1. HORMONE THERAPY IN BREAST CANCER
By Dr. Rajib Bhattacharjee

2. Sir George Thomas Beatson
“ovaries may be the
exciting cause of
cancer of breast”
Beatson CT. On treatment of inoperable cases of
carcinoma of the mamma: suggestions for a new
method of treatment with illustrative
cases. Lancet1896;2:104–7.

3. Hormone -
definition
“A hormone is a class of
regulatory biochemical that
is produced in all organisms
by glands, and transported
by the circulatory system to
a distant target organ to
coordinate its physiology
and behavior.”
----wiki

4. Hormone responsive malignancies
Endometrium
Prostate
Breast

7. Hormone receptor +ve breast cancer
histology-ductal,lobular,mixed,metaplastic (STAGE I-III)
HER2neu +ve
Node +ve node –ve
HT+CT
<= 5mm 5-10mm >10mm
HT HT +/- CT HT+CT
CT includesTrustuzumab
HER2neu –ve
Node +ve Node –ve
HT+CT
>5mm <=5mm
HT
21 gene RT-PCR assay
LRR IRR HRR
HT HT+/-CT HT+CT
# NCCN

8. Hormone receptor +ve breast cancer
Histology- Tubular, Mucinous (STAGE I-III)
node +ve node –ve
HT+/- CT <=1cm 1-2.9cm >=3cm
Ovb +/-HT HT+/-CT
The variation in treatment in early breast cancer & locally advanced breast cancer is
loco-regional.The principle of endocrine manipulation is same in these two situations.
# NCCN

9. Hormone receptor +ve breast cancer
STAGE IV or recurrent disease
No prior HT within 1 yr Prior HT within 1 yr
premeno postmeno visc crisis premeno postmeno visc crisis
OA/OS/HT HT iCT OA/OS/SERM AI/SERM/SERD iCT
progression
try upto 3 HT regimens
yes CT
no clinical benefit
symptomatic visc mets
no new HTTrials #NCCN

10. Adjuvant hormone therapy
pre-menopausal @ diagnosis post-menopausal @ diagnosis
Tamoxifen(5 yrs) / OS / OA AI(5 yrs) AI(2-3 yrs) Tamox(2-3yrs) Tamox(5 yrs)
Pre-menopausal post-menopausal
No HT AI(5 yrs) tamox(2-3 yrs) AI(2-3 yrs) AI(5 yrs)
C/I to AI Tamoxifen (5 yrs)
#NCCN

11. Endocrine therapy
surgical radiotherapy hormonal agents
Oophorectomy Ovarian ablation

12. Hormone receptor status &
probability of response to therapy
ER status PR status Response probability
Positive Positive high (50-70%)
Positive Negative intermediate(33%)
Negative Positive intermediate(33%)
Negative Negative low(<10%)

13. Hormonal agents in breast cancer
Class of drug Individual drug dose Route of
delivery
Frequency of
delivary
SERM Tamoxifen,
Raloxifen,
Toremifen
20 mg
60 mg
60 mg
Oral
Oral
Oral
OD
OD
OD
Aromatase
Inhibitor
Anastrazole,
Letrozole,
Exemestane
1 mg
2.5 mg
25 mg
Oral
Oral
Oral
OD
OD
OD
SERD Fulvestrant 500 mg IM Once a month
GnRH
Analogues
Goserelin
Leuprolide
3.6 mg
7.5 mg
IM
IM
Once a month
Once a month
Anti-androgens Bicalutamide 50 mg Oral OD
Androgen fluoxymesterone 10 mg Oral BD
Progestational
agents
Megestrol,
Medroxyprogesterone
acetate
Varies
Varies
Oral
Oral / IM
OD
Varies

14. SERM
3rd Generation
Lasofexifen
2nd Generation
Raloxifen
1st Generation
Tamoxifen Toremifen

15. Tamoxifen
Mechanism of action
 Tamoxifen binds competitively to ER Tamox-ER dimer
binds to ER elements nucleus
inhibits transcription & signal transduction pathways
inhibits cellular growth & proliferation
 Tamoxifen TGF beta inhibits TGF alfa & IGF 1
Inhibits cell growth & proliferation

16. Tamoxifen
FDA approved indications
 Prevention of premenopausal breast cancer
 Treatment of DCIS
 Treatment of surgically resected premenopausal ER+ve breast
cancer
Estrogenic effects
 Beneficial effects- decrease in total cholesterol in blood,
preservation of bone density in postmenopausal women.
 Deleterious effects- hot flushes, vaginal symptoms(dryness,
discharge, bleeding), thromboembolic events, Endometrial cancer.

