Hormonal therapy in breast cancer

1. Hormonal therapy in Breast Cancer
Dr Deepika Malik
Resident Radiation Oncology- IIIrd year

2. Estrogen- risk factor for breast cancer
• increased exposure to endogenous estrogens– RISK FACTOR
• Early age at menarche,
• nulliparity or late age at first full-term pregnancy,
• late age at menopause increase
• In postmenopausal women, obesity and postmenopausal hormone
replacement therapy, both of which are positively correlated with plasma
estrogen
• Furthermore, in utero exposure to high concentrations of estrogen may also
increase breast cancer risk. ( DES).

3. How hormones
help in breast
development

4. GnRH

5. HISTORY AND EVOLUTION-
Oopherectomy
• Its role in the treatment of breast cancer-- 100
years.
• Thomas William Nunn - first to report a relationship
between ovarian function and breast cancer.1
(mn)
• Albert Schinzinger, a German surgeon- first to
propose oophorectomy as a treatment for breast
cancer 2

6. • George Thomas Beatson
• first performed a bilateral
oophorectomy on a woman with
breast cancer in 1895.
• He reported on three patients in
the Lancet in 1896.
-Significant tumor regression
-Sense of well being
-A subsequent report ---one
patient survived 4 years after the
surgery.
• procedure never became popular -
high morbidity, not curative, no
therapeutic rationale

7. • 1940’s, Charles Huggins described
the hormonal responsiveness of
prostatic cancer
• Interest in the hormonal treatment
of breast cancer was resurrected
• 1950’s, Charles Huggins and
Thomas Dao popularized
oophorectomy
- mainstream of breast cancer
therapy

8. It took 30 years ( after oopherectomy was first explored), however, for
the discovery of Estrone, the first estrogen, by Edward Doisy in 1929

9. • No large randomized trials until the middle of
the 20th century.
•
• Few small randomized trials -- inconsistent
results.

10. • Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG) in 1984.- The first large body of evidence in
favour of oophorectomy
• subsequent overview (2005)
-ovarian ablation had a large positive effect on both
disease-free survival (DFS) and overall survival (OS) in
premenopausal women when compared to no adjuvant
treatment

11. • 1966 – Dr Arthur L Walpole/Dr
Dora Richardson
▫ Developed Tamoxifen (ICI-46474)
▫ as a Contraceptive “Morning After
Pill”
▫ Never proved useful in human
contraception
HISTORY AND EVOLUTION

12. • 1971 – Christie Hospital, Manchester
▫ 1st Clinical study of Tamoxifen in Advanced Breast
Cancer
HISTORY AND EVOLUTION

13. • 1973 – Queen Elizabeth Hospital, Birmingham
HISTORY AND EVOLUTION

14. • 1973 – 1st work done on Aromatase Inhibitors in
treatment of Breast cancer
HISTORY AND EVOLUTION

15. TIMELINE OF DEVELOPMENT OF
AGENTS IN BREAST CANCER

16. •Breast cancers are mediated through ERs and PRs, by estrogen
•
•Receptors significance in breast cancer ------40 years ago
Hormone receptors in breast cancer
© 2010 by American Society of Clinical Oncology
American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical
Testing of Estrogen and Progesterone Receptors in Breast Cancer
•In 1970s--- Ligand Binding Assays ( concentration of radiolabelled LBA’s was
measured.
•Cytosol protein 10 fmol/mg
•Mid 90’s- IHC
•ASCO Panel (2010) recommended a cutoff of a minimum of 1% of tumor cells
positive for ER/PgR for a specimen to be considered positive.
•There is no agreement about a range for receptor equivocal, so this term should
not be used.

17. MOLECULAR BASIS
• Overexpression of Estrogen receptors is seen in
a large number of breast cancer patients (~70%)
• Estrogen :
▫ Steroid hormone
▫ Exerts its actions through both genomical and
nongenomical mechanisms

18. Classical genomic mechanism:
(1) Estrogen binds to an intracellular
Estrogen receptor (ER)
(2) ER dimerizes with another ER
(3) ER complex translocates to the
nucleus and then binds to the
Estrogen response element (ERE)
leading to transcription
Non Classical genomic
mechanism:
(1) Estrogen binds to a membrane
bound ER
(2) Second messenger systems are
activated
(3) molecules from second
messenger systems bind to DNA
regulatory regions such as cAMP
response element (CRE) and
serum response element (SRE)
regions to activate transcription
Genomic Mechanism :
•binding of hormones to their respective
receptors, transcription of the specific
genes, and protein synthesis
•hours to days

19. - Believed to result from the
hormone-dependent activation
of membrane-bound and/or
cytosolic ERs.
- These nonnuclear ER actions
result in very rapid
phosphorylation and activation
of important growth regulatory
kinases including
- EGFRs
- IGF-1R
- c-Src
- Shc
- p85 regulatory subunit of
PI3-K
Non Genomic Mechanism
:modulation of neurotransmission unrelated
to the transcription of genes
seconds to minutes

21. • Mechanism of action of Hormonal therapies :
▫ All the hormonal therapies target either the
Estrogen directly or the Estrogen receptor at one
level or the other
MOLECULAR BASIS

