Defining ovarian failure in amenorrheic young breast cancer patients

The Breast 19 (2010) 545e548

Contents lists available at ScienceDirect

The Breast journal homepage: www.elsevier.com/brst

Viewpoints and debate

Defining ovarian failure in amenorrheic young breast cancer patients Eitan Amir a, *, Orit Freedman b, Lisa Allen c, Terence Colgan d, Mark Clemons e a

Division of Medical Oncology, Princess Margaret Hospital, Toronto, Canada Medical Oncology, Durham Regional Cancer Centre, Oshawa, Canada c Department of Gynecology, Mount Sinai Hospital, Toronto, Canada d Department of Pathology, Mount Sinai Hospital, Toronto, Canada e Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 November 2009 Received in revised form 14 June 2010 Accepted 15 June 2010 Available online 7 July 2010

At present, there is no gold standard test for the investigation of ovarian function in pre-menopausal breast cancer patients who develop amenorrhea after chemotherapy. Clinical, biochemical and biophysical investigations continue to be utilized in clinical practice, despite concerns regarding their predictive value for menopause. The resulting uncertainty about a woman’s actual menopausal status has important consequences for patient management. These include choice of appropriate endocrine therapy, assessment of residual ovarian function and its effect on breast cancer recurrence, fertility issues and the prediction of the likelihood of conception. It is hoped that the development of novel surrogates may allow clinicians to more accurately assess menopausal status and thereby facilitate tailored and individualised therapy for this common group of patients. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: Breast cancer Menopause Diagnosis Hormone therapy

Introduction Worldwide, over 400,000 pre- or peri-menopausal women will be diagnosed with breast cancer each year and around threequarters of these women will also have hormone receptor positive disease.1 Many of these patients will be treated with cytotoxic chemotherapy followed by endocrine therapy.2,3 An important and well-recognised consequence of chemotherapy is the risk of either transient or permanent amenorrhea. Furthermore, for those women who continue to menstruate, or who recover their cycles after a period of amenorrhea, the possibility of an early menopause remains.4 Currently, many important and practical questions regarding ovarian function in breast cancer patients remain unanswered. These questions vary from the assessment of residual ovarian function and its effect on choice of endocrine therapy (i.e. tamoxifen versus an aromatase inhibitor), to fertility issues as well as factors relating to sexual and bone health. This lack of data can cause significant challenges for both patients and their physicians. Accurate assessment of ovarian function and menopausal status is crucial for good patient management. For oncologists, the need for such assessment is most acute with regard to the management of breast cancer risk with endocrine therapy. Despite their * Corresponding author at: Division of Medical Oncology, Room 5-224, Princess Margaret Hospital, 610 University Ave, Toronto, ON M5G 2M9, Canada. Tel.: þ1 416 946 4534; fax: þ1 416 946 2983. E-mail address: [email protected] (E. Amir). 0960-9776/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2010.06.003

contraindication in this setting, an increasing number of women who are pre- or peri-menopausal at the time of diagnosis and whose menses stop with adjuvant chemotherapy are being given aromatase inhibitors (AIs) without concomitant ovarian suppression or ablation. Such practice has ethical and medico-legal implications. For example, if patients are incorrectly assumed to be post-menopausal, the consequences may include pain from ovarian hyperstimulation induced by AIs,5e7 an increased risk of unplanned pregnancy8 and finally an AI induced rise in serum estradiol levels.8 The paucity of effective and practical research in this area has been recognized amongst breast cancer advocacy groups,9 has been raised at the plenary breast cancer session at the 2009 Annual Meeting of the American Society of Clinical Oncology10 and has been described in the general medical literature.11 The definitions of menopause and the resulting biochemical changes in breast cancer patients are complex. A comprehensive literature review of MEDLINE (1950 to August 2009) was therefore carried out with the search restricted to English articles using the following subject headings: “breast cancer”, “pre-menopausal”, “amennorrhea” and “diagnosis”. Available data were then synthesized and are presented in this article. Current definition of menopausal status in the non-breast cancer patient Menopause is classically defined as the absence of menstrual periods for 12 consecutive months with no other biological or

