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Meta-Analysis
. 2020 Mar 6;3(3):CD013538.
doi: 10.1002/14651858.CD013538.

Ovarian suppression for adjuvant treatment of hormone receptor-positive early breast cancer

Kim Tam Bui  1 , Melina L Willson  2 , Shom Goel  3   4 , Jane Beith  5 , Annabel Goodwin  1   6   7
Affiliations
Meta-Analysis

Ovarian suppression for adjuvant treatment of hormone receptor-positive early breast cancer

Kim Tam Bui et al. Cochrane Database Syst Rev. .

Abstract

Background: Approximately 80% of breast cancers amongst premenopausal women are hormone receptor-positive. Adjuvant endocrine therapy is an integral component of care for hormone receptor-positive breast cancer and in premenopausal women includes oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, and permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Recent international consensus statements recommend single-agent tamoxifen or aromatase inhibitors with ovarian function suppression (OFS) as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy). This review examined the role of adding OFS to another treatment (i.e. chemotherapy, endocrine therapy, or both) or comparing OFS to no further adjuvant treatment.

Objectives: To assess effects of OFS for treatment of premenopausal women with hormone receptor-positive early breast cancer.

Search methods: For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 26 September 2019. We screened the reference lists of related articles, contacted trial authors, and applied no language restrictions.

Selection criteria: We included all randomised trials assessing any method of OFS, that is, oophorectomy, radiation-induced ovarian ablation, or LHRH agonists, as adjuvant treatment for premenopausal women with early-stage breast cancer. We included studies that compared (1) OFS versus observation, (2) OFS + chemotherapy versus chemotherapy, (3) OFS + tamoxifen versus tamoxifen, and (4) OFS + chemotherapy + tamoxifen versus chemotherapy + tamoxifen.

Data collection and analysis: Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Toxicity, contralateral breast cancer, and second malignancy were represented as risk ratios (RRs), and quality of life data were extracted when provided.

Main results: This review update included 15 studies involving 11,538 premenopausal women with hormone receptor-positive early breast cancer; these studies were conducted from 1978 to 2014. Some of these treatments are not current standard of care, and early studies did not assess HER2 receptor status. Studies tested OFS versus observation (one study), OFS plus chemotherapy versus chemotherapy (six studies), OFS plus tamoxifen versus tamoxifen (six studies), and OFS plus chemotherapy and tamoxifen versus chemotherapy and tamoxifen (two studies). Of those studies that reported the chemotherapy regimen, an estimated 72% of women received an anthracycline. The results described below relate to the overall comparison of OFS versus no OFS. High-certainty evidence shows that adding OFS to treatment resulted in a reduction in mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.78 to 0.94; 11 studies; 10,374 women; 1933 reported events). This treatment effect was seen when OFS was added to observation, to tamoxifen, or to chemotherapy and tamoxifen. The effect on mortality was not observed when OFS was added to chemotherapy without tamoxifen therapy (HR 0.95, 95% CI 0.82 to 1.09; 5 studies; 3087 women; median follow-up: range 7.7 to 12.1 years). The addition of OFS resulted in improved DFS (HR 0.83, 95% CI 0.77 to 0.90; 10 studies; 8899 women; 2757 reported events; high-certainty evidence). The DFS treatment effect persisted when OFS was added to observation, to tamoxifen, and to chemotherapy and tamoxifen. The effect on DFS was reduced when OFS was added to chemotherapy without tamoxifen therapy (HR 0.90, 95% CI 0.79 to 1.01; 5 studies; 2450 women). Heterogeneity was low to moderate across studies for DFS and OS (respectively). Evidence suggests that adding OFS slightly increases the incidence of hot flushes (grade 3/4 or any grade; risk ratio (RR) 1.60, 95% CI 1.41 to 1.82; 6 studies; 5581 women; low-certainty evidence, as this may have been under-reported in these studies). Two other studies that could not be included in the meta-analysis reported a higher number of hot flushes in the OFS group than in the no-OFS group. Seven studies involving 5354 women collected information related to mood; however this information was reported as grade 3 or 4 depression, anxiety, or neuropsychiatric symptoms, or symptoms were reported without the grade. Two studies reported an increase in depression, anxiety, and neuropsychiatric symptoms in the OFS group compared to the no-OFS group, and five studies indicated an increase in anxiety in both treatment groups (but no difference between groups) or no difference overall in symptoms over time or between treatment groups. A single study reported bone health as osteoporosis (defined as T score < -2.5); this limited evidence suggests that OFS increases the risk of osteoporosis compared to no-OFS at median follow-up of 5.6 years (RR 1.16, 95% CI 1.10 to 28.82; 2011 women; low-certainty evidence). Adding OFS to treatment likely reduces the risk of contralateral breast cancer (HR 0.75, 95% CI 0.57 to 0.97; 9 studies; 9138 women; moderate-certainty evidence). Quality of life was assessed in five studies; four studies used validated tools, and the fifth study provided no information on how data were collected. Two studies reported worse quality of life indicators (i.e. vaginal dryness, day and night sweats) for women receiving OFS compared to those in the no-OFS group. The other two studies indicated worsening of symptoms (e.g. vasomotor, gynaecological, vaginal dryness, decline in sexual interest, bone and joint pain, weight gain); however these side effects were reported in both OFS and no-OFS groups. The study that did not use a validated quality of life tool described no considerable differences between groups.

