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  In this article
 »  Abstract
 » Historical Aspects
 »  Need for Adjuvan...
 »  Evidence for OFS...
 » Concerns
 »  Side Effect of O...
 » Discussion
 »  References
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REVIEW ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 4  |  Page : 293-296
 

Revisiting adjuvant ovarian suppression in premenopausal breast cancer patients


Department of Medical Oncology, Max Institute of Cancer Care, Shalimar Bagh, New Delhi, India

Date of Web Publication11-Oct-2019

Correspondence Address:
Waseem Abbas
Department of Medical Oncology, Max Institute of Cancer Care, Shalimar Bagh, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_697_18

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 » Abstract 

Adjuvant ovarian suppression, on addition to chemotherapy, reduces the risk of breast cancer in pre-menopausal women after surgery and adjuvant hormonal therapy. Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) showed greater benefit with exemestane in high risk females in comparison to Tamoxifen. Ovarian Function Suppression (OFS) and exemestane became the standard of care, with 30% patients experiencing grade 3 and more side effects. Much higher benefit was seen in high risk group. But there are concerns about incomplete OFS (estrogen escape) with exemestane plus OFS. Updated analysis of TEXT AND SOFT showed better survival benefit with OFS plus Tamoxifen as compared to OFS plus exemestane. Overall survival is a better end point. Should preference be given to Tamoxifen over exemestane? Further research is required to get the final answer.


Keywords: Adjuvant ovarian suppression, adjuvant treatment, ovarian suppression, premenopausal breast cancer treatment, premenopausal high risk breast cancer


How to cite this article:
Abbas W, Rao RR. Revisiting adjuvant ovarian suppression in premenopausal breast cancer patients. Indian J Cancer 2019;56:293-6

How to cite this URL:
Abbas W, Rao RR. Revisiting adjuvant ovarian suppression in premenopausal breast cancer patients. Indian J Cancer [serial online] 2019 [cited 2019 Nov 22];56:293-6. Available from: http://www.indianjcancer.com/text.asp?2019/56/4/0/267601




Currently available data, including ASCO (American Society of Clinical Oncology) guidelines, support adjuvant ovarian suppression, in addition to standard chemotherapy, post surgery in premenopausal breast cancer women patients. According to Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT), women with high risk of recurrence showed greater benefit with exemestane (10-15% Recurrence-Free Survival). Tamoxifen did not show greater benefit. So Ovarian Function Suppression (OFS) and Exemestane became standard of care. 30% patients observed grade 3 and more side effects with OFS plus Exemestane.

For high risk group, there is huge benefit in recurrence free interval and for intermediate risk group, benefit in recurrence-free interval is seen in only 5%. For high risk patients one should offer Aromatase Inhibitors (AI) plus OFS and for intermediate group, side effects versus benefits from OFS should be discussed.

In Austrian Breast and Colorectal Cancer Study Group (ABCSG-12), Anastrazole patients did worse with respect to OS versus Tamoxifen. There are concerns about incomplete OFS which needs to be studied further. What made it more confusing is that, updated analysis of SOFT and TEXT showed better survival benefit with OFS plus Tamoxifen than OFS plus Exemestane but disease free survival was better with Exemestane and OFS. OS is a better end point. Should preference be given to Tamoxifen over exemestane, we need to wait for a few more years to get the final answer especially for Overall Survival (OS) from TEXT and SOFT Study.

In light of evidence showing superiority of aromatase inhibitors over tamoxifen in postmenopausal women with early breast cancer, oncologists have revisited the role of ovarian suppression to optimize outcomes in premenopausal women, either in combination with tamoxifen or to facilitate treatment with aromatase inhibitors.


