Study of Preservation of Ovarian Reserve During Chemotherapy for Young Breast Cancer Patients
Study Details
Study Description
Brief Summary
The purpose of this study is to assess efficacy of gonadotropin-releasing hormone agonist (goserelin) on the preservation of ovarian reserve function in breast cancer patients of reproductive age treated with (neo)adjuvant chemotherapy by serial measuring ovarian reserve markers (AMH and AFC.etc) before and after chemotherapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Detailed Description
6.6-12% of women with breast cancer were diagnosed before the age of 40 year and breast cancer accounted for 40% of all cancer in women before the age of 40 year.Attributed to improved treatment, of which chemotherapy plays a major role, more than 70% of breast cancer patients at reproductive age obtain 10-year survival rates. Consequently, the question of pregnancy and premature ovarian failure after breast cancer treatment are presented more frequently. Fortunately, most of the available literature provides good evidence that pregnancy after breast cancer may improve survival. Unfortunately, no therapy has been shown to preserve fertility in patients receiving chemotherapy so far, although chemotherapy induced ovarian failure ,which finally results in infertility and premature ovarian failure, has been reported 60 years before. The greater rate of prepubertal than of postpubertal women with normal ovarian function after chemotherapy supports the concept that the suppressed ovary has a greater tolerance during cytotoxic treatments.While inhibiting the pituitary ovarian axis, Gonadotropin-releasing hormone agonist (GnRHa) is thought to block follicular development and reduce chemotherapy toxicity. Several studies had revealed GnRHa co-treatment yielded a statistically significant improvement in the proportion of spontaneous menstrual resumption after chemotherapy, compared to controls.It is noteworthy that menses and fertility are not necessarily linked. Absence of regular menses, particularly if the patient is taking tamoxifen(endocrine therapy for breast cancer), does not necessarily imply lack of fertility. Conversely, the presence of menses does not guarantee fertility.Currently, anti-Müllerian hormone(AMH) is considered as the best biochemical marker for assessment of reproductive capacity in reproductive medicine settings. Because it is produced by granulosa cells of growing antral follicles, AMH is significant positive correlation with both quantity and quality of oocytes. Moreover, it can be measured on any day for minimal fluctuation during the menstrual cycle.Antral follicle count (AFC) by vaginal ultrasound is also a good predictor of response to exogenous FSH and correlates independently with the number of oocytes retrieved during in vitro fertilization(IVF). Our study is designed to make sure the effect of GnRHa on the preservation of ovarian reserve function in breast cancer patients at reproductive age treated with (neo)adjuvant chemotherapy by observing the dynamic changes of ovarian reserve marker (AMH, AFC, E2 and FSH) pre and post chemotherapy.
Patients: Premenopausal patients aged 18-45 years were eligible for enrollment, with stages I to III of newly diagnosed breast cancer, for which treatment with adjuvant or neoadjuvant chemotherapy was planned. Exceptions were made up of the use of hormonal contraception, previous chemotherapy, bilateral oophorectomy or ovarian irradiation before enrollment, and GnRHa -containing endocrine therapy planned.
Study Design: In our study, patients will be informed comprehensively and assigned without interference to receive either (neo)adjuvant chemotherapy with goserelin (goserelin group) or without goserelin (chemotherapy group) as their own selection.AMH, follicle stimulating hormone (FSH), and estradiol (E2) are used as biochemical markers and AFC is used as biophysical marker. The markers and menstrual status will be evaluated before, during, and at 0.5-year, 1-year, 2-year after chemotherapy. Patients in goserelin group are given a subcutaneously dose of 3.6 mg (Zoladex, AstraZeneca) at least 1 week before the first cycle of chemotherapy and then every 4 weeks for the duration of chemotherapy. Subgroup analysis is stratified by age (≤ 40 years and 41-45 years), baseline level of AMH(≤1ng/ml and >1ng/ml), chemotherapy regimen (AC, AC-T(H)) and endocrine therapy regimen (with or without Tamoxifen).
The primary end point is to compare the recovery rate of AMH value (≥ 0.5ng/ml) (according to the "the Bologna criteria") between the two treatment groups at 2-year after chemotherapy. Secondary endpoints included descriptions of the dynamic changes of each marker from pre- to post-chemotherapy and time to resumption of menstrual activity (reappearance of two consecutive menstrual periods within 21 to 35 days); recovery rate of AMH value at 1 year and the rates of the other markers returning to the premenopausal range (E2 ≥ 40 pg/ml, FSH < 25 U/L, AFC ≥ 5) were assessed at both 1 year and 2 years. Events in the analysis of disease-free survival (DFS) included local recurrence, distant metastases, contralateral or ipsilateral breast tumor, second primary malignancy, and death due to any cause.