22. HORMONAL THERAPY
• Selective Estrogen
Receptor Modulators
(SERM)
▫ Tamoxifen
▫ Raloxifen
▫ Torimefene
• Anti Estrogens
▫ Fulvestrant
• Aromatase Inhibitors
▫ Letrozole
▫ Anastrazole
▫ Exemestane
• LHRH Agonists
Leuprolide
Goserlin
• Progestins
Megestrol acetate
Medroxyprogesterone
acetate
Ovarian function supression
1. Oopherectomy
2. RT ablation
3. LHRH agonists

23. SELECTIVE ESTROGEN RECEPTOR MODULATORS
(SERMs)
• Tamoxifen
•Raloxifen
•Torimefene

24. (SERMs)
• The SERMs lack the steroid structure of estrogens but
possess a tertiary structure that allows them to bind to
the estrogen receptor
• Selective modulation--
▫ Differential estrogen-receptor expression in a given target tissue
▫ Differential estrogen-receptor conformation on ligand binding
▫ Differential expression and binding to the estrogen receptor of co
regulator proteins

25. (SERMs)
• TAMOXIFEN
• First synthesized in 1966,
• but wasn’t until 1980 that it showed
benefit in early stage breast cancer
• 1st hormonal drug approved by the
FDA for usage in Breast CanceR
• Chemically : Triphenylethylene
• Blocks the cell cycle in G1 phase

26. • Selective Estrogen Receptor Modulator
(SERM)
▫ A drug that targets estrogen receptors in
specific tissues
• How Tamoxifen Works
▫ Antagonist in breast and brain
 No transcription
 Cell growth arrest/apoptosis
▫ Agonist in lung, liver, bone, and uterus
 Normal function

27. Actions
• complex,
• partial estrogen-agonist effects.
• beneficial,
- prevent bone demineralization in
postmenopausal women
- cardioprotective
• detrimental,
-increased risks of uterine cancer
- thromboembolism

28. Toxicity of Tamoxifen
• Menopausal symptoms:
▫ 50% - 60% ( N.B. 40% - 50% in
placebo)
▫ MC in premenopausal
▫ Vaginal dryness and discharge may
occur in excess.
• Depression:
▫ Maybe seen in as high as 10% of
patients.
▫ But no randomized comparisons
available.
• Ocular toxicity:
▫ Keratopathy, maculopathy & cataract
▫ Reported with high doses
▫ However NSABP studies have found
no increase in vision threatening
ocular toxicity.
• Thromboembolism:
▫ Severe thromboembolism
seen in ~ 1% patients
▫ 10 times risk compared to
healthy women
• Carcinogenesis:
▫ Increased risk of endometrial
cancers
▫ (hazard rate of 1.7 per 1000 –
NSABP B 14 data)
• Other tumors:
▫ Hepatomas
▫ Clear cell sarcomas of ovary

29. ANTI ESTROGENS
(SELECTIVE ESTROGEN RECEPTOR DOWNREGULATOR)
Fulvestrant
Pure antagonists
No agonist activity

30. ANTI ESTROGENS
• FULVESTRANT
▫ Steroidal antiestrogen.
▫ Considerably higher affinity for Estrogen receptor than tamoxifen
 Promotes accelerated ER turnover,
 Suppression of ER protein levels,
 Inhibition of ER dimerization,
 Reduced shuttling of the ER from the cytoplasm to the nucleus
• an intramuscular injection (500 mg loading dose on days 1, 14, and
29 of the first month, then maintenance dosing monthly at day 28,
±3 days).
• Although originally approved as a monthly intramuscular injection
(250 mg per month), use of the higher dose was proven to be more
effective in subsequent trials and is now the preferred schedule
• ( ref- Final Overall Survival: Fulvestrant 500mg vs 250mg in the Randomized CONFIRM Trial, 2014)

31. AROMATASE INHIBITORS
-inhibiting “aromatization”
-Aromatase enzyme-
-Residual estrogen
production after menopause
is solely from nonglandular
sources, mainly
subcutaneous fat.
N Engl J Med 2003;348:2431-42. Copyright © 2003
Massachusetts Medical Society
•September, 2000 – first AI –
Arimidex – FDA approved for
breast cancer
•Block production of Estrogen

32. AROMATASE INHIBITORS
Aminoglutethimide (anticonvulsant), toxicity-adrenal insufficiency.
• inhibit adrenal steroidogenesis , then redeveloped for use as “medical
adrenalectomy” against advanced breast cancer.
• Side effects, drowsiness and rash, limited its use
• discovery that its efficacy was mainly due to aromatase inhibition stimulated the
development of numerous new inhibitors

33. AROMATASE INHIBITORS
Second-generation aromatase inhibitors
found to have clinical efficacy, but
Disadvantage-- formestane requires intramuscular injection
--fadrozole causes aldosterone suppression( limiting its use to doses
that produce only about 90 percent)

34. AROMATASE INHIBITORS
Third-generation inhibitors
• developed in the early 1990s
Dosing — :
●Anastrazole (1 mg daily)
●Letrozole (2.5 mg daily)
●Exemestane(25 mg daily