 » Historical Aspects Top


Over 100 years ago, Thomas Nunn reported a relationship between menopause and regression of breast cancer.[1] This incited interest in the induction of menopause as an anticancer therapy, and in 1896, a report on the efficacy of bilateral oophorectomy in three women with breast cancer was published in The Lancet.[2]

An overview conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTG), demonstrated disease-free survival and overall survival benefits among women less than 50 years old, treated with ovarian ablation or suppression, compared to those receiving no adjuvant endocrine therapy.[3] Further four trials performed failed to demonstrate a significant advantage of Ovarian Function Suppression (OFS) (ABCSG-12,[4] IBCSG 11-93,[5] INT0101,[6],[7] Zipp [8]).


 » Need for Adjuvant Ovarian Function Suppression in Premenopausal Patients Top


Recently Hongchao Pan et al. from EBCTG showed that for women with Estrogen Receptor (ER) positive breast cancer diagnosed before the age of 75, with each category of nodal status, distant recurrences occurred throughout the 20-year period.[9]

Colleoni et al. showed that during the first 10 years after diagnosis of breast cancer, risk of recurrence and death decreased consistently and from years 10–25 remained stable.[10] It is important to identify such patients who have high chance of relapse during the first 5–10 years of treatment.


 » Evidence for OFS in Adjuvant Settings Top


E-3193, INT-0142 trial did not show any benefit with addition of OFS to Tamoxifen, where use of chemotherapy was not allowed for 345 premenopausal women at low clinical risk of recurrence.[11] [Table 1] In this study, many questions remained unanswered and investigators did not look into the sub-group of patients with high risk features who might be benefitting and also use of chemotherapy was not allowed, which means all the patients included were very low risk. In addition, sample size was limited.
Table 1: 5-year DFS and OS in E-3193, INT-0142 trial

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In 2003, the International Breast Cancer Study Group (IBCSG) initiated two randomized, phase 3 trials, Tamoxifen and Exemestane Trial (TEXT) and Suppression of Ovarian Function Trial (SOFT), which showed disease-free survival was better with exemestene plus OFS.[12]

In 2016, Regan et al. presented the updated analysis of TEXT and SOFT, and showed the absolute benefit of adjuvant endocrine therapies for premenopausal women with ER positive, Progesterone Receptor (PR) positive, Human Epidermal growth factor Receptor 2 (Her2neu) negative early breast cancer.[13] BCFI (Breast Cancer Free interval) was taken as the end point for this analysis, which was defined as the time from enrolment to first recurrence (local, regional, distant, or contralateral breast recurrence). It was a complicated end point, but it proved to be effective. Disease-free interval was not chosen as the end point because they wanted to disregard second malignancies and few deaths which occurred without prior cancer event. Median follow up was 6 years in TEXT and 5.6 years in SOFT. Both trials had different control groups so, a cox proportional hazards model for BCFI, stratified by cohort (defined by trial and chemotherapy use) and treatment assignment, was estimated. It was important to examine the patient population from both trials using same risk scale. In addition, it was important to determine the cut point to be used for grouping, which was done on the basis of clinical cut points and prior St Gallen Consensus statements [14] [Table 2].
Table 2: Cox proportional hazards model for defining the composite measure of recurrence risk for the hormone receptor positive, Her2 Neu-negative population analysis of TEXT and SOFT

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The relation of each factor with BCFI, without regard for cohort or treatment assignment, is summarised in [Table 2]. The clinicopathologic characteristics with greatest contribution to the composite measure of recurrence were more positive lymph nodes, and grade 2 to 3 tumor.[15]

Patients considered by clinicopathologic features or an assay (ER, PR, Her2Neu status, and tumor grade) to be at high risk of recurrence, have potential for large absolute benefit with the use of adjuvant exemestane plus OFS.