17. Tamoxifen
Drug interactions --Tamoxifen inhibits hepatic P450 system
metabolism
Warfarin Cyclophosphamide
Antidepressants(SSRI/SNRI) Antipsychotics
CYP2D6
Tamoxifen Endoxifen (active metabolite)
activity ofTamoxifen

18. Tamoxifen
Caution
 Vaginal bleeding, pelvic pain
refer to gynaecologist
 Abnormal liver function
drug accumulation
toxicity
 Thromboembolism or
hypercoagulable state
 Transient tumor flare
 Premenopausal women
amenorrhoea
Toxicity
 Menopausal symptoms
 Fluid retention & peripheral
edema
 Tumor flare
 Visual disturbances
 Skin rash, pruritus, hair fall
 Thromboembolic complications
 Endometrial hyperplasia, polyps
& endometrial cancer

19. Tumor flare
 Incidence:
4% to 7% with high-dose estrogen
3% to 13% with tamoxifen
 Dramatic  in bone pain, an  in size & number of
metastatic skin nodules, and erythema.
 Within days to several weeks after starting treatment
 Hypercalcemia in 5%
 Tumor regression may occur as the flare reaction
subsides
 Look for objective evidence of disease progression if
the patient's symptoms have not resolved by 4 to 6
weeks as flare is transient

20. Contra-indications of Tamoxifen
ABSOLUTE
 Retinal macular edema or
degeneration
 H/O benign or malignant liver
tumor secondary to oral
contraceptives
 Pregnancy
 Other hormonal treatment or
OCP
RELATIVE
 H/O thrombophlebitis
 H/O depression
 Cataract
 Severe vasomotor symptoms
 Polycystic ovaries

21. Raloxifen
Estrogen agonist action Estrogen antagonist action
Bone liver breast endometrium
Treat osteoporosis cholesterol growth & proliferation
NSABP P2Trial compared Raloxifen withTamoxifen
advantages disadvantages
Lower risk of thrombolic
events & endometrial cancer
Inferior toTamoxifen in cancer
control

22. Arometase inhibitor
Steroidal AI (type 1) Non steroidal AI(type 2)
MOA Steroidal AI
Binds irreversibly with
active site of aromatase
enzyme
Irreversible enzyme
inhibition
non steroidal AI
reversible bond to the
heme iron atom
Reversible enzyme
inhibition
1st generation Aminoglutethimide
2nd generation Formestane Rogletimide
Fadrozole
3rd generation Exemestane Anastrazole
Letrozole
vorozole

23. Anastrazole & Letrozole
Anastrazole
 Bone density measurement needs
to be performed prior to initiation
of treatment & at regular intervals
 No dose adjustments needed in
case of renal or hepatic failure
 No marked effect on lipid profile
 Toxicities-Asthenia(20%),
arthralgia(10-15%), hot
flashes(10%), peripheral
edema(7%)
 Advantages- no thrombembolic
events
no endometrial effects
Letrozole
 Bone density measurement
 Drug interactions-
1. Warfarin – increased PT, INR
2. Clopidogrel- reduce effect
 Caution in deranged liver function
– dose adjustment
 Toxicities- myalgia, arthralgia,
hot flushes
 Advantages- no thrombembolic
events
no endometrial effects

24. SERD-Fulvestrant
 MOA- High affinity for ER
Downregulates expression of ER
 Indications- metastatic hormone receptor positive breast cancer in post
menopausal women who have progressed on anti-estrogen therapy
 Dose – 500 mg IM on D1, D15, D29 Monthly
 Caution – bleeding diathesis, on anticoagulant, thrombocytopenia
avoid pregnancy, avoid breast feeding
 Toxicities – asthenia (25%),hot flushes(20%),flu like symptoms(10%)