35. Toxicity management
• Hot Flushes:
▫ Usually self limiting and respond well to placebos.
▫ Best managed by life style changes.
• Vaginal Bleeding:
▫ Routine work up indicated.
▫ Watch out for an endometrial CA in post menopausal females.
• Osteoporosis:
▫ Calcium supplements, Vitamin D and bisphosphonates

36. AI-associated musculoskeletal syndrome
• arthralgia, joint stiffness, and/or bone pain,
• can be severe in almost a third of patients
• responsible for treatment discontinuation in 10 to 20 percent of patients
• Understanding the etiology is complicated, -rheumatologic symptoms are present in
a significant number of women who on complain of AI-associated MSK.
• Management-
• 1.Exercise
In the Hormones and Physical Exercise (HOPE) trial, 121 postmenopausal women with
AI-associated arthralgias were randomly assigned to an exercise regimen or to usual
care
(The exercise regimen consisted of twice-weekly supervised resistance and strength
training plus moderate aerobic exercise for 150 minutes per week.
•A significantly greater reduction in their worst pain score (20 versus 1 percent average
score reduction, respectively) and pain severity (21 versus 0 percent reduction)
compared with usual care
•More weight loss and improvement in their exercise capacity
• 2. Nonsteroidal antiinflammatory drugs (NSAIDs- as a mainstay for pain

37. • If do not respond to NSAIDs, subsequent decisions depend on whether a woman is willing to stay
on an AI:
•
If willing to stay on an AI,( provided the
symptoms of AIMSS can be controlled, )
discontinue treatment for two to eight
weeks and then begin a different AI.
If not willing to continue on an AI
due to AIMSS,
administer tamoxifen
If opt to continue an AI despite MSK
complaints, duloxetine.
(the most common adverse events were minor (grade 1 or
2) fatigue, xerostomia, nausea, and headache).

38. AI Contraindicated in women with
functional ovaries!!!!!
• Ultimate action of SERM or AI
estrogen
• FSH = Estrogen
• If on tamoxifen, then increased
estrogen is not an issue as estrogen
receptors are blocked

39. AI Contraindicated in women with
functional ovaries!!!!!
• Ultimate action of SERM or AI
estrogen
• FSH = Estrogen
• If on AI, however, then increased
estrogen can lead to stimulation of
estrogen positive breast cancers
estrogen

40. LHRH AGONISTS
Leuprolide
Goserelin
Triptorelin

41. LHRH ANALOGUES
• Analogue that activates the GnRH receptor
resulting in increased secretion of FSH and LH
• After their initial stimulating action –“flare”
effect - eventually causes a paradoxical and
sustained drop in gonadotropin secretion
• “downregulation” (observed after about 10
days.)

42. PROGESTINS
Megestrol acetate
Medroxyprogesterone acetate

43. PROGESTINS
• Powerful antiandrogenic and antiestrogenic effects
• Significantly lowers the expression of the androgen
receptor (AR) and the Estrogen receptor (ER) in the
body
• The antineoplastic action of progestins on
carcinoma of the breast is effected by
▫ modifying the action of other steroid hormones and
▫ by exerting a direct cytotoxic effect on tumor cells

44. Definition of menopause
• women 60 years and older
• women less than 60 years with one of the following conditions
-----
• previously underwent a bilateral oophorectomy.
• not had any 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.
• are amenorrheic on tamoxifen, and follicle-stimulating
hormone (FSH) and serum estradiol are in the
postmenopausal range

45. HORMONAL THERAPY IN ADJUVANT SETTING
• Tamoxifen - has been agent of choice for all pre
menopausal patients with Estrogen receptor
positivity

46. Meta-analysis of 20 trials (n=21,457) in early breast cancer
of about 5 years of tamoxifen versus no adjuvant
tamoxifen, with about 80% compliance.
Tamoxifen increased uterine cancer incidence, RR 2·40

47. In the EBCTSG meta-analysis 5 yr tamoxifen reduced the risk of recurrence
and death twice as much as 2 yr tamoxifen therapy.
In two large European trials from Britain and Sweden, women treated with
tamoxifen for 5 years, had fewer recurrences and deaths than those treated
for only 2 years
HORMONAL THERAPY IN ADJUVANT SETTING- Tamoxifen
Duration of therapy :
Earlier 5 years of Tamoxifen was the recommendation
1. Swedish Breast Cancer Cooperative Group. Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early
stage breast cancer. Swedish Breast Cancer Cooperative Group. J Natl Cancer Inst 1996;88:1543–1549.
2. Current Trials Working Party of the Cancer Research Campaign Breast Cancer Trials Group. Preliminary results from the cancer
research campaign trial evaluating tamoxifen duration in women aged fifty years or older with breast cancer. Current Trials Working
Party of the Cancer Research Campaign Breast Cancer Trials Group. J Natl Cancer Inst 1996;88:1834–1839.