2015 St Gallen Consensus Panel considered age younger than 35 years, four or more positive lymph nodes, persistent premenopausal estrogen level after adjuvant chemotherapy (i.e., the SOFT chemotherapy cohort) and grade 3 tumor as factors warranting the use of OFS or an Aromatase Inhibitor (AI) plus OFS.[14]

ABSCG-12 raised some concerns regarding the use of Aromatase inhibitors plus OFS in premenopausal women.[15] Patients receiving Anastrozole had worse OS versus Tamoxifen, probably with respect to post-relapse treatment [Table 3].
Table 3: Hazard Ratio for Disease-Free Survival and Overall Survival

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ASTRRA study showed only DFS benefit with the addition of OFS to Aromatase inhibitor.[16]


 » Concerns Top


In ABCSG-12 study, risk of death increased with OFS plus AI which was attributed to post recurrence treatment, but this has to be taken with a word of caution.[15]

In the study by Dowsett et al.,[17] plasma estradiol levels decreased to a mean of 18 pmol/L after one month of goserelin administration but subsequently increased, in 15 of 18 patients, to values in the upper postmenopausal range (36 pmol/L after 6 months) in parallel with increased Follicle Stimulating Hormone (FSH) levels.

Serum FSH recovery stimulates estradiol secretion. It was seen that by adding concurrent tamoxifen, recovery of FSH was prevented which is because tamoxifen has agonist action on the hypothalamic-pituitary axis especially when estradiol levels are low.[18]

In the study by Walker et al.,[19] plasma estradiol levels were significantly lower in the group receiving tamoxifen and goserelin, supporting FSH stimulation of ovary. This can give rise to incomplete OFS.[20]

A substudy by Dowsett from SOFT,[21] named SOFT-EST, was consistent with these observations. The substudy evaluated the endocrine effects during the first 12 months of Gonadotropin Releasing Hormone (GnRH) analogue (triptorelin) with either tamoxifen or exemestane.

The serum estradiol levels were found to be lower with exemestene than tamoxifen. A total of 27 of 79 patients had suboptimal estradiol suppression with exemestene (estradiol >10 pmol/L) based on earlier guidelines,[22] on at least one of the three points during treatment. FSH levels were suppressed by 78% after 3 months, but only by 62% and 66% after 6 and 12 months, respectively.

Patients who did not receive chemotherapy correlated with an estradiol level of less than 10 pmol/L on exemestane, indicating a greater likelihood of incomplete estrogen suppression for patients with full ovarian function. There was a significant correlation between estradiol level and Body Mass Index (BMI). Estradiol level was found to be higher in patients with a higher Body Mass Index.[23]

It remains unclear whether GnRH analogue in addition to Aromatase Inhibitors results in increase in FSH and estradiol, which occurs across all subgroups, whose use might not be therapeutically advantageous as shown in ABCSG12 study. The same results have been seen with the fulvestrant.[24]


 » Side Effect of Ovarian Function Suppression Top


Adverse events remain a concern with Ovarian Function Suppression, especially with the addition of Aromatase Inhibitors [Table 4].
Table 4: Adverse events recorded during follow-up of TEXT study

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Gynecologic cancer occurred in seven patients assigned to exemestane plus ovarian suppression and in nine assigned to tamoxifen plus ovarian suppression, including endometrial cancers in two and five patients, respectively.[25]


 » Discussion Top


In postmenopausal women, better results are seen with AI compared to tamoxifen; can the same results be seen in premenopausal women? In young, premenopausal women more recurrences occur during the first 5 years of treatment. These young premenopausal women require aggressive management.

In SOFT and TEXT, the clinical parameters on which women, who did not require adjuvant chemotherapy and were considered low risk, were selected remains unclear. The selection criteria defining low risk was not published. Presumably, the parameters must have been elderly, small breast primary, well differentiated, lymph node negative, ER, PR Positive, and Her2 Neu negative. Either, gene expression profile can be used to select such patients with low risk. These patients did very well in the updated analysis by Prudence et al.[26] [Table 5].
Table 5: OS and RFS for low risk patients

