancer efficacy; second, AI stimulation of unexpected ovulation would expose the patient to the risk of unwanted pregnancy. Unfortunately, predicting which patients will have return of ovarian function is not possible at present. In our audit, it is striking that this could occur up to the age of 50, and after many months of amenorrhoea. These women appear to be in perimenopausal transition, a situation in which a single measurement of FSH, LH, estradiol, and beta-inhibin reflects function only at that time point, and therefore is not useful for predicting the potential for recovery.11,12 Taken together, these concerns suggest that estradiol, LH, and FSH levels should be monitored serially in premenopausal women with hormone receptor–positive breast cancer who become amenorrheic after chemotherapy if they are treated with an AI. Monitoring of ovarian function in such women has its own problems, however; most clinical assays in routine use are automated or kit-based immunoassays that do not involve the extraction of estradiol. These technologies are notoriously unreliable in accurately quantifying estradiol levels in the perimenopausal ranges. Most have been optimized for speed, ease of analysis, and small sample volume. A key element of this is that they do not extract or purify the estradiol from the plasma, and this leads to interferences and nonspecificity that varies between patients. In one study, this amounted to a mean of about 75 pmol/L and varied between 50 and 100 pmol/L.13 Accurate assessment requires the application of highly sensitive immunoassays that include an extraction step or tandem gas chromatography and mass spectrometry assays.13 Unfortunately, these assays are only available in a few laboratories: their provision may need to be expanded to allow widespread practice of monitoring. Measuring estradiol levels in patients receiving a steroidal AI, such as exemestane, is particularly problematic because the metabolites of this agent cross react even in most specialized immunoassays.14 Because of these considerations, we therefore propose the following guidelines to help in the management of patients with hormone receptor–positive breast cancer for whom therapy with an AI is considered in the adjuvant setting. These guidelines pertain particularly to women age 50 years or younger who were menstruating before chemotherapy but developed chemotherapy-induced amenorrhea. They may also be considered for slightly older women, whom we are also now auditing. Patients who have overt return of ovarian function should be considered for recruitment to the Suppression of Ovarian Function (SOFT) trial.15 First, women age younger than 40 years should not receive an AI alone. If estrogen depletion is the desired endocrine strategy, this should be by ovarian function suppression (oophorectomy or chemical suppression with a gonadotropin-releasing hormone agonist) concomitant with an AI. Second, for women older than 40 years, if monitoring is not favored or an accurate estradiol service is not available, AIs should be used alone with great caution. It may be preferable to treat these patients with tamoxifen alone, or if estrogen depletion is preferred, with concurrent ovarian function suppression (surgical ovariectomy or gonadotropin-releasing hormone agonist) plus an AI. Third, for women older than 40 years, if monitoring is favored and an accurate estradiol service is available, monitoring of serial estradiol and gonadotropin levels, using validated and accurate assays, should be carried out at baseline. If levels are within the premenopausal range (ie, normal gonadotropin levels and estradiol > 20 pmol/L) these women are eligible for the SOFT trial.14 Outside of a trial, it is recommended the clinician choose tamoxifen alone, or ovarian ablation (medical or surgical) with tamoxifen, or ovarian ablation with an AI. If levels are consistent with postmenopausal status (elevated gonadotropin levels and estradiol < 10 pmol/L), an AI is appropriate, but serial monitoring should be continued for 6 months. For women starting an AI after recent tamoxifen, monitoring beyond 6 months monitoring might be advisable. If estradiol decreases to and remains below 10 pmol/L, the patient can be considered postmenopausal and ongoing therapy with an AI alone is appropriate. If estradiol remains above 10 pmol/L, the AI is not exerting full effectiveness and the clinician may wish to consider ovarian ablation or switch from the AI to tamoxifen. The following additional recommendations apply. All women in this age group receiving an AI should be instructed to contact their clinician at once should they have what might be a menstrual bleed or should hot flashes stop abruptly. Adequate contraception should be practiced during the monitoring period. There are anecdotal reports of resumption of ovarian function with an AI even while patients are receiving an LH-releasing hormone agonist, and surgical ablation may be more secure. These recommendations represent a rational approach, but are only partly evidence based; the benefits are unproven. Carefully designed, controlled studies are urgently needed in this clinical area. We would also welcome the reports of experiences in the application of these guidelines so that the guidelines can be modified as appropriate.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
We thank Elizabeth Folkerd for all of her hard work with assaying the blood samples for hormone levels, and Donna Saffery for her skills in manuscript preparation.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. ATAC Trialists' Group: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline] 2. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two or three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 3. BIG 1-98 Collaborative Group: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 4. Jakesz R, Samonigg H, Greil R, et al: Extended adjuvant treatment with anastrozole: Results from the ABCSG 6a Trial. J Clin Oncol 23:10s, 2005 (suppl; abstr 527) 5. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer: Status report 2004. J Clin Oncol 23:619-629, 2005 6. Bines J, Oleske DM, Cobleigh MA: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 14:1718-1729, 1996 7. Goodwin PJ, Ennis M, Pritchard KI, et al: Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 17:2365-2370, 1999 8. Bianco AR, Del Mastro L, Gallo C, et al: Prognostic role of amenorrhea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer 63:799-803, 1991[Medline] 9. Mitwally MF, Casper RF: Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 75:305-309, 2001[CrossRef][Medline] 10. Fisher SA, Reid RL, Van Vugt DA, et al: A randomized double-blind comparison of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril 78:280-285, 2002[CrossRef][Medline] 11. Dowsett M, Richner J: Effects of cytotoxic chemotherapy on ovarian and adrenal steroidogenesis in pre-menopausal breast cancer patients. Oncology 48:215-220, 1991[CrossRef][Medline] 12. Singh KL, Davies M, Chatterjee R: Fertility in female cancer survivors: Pathophysiology, preservation and the role of ovarian reserve testing. Hum Reprod Update 11:69-89, 2005 13. Dowsett M, Folkerd E: Deficits in plasma oestradiol measurement in studies and management of breast cancer. Breast Cancer Res 7:1-4, 2005[CrossRef][Medline] 14. Johannessen DC, Engan T, DiSalle 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[Abstract] 15. Krop IE, Winer EP: Ovarian suppression for breast cancer: An effective treatment in search of a home. J Clin Oncol 23:5869-5872, 2005 Submitted December 21, 2005; accepted March 8, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40 with hormone receptor–positive early breast cancer and chemotherapy-induced amenorrhea has been audited clinically and biochemically. 