48. • Duration of therapy :
▫ 2 trials : ATLAS and aTTom advantage of giving
Tamoxifen for more than 5 years (10 Years) in high risk
patients
▫ ASCO 2014 Update on adjuvant Hormonal therapy in
Breast Cancer--- recommends the use of Tamoxifen for
10 years in pre and peri menopausal females with
Estrogen receptor positivity
HORMONAL THERAPY IN ADJUVANT SETTING- Tamoxifen

49. ATLAS TRIAL
(12, 894 women) (36 countries) 6846, 1996-2005 , on Tamoxifen
Continue till 10 years stop at 5 years
With increased risk of endometrial cancer
5 years tamoxifen : absolute 15 year endometrial cancer risk of 2–3%,
10 years tamoxifen :additional risk by year 15 of 2%.

50. aTTom study (Adjuvant Tamoxifen Treatment Offer More?)
• “that 10 years of adjuvant tamoxifen is superior to 5 years of tamoxifen in
reducing the risk of breast cancer recurrence or death but that the full survival
benefits of extended treatment do not emerge until after the 10 years of
treatment.
• presented at the ASCO Annual Meeting, in 2013
• Similar to ATLAS”
“ ASCO report 2013”
J Clin Oncol 31, 2013 (suppl; abstr 5)
-results indicate that 10 years of adjuvant tamoxifen, compared to no tamoxifen, reduces
breast cancer mortality by about one third in the first 10 years following diagnosis and
by a half subsequently..

52. ▫ Have been proven beneficial in Post menopausal
setting
▫ Presently considered the 1st line hormonal therapy in
Post menopausal setting
HORMONAL THERAPY IN ADJUVANT SETTING- Aromatase Inhibitors

53. ATAC trial- Arimidex Tamoxifen Alone or in
Combination trial
• single agent anastrozole ---significant increase in TTR compared
with tamoxifen in patients with hormone-sensitive tumors
• relative efficacy of anastrozole compared to tamoxifen is greater
in thin postmenopausal women a(nd higher doses might be more
effective in overweight women)
a (1:1:1) randomized, double-blind trial, 4900 post menopausal females, non metastatic
1mg anastrozole 20 mg tamoxifen combination
x 5 years x 5 years x 5 years

54. NCIC CTG MA.17 trial Canadian Cancer Society Research Institute
• phase III, randomized, double-blind, placebo controlled trial
•Postmenopausal women with hormone receptor–positive primary breast cancer
who were disease-free and within 3 months of completing approximately 5
years of adjuvant tamoxifen.
•letrozole (2.5 mg orally daily) x 5 years placebo x 5 years
• result -extended adjuvant letrozole was superior to placebo in DFS, DDFS, and OS.

55. BIG 1-98 trial ( breast intergroup)
•
•a randomized, phase III, double-blind trial of 8010 postmenopausal women with hormone receptor-positive
early breast cancer
•Results- in post menopausal HR +ve , letrozole monotherapy was superior to tamoxifen in reducing
recurrence and mortality
•Sequential t/t- do not improve outcome compared to tamoxifen, but represent useful strategies considering
indivisula patient risk of recurrence and treatment tolerability

56. MA -
17
ATAC BIG IES
Vaginal
Complications
-
1.7%
-
14%
-
3.3%
-
1.5%
Tamoxif
en
poorerEndometrial Cancer NA -
0.6%
-
0.4%
NA
Thromboembolic
events
NA -
1.7%
-
1.2%
- .9%
Cardiac
complications
0.5% 0% 0.4% NA AI
poorer
Arthalgia /Myalgia 23% 7% NA 6%
Osteoporotic
fractures
2.3% 2.2% 1.7& 2%
Hot flushes 6% 5% 4% 2%
TOXICITY OF AROMATASE INHIBITORS
VERSUS TAMOXIFEN

57. Duration of AI’s

58. • LHRH Agonists in Early breast Cancer
HORMONAL THERAPY IN ADJUVANT SETTING-LHRH
agonists
EBCTCG meta-analysis from 2007
No benefit to adding OFS to tamoxifen except maybe in
women under 40 and very high risk patients
ECOG 3193 (345 women)
Tamoxifen vs tamoxifen + OFS
No difference in outcomes

59. SOFT/TEXT trial Suppression of Ovarian Function Trial
Tamoxifen and Exemestane Trial
Combined analysis of the 2 trials
At 5 years: 92.8% of pts in Exe/OFS cancer free
88.8% of pts in Tam/OFS cancer free
---Relative improvement in disease free survival of 36% with Exe/OFS vs Tam/OFS
No difference in OS (95.9% vs 96.9%)

60. • Subgroup analysis:
• Patients who were treated with chemotherapy
• Patients <35 years at diagnosis of breast cancer
• higher-risk breast cancer that warranted chemotherapy administration
may benefit from ovarian suppression plus aromatase inhibition
or tamoxifen in terms of DFS
• a/e-