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What should be used, OFS plus tamoxifen or OFS plus exemestene? In the updated analysis by Prudence et al.,[26] OFS plus tamoxifen resulted in 2.1% benefit in distant events but survival benefit was 4.3%, whereas OFS plus exemestene resulted in 4.5% reduction in distant events but only 2.1% reduction in death at 8 years. Could it be by chance or is it because in SOFT, patients with permanent ovarian suppression were excluded but not in TEXT, where patients entered in study before chemotherapy was started. According to TEXT, permanent ovarian failure was because of chemotherapy and not because of OFS, and as known, exemestene works better with non-functioning ovaries, and will work better where ovarian suppression is induced by chemotherapy and not from OFS alone. This is a good hypothesis as far as reduction in distant recurrences is concerned, but does not explain only 2.1% reduction in death in OFS plus exemestene arm, compared to 4.35% in OFS plus tamoxifen arm [Table 6].
Table 6: Reduction in death and DFS in high risk patients

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A major concern is, in updated analysis by Prudence et al.,[26] there is only 2.1% reduction in death in exemestene arm compared to 4% in tamoxifen arm. The observation noted earlier was, ABCSG12 patients who expressed on-treatment FSH levels greater than the trial population, had significantly worse distant metastasis–free survival. The recovery in FSH level has been ascribed to feedback through inhibin. Comparatively less attention has been paid to the FSH increase, because it was inconsequential, but this is far from the case. Much discussion has happened on measuring the estradiol, Luteinzing Hormone (LH) and FSH Levels. Many questions still remain unanswered. Should they be checked weekly, monthly, or quarterly, as it is difficult to predict the estrogen escape or rebound phenomenon? At what time of the day should the levels be measured? Should we check levels of both FSH and estradiol or only estradiol? It is difficult to predict when and on which day of the month estradiol levels will be high in body? How does one proceed when estradiol levels are raised? Should we stop OFS and switch to exemestene?

In 2016 Regan et al.[13] showed that not every high-risk group benefits from ovarian function suppression. Patients less than 35 years of age, grade 3 tumors and patients with 4 or more than 4 nodes derive the highest benefit, up to 15% in recurrence-free interval. These are the patients who should be started on hormonal therapy plus OFS. In intermediate risk patients, benefit is only 5%. Five percent is definitely a huge benefit, but at the cost of side effects. In TEXT and SOFT, there were 30% grade 3 and 4 side effects which amount to poor quality of life. In SOFT, 20% of patients stopped ovarian function suppression early, and the assigned oral hormonal therapy was stopped in 28% of patients on exemestane plus ovarian function suppression. With many documented side effects, one has to maintain a balance between benefits and side effects.

In updated analysis by Prudence et al.,[26] better survival benefit was seen with OFS plus tamoxifen than OFS plus exemestane, but disease-free survival was better with OFS plus exemestene. OS is a better end point. Should tamoxifen be preferred over exemestane? Further analysis in future, especially for OS from TEXT and SOFT, will shed light on the same.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Nunn TW. Cancer of the Breast. London: J & A Churchill: Royal College of Physicians of Edinburgh; 1882. p. 71.  Back to cited text no. 1
    
2.
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Early Breast Cancer Trialists' Collaborative Group. Ovarian ablation for early breast cancer. Cochrane Database Syst Rev 2000:CD000485.  Back to cited text no. 3
    
4.
Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, et al. ABCSG-12 Trial Investigators. Endocrine therapy plus zolendronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679-91.  Back to cited text no. 4
    
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Paridaens RJ, Gelber S, Cole BF, Gelber RD, Thürlimann B, Price KN, et al. Adjuvant on-line estimation of chemotherapy effectiveness when added to ovarian function suppression plus tamoxifen for premenopausal women with estrogen receptor positive breast cancer. Breast Cancer Res Treat 2010;123:303-10.  Back to cited text no. 5
    
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Krop IE, Winer EP. Ovarian suppression for breast cancer: An effective treatment in search of a chance. J Clin Oncol 2005;23:5869-72.  Back to cited text no. 6
    
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Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, et al. Chemoendocrine therapy for premenopausal women with axillary lymph node positive, steroid hormone receptor-positive breast cancer: Results from INT 0101 (E5188). J Clin Oncol 2005;23:5973-82.  Back to cited text no. 7
    