25. GnRH Analogues
Goserelin & Leuprolide
 They are used for Medical Ovarian Suppression
 MOA- Desensitisation of pituitary to GnRH
Secretion of LH & FSH from Pituitary
 Dose – Goserelin- 3.6 mg SC every 28 days or 10.8 mg SC every 90
days
Leuprolide- 22.5 mg SC every 3 months or 30 mg SC every 4
months
 Caution-Transient tumor flare due to initial release of LH & FSH.
May occur in upto 20% of patients usually within 1st 2 weeks of
starting therapy

26. Megestrol acetate
 MOA- Direct anti-estrogenic effect
inhibits LH receptor
inhibits stability, availability & turnover of ER
 Dose – 160 mg PO/day in advanced breast cancer
320 mg/day in cancer related cachexia
20 - 40 mg/day in hot flushes
 Caution – H/O thromboembolic events
Diabetes Mellitus
Abnormal liver function- dose reduction may be needed
Risk of weight gain & fluid retention- SRD
 Toxicities- weight gain, thromboembolism, hyperglycemia,
breakthrough menstrual bleeding, tumor flare

27. Antiandrogens
Luminal ER-/AR+ Breast cancer
 A molecular subtype of breast cancer which is not sensitive to
antiestrogens but show an overexpression of Androgen
Receptors(AR+)
 Increased overexpression of AR is associated with resistance to
antiestrogens which act via ERs
 Antiandrogen Bicalutamide may be a useful targeted therapy in such
situations
 Recently Enzalutamide has been studied in vitro and in preclinical
models of ER+/- Breast cancer which express AR.This study supports
initiation of clinical studies evaluating enzalutamide in AR+ tumors
irrespective of ER status
Cochrane et al. Breast Cancer Research 2014 16:R7

28. So many arrows in our repertoire…..which
one to shoot….
Tamoxifen for 5 years
 41% reduction in the annual rate of breast cancer reccurence
 34% reduction in annual death rate for woman with ER +ve breast
cancer
 Longer and shorter durations of treatment had less impact
 Not effective for preventing recurrence in hormone receptor
negative breast cancer
Early Breast CancerTrialistsGroup. Effects of chemotherapy and hormonal therapy for early breast cancer on
recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365(9472):1687.

29. Tamoxifen for how long…?
Tamoxifen is recomended for 5 years in our clinical practice
Cause – 1. Carry over effect
2. Risk of endometrial cancer increases with longer
duration of tamoxifen therapy
Trials – 1. In the EBCTSG meta-analysis 5 yr tamoxifen reduced
the risk of recurrence and death twice as much as 2 yr
tamoxifen therapy.
2.Three trials including one large NSABP trial have
compared 5yrs ofTamoxifen treatment with longer
treatment- no convincing evidence that treatment lasting
longer than 5 years is beneficial. Rather a detrimental effect is
seen in longer duration therapy.
Two trials investigating these issues- ATLASTrial & ATTOMTrial

30. To AI or not to AI… that is the problem…
Timing /
setting
Trial AI No. of pt Hazard ratio
for DFS
Absolute diff
in DFS
Upfront; y O ATAC
BIG1-98
ANZ
LET
9366
8010
0.87
0.81
2.8@ 5 yrs
2.6@ 5 yrs
Sequential;
After 2-3 yrs
ofTAM
IES
ARNO/ABCSG
ITA
EXE
ANZ
ANZ
4742
3224
448
0.68
0.60
0.57
4.7@ 3 yrs
3.1@ 3 yrs
Extended ;
After 5 yrs of
TAM
MA17
NSABP B33
LET
EXE
5187
1598
0.58
0.68
4.6@ 4 yrs
2.0@ 4yrs

31. How to attack.....??
ATAC Trial
ER +ve Breast Cancer in a postmenopausal woman (n=9366)
Arimidex Tamoxifen combination
1mg for 5 yrs 20mg for 5 yrs A+T for 5 yrs
(n=3125) (n=3116) (n=3125)
Median fallow up 68 months
Conclusion – Arimidex alone is better than tamoxifen alone.
Similar survival in combination arm

32. A big trial comparing four arms
BIG 1-98Trial
Post menopausal ER positive breast cancer(n=8010)
LTZ for 5 yrs TAM for 5 yrs LTZ for 2 yrs TAM for 2 yrs
TAM for 3 yrs LTZ for 3 yrs
Median fallow up 28.5 months
Conclusion- 4 year DFS significantly higher in favour of Letrozole