Authors' conclusions: This review found evidence that supports adding OFS for premenopausal women with early, hormone receptor-positive breast cancers. The benefit of OFS persisted when compared to observation, and when added to endocrine therapy (tamoxifen) or chemotherapy and endocrine therapy (tamoxifen). The decision to use OFS may depend on the overall risk assessment based on tumour and patient characteristics, and may follow consideration of all side effects that occur with the addition of OFS.

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Conflict of interest statement

Tam Bui: none known. Received funding to travel to the annual scientific meetings in 2019 (Australian and New Zealand Urogenital and Prostate Cancer Trials Group and Clinical Oncology Society of Australia) and in 2018 (Medical Oncology Group of Australia) to present PhD work on 'scanxiety: scan‐associated anxiety in people with cancer'. Payments did not support the design, conduct, or reporting of this research. Melina Willson: none known. Shom Goel: none related to this review. Shom has not received any payments from pharmaceutical companies directly related to this research project. Shom has received payments from Eli Lilly, Novartis, and G1 Therapeutics for serving on advisory boards for unrelated matters, and has received funding paid to his institution for laboratory and clinical research (in research areas unrelated to this Cochrane Review) from Eli Lilly and Novartis. Jane Beith: none related to this review. Jane received funding to travel to conferences from Roche and Novartis. Jane has served on advisory boards for Pfizer, Roche, Novartis, Lilly and Specialised Therapeutics for unrelated matters and payment has been made to her institution. Annabel Goodwin: none related to this review. There is no competing interest associated with funding of travel to attend a national and international educational meeting, or to provide expertise regarding Cancer Genetic counselling in Australia. Annabel has served on advisory boards for Pfizer in August 2019 and for AstraZeneca in 2018 for unrelated matters.

Figures

1
1
Study flow diagram: 2019 review update.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 OFS versus no OFS, outcome: 1.1 Overall survival.
4
4
Funnel plot of comparison: 1 OFS versus no OFS, outcome: 1.1 Overall survival.
5
5
Forest plot of comparison: 1 OFS versus no OFS, outcome: 1.2 Disease‐free survival.
6
6
Funnel plot of comparison: 1 OFS versus no OFS, outcome: 1.2 Disease‐free survival.
7
7
Forest plot of comparison: 1 OFS versus no OFS, outcome: 1.5 Hot flushes.
See this image and copyright information in PMC

