Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole.

PURPOSE This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor-positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. PATIENTS AND METHODS Women age 40 to 49 with estrogen receptor-positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. RESULTS The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. CONCLUSION These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

[1]  R. Greil,et al.  Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[2]  P. Lønning,et al.  Interpreting plasma estrogen levels in breast cancer: caution needed. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  M. Banerjee,et al.  Predictors of recovery of ovarian function during aromatase inhibitor therapy. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[4]  M. Climent,et al.  Incidence and predictors of ovarian function recovery (OFR) in breast cancer (BC) patients with chemotherapy-induced amenorrhea (CIA) who switched from tamoxifen to exemestane. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  M. Dowsett,et al.  Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  R. Kreienberg,et al.  Endocrine therapy in obese patients with primary breast cancer: another piece of evidence in an unfinished puzzle , 2012, Breast Cancer Research and Treatment.

[7]  G. Greendale,et al.  Bone mineral density loss in relation to the final menstrual period in a multiethnic cohort: Results from the Study of Women's Health Across the Nation (SWAN) , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[8]  P. Neven,et al.  Undetectable antimüllerian hormone levels and recovery of chemotherapy-induced ovarian failure in women with breast cancer on an oral aromatase inhibitor , 2011, Menopause.

[9]  R. Greil,et al.  Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  R. Kelley,et al.  Evidence for drugs and biomarkers in oncology guidelines (GLs): A survey of the National Comprehensive Cancer Network (NCCN) colon cancer panel. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  H. Rugo,et al.  Which factors should be taken into account in perimenopausal women with early breast cancer who may become eligible for an aromatase inhibitor? Recommendations of an expert panel. , 2011, Cancer treatment reviews.

[12]  Richard A. Anderson,et al.  Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. , 2011, The Journal of clinical endocrinology and metabolism.

[13]  V. Valero,et al.  Phase II trial of anastrozole plus goserelin in the treatment of hormone receptor-positive, metastatic carcinoma of the breast in premenopausal women. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  J. Griggs,et al.  American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  S. Singletary,et al.  Incidence and time course of bleeding after long‐term amenorrhea after breast cancer treatment , 2010, Cancer.

[16]  E. Perez,et al.  Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. , 2010, The New England journal of medicine.

[17]  A. DeMichele,et al.  Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive‐aged breast cancer survivors , 2010, Cancer.

[18]  Yusuke Nakamura,et al.  Serum estradiol should be monitored not only during the peri-menopausal period but also the post-menopausal period at the time of aromatase inhibitor administration , 2009, World journal of surgical oncology.

[19]  B. Nan,et al.  Estradiol rates of change in relation to the final menstrual period in a population-based cohort of women. , 2008, The Journal of clinical endocrinology and metabolism.

[20]  D. Ziegler,et al.  Erratum to ‘Clinical use of aromatase inhibitors (AI) in premenopausal women’ [J. Steroid Biochem. Mol. Biol. 95 (2005) 121–127] , 2008, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  J. Cauley,et al.  Bone Mineral Density Changes during the Menopause Transition in a Multiethnic Cohort of Women , 2008 .

[22]  K. Blackwell,et al.  A Pilot Study of Predictive Markers of Chemotherapy-Related Amenorrhea Among Premenopausal Women with Early Stage Breast Cancer , 2008, Cancer investigation.

[23]  M. Ellis,et al.  Adjuvant Aromatase Inhibitors for Early Breast Cancer After Chemotherapy-Induced Amenorrhoea: Caution and Suggested Guidelines , 2007 .

[24]  C. Hudis,et al.  Inadvertent use of aromatase inhibitors in patients with breast cancer with residual ovarian function: cases and lessons. , 2006, Clinical breast cancer.

[25]  S. Nakajima,et al.  Resumption of Menses with Initiation of Letrozole After Five Years of Amenorrhea on Tamoxifen: Caution Needed When Using Tamoxifen Followed by Aromatase Inhibitors , 2006, Cancer investigation.

[26]  P. Lønning,et al.  Endocrine effects of aromatase inhibitors and inactivators in vivo: Review of data and method limitations , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[27]  D. Ziegler,et al.  Clinical use of aromatase inhibitors (AI) in premenopausal women , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[28]  N. Skakkebæk,et al.  Inhibin A and B as markers of menopause: a five‐year prospective longitudinal study of hormonal changes during the menopausal transition , 2005, Acta obstetricia et gynecologica Scandinavica.

[29]  A. Goldhirsch,et al.  Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[30]  D. Seifer,et al.  Dimeric inhibin: a direct marker of ovarian aging. , 1998, Fertility and sterility.

[31]  M. Cobleigh,et al.  Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Sherry Sherman,et al.  Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. , 2012, Fertility and sterility.

[33]  I. Henderson Longer Therapy, Iatrogenic Amenorrhea, and Survival in Early Breast Cancer: Swain SM, Jeong J-H, Geyer CE Jr, et al (Washington Cancer Inst at Washington Hosp Ctr, DC; Univ of Pittsburgh, PA; et al) N Engl J Med 362:2053-2065, 2010§ , 2011 .

[34]  A. Goldhirsch,et al.  The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause , 2011, Breast Cancer Research and Treatment.

[35]  A. Buzdar Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  C. Welt,et al.  Female reproductive aging is marked by decreased secretion of dimeric inhibin. , 1999, The Journal of clinical endocrinology and metabolism.