33. ITA- a sequential trial
ER+ postmenopausal node positive breast ca(n=448)
TAM for 5 yrs TAM for 2-3 yrs
ANZ for 3-2 yrs
median Follow up- 64 months
Event free survival hazard ratio – 0.57
Conclusion –Tamoxifen fallowed by Anastrazole is better thanTamoxifen
alone

34. Mother of all trials...?
MA.17Trial
Post menopausal, receptor +ve woman, who have completed 4.5 - 6yrs of
Tamoxifen and remained disease free
LET(5 yrs) Placebo
ER+/PR+ 51% reduction in recurrence
ER+/PR- 23% reduction in recurrence
ER-/PR+ 44% reduction in recurrence
Letrozole group showed 42% improvement in OS
Conclusion– Addition of Letrozole toTamoxifen has clear benifit over
Tamoxifen alone.

35. Upfront vs Sequential or Extended
therapy
ITA & ARNO/ABCSGTrials support the benifits of switching from
Tamoxifen to Anastrazole
but......
 Not yet offered long term fallow up analysis
 No head to head comparison between upfront Anastrazole vs
Switching or Extended therapy
 Point at which switching to be done is hitherto undecided
In the absence of experimental evidences, these issues have been
addressed with the help of computar models.....

36. Upfront vs Sequential or Extended
therapy
Punglia et al (JCO 2005; 23; 5178 - 87) developed Markov models to simulate 10
yrs DFS among patients treated with
 5 yrs ofTamoxifen The model is based on ...
 5 yrs of AI * Available clinical data
 Switching to AI after 2.5 or *Assuming all commercially
5 yrs ofTamoxifen availableAIs would have
similar efficacy and tolerability
Results – Best adjuvent therapy is switching to AI after 2.5 yrs ofTAM
With this regimen. Absolute DFS rates at 10 yrs would be 83.7% & 67.6% for
node –ve and node +ve patients respectively.
Upfront therapy with A yielded rates of 82.6% & 65.5% respectively

37. Upfront vs Sequential or Extended
therapy
 An update of Markov model analysis (Cancer 2006; 106:2576-82)
further showed that different subpopulation of patients might
benefit from different therapeutic regimens :-
1. ER+/PR+ Sequential treatment.
2. ER+/PR- Up-front treatment with AI.
3. Switching to AI after 5 yrs of ‘T’ did not further improve the DFS rates
at 10 years.
Another computer model analysis proposed by Hilsenbeck et al (Clin
Cancer Res 2006; 12:1049-1055) supported the predictions of Markov
model.

38. Anastrazole 1st line…
North American Trial andTARGET trial (Tamoxifen and
Anastrazole Randomised Group Efficacy andTolerability)
Post menopausal ER/PR + Advanced Breast CA
Tamoxifen Anastrazole
Result – Anastrazole showed greater clinical benefit than
Tamoxifen
Inference- Anastrazole is the approved 1st line hormonal agent
in post menopausal hormone receptor positive breast cancer

39. NCCN, ASCO, ESMO & St Galen Expert Committee
Recommendations
pre & perimenopausal ER+Woman post menopausal ER+ woman
Tamoxifen Aromatase Inhibitor
“Role ofTamoxifen in receptor negative tumor needs further
evaluation”
Early Breast CancerTrialists Collaborative Group

40. Emerging hormonal therapy sequence
Postmenopausal woman with ER+ Advanced
breast cancer
1st line Tamoxifen AI
2nd line Fulvestrant AI Fulvestrant Tamoxifen
3rd line AI Fulvestrant MA Fulvestrant
4th line MA MA Tamoxifen MA
#MD ANDERSON CANCER CENTER

41. Anastrazole as Neo-Adjuvant therapy

42. Hormone therapy with EBRT
Node negetive ER positive breast ca withT size upto 10 mm(n=1009)
Lumpectomy
Tamoxifen (n=336) XRT (n=336) TAM + XRT(n=337)
Results: XRT and placebo resulted in a 49% lower hazard rate of IBTR than
didTAM alone;
XRT andTAM resulted in a 63% lower rate than did XRT and placebo.
When compared withTAM alone, XRT plusTAM resulted in an 81%
reduction in hazard rate of IBTR.
Conclusion: In women with tumors < 1 cm, IBTR occurs with enough
frequency after lumpectomy to justify considering XRT, regardless of
tumor ER status, andTAM plus XRT when tumors are ER positive.
#J Clin Oncol 20:4141-4149. © 2002 by American Society of Clinical Oncology.
 Tamoxifen, Radiation Therapy, or Both for Prevention of Ipsilateral Breast Tumor Recurrence After Lumpectomy in
Women With Invasive Breast Cancers of One Centimeter or Less By Bernard Fisher, John Bryant, James J. Dignam, D.
Lawrence Wickerham, Eleftherios P. Mamounas, Edwin R. Fisher,Richard G. Margolese, Lois Nesbitt, Soonmyung Paik,
Thomas M. Pisansky, and Norman Wolmark for the National Surgical Adjuvant Breast and Bowel Project