Statistical Analysis: Sample size calculation was based on the GBG 37 ZORO study. Out of 60 patients, 17 were accessible for AMH assessment during follow up to estimate ovarian function in 24 months after end of chemotherapy. Out of these 17 patients, 8 received goserelin and 9 were treated without goserelin. Recovery to normal AMH level was seen in 3 of 9 (33%) patients in chemotherapy group vs 4 of 8 (50%) patients in goserelin group respectively. To have 80% power to detect a 17% improvement in recovery to normal AMH level in 2 years, with a two-sided type I error rate of 0.05, 230 patients were needed to be assigned (calculated by NCSS-PASS). Finally, considering dropping off of patients, the target enrollment was 240 eligible patients. Descriptive statistics of baseline demographics and clinicopathologic characteristics were considered in the two treatment groups.The recovery rates of ovarian reserve markers and menses at 1-year and 2-year follow-up after chemotherapy were compared by a Pearson chi-square test. Logistic regression was performed to study the effect of age, baseline level of AMH, chemotherapy regimen and tamoxifen possible interactions on the probability of ovarian recovery. The differences in the baseline clinicopathological characteristics between the two groups were adjusted through propensity score weighting. The propensity score for each patient was estimated by a logistic regression model using group (the chemotherapy group or the goserelin group) as dependent variable and all patient characteristics as independent variables. Next, adjusted recovery rates of these markers and menses were compared by the chi-square test. Hormone concentrations and AFC at each time point were compared using the Mann-Whitney test. Log-rank statistics was used to compare time to return of menses between the two groups. Finally, Kaplan-Meier curve for disease-free will be calculated and compared by log-rank test. P values less than 0.05 are considered statistically significant. Analyses are performed by using SPSS version 18 software.
In summary: our study is the first prospective cohort study that focus on the premenopausal breast cancer patients who would like to preserve the ovarian function in China. The results will be more adaptable in China and other countries in Asia where breast cancer patients' age at diagnosis is younger. The outcome of this study may offer breast cancer patients at reproductive age hope of becoming mothers and possessing vigour of youth.
Recent breast cancer treatment guidelines strongly recommended that moderate and high-risk young patients with hormone receptor-positive disease should receive ovarian function suppression as part of adjuvant endocrine therapy, based largely on the results of the SOFT and TEXT Trials. Consequently, more than 20% patients in the two treatment group in this study who had hormone receptor-positive disease were estimated to directly receive or to change from tamoxifen to a GnRHa-containing endocrine therapy regimen and would not be assessed at the 2-year follow-up after chemotherapy. Therefore, an interim statistical analysis was determined to perform on the eligible patients who could be evaluated at 1 year after chemotherapy in the two treatment groups. The cutoff date for this analysis was November 30, 2019.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Chemotherapy plus GnRHa Patients of the group will receive (neo)chemotherapy plus GnRHa ( Goserelin 3.6mg will be administered every 28 days by subcutaneous injection starting at least 7-14 days before the first cycle of chemotherapy and continued throughout chemotherapy duration). |
Drug: Goserelin 3.6 MG
In goserelin group, goserelin 3.6mg will be administered every 28 days by subcutaneous injection starting at least 7-14 days before the first cycle of chemotherapy and continued throughout chemotherapy duration.
Other Names:
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| Chemotherapy Patients of the group will receive (neo)chemotherapy merely. |
Outcome Measures
Primary Outcome Measures
- Recovery of serum AMH value(≥0.5ng/ml) in 2 years of post-chemotherapy [Phlebotomy will be carried out at 2 years (one month ahead or one month delayed could be accepted) after chemotherapy in both groups.]
AMH can be measured on any day during the menstrual cycle.Serum AMH concentrations will be measured using the AMH Gen II ELISA, according to the manufacturer's instructions
Secondary Outcome Measures
- Recovery of AFC (≥5) by ultrasound per vagina in 1 year and 2 years of post-chemotherapy [AFC will be performed at 1 year and 2 years (one month ahead or one month delayed could be accepted) after chemotherapy in both groups.]
AFC by ultrasound per vagina will be performed by the physician from Peking University People's Hospital Reproductive Medicine Center. AFC for virginity will be performed by ultrasound per rectum. The optimal date of measuring AFC is the days after menstruation.
Other Outcome Measures
- Recovery of serum Follicle-Stimulating Hormone (FSH<25U/L) in 1 year and 2 years of post-chemotherapy [Phlebotomy will be carried out at 1 year and 2 years (one month ahead or one month delayed could be accepted) after chemotherapy in both groups.]
When menses are regular, the optimal date of phlebotomy is on day 2-5 during the cycle.
- Recovery of serum Estradiol (E2≥40pg/ml) in 1 year and 2 years of post-chemotherapy [Phlebotomy will be carried out at 1 year and 2 years (one month ahead or one month delayed could be accepted) after chemotherapy in both groups.]
