hormone therapy in ca breast

1. Hormone therapy
in
nonmetastatic carcinomabreast
DR SAILENDRA
SENIOR RESIDENT
DEPT OF RADIOTHERAPY
MAULANA AZAD MEDICAL COLLEGE

2. IDEAL CANDIDATES FOR HORMONE
THERAPY
POSITIVE
ER
PR

3. menopause
Women 60 years and older
Post bilateral oophorectomy.
No menstrual periods for 12 months or more in the absence
of tamoxifen, chemotherapy, or ovarian suppression and the
serum estradiol is in the postmenopausal range.
Amenorrheic on tamoxifen and follicle-stimulating hormone
(FSH) and plasma estradiol are in the postmenopausal range.

4. FSH
> 40 mIU/ml
Estradiol
< 30 pg/ml
MENOPAUSE

5. •TVS
•SERUM FSH AND
ESTRADIOL
•ROUTINE CARDIAC
STATUS
ASSESMENT
INVESTIGATIONS

6. Treatment options
SERM
TAMOXIFEN
AROMATASE
INHIBITORS
LETROZOLE
ANASTROZOLE
EXEMESTANE
OVARIAN
SUPPRESSION
GNRH AGONISTS
OVARIAN
ABLATION
RADIATION
THERAPY
OOPHORECTOMY

7. MECHANISM OF ACTION

8. TAMOXIFEN
DOSE 20mg once daily per oral
Cell cycle specific mid G1 phase

9. Side effects of tamoxifen
• Deep vein thrombosis and pulmonary emboli
• Stroke
• Endometrial hyperplasia,polyp and carcinoma
• Hot flushes
• Vaginal discharge
• Sexual dysfunction
• Menstrual irregularities
• Transient tumour flare
• Fluid retention and peripheral edema

10. Mechanism of resistance
Decreased
expression of
ER
Mutation in ER
Over
expression of
other growth
factor
receptors like
EGFR,HER
2,IGFR etc

11. AROMATASE
INHIBITORS
ANASTRAZOLE
(1 mg daily)
LETROZOLE
(2.5 mg daily)
EXEMESTANE
(25 mg daily)

12. Side effects of AI
MUSCULOSKELETAL SIDE EFFECTS
• Carpal tunnel syndrome
• AI-associated musculoskeletal syndrome (AIMSS), characterized
by joint pain and stiffness
• AIMSS is responsible for treatment discontinuation in 10 to 20
percent of patients
REACTIVATE OVARIAN FUNCTION
OSTEOPOROSIS
CARDIOVASCULAR RISK
HOT FLUSHES
FATIGUE
FORGETFULNESs
SEXUAL DYSFUNCTION

13. AIMSS
• A significantly greater reduction in worst pain score
and pain severity occurs in patients doing regular
physical exercise compared with usual care.
TREATMENT
• NSAIDS
• DULOXETIN
• DISCONTINUE AI
HOPE TRIAL,
J Cancer Surviv. 2016 Aug;10(4):654-62

14. TAMOXIFEN
VENOUS THROMBOSIS
ENDOMETRIAL
CANCER
AROMATASE
INHIBITORS
OSTEOPOROSIS
FRACTURES
CARDIOVASCULAR RISK
HYPERCHOLESTEROLEMIA

15. TREATMENT APPROACH
PREMENOPAUSAL
HIGH RISK
OVARIAN
SUPPRESSION
+ AI
LOW RISK
TAMOXIFEN
POST
MENOPAUSAL
AROMATASE
INHIBITORS

16. HIGH RISK FEATURES
Pathologically involved lymph nodes
Large tumor size
High tumor grade
Lymphovascular invasion
Younger age (i.e, age ≤35 years)

17. Suppression
of Ovarian
Function
Trial (SOFT)
Tamoxifen
and
Exemestane
Trial
(TEXT)

18. ALL POSTMENOPAUSAL WOMEN WHO ARE
CANDIDATES FOR ENDOCRINE THERAPY
SHOULD BE OFFERED TREATMENT,
REGARDLESS OF AGE.

19. SOFT TRIAL
N Engl J Med 2015;372:436-46

20. NO DIFFERENCE IN DFS AND FREEDOM FROM BREAST CANCER AT 5 YEARS

21. Exemestane plus Ovarian Suppression had a higher rate
of Freedom From Breast Cancer

22. TAMOXIFEN AND EXEMESTANE
TRIAL(TEXT)
• 2 ARMS
• TRIPTORELIN + EXEMESTANE
VS
• TRIPTORELIN + TAMOXIFEN
• AUGUST 2003
• PRIMARY COMPLETION DATE – JUNE 2014

23. COMBINED ANALYSIS
• 4690 women were included in the intention
to treat population
• Median follow up period – 68months
N Engl J Med 2014;371:107-18

24. DFS IS BETTER WITH EXEMESTANE AFTER 5 YEARS
NO DIFFERENCE IN OVERALL SURVIVAL
TREATMENT DISCONTINUE IS MORE WITH EXEMESTANE
(16% Vs 11%)