546

E. Amir et al. / The Breast 19 (2010) 545e548

physiological cause being identified.12 Clinicians frequently attempt to verify this clinical diagnosis with biochemical tests such as elevated follicle stimulating hormone (FSH) or luteinising hormone (LH) or depressed levels of estradiol. However, there are a number of problems with this approach. Firstly, there is no cutoff point for these biomarkers; evidence supports a dynamic and highly variable process occurring during the perimenopause, and early menopause years. This means that at a single time point, testing for FSH, LH and estradiol is not sufficient to confirm menopause (Fig. 1). It is possible that assessment of these biomarkers at more than one time point would be more accurate, but unfortunately, there is little data to advise how many time points are needed or the interval between them. Secondly, despite improvements to current radioimmunoassays for plasma estradiol, these remain neither sensitive nor specific enough to detect the low levels of estradiol present in post-menopausal women.13 Tandem mass spectrometry, a method that has been validated to quantitate steroids in the picogram/ millilitre range,14 is unfortunately rarely available in non-research settings. Consequently, in women in whom cessation of menstruation cannot be used as an indicator of menopause, the use of FSH, LH and estradiol assays, is unable to provide definitive information on menopausal status. Consequently, there remains no international consensus as to the gold standard investigation for assessment of menopause, although there is agreement in the form of a World Health Organization report that the absence of primordial follicles in the ovarian cortex, and consequently an absence of any maturing follicles (Graafian follicle shown in Fig. 2) or regressed corpora lutea, is generally associated with ovarian failure.15 The role of selective ovarian biopsy to diagnose menopause has been evaluated, however, in view of the significant heterogeneity of follicle distribution within the ovary, ovarian sampling commonly misses both primary and secondary follicles. Ovarian biopsy is therefore associated with a low negative predictive value and adds little to the ovarian reserve tests currently in practice.16 Defining menopause in amenorrheic breast cancer patients on endocrine therapy The clinical definitions described above can be difficult to use in patients who are receiving tamoxifen, as menstruation tends to be unpredictable. Indeed, clinical trials of endocrine therapy in breast cancer have used a number of definitions of menopause.17 Confirmatory biochemical tests can also be problematic in this setting because tamoxifen use in both pre-menopausal patients with chemotherapy-induced amenorrhea and post-menopausal women is associated with a marked fall of FSH levels.18,19 Furthermore, estradiol levels can themselves be elevated by tamoxifen due to cross-reactivity of tamoxifen and its metabolites and the estradiol

Fig. 2. Graafian Follicle in a 39-year-old amenorrheic patient on Tamoxifen.

assay.19,20 Therefore, the significance of FSH and estradiol as surrogate markers for menopause and the clinical significance of amenorrhea in this setting are unclear.11 Defining menopause in amenorrheic breast cancer patients after chemotherapy The use of chemotherapy is associated with a reduction in ovarian reserve, with ovarian failure being more common those over >35 years of age. This risk also increases with the use of higher cumulative doses of chemotherapy, especially with alkylating drugs such as cyclophosphamide and the addition of taxanes to anthracyclines.21e23 Incidence rates for return of menses after selected modern chemotherapy regimens are shown in Table 1. Most long-term follow-up studies assessing postchemotherapy ovarian function rely on menstruation as the only surrogate marker of menopause,22,23 but this can be misleading as there have been case reports describing spontaneous conception in women with amenorrhea secondary to premature ovarian failure.30 Indeed, a review of early breast cancer patients treated with AI therapy after chemotherapy-induced amenorrhea showed that 27% regained ovarian function after initiation of AI therapy at a median of 12 months (range 4e59 months), demonstrating that in a perimenopausal woman who has received chemotherapy, an arbitrary cutoff of 12 months of amenorrhea is not only inappropriate but also potentially dangerous for the patient.31 Therefore, in clinical practice, in order to predict for menopause, physicians tend to use an arbitrary collection of clinical signs such as age, menstrual history, presence of menopausal symptoms and likelihood of

Fig. 1. Daily concentrations of urinary gonadotrophins (Adapted from O’Connor KA, Holman DJ, Wood JW. Menstrual cycle variability and the perimenopause. Am J Hum Biol. 2001; 13: 465-78. Copyright 2001, John Wiley & Sons; Reprinted with permission of John Wiley & Sons, Inc.).

E. Amir et al. / The Breast 19 (2010) 545e548 Table 1 Incidence of return of menses by adjuvant chemotherapy regimen type. Chemotherapy regimen

Incidence of return of menses

Classic CMF24

39% (<40 yrs) 5% (40 yrs) 66% 67% 48% 28% 32% 85% (<40 yrs) 50% (40 yrs)