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Baum M, Hackshaw A, Houghton J, Rutqvist LE, Fornander T, Nordenskjold B, et al. Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study. Eur J Cancer 2006;42:95-904.  Back to cited text no. 8
    
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Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, et al. 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med 2017;377:1836-46.  Back to cited text no. 9
    
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Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thürlimann B, et al. Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: Results from the international breast cancer study group trials I to V. J Clin Oncol 2016;34:927-35.  Back to cited text no. 10
    
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Tevaarwerk AJ, Wang M, Zhao F, Fetting JH, Cella D, Wagner LI, et al. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): A trial of the Eastern cooperative oncology group. J Clin Oncol 2014;32:3948-58.  Back to cited text no. 11
    
12.
Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, et al. Adjuvant exemestane with ovarian suppression in pre-menopausal breast cancer. N Engl J Med 2014;371:107-18.  Back to cited text no. 12
    
13.
Regan MM, Francis PA, Pagani O, Fleming GF, Walley BA, Viale G, et al. Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer: TEXT and SOFT trials. J Clin Oncol 2016;34:2221-31.  Back to cited text no. 13
    
14.
Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies-improving the management of early breast cancer: St Gallen International expert consensus on the primary therapy of early breast cancer. Ann Oncol 2015;26:1533-46.  Back to cited text no. 14
    
15.
Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozole plus ovarian function suppression in premenopausal early breast cancer: Final analysis of the Austrian breast and colorectal cancer study group trial 12. Ann Oncol 2015;26:313-20.  Back to cited text no. 15
    
16.
Kim H-A, Ahn SH, Nam SJ, Park S, Ro J, Im SA, et al. The role of the addition of ovarian suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or regain menstruation after chemotherapy (ASTRRA): Study protocol for a randomized controlled trial and progress. BMC Cancer 2016;16:319.  Back to cited text no. 16
    
17.
Dowsett M, Lønning PE, Davidson NE. Incomplete estrogen suppression with gonadotropin-releasing hormone agonists may reduce clinical efficacy in premenopausal women with early breast cancer. J Clin Oncol 2016;34:1580-83.  Back to cited text no. 17
    
18.
Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, et al. The efficacy and safety of degarelix: A 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008;102:1531-8.  Back to cited text no. 18
    
19.
Walker KJ, Walker RF, Turkes A, Robertson JF, Blamey RW, Griffiths K, et al. Endocrine effects of combination antioestrogen and LH-RH agonist therapy in premenopausal patients with advanced breast cancer. Eur J Cancer Clin Oncol 1989;25:651-4.  Back to cited text no. 19
    
20.
Casper RF, Mitwally MF. Review: Aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab 2006;91:760-71.  Back to cited text no. 20
    
21.
Bellet M, Gray KP, Francis PA, Láng I, Ciruelos E, Lluch A, et al. Twelve-month estrogen levels in premenopausal women with hormone-receptor positive breast cancer receiving adjuvant triptorelin plus exemestane or tamoxifen in the SOFT trial: The SOFT-EST substudy. J Clin Oncol 2016;34:584-1593.  Back to cited text no. 21
    
22.
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;24:2444-7.  Back to cited text no. 22
    
23.
Thomas EJ, Walton PL, Thomas NM, Dowsett M. The effects of ICI 182,780, a pure anti-oestrogen, on the hypothalamic-pituitary-gonadal axis and on endometrial proliferation in pre-menopausal women. Hum Reprod 1994;9:1991-6.  Back to cited text no. 23
    
24.
Young OE, Renshaw L, Macaskill EJ, White S, Faratian D, Thomas JS, et al. Effects of fulvestrant 750 mg in premenopausal women with oestrogen-receptor-positive primary breast cancer. Eur J Cancer 2008;44:391-9.  Back to cited text no. 24
    
25.
Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, et al. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol 2015;16:848-58.  Back to cited text no. 25
    
26.
Francis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, Lang I, et al. Tailoring Adjuvant Endocrine therapy for Premenopausal Breast Cancer. N Engl J Med 2018;379:122-37.  Back to cited text no. 26
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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