61. Timing of adjuvant hormonal therapy
With or following radiation therapy —
• some initiate concurrently with RT,
• other experts initiate sequentially,
• Multiple studies show that the timing of
endocrine therapy in relation to RT does
not impact survival
• (Pierce LJ, Hutchins LF, Green SR, Lew DL, Gralow JR, Livingston RB,
Osborne CK, Albain KS
• SOJ Clin Oncol. 2005;23(1):24AU
• Ahn PH, Vu HT, Lannin D, Obedian E, DiGiovanna MP, Burtness B,
Haffty BGSOJ Clin Oncol. 2005;23(1):17.
• Harris EE, Christensen VJ, Hwang WT, Fox K, Solin LJSOJ Clin Oncol.
2005;23(1):11.)
• Although older studies -concurrent treatment
increases the risks of treatment complications
(including pulmonary and/or breast fibrosis
other studies do not
Radiotherapy-related lung fibrosis enhanced by tamoxifen. Bentzen SM,
Skoczylas JZ, Overgaard M, Overgaard J Natl Cancer Inst.
1996;88(13):918.
• Factors influencing cosmetic outcome and complication risk after
conservative surgery and radiotherapy for early-stagbreast
carcinoma.Wazer DE, DiPetrillo T, Schmidt-Ullrich R, Weld L, Smith TJ,
Marchant DJ, Robert NJJ Clin Oncol. 1992;10(3):356.
Hormone receptor-positive who are not recommended to receive other adjuvant
therapy (CT , RT ) endocrine therapy is usually initiated four to six weeks after surgery.
With or following chemotherapy —
sequentially rather than concurrently.
North American Intergroup trial,
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)
EBCTCG meta-analysis similar reductions in the
rate of recurrence (RR 0.62 and RR 0.71,
respectively)

62. Special situations
• Women of childbearing potential should be advised to use an effective
means of contraception while on tamoxifen treatment (tamoxifen can
induce ovulation)
• After 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
• For women who become pregnant on tamoxifen,---- tamoxifen should be
discontinued .( high frequency of congenital anomalies.)
Use of tamoxifen before and during pregnancy.Braems G, Denys H, De Wever O, Cocquyt V, Van den Broecke R
Oncologist. 2011;16(11):1547.

63. HORMONAL THERAPY IN METASTATIC SETTING-
premenopausal females
• Ovarian suppression or ablation
• Selective estrogen receptor modulator (SERM)
• Combination treatment ( tamoxifen plus ovarian
suppression)

64. HORMONAL THERAPY IN METASTATIC SETTING- premenopausal
females
• Ovarian suppression ([GnRH] agonists) or
ablation (oophorectomy or ovarian irradiation)
• In one trial, 136 premenopausal women were randomly
assigned treatment with the goserelin o OR oophorectomy
• Although the study did not complete due to poor accrual,
goserelin resulted in:
• Similar overall survival (OS) (compared with oophorectomy (hazard ratio
[HR] for mortality 0.80, 95% CI 0.53-1.20), though the study was underpowered to
show a benefit.
• Significantly higher rate of mild hot flashes (66 versus 43
percent). However, neither arm resulted in serious toxicities.

65. Ref : Facts and Controversies in Systemic Treatment of
Metastatic Breast Cancer ; CHANTAL BERNARD-
MARTY, FATIMA CARDOSO, MARTINE J. PICCART ;
The Oncologist 2004;9:617-632
Tamoxifen versus ovarian ablation
Tamoxifen

66. Ref : Facts and Controversies in Systemic Treatment of
Metastatic Breast Cancer ; CHANTAL BERNARD-
MARTY, FATIMA CARDOSO, MARTINE J. PICCART ;
The Oncologist 2004;9:617-632
Tamoxifen plus ovarian suppression —

67. • Aromatase inhibtors
The efficacy of AIs as a first-line treatment for advanced or metastatic breast cancer
in postmenopausal women was shown in a 2006 meta-analysis of 23 randomized
trials (n = 8504 patients)
Treatment with an AI resulted in an improvement in OS compared
with tamoxifen (HR 0.89, 95% CI 0.80-0.99) and with other endocrine therapies
(HR 0.87, 95% CI 0.82-0.93).
HORMONAL THERAPY IN METASTATIC SETTING- post
menopausal women

68. HORMONAL THERAPY IN METASTATIC SETTING- post
menopausal women
• palbociclib plus letrozole —
• Palbociclib (formerly known as PD 0332991), orally administered inhibitor
of (CDK 4/6).
• Combination received (FDA) accelerated approval as first-line therapy for
metastatic, ER-positive, (HER2)-negative breast cancer in February 2015
• Treatment with letrozole plus palbociclib resulted in:
• A significant improvement in PFS compared with letrozole alone (median,
20 versus 10 months; HR 0.49, 95% CI 0.32-0.75)
• An improvement in OS, although it was not statistically significant (median,
37.5 versus 33 months; p = 0.81)
• A higher incidence of serious (grade 3/4) toxicities, including neutropenia
(54 versus 1 percent) and fatigue (4 versus 1 percent)
• Ref---FDA approves Ibrance for postmenopausal women with advanced breast cancer
http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm432871.htm.
•

69. HORMONAL THERAPY IN METASTATIC SETTING- post menopausal
women
• Fulvestrant
• The benefit of fulvestrant as first-line therapy was shown in the randomized
phase II trial, First-Line Study Comparing Endocrine Treatments (FIRST),
in which 205 patients were randomly assigned treatment with
• fulvestrant (500 mg dosing schedule) versus anastrozole (1 mg orally
daily)
●A similar rate of clinical benefit compared with anastrozole (73 versus 67
percent, respectively)
●A significantly longer time to treatment progression (median, 23 versus 13
months; HR 0.66, 95% CI 0.47-0.92)
●Significantly longer overall survival (median, 54 versus 48 months; HR 0.70,
95% CI 0.50-0.98)
• A phase III trial comparing fulvestrant and anastrozole as first-line therapy
for metastatic ER-positive breast cancer (FALCON trial) has completed
accrual and results are pending.