References

References to studies included in this review

ABCTCG {published data only}
    1. Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the International Adjuvant Breast Cancer Ovarian Ablation or Suppression Randomized Trial. Journal of the National Cancer Institute 2007;99(7):516‐25. - PubMed
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    1. Brunt AM, Bliss JM, Benghiat A, Dawson C, Dewar J, Harnett AN, et al. The impact on quality of life of adding chemotherapy (CT) or ovarian suppression (OS) to adjuvant tamoxifen (TAM): outcomes from the UK NCRI Adjuvant Breast Cancer (ABC) trial. Journal of Clinical Oncology 2004;22(14 Suppl):8015.
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    1. George WD. Phase III randomised study of adjuvant tamoxifen with or without ovarian suppression and/or cyclophosphamide/methotrexate/fluorouracil (CMF) in premenopausal women with operable invasive breast cancer. Physician Data Query (PDQ) 1994.
Arriagada 2005 {published data only}
    1. Arriagada R. Phase III randomised study of ovarian suppression in premenopausal women receiving adjuvant chemotherapy for poor‐prognosis nonmetastatic breast cancer. Physician Data Query (PDQ) 1995.
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ASTRRA {published data only}
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E‐3193, INT‐0142 {published data only}
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IBCSG II {published data only}
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SOFT {published data only}
    1. Bellet M, Gray KP, Francis PA, Lang I, Ciruelos E, Lluch A, et al. Estrogen levels in premenopausal (prem) patients (pts) with hormone‐receptor positive (HR+) early breast cancer (BC) receiving adjuvant triptorelin (Trip) plus exemestane (E) or tamoxifen (T) in the SOFT trial: SOFT‐EST substudy. Journal of Clinical Oncology 2014;32(15 Suppl 1):Abstract no. 585. - PMC - PubMed
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SWOG 1996 {published data only}
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Uslu 2014 {published data only}
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Yang 2013 {published data only}
    1. Yang H, Yu X, Zong X, Chen D, Ding X, Yu Y, et al. Goserelin plus tamoxifen versus tamoxifen alone in pre‐or peri‐menopausal patients with hormone receptor‐positive early‐stage breast cancer: a randomized, controlled clinical trial in China. Journal of Clinical Oncology 2016;34(Suppl 15):Abstract no. 562.
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Yi 2016 {published data only}
    1. Heo JY, Yi H, Fava M, Mischoulon D, Kim K, Yoon S, et al. Agoraphobia and follicle‐stimulating hormone levels between tamoxifen and goserelin versus tamoxifen alone in premenopausal hormone receptor‐positive breast cancer: a 12‐month prospective randomized study. Psychiatry Investigation 2017;14(4):491‐8. - PMC - PubMed
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ZBCSG Trial B {published data only}
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ZIPP {published data only}
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References to studies excluded from this review

