1. The role and side effects of ovarian
suppression: Who need it?
Dr Ajeet Kumar Gandhi
MD (AIIMS); DNB; UICCF (MSKCC, USA)
Assistant professor, Radiation oncology
Dr RMLIMS, Lucknow

2. 1882: Thomas William
Nunn suggested
regression of breast
cancer with
menopause

3. The father of endocrine ablation in
cancer management: George Thomas
Beatson

5.  6/100 node-negative women and 12/100 node-positive
women have survival advantage at 15 years follow up

6. Evolution of OFS trials
• 1950s: OFS with RT/Surgery
• 1960s: Chemotherapy
• 1990s: OFS vs. CT [ZEBRA study; Zoladex vs CMF]
• Not included Tamoxifen
• 2000s: OFS with Tamoxifen/AIs
• SOFT; TEXT; ABCSG12; ECOG; ABC etc

7. Introduction
 Adjuvant TAM for 5-10 years is recommended for
pre-menopausal women with hormone receptor
positive disease
 The value of therapeutic suppression of ovarian
estrogen production in premenopausal women who
receive TAM was uncertain recently

10. OFS in breast cancer
 Benefits of OFS in the era of adjuvant
chemotherapy/hormone therapy
 Which patients would benefit?
 Optimum method of OFS?
 Duration of OFS?
 QOL and adverse effects of OFS?

11. Benefits of OFS in the era of
adjuvant chemotherapy/hormone
therapy

12. The SOFT trial

14. Summary – SOFT Trial
SOFT Tamoxifen-
OFS
Tamoxifen P value
5-yr DFS 86.6% 84.7% 0.10
5-yr OS 96.7% 95.1% 0.13
5-yr BC
freedom rate
88.4% 86.4% 0.09
949 premenopausal women (>40 years of age, small,
node-negative tumors, low to intermediate
Grade)
Freedom from recurrence > 95% at 5 years with TAM
alone

15.  Most recurrences of
breast cancer were in
patients who remained
premenopausal after
receiving chemo.

18. TEXT-SOFT combined
analysis
Tamoxifen-
OFS
Exemestane-
OFS
P-value
5-yr DFS 87.3% 91.1% P<0.001
5-yr BC free interval 88.8% 92.8% P<0.001
Freedom from
recurrence of breast
cancer at a distant site
92% 93.8% P=0.02
5-yr OS 95.9% 96.9% p=0.37
• Median follow-up : 68 months
Among patients who received chemotherapy, the absolute improvement in the 5-
year BC-free rate with Exemestane-OFS as compared with tamoxifen- OFS was
5.5% in TEXT and 3.9% in SOFT.

19.  Absolute improvement in breast cancer-free interval (BCFI)
based on a continuous, composite measure of recurrence
risk.
 Absolute improvement in 5-year BCFI:
 5-15% for intermediate to high composite risk
 Patient with lowest composite risk: No benefit
19 (July 2016)
2221-2231

20. Age <35 years
Those who remained premenopausal after chemotherapy
Large/ node-positive tumors, higher-grade tumour features.

21. Optimum method of OFS
 Pharmacotherapy
 Most commonly used in the current trials
 Cost
 Reversibility
 Incomplete suppression and adverse events
 Permanent ablative techniques [16% SOFT/TEXT]:
 Irradiation: 20 Gray/10#; 15 Gray/5#
 Surgical oophorectomy
 Cost effective, irreversible, fertility preservation not an
issue, GnRH analogues contraindicated

22. Which pharmacotherapy??
 Triptorelin pamoate/acetate (GnRH analogue):
3.75 mg q 4 weekly [SOFT/TEXT trials]
 Goserelin (LHRH analogue): 3.6 mg monthly
 Leuprolide depot (LHRH analogue): 3.75 mg
monthly
 3 monthly schedule could be used [ASCO
guideline 2016]
 Optimum duration: Not known (5 years)
 Used in majority trials
 St Gallen recommendations
 ASCO recommendations

23. Optimum combination for OFS
 LHRH analogue alone: Inferior results; Improve
recurrence (12%) and death fro recurrence (15%) in
combination with TAM/CT
[Klijn et al. JCO 2001 Meta-Analysis
EBCTCG meta-analysis; Lancet 2007]
 TEXT trial showed superiority of Exemestane over
Tamoxifen
 ABCSG-12 showed no difference between TAM and
AI; albeit an inferior outcome with AIs
 Issues with AIs: poor adherence, incomplete
suppression (7-10%; TABLE and SOFT-Substudy),
genetic polymorphism (CYP191A)
 Either of Tamoxifen or AIs could be used [ASCO
recommendation 2016]

24. Optimum timing of LHRH analogue
 Concurrent in TEXT and sequential in SOFT
 No beneficial/detrimental effect seen

26. Optimum timing of LHRH analogue
Prefer to give sequentially!!!

27. Biochemical Monitoring

28. Optimal method to measure plasma concentration is
debated
High sensitivity assays not widely available
Measurement of estradiol levels in patients on
exemestane unreliable due to cross-reactions
Serial biochemical monitoring every 3 to 6 months
during treatment, especially for patients younger than 50
years

29. QOL and Adverse events

30. Adverse events: SOFT trial

31. The events of grade 3 or 4 that were reported most frequently were hot flushes,
musculoskeletal symptoms, and hypertension.

35.  Short follow up: 5 years in 15 years disease
 Endpoints: DFS vs. OS
 Late switch to AI after 5 years of TAM vs.
OFS+AI [Improved DFS in MA.17]
 Therapy after 5 years of OFS+AI unknown

36. Questions unanswered??
 Role of OFS in patients receiving 10 years of TAM or TAM+AIs
 Role of OFS versus Chemotherapy
 Should all patients who remain premenopausal after adjuvant
chemotherapy receive OFS?
Adjuvant Ovarian Suppression plus AI
or Tamoxifen (ASPAIT)
Sun yat sen University (Recruiting)
Neoadjuvant Aromatase Inhibitor(AI)
With Ovarian Suppression Versus
Chemotherapy in Premenopausal
Breast Cancer Patients (COMPETE)
Li Zhu, Rujin Hospital (China)
Evaluating the Role of the Addition of
Ovarian Function Suppression (OFS) to
Tamoxifen in Young Women (ASTRRA)
Korean breast cancer study group

37. Take home message!!
 OFS benefits patients with high risk of
relapse (patient selection evolving)
 LHRH/GnRH analogues with TAM/AI for 5
years along with biochemical monitoring
 QOL and adverse events should be kept in
mind before embarking on the routine use of
OFS
 Time has not yet come to recommend it to all
premenopausal women of hormone receptor
positive breast cancer

38. Thank youfor your kind
attention