70. second-line endocrine treatment
• For women who continue to menstruate---- ovarian
ablation.
Once achieved, recommend treatment using agents
approved for use in postmenopausal women.
• For postmenopausal women who progress following
an AI, options
- fulvestrant
-exemestane plus everolimus
HORMONAL THERAPY IN METASTATIC SETTING– progression on
hormonal therapy

71. • Studies show that the mechanistic target of rapamycin (mTOR) inhibitor everolimus (in
combination with endocrine therapy) is an option for postmenopausal women for the
treatment of AI-resistant advanced ER+ breast cancer.
• BOLERO 2 Trial : (Breast Cancer Trials of Oral Everolimus )
▫ Randomized controlled Phase III trial
▫ HR–positive advanced breast cancer who had recurrence or progression while
receiving previous therapy with a nonsteroidal aromatase
exemestane and everolimus exemestane and placebo
• Combination improved PFS
• No improvement in OS
HORMONAL THERAPY IN METASTATIC
SETTING- everolimus

72. • Radiation Oopherectomy
▫ First series reported by Foveau de Courmelles in 1922
▫ Non invasive and cheap procedure.
▫ Low dose carries little additional morbidity.
▫ However takes time for effect to appear usually 2-3 months
▫ Dose : 4.5 Gy in single fraction to 10-20 Gy in 5-6 fractions
HORMONAL THERAPY IN METASTATIC SETTING

73. Technique
• Position: Supine
• Field selection: Parallel opposing AP-PA
• Energy : Co60 or 6 MV LINAC
• Field borders:
Ref-

74. HORMONAL THERAPY IN NEO ADJUVANT SETTING
• Limited data
• Mostly used in patients with locally advanced
breast cancer who are deemed unfit for systemic
chemotherapy
• Responses are slower than neo adjuvant
chemotherapy

75. • IMPACT Trial :
▫ Immediate Pre operative Anastrazole, Tamoxifen or Combined with Tamoxifen Trial
▫ 330 Estrogen receptor positive post menopausal females randomised to 1:1:1
▫ Rates of breast conservation after 3 months of neo adjuvant hormone treatment were
highest in the anastrozole-alone arm
HORMONAL THERAPY IN NEO ADJUVANT SETTING
PROACT Trial :
Pre operative “Arimidex” compared to Tamoxifen Trial
Objective responses for anastrozole and tamoxifen occurred in 39.5% and 35.4% of
patients, respectively (ultrasound measurements), and 50.0% and 46.2% of patients
respectively (caliper measurements).
Anastrozole is an effective and well-tolerated preoperative therapy,producing clinically
beneficial tumor downstaging and reductions in tumor volume
Anastrozole appears to be at least as effective as tamoxifen

76. HORMONAL THERAPY IN PREVENTION
OF BREAST CANCER
• The BCPT trial (NSABP P1) was designed to evaluate the efficacy of
Tamoxifen given for 5yrs in high risk population
▫
▫ 49% reduction in invasive breast cancer
▫ 50% reduction in non invasive cancers
▫ ER +ve tumors were much less frequent in women receiving tamoxifen
▫ Incidence of ER –ve tumors remained same
▫ Reduction in rates of occurrence of tumors of all sizes
▫ Women more than 35 yrs, who have completed family with high risk as defined by
the Gail model (5 yr risk > 1.66%)
▫ Age > 60 yrs ( intrinsic risk > 1.66%)
▫ Presence of LCIS
• The FDA has now approved the use of tamoxifen in high risk women to
reduce breast cancer incidence.
• STAR trial evaluated role of Raloxifen in prevention of breast cancer

77. HORMONAL THERAPY IN PREVENTION
OF BREAST CANCER
• Validated approach for only selected high risk
females:
• Duration of follow up is too limited (5 yrs)
• Duration of beneficial effect not known
• Optimal time at which to start tamoxifen in high risk
patients is not known
• Finally who all should be screened for high risk
factors not known