When menses are regular, the optimal date of phlebotomy is on day 2-5 during the cycle.
- Recovery of serum AMH value(≥0.5ng/ml) in 1 year of post-chemotherapy [Phlebotomy will be carried out at 1 year (one month ahead or one month delayed could be accepted) after chemotherapy in both groups.]
AMH can be measured on any day during the menstrual cycle.Serum AMH concentrations will be measured using the AMH Gen II ELISA, according to the manufacturer's instructions
- Resumed menses in 1 year and 2 years of post-chemotherapy [Evaluation of menses at 1 year and 2 years after chemotherapy in both groups.]
reappearance of two consecutive menstrual periods within 21 to 35 days after chemotherapy
- Disease-free survival [Evaluation of disease-free survival at 1 year and 2 years after chemotherapy in both groups.]
Events in the analysis of disease-free survival include local recurrence, distant metastases, contralateral or ipsilateral breast tumor, second primary malignancy, and death due to any cause.
Eligibility Criteria
Criteria
Inclusion Criteria:
For inclusion in the study patients must fulfil all of the following criteria:
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Aged 45 years or younger
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Have regular menstrual cycle
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Newly diagnosed early-stage breast cancer (stages I to III)
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Planned (neo)adjuvant chemotherapy
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Signed informed consent document on file
Exclusion Criteria:
Any of the following is regarded as a criterion for exclusion from the study:
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Pregnancy or lactation
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Oral contraceptives before enrollment
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Prior chemotherapy
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Bilateral oophorectomy or ovarian irradiation before enrollment
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History of other cancers
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GnRHa -containing adjuvant endocrine therapy
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Peking University People's Hospital | Beijing | Beijing | China | 100044 |
Sponsors and Collaborators
- Peking University People's Hospital
Investigators
- Principal Investigator: Shu Wang, Peking University People's Hospital Breast Center
Study Documents (Full-Text)
None provided.More Information
Publications
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- Anderson RA, Rosendahl M, Kelsey TW, Cameron DA. Pretreatment anti-Müllerian hormone predicts for loss of ovarian function after chemotherapy for early breast cancer. Eur J Cancer. 2013 Nov;49(16):3404-11. doi: 10.1016/j.ejca.2013.07.014. Epub 2013 Aug 19.
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- Eldar-Geva T, Ben-Chetrit A, Spitz IM, Rabinowitz R, Markowitz E, Mimoni T, Gal M, Zylber-Haran E, Margalioth EJ. Dynamic assays of inhibin B, anti-Mullerian hormone and estradiol following FSH stimulation and ovarian ultrasonography as predictors of IVF outcome. Hum Reprod. 2005 Nov;20(11):3178-83. Epub 2005 Aug 19.
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- Grynnerup AG, Lindhard A, Sørensen S. The role of anti-Müllerian hormone in female fertility and infertility - an overview. Acta Obstet Gynecol Scand. 2012 Nov;91(11):1252-60. doi: 10.1111/j.1600-0412.2012.01471.x. Review.
- Henry NL, Xia R, Schott AF, McConnell D, Banerjee M, Hayes DF. Prediction of postchemotherapy ovarian function using markers of ovarian reserve. Oncologist. 2014 Jan;19(1):68-74. doi: 10.1634/theoncologist.2013-0145. Epub 2013 Dec 6.
- Horning SJ, Hoppe RT, Kaplan HS, Rosenberg SA. Female reproductive potential after treatment for Hodgkin's disease. N Engl J Med. 1981 Jun 4;304(23):1377-82.
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- La Marca A, Broekmans FJ, Volpe A, Fauser BC, Macklon NS; ESHRE Special Interest Group for Reproductive Endocrinology--AMH Round Table. Anti-Mullerian hormone (AMH): what do we still need to know? Hum Reprod. 2009 Sep;24(9):2264-75. doi: 10.1093/humrep/dep210. Epub 2009 Jun 11.
- Lutchman Singh K, Davies M, Chatterjee R. Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing. Hum Reprod Update. 2005 Jan-Feb;11(1):69-89. Epub 2004 Nov 29. Review.
- Moore HC, Unger JM, Phillips KA, Boyle F, Hitre E, Porter D, Francis PA, Goldstein LJ, Gomez HL, Vallejos CS, Partridge AH, Dakhil SR, Garcia AA, Gralow J, Lombard JM, Forbes JF, Martino S, Barlow WE, Fabian CJ, Minasian L, Meyskens FL Jr, Gelber RD, Hortobagyi GN, Albain KS; POEMS/S0230 Investigators. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med. 2015 Mar 5;372(10):923-32. doi: 10.1056/NEJMoa1413204.
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