25. EBCTCG METAANALYSIS
REDUCED BREAST CANCER RECURRENCE AND 1OYR MORTALITY
WITH AROMATASE INHIBITOR
5 years of Aromatase inhibitor versus 5 years of Tamoxifen

26. 5 years of aromatase inhibitor versus tamoxifen to years 2–3
then aromatase inhibitor to year 5
•A trend towards reduced breast cancer mortality,
which did not reach statistical significance
•Lower recurrence in 0-1 yr

27. Tamoxifen to years 2–3 then aromatase inhibitor to year 5
versus 5 years of tamoxifen
Reduced recurrence as well as reduced 10yr breast cancer
mortality

28. OBESRVATION
Highest risk for recurrence is within the first few
years after initial diagnosis
Aromatase inhibition, is preferable
to tamoxifen during that time
However, once patients have remained disease-free
for a few years, switching to tamoxifen is similarly
effective to continuation of AI treatment

29. Is there a preferred aromatase
inhibitor?
All AIs appear to have similar efficacy in the
adjuvant setting. Therefore, no one AI is
preferred over another

30. Duration of endocrine treatment
• AI only 5yrs
• AI to tamoxifen 5yrs
• Tamoxifen to an AI 5-10 yrs
• Tamoxifen only 10 years

31. •MA-17 TRIAL
•NSABP B-33 TRIAL
•ATLAS TRIAL
•aTTom TRIAL
4 TRIALS
PROVIDED
INFORMATION

32. NCIC CTG MA.17 trial
• over 5000 postmenopausal women who had completed a five-
year course of Tamoxifen were randomly assigned to treatment
with an additional five-year course of letrozole or placebo.
• Median follow-up period was 64 months
Letrozole was associated with
• Improvement in DFS compared with placebo (HR 0.52, 95% CI
0.45-0.61)
• Improvement in OS (HR 0.61, 95% CI 0.52-0.71)
• Interestingly, women who had been randomized to placebo and
subsequently chose to take letrozole after the trial results were
published still experienced an improvement in DFS, despite a
substantial lapse in time between therapies (median, 2.8 years)

33. NSABP B-33 TRIAL
• Suggested a benefit to exemestane over
placebo after an initial five-year course
of tamoxifen.
• However, the trial was terminated early due
to the positive results of the MA.17 trial.

35. RECURRENCE MORTALITY
Significant reduction in the risk of recurrence and
breast cancer mortality with 10yr of tamoxifen
compared with a five-year treatment course

36. Timing of endocrine therapy
• For women with hormone receptor-positive
breast cancer who are not recommended to
receive other adjuvant therapy (eg,
chemotherapy and/or radiotherapy),
endocrine therapy is usually initiated four to
six weeks after surgery.

37. WITH OR AFTER
CHEMOTHERAPY
• North American Intergroup trial, 637
postmenopausal women with node-positive,
hormone receptor-positive breast cancer were
treated with chemotherapy and randomly assigned
to treatment with tamoxifen initiated during or
following completion of chemotherapy.
• At 13 years of follow-up, sequential treatment
resulted in:
• A trend towards improvement in DFS compared
with concurrent treatment (HR 0.84, 95% CI 0.70-
1.01)
• No improvement in OS (HR 0.90, 95% CI 0.73-1.10)

38. With or following radiation
therapy
• Multiple studies show that the timing of
endocrine therapy in relation to RT does not
impact survival
• Some older studies suggest that concurrent
treatment increases the risks of treatment
complications (including
pulmonary and/or breast fibrosis)

39. • Women of childbearing potential — Women
who are of childbearing potential should be
advised to use an effective means of
contraception while on Tamoxifen treatment
because tamoxifen can induce ovulation.
• Following completion of Tamoxifen treatment,
a waiting period of two months from drug
discontinuation prior to attempting pregnancy
is suggested to ensure that it has been cleared
from the body

40. Pregnancy and tamoxifen
Tamoxifen use is contraindicated during
pregnancy as it can cause congenital
anomaly

41. summary
• High-risk breast cancer - ovarian suppression
plus exemestane
• Low risk breast cancer - Tamoxifen as single-
agent therapy
• As single-agent therapy, aromatase inhibitors
(AIs) should not be used in women with intact
ovarian function.
• Postmenopausal women - aromatase inhibitor
• For women who start on Tamoxifen,switch to
an AI within the first three years of treatment
to complete at least five years of endocrine
therapy

42. summary
• For women treated with Tamoxifen for five years
who are not candidates for an AI for whatever
reason (including women who are not menopausal
after tamoxifen and those who cannot tolerate an
AI), we recommend extended treatment with
tamoxifen for 10 rather than five
• Women with childbearing potential should use an
effective means of contraception while
on Tamoxifen.
• Wait for 2-3 months before attempting pregnancy
• Frequency of congenital anomalies associated with
tamoxifen if taken during pregnancy.