78. Role of hormonal therapy in male
breast cancer
• Hormone receptor positive cases- adjuvant hormonal
therapy recommended.
• Adjuvant tamoxifen for male breast cancer (MBC).Ribeiro G, Swindell RBr J Cancer. 1992;65(2):252.
• Adjuvant systemic therapy for male breast carcinoma.Giordano SH, Perkins GH, Broglio K, Garcia SG, Middleton LP, Buzdar
AU, Hortobagyi GN Cancer. 2005;104(11):2359.
• Carcinoma of the male breast: a review of 41 cases.Digenis AG, Ross CB, Morrison JG, Holcomb GW 3rd, Reynolds VHSouth
Med J. 1990;83(10):1162.
Tamoxifen OR AI--- Tamoxifen!!!
•Insufficient data to support AI use
• retrospective analysis ---257 men with stage I to III breast
cancer ((an AI (n = 50) or tamoxifen (n = 207) With a
median follow-up of 42 months, AI was associated with a
higher risk of death during follow-up compared with
tamoxifen (32 versus 18 percent had died, hazard ratio [HR]
1.55, 95% CI 1.13-2.13).
Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast
cancer patients.Eggemann H, Ignatov A, Smith BJ, Altmann U, von Minckwitz G, Röhl FW,
Jahn M, Costa SBreast Cancer Res Treat. 2013 Jan;137(2):465-70. Epub 2012 Dec 9
Duration
Based on ATLAS trial in
women.

79. TAKE HOME
Premenopausal women with non-metastatic, hormone receptor-positive breast cancer is as follows:
• For women with high-risk breast cancer, ovarian suppression plus exemestane rather than tamoxifen
• For women not at have a high-risk breast cancer, tamoxifen as single-agent therapy (10years)
• As single-agent therapy, aromatase inhibitors (AIs) should not be used in women with intact ovarian
function.
Postmenopausal women is as follows:
• Aromatase inhibitors rather than tamoxifen as adjuvant endocrine treatment
• For women receiving adjuvant endocrine therapy, we recommend at least a five-year course of treatment
• For women who have completed a five-year course of an AI (with or without preceding tamoxifen, continue
the AI for an additional five years . (10 years) but at risk of additional arthralgia and bone related
complications.
• For those on tamoxifen, prefer switching to an AI
• Women who are of childbearing potential should use an effective means of contraception while
on tamoxifen. Following completion of tamoxifen treatment, women should wait for at least two months
after tamoxifen has been discontinued before attempting pregnancy.
• For women who become pregnant, on tamoxifen - discontinuation of tamoxifen during pregnancy

80. TAKE HOME
• Metastaic hormone receptor positive breast cancer
• •For premenopausal women, a combination of tamoxifen
alone or with ovarian suppression.
• •For postmenopausal women ----aromatase inhibitor
(AI), letrozole, or fulvestrant.
• ( for HR +ve --- endocrine therapy as first line, if rapidly
progresssing visceral metastasis- systemic chemotherapy.
• If Her 2 neu +ve- trastuzumab plus hormonal therapy.)
• There is insufficient data on neo adjuvant hormonal therapy
presently
• However, it can be considered in hormone positive females
who have a poor general condition or have contraindications
for systemic chemotherapy

81. LHRH AGONISTS FOR FERTILITY PRESERVATION
• The phase III Prevention of Early Menopause Study (POEMS)/southwest Oncology Group (SWOG) S0230 recruited 257
premenopausal women, aged 18 to 49, with stage I to IIIA estrogen receptor–negative and progesterone receptor–negative
breast cancer, and 218 patients were evaluable. The primary endpoint of the study was the rate of ovarian failure at 2 years,
defined as having no menstrual periods for the prior 6 months and postmenopausal levels of follicle-stimulating hormone
(FSH).
• “By this definition, the ovarian failure rate was 22% in the standard chemotherapy arm and 8% in the goserelin arm,” Dr.
Moore reported at an ASCO press briefing on patient care and quality of life. “In the stratified analysis, this represented a 70%
reduction in ovarian failure with a P value of .04. Using a less stringent ovarian failure definition of either postmenopausal
FSH or absent menstrual periods for the prior 6 months, 45% of patients in the standard arm vs 20% in the goserelin arm
experienced ovarian failure. This difference was highly significant with an adjusted P value of .006,” she added.
• Among women receiving chemotherapy alone, 11% reported becoming pregnant, with 7% actually delivering a total of 12
babies, and two other women still pregnant at the time of data submission. Among women who also received goserelin, 21%
became pregnant, with 15% actually delivering a total of 18 babies, and three other women still pregnant at the time of data
submission. “The greater-than-twofold differencea in becoming pregnant and having a successful outcome was associated
with P values between .03 and .05,” Dr. Moore noted.
• The pregnancy results applied only to the 5-year study period, and “not all patients on study were actually interested in
becoming pregnant,” Dr. Moore pointed out in the interview with The ASCO Post. “The rates might be higher in a highly
motivated group or in a younger patient population.”
• Goserelin Injections
• Goserelin injections were started at least 1 week before chemotherapy and continued once a month for the duration of the
chemotherapy. The monthly goserelin dose was 3.6 mg.
• “It takes about 10 days to fully suppress ovarian function with this medication,” Dr. Moore noted. “But we also didn’t want to
limit patients’ interest in the study by making them wait too long before starting their chemotherapy. We didn’t want to do
anything that would delay their chemotherapy in any significant way. So we compromised at starting at least 1 week prior to
the first chemotherapy dose. One week actually appeared to work very well.”
• The chemotherapy regimens used for early-stage breast cancer typically extend over a period of 3 to 6 months, Dr. Moore
explained, “and the most common regimen that we use in the United States in this population is about a 4-month regimen,
which would be about four injections of goserelin for the average patient.”
• Goserelin is currently approved by the U.S. Food and Drug Administration for advanced breast cancer, but not for early-stage
disease.