43. Hormone therapy & chemotherapy
 ADVANTAGE- 1. Synergistic effect
2. Inhibition of p-glycoprotein
3. Downregulation of bcl-2
 DISADVANTAGE- 1. Cytostatic mode of action
2. Calmodulin antagonism
 TRIALS – Premenopausal- NSABPTrial- 35% decrease in recurrence
Other trials inconclusive
The 1995 Oxford meta-analysis showed a significant reduction in
recurrence rates and deaths.
Postmenopausal- Benefits are less certain
Best in node+ve 50-60 yr pt with Doxo
NSABP P20, SWOG8814, IBCSGTrial IX
 SEQUENCE- INTERGROUP 0100Trial- sequential vs concurrent
CT/HT- Improved 8 yr DFS in sequential group

44. Ovarian ablation & suppression

45. Surgical overian ablation
 First report of surgical oophorectomy for the treatment of
advanced breast cancer published by Dr. George Beatson in
1896 who saw a young lactating woman with advanced breast
cancer and had tumor regression after removing both her
ovaries.
 Oophorectomy reliably and promptly reduces circulating
estrogens to postmenopausal levels in nearly 100% of women,
and has the advantage of simultaneously reducing ovarian
cancer risk. It is also the most cost-effective method of
ovarian ablation.
 But oophorectomy may require hospitalization and carries
potential operative and anesthesia-related morbidity and
mortality. It also irreversibly induces premature menopause
with sequelae including osteoporosis, an increased risk of
coronary artery disease and permanent loss of fertility.

46. Radiation induced ovarian ablation
Features
• Non invasive &
cheap
• Low dose radiation
• Takes 2-3 months
for effects to appear
Technique
• Position-Supine
• Field-Parallel
opposed
• Energy-Co60/6MV
LINAC
• Field borders-
encompasses entire
true pelvis; lower
border just below
the superior border
of symphysis pubis
• Field size- 10*15 cm
• Dose - 10-12 Gy in
5-6 #
Results
• The first series was
reported by Foveau
de Courmellles in
1922
• Treves in 1957
showed that
fallowing ovarian
irradiation 10 yrs
survival improved
from 33.8%-42.3%
• Benifit was greater
in node negative
patients

47. Other uses of endocrine therapy in breast
cancer
 Risk reduction in LCIS- NSABP P1 trial and STAR trial
 Use in DCIS- NSABP B24 trial and UK-DCIS trial
 Male breast cancer

48. Questions without answers.....yet
 The use of anastrozole is well established, but we still do not
know if anastrozole is superior to other steroidal or non-
steroidal AIs.
 Some trials have shown the efficacy on Exemestane and
Formestane in Anastrozole & Letrozole failure patients.
 No direct comparison between up-front use of anastrozole vs.
after 2-3 years ofTAM.
 Benefits of extended anastrozole adjuvant therapy ?
 Long term side effects of AIs ?
 NACT converts 10 % receptor +ve tumours into receptor – ve.
Is it unidirectional ?

49. Where we stand......for now
 50 % of our patients are Pre-menopausal.
 AIs have no role on them even if they are ER +ve.
 TAM should be given in ER +ve pre-menopausal
patients.
 TAM reduces the incidence of contralateral breast
cancer even in “ER poor” tumours (EBCTCG meta-
analysis).
 SERMs have been successful as ‘Chemo-prevention’
in women with ‘High Risk’ for breast cancer.
 Incidence ER positivity increases with age &
menopausal status. CanTAM may be given in
Chemotherapy induced menopausal patients with
unknown or –ve ER status ?

50. Prostate & other hormone responsive cancers….
By Dr. Imran Khan
THANK YOU