ABCSG‐12 {published data only}
    1. Gnant M, Mlineritsch B, Schippinger W, Luschin‐Ebengreuth G, Postlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. New England Journal of Medicine 2009;360(7):679‐91. - PubMed
ABCSG 5 {published data only}
    1. Gnant M, Greil R, Kubista E, Menzel C, Schippinger W, Seifert M, et al. The impact of treatment‐induced amenorrhea on survival of premenopausal patients with endocrine‐responsive breast cancer: 10‐year results of ABCSG‐05 (CMF vs. goserelin+tamoxifen). Breast Cancer Research and Treatment 2006;100 Suppl 1:10‐1 (abstract 17).
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Baum 1996 {published data only}
    1. Baum M. Phase III randomised study of adjuvant therapy with camomile vs endocrine ablation vs camomile plus endocrine ablation vs no adjuvant therapy in patients under age 50 with operable breast cancer. PDQ 1996.
FASG 06 {published data only}
    1. Roche H, Kerbrat P, Bonneterre J, Fargeot P, Fumoleau P, Monnier A, et al. Complete hormonal blockade versus epirubicin‐based chemotherapy in premenopausal, one to three node‐ positive, and hormone‐receptor positive, early breast cancer patients: 7‐year follow‐up results of French Adjuvant Study Group 06 randomised trial. Annals of Oncology 2006;17(8):1221‐7. - PubMed
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GABG IV‐A‐93 {published data only}
    1. Minckwitz G, Graf E, Geberth M, Eiermann W, Jonat W, Conrad B, et al. Goserelin versus CMF as adjuvant therapy for node‐negative, hormone receptor‐positive breast cancer in premenopausal women. The GABG trial IV‐A‐93 Trial. Proceedings of the American Society of Clinical Oncology. 2004:11s (abstract 534).
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Grocta 02 {published data only}
    1. Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Romeo D, Sismondi P, et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of oestrogen receptor‐positive pre‐/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomised trial. Journal of Clinical Oncology 2000;18(14):2718‐27. - PubMed
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HMFEC {published data only}
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Li 2019 {published data only}
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MAM 01 GOCSI {published data only}
    1. Bianco AR, Costanzo R, Lorenzo G, et al. The MAM‐1 GOCSI trial: a randomised trial with factorial design of chemo‐endocrine adjuvant treatment in node positive (N+) early breast cancer (ebc). Proceedings of the American Society of Clinical Oncology. 2001:27a (abstract 104).
    1. Placido S, Laurentiis M, Lena M, Lorusso V, Paradiso A, et al. A randomised factorial trial of sequential doxorubicin and CMF vs CMF and chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment of node‐positive breast cancer. British Journal of Cancer 2005;92(3):467‐74. - PMC - PubMed
Manson 2019 {published data only}
    1. Manson JE, Aragaki AK, Bassuk SS, Chlebowski RT, Anderson GL, Rossouw JE, et al. Menopausal estrogen‐alone therapy and health outcomes in women with and without bilateral oophorectomy: a randomized trial. Annals of Internal Medicine 2019;171:406‐14. - PMC - PubMed
PERCHE {published data only}
    1. Premenopausal endocrine responsive chemotherapy trial (PERCHE). clinicaltrials.gov/show/NCT00066807 (date first received 7 August 2003).
Pretoria {published data only}
    1. Falkson CI, Falkson HC, Falkson G. The effect of chemotherapy with or without GnHRA on serum hormone levels in premenopausal women with breast cancer. Proceedings of the American Society of Clinical Oncology. 1990:(abstract 90).
    1. Falkson CI, Jooste R, Falkson HC, Falkson G, Rens D, Aarde R, et al. Cyclophosphamide, methotrexate and fluorouracil (CMF) plus or minus depo‐buserelin in premenopausal women with lymph node positive breast cancer. Proceedings of American Society of Clincial Oncology 2001;20(Pt 2):Abstract no.1777.
    1. Falkson CI, Jooste R, Falkson HC, et al. Cyclophosphamide, methotrexate and fluorouracil (CMF) plus or minus depo‐buserelin in pre‐menopausal women with lymph node positive breast cancer. Proceedings of the American Society of Clinical Oncology. 2001:7b (abstract 1777).
Ragaz 1997 {published data only}
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    1. Ragaz J, Jackson SM, Le N, Plenderleith IH, Wilson K, Knowling M, et al. Can ovarian ablation improve outcome of stage I‐II premenopausal breast cancer patients with estrogen receptor positive tumors treated with adjuvant chemotherapy? Long‐term analysis of British Columbia randomized trial. Proceedings of the American Society of Clinical Oncology 1997;16(142a):Abstract 501.
Soreide 2002 {published data only}
    1. Söreide JA, Varhaug JE, Fjösne HE, Erikstein B, Jacobsen AB, Skovlund E, et al. Adjuvant endocrine treatment (goserelin vs tamoxifen) in pre‐menopausal patients with operable node positive stage II breast cancer. A prospective randomised national multicenter study. European Journal of Surgical Oncology 2002;28(5):505‐10. - PubMed
TABLE {published data only}
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    1. Schmid P, Untch M, Wallwiener D, Kossé V, Bondar G, Vassiljev L, et al. Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node positive, premenopausal breast cancer patients: preliminary results of the TABLE‐study (Takeda Adjuvant Breast Cancer Study with Leuprorelin acetate). Anticancer Research 2002;22(4):2325‐32. - PubMed
    1. Untch M, Kahlert S, Kosse V, et al. LHRH‐analogue therapy with leuprorelin‐acetate three‐month depot offers similar efficacy to conventional adjuvant CMF chemotherapy in receptor positive, node positive breast cancer patients. San Antonio Breast Cancer Symposium. 2003:abstract 40.
Yu 2019 {published data only}
    1. Yu KD, Wu SY, Liu GY, Wu J, Di GH, Hu Z, et al. Concurrent neoadjuvant chemotherapy and estrogen deprivation in patients with estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative breast cancer (CBCSG‐036): a randomized, controlled, multicenter trial. Cancer 2019;125:2185‐93. - PubMed
ZEBRA {published data only}
    1. Jonat W, Kaufman M, Sauerbrei W, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in pre‐menopausal patients with node‐positive breast cancer: the Zoladex Early Breast Cancer Research Association study. Journal of Clinical Oncology 2002;20:4628‐35. - PubMed
    1. Kaufmann Ma, Jonat W, Blameyc R, Cuzick J, Namere M, Fogelman I, et al. on behalf of the Zoladex Early Breast Cancer Research Association (ZEBRA) Trialists’ Group. Survival analyses from the ZEBRA study: goserelin (ZoladexTM) versus CMF in premenopausal women with node‐positive breast cancer. European Journal of Cancer 2003;39:1711‐7. - PubMed
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References to ongoing studies

NCT02132390 {published data only}
    1. NCT02132390. Adjuvant toremifene with or without goserelin in premenopausal women with stage I‐IIIA, hormonal receptor positive breast cancer accompanied with or without chemotherapy induced amenorrhoea. clinicaltrials.gov/show/NCT02132390 (date first received: 7 May 2014).

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References to other published versions of this review

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