82. • Not Mutually Exclusive
• Goserelin injections and cryopreservation of embryos, the most established fertility-preservation methods for women
undergoing chemotherapy, are not mutually exclusive options. While goserelin must be started at least 1 week before
chemotherapy, the entire process of cryopreservation takes between 2 and 6 weeks.2The process includes stimulating the
ovaries to mature multiple eggs, removing the mature eggs, and then fertilizing them in the lab with sperm from a partner or
donor to create embryos through in vitro fertilization, before freezing them for future use.
• “With some other cancers, you may not have the luxury of time to pursue those treatments,” Dr. Moore said. “We were
looking at operable breast cancer. So even though assisted reproduction might delay treatment by a month or two or even
more, if somebody has had their surgery and the cancer is out, that might be okay in breast cancer, whereas if you have an
aggressive lymphoma, you really may not have the opportunity to take the time to do this.”
• Interrupting Endocrine Therapy
• The International Breast Cancer Study Group, one of the key participants in the POEMS/SWOG S0230 trial, “is planning a
study addressing a somewhat different question. It is called the Positive Study, and it is going to look at women with
hormone receptor–positive breast cancer and whether it is safe to interrupt endocrine therapy to have a pregnancy,” Dr.
Moore noted. “It would be contraindicated to attempt a pregnancy while on tamoxifen, so the study is looking at stopping the
tamoxifen in women with hopes of becoming pregnant, and then resuming after the pregnancy, with a plan to be off of the
endocrine therapy for no more than 2 years.”
• Recommendations to continue tamoxifen for 5 to 10 years present particular challenges for a woman who is diagnosed with
breast cancer in her late 20s and hasn’t had children yet. After chemotherapy and 5 years of tamoxifen, the woman would be
in her early 30s, and “she still may have an opportunity to have children. It might be difficult, but it is still an option,” Dr.
Moore said. “If you add another 5 years of hormonal therapy, that makes it even more difficult. So I think it is a very
important question to address for these patients.”
• Currently, “if someone really wants to have a child, we recommend that the tamoxifen be stopped first. You could conceive
on it, but it should be stopped immediately if that were to happen. So we recommend using barrier contraceptives while on
tamoxifen.”
• Surprising Survival Improvement
• After adjusting for disease stage, women who received goserelin in the POEMS/S0230 study had a 50% reduction in
mortality 4 years after starting chemotherapy compared with those who received chemotherapy alone, a result considered
somewhat surprising. One possible explanation, Dr. Moore said, is the observation that many breast cancers, including
triple-negative breast cancers, have LHRH receptors, and preclinical studies suggest that LHRH agonists and antagonists
increase cell death.
• Another possible explanation was offered by a study presented during the ASCO Annual Meeting Breast Cancer–HER2/ER
poster session. In that study, Recchia et al found that administering an LHRH agonist to premenopausal women with high-
risk early breast cancer after surgery but before chemotherapy resulted in a reduction in vascular endothelial growth factor
(VEGF) and regulatory T cells, which are considered fundamental for the development of breast cancer. ■
• Disclosure: Dr. Moore reported

83. • Thank you

84. Gail model
• Breast Cancer Risk Assessment Tool (Gail model) — The most widely available tool to calculate breast cancer risk is
the Breast Cancer Risk Assessment Tool (BCRAT), sometimes called the Gail model after Dr. Mitchell Gail, its developer at
the National Cancer Institute
• The tool is based upon data from the Breast Cancer Detection Demonstration Project (BCDDP) and the Care Trial [10]. It
allows calculation of a woman's individual risk of developing breast cancer over the next five years and until age 90, based on
the following data for the individual:
• 1●Current age (the tool is for women age 35 and older)
• 2●Age of menarche
• 3●Age at first live birth of a child
• 4●Number of first degree relatives with breast cancer
• 5●Number of previous breast biopsies
• 6●Whether any breast biopsy has shown atypical hyperplasia
• 7●Race (and sub-race/ethnicity if the woman is Asian American)
• An individual's risk is compared with that of a woman the same age and with average risk factors, although no confidence
intervals are used around the estimates
• . The tool can be accessed online at www.cancer.gov/bcrisktool/.
• The Gail Model has been developed using data primarily from studies of white and black women. Risk estimates for races or
ethnicities other than Caucasian and black may not be as accurate, either because no studies have been conducted or less
data have been analyzed.
• The BCRAT is intended for women who have never had a diagnosis of breast cancer, DCIS or LCIS, and who do not have a
strong family history suggesting inherited breast cancer. It is not applicable to women with more than two first-degree
relatives with breast cancer and does not consider more distant relatives, the age at which relatives developed breast cancer,
or a family history of ovarian cancer. It is not useful for women with a strong family history of breast cancer on the paternal
side. Most importantly, it does not estimate the risk of carrying a deleterious BRCA1 or BRCA2 gene.