25

AC FAC26 TAC26 FEC27 FEC-D27 AC-Taxane28 AC-Taxane29

547

cancer therapies such as chemotherapy, tamoxifen and/or LHRH agonists. Physicians and patients should therefore consider either using tamoxifen, an agent with known activity irrespective of menopausal status. If AIs are indicated, ovarian ablation or suppression to ensure that patients are truly post-menopausal must be considered. In the future, it is hoped that novel biochemical surrogates will allow clinicians to more accurately assess menopausal status and thereby allow for better-tailored therapy for this group of patients. Conflict of Interest Statement

gonadal toxicity from chemotherapy together with biochemical surrogates. The evidence summarised above would suggest this practice is suboptimal. Future directions In the setting of fertility and assisted reproduction, non-invasive investigations of ovarian reserve have become established32 and these tests may be of value in assessing ovarian function in cancer patients. These have included biophysical tests such as sonographic assessment of antral follicle count (AFC), and ovarian volume. Measurement of the thickness of the endometrial lining as a surrogate for absolute levels of circulating estrogens has been investigated, but this association is clearly confounded by the use of tamoxifen.33 Biochemical parameters such as basal FSH, LH, estradiol, FSH/LH ratio, clomiphene citrate challenge test, inhibin-B levels, anti-Müllerian hormone levels, GnRH agonist stimulation test, and exogenous FSH ovarian reserve test, have all been proposed.34e38 Of these tests, anti-Müllerian hormone (AMH) has been suggested as the most reliable marker of ovarian reserve.39 In the cancer setting, AMH showed a more rapid and sustained change after chemotherapy than either estradiol or FSH.19 Furthermore, evidence shows that compared with FSH and inhibin-B, AMH constitutes the most sensitive predictor for ovarian reserve in women treated with chemotherapy for Hodgkin’s lymphoma.40 A recent study41 exploring predictors of ovarian reserve in premenopausal women with breast cancer evaluated a number of biochemical and biophysical parameters of ovarian reserve. This study used a control group of age-matched patients with no medical illness, proven fertility and normal menstrual history for validation. Results showed that AFC as measured by transvaginal ultrasound was the only biophysical parameter to show a good correlation with menopause. Amongst the biochemical markers, basal and stimulated serum AMH, FSH, inhibin-B and estradiol were all different in breast cancer patients as compared to controls. It is hoped that further refinement of these biomarkers in cancer patients will allow a more accurate, non-invasive technique for assessment of menopausal status in young breast cancer patients. Patients undergoing oophorectomy, a procedure that leads to a definitive menopausal state, would be an ideal patient group in whom to study the sensitivity and specificity of these novel biomarkers, which could then be compared to pathological examination of the whole ovary, a method that negates the problem of follicle heterogeneity. Conclusion It is difficult to accurately assign post-menopausal status to amenorrheic women who were pre- or peri-menopausal at the time of breast cancer diagnosis. The lack of a specific biochemical or biophysical surrogate of menopausal status is a further source of diagnostic uncertainty; a setting not aided by concurrent breast

None declared. References 1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002. Cancer incidence, mortality and prevalence worldwide. IARC cancerbase No. 5, version 2.0. Lyon: IARCPress; 2004. 2. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451e67. 3. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930e42. 4. Partridge A, Gelber S, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Winer E. Age of menopause among women who remain premenopausal following treatment for early breast cancer: long-term results from International Breast Cancer Study Group Trials V and VI. Eur J Cancer 2007;43:1646e53. 5. Schinzinger A. 18th Congress of the German Society for Surgery. Beilage zum Centralblatt fur Chirurgie 1889;16:55e6. Ueber carcinoma mammae [abstract]. 6. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003;348:2431e42. 7. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305e9. 8. Smith IE, Dowsett M, Yap YS, Walsh G, Lønning PE, Santen RJ, et al. Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhea: caution and suggested guidelines. J Clin Oncol 2006;24:2444e7. 9. Young Survival Coalition. Young women and breast cancer, http://www. youngsurvival.org/young-women-and-bc/ [Accessed 09.09.08]. 10. Davidson NE. Adjuvant therapy for premenopausal women with endocrineresponsive disease. ASCO; 2009. 11. Amir E, Seruga B, Freedman OC, Clemons M. Endocrine therapy for breast cancer: prolonged amenorrhoea is not necessarily indicative of menopause. BMJ 2009;339:b4261. 12. World Health Organization. Technical report series 670: research on the menopause. Geneva, Switzerland: WHO; 1991. 13. Wang S, Paris F, Sultan CS, Song RX, Demers LM, Sundaram B, et al. Recombinant cell ultrasensitive bioassay for measurement of estrogens in postmenopausal women. J Clin Endocrinol Metab 2005;90:1407e13. 14. Sundaram B, Ohorodnik S, Settlage J, Taylor P. A bioanalytical method for the quantitation of estradiol, estrone, testosterone and dihydrotestosterone in human serum. AAPS PharmSci 2003;5(S1). 15. World Health Organization. Report of a WHO Scientific Group Research on the menopause. Geneva: World Health Organization; 1981. WHO Technical Report Series No. 670. 16. Sharara FI, Scott RT. Assessment of ovarian reserve. Is there still a role for ovarian biopsy? First do no harm! Hum Reprod 2004;19:470e1. 17. Clemons M, Simmons C. Identifying menopause in breast cancer patients: considerations and implications. Breast Cancer Res Treat 2007;104:115e20. 18. Delrio G, De Placido S, Pagliarulo C, d’Istria M, Fasano S, Marinelli A, et al. Hypothalamicepituitaryeovarian axis in women with operable breast cancer treated with adjuvant CMF and tamoxifen. Tumori 1986;72:53e61. 19. Rossi E, Morabito A, Di Rella F, Esposito G, Gravina A, Labonia V, et al. Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial. J Clin Oncol 2009 Jul 1;27(19):3192e7. 20. Lum SS, Woltering EA, Fletcher WS, Pommier RF. Changes in serum estrogen levels in women during tamoxifen therapy. Am J Surg 1997;173(5):399e402. 21. Anderson RA, Themmen AP, Al-Qahtani A, Groome NP, Cameron DA. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod 2006;21:2583e92. 22. Petrek NA, Naughton MJ, Case LD, Paskett ED, Naftalis EZ, Singletary SE, et al. Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study. J Clin Oncol 2006;24:1045e51. 23. Tham YL, Sexton K, Weiss H, Elledge R, Friedman LC, Kramer R. The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. Am J Clin Oncol 2007;30:126e32.

548

E. Amir et al. / The Breast 19 (2010) 545e548

24. Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients: the International Breast Cancer Study Group. Ann Oncol 1990;1:183e8. 25. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996;14:1718e29. 26. Nabholtz J, Pienkowski T, Mackey J, Pawlicki M, Guastalla J, Vogel C, et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 2002;21:36a [abstr 141]. 27. Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol 2006;24:5664e71. 28. Fornier MN, Modi S, Panageas KS, Norton L, Hudis C. Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer 2005;104:1575e9. 29. Oktay K, Libertella N, Oktem O, Beck L, Cil A. The impact of paclitaxel on menstrual function. Breast Cancer Res Treat 2005;94:S271 [abstr 6067]. 30. Vital-Reyes V, Tellez-Velasco S, Chhieng D, Grizzle W, Reyes-Fuentes A. Spontaneous pregnancy in a woman with premature ovarian failure: a case report. J Reprod Med 2004;49:989e91. 31. Smith IE, Dowsett M, Yap YS, Walsh G, Lønning PE, Santen RJ, et al. Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol 2006;24:2444e7. 32. Bukulmez O, Arici A. Assessment of ovarian reserve. Curr Opin Obstet Gynecol 2004;16(3):231e7.

33. Sit AS, Modugno F, Hill LM, Martin J, Weissfeld JL. Transvaginal ultrasound measurement of endometrial thickness as a biomarker for estrogen exposure. Cancer Epidemiol Biomarkers Prev 2004;13:1459e65. 34. Sharara FI, Scott Jr RT, Seifer DB. Contemporary investigation of ovarian reserve in infertile women. Am J Obstet Gynecol 1998;179:804e12. 35. VanRooij IAJ, Broekmans FJM, te Velde ER, Fauser BC, Bancsi LF, de Jong FH, et al. Serum anti-mullerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002;17:3065e71. 36. Kwee J, Elting MW, Schats R, Bezemer PD, Lambalk CB, Schoemaker J. Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment: results of a prospective randomized study. Hum Reprod 2003;18:1422e7. 37. Larsen EC, Muller J, Rechnitzer C, Schmiegelow K, Andersen AN. Diminished ovarian reserve in female childhood cancer survivors with regular menstrual cycles and basal FSH <10 IU/l. Hum Reprod 2003;18:417e22. 38. Larsen EC, Muller J, Schmiegelow K, Rechnitzer C, Andersen AN. Reduced ovarian function in long-term survivors of radiation- and chemotherapytreated childhood cancer. J Clin Endocrinol Metab 2003;88:5307e14. 39. Kwee J, Schats R, McDonnell J, Themmen A, de Jong F, Lambalk C. Evaluation of anti-Müllerian hormone as a test for the prediction of ovarian reserve. Fertil Steril 2008;90:737e43. 40. van Beek RD, van den Heuvel-Eibrink MM, Laven JS. Anti-Mullerian hormone is a sensitive serum marker for gonadal function in women treated for Hodgkin’s lymphoma during childhood. J Clin Endocrinol Metab 2007;92:3869e74. 41. Lutchman Singh K, Muttukrishna S, Stein RC, McGarrigle HH, Patel A, Parikh B, et al. Predictors of ovarian reserve in young women with breast cancer. Br J Cancer 2007;96:1806e16.