HORMONE THERAPY IN BREAST CANCER

By Dr. Rajib Bhattacharjee

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.

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

Hormone responsive malignancies

Endometrium

Prostate

Breast

Hormone receptor +ve breast cancerhistology-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 includes Trustuzumab

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

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

Hormone receptor +ve breast cancerSTAGE 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 HT Trials #NCCN

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

Endocrine therapy

surgical radiotherapy hormonal agents

Oophorectomy Ovarian ablation

Hormone receptor status & probability of response to therapyER status

PR status

Response probability

Positive

Positive high (50-70%)

Positive Negative intermediate(33%)

Negative Positive intermediate(33%)

Negative Negative low(<10%)

Hormonal agents in breast cancer

Class of drug Individual drug dose Route of delivery

Frequency of delivary

SERM Tamoxifen, Raloxifen, Toremifen

20 mg60 mg60 mg

OralOralOral

ODODOD

Aromatase Inhibitor

Anastrazole, Letrozole,Exemestane

1 mg2.5 mg25 mg

Oral Oral Oral

ODODOD

SERD Fulvestrant 500 mg IM Once a month

GnRH Analogues

Goserelin Leuprolide

3.6 mg7.5 mg

IMIM

Once a monthOnce a month

Anti-androgens

Bicalutamide 50 mg Oral OD

Androgen fluoxymesterone 10 mg Oral BD

Progestational agents

Megestrol, Medroxyprogesterone acetate

VariesVaries

Oral Oral / IM

ODVaries

SERM

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

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.

TamoxifenDrug interactions --Tamoxifen inhibits hepatic P450

system

metabolism

Warfarin Cyclophosphamide

Antidepressants(SSRI/SNRI) Antipsychotics

CYP2D6

Tamoxifen Endoxifen (active metabolite)

activity of Tamoxifen

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

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

Contra-indications of TamoxifenABSOLUTE 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

Raloxifen Estrogen agonist action Estrogen

antagonist action

Bone liver breast endometrium

Treat osteoporosis cholesterol growth & proliferation

NSABP P2 Trial compared Raloxifen with Tamoxifen

advantages disadvantages

Lower risk of thrombolic events & endometrial cancer

Inferior to Tamoxifen in cancer control

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 RogletimideFadrozole

3rd generation Exemestane AnastrazoleLetrozolevorozole

Anastrazole & LetrozoleAnastrazole

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

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%)

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

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

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

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 Cancer Trialists Group. 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.

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 of Tamoxifen 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- ATLAS Trial & ATTOM Trial

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

ATACBIG1-98

ANZLET

93668010

0.870.81

2.8@ 5 yrs2.6@ 5 yrs

Sequential; After 2-3 yrs of TAM

IESARNO/ABCSGITA

EXEANZANZ

47423224 448

0.680.600.57

4.7@ 3 yrs3.1@ 3 yrs

Extended ; After 5 yrs of TAM

MA17NSABP B33

LETEXE

51871598

0.580.68

4.6@ 4 yrs2.0@ 4yrs

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

A big trial comparing four arms

BIG 1-98 Trial 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

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 than Tamoxifen alone

Mother of all trials...? MA.17 Trial

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 to Tamoxifen has clear benifit over Tamoxifen alone.

Upfront vs Sequential or Extended therapy ITA & ARNO/ABCSG Trials 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.....

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 of Tamoxifen The model is based on ... 5 yrs of AI * Available clinical

data Switching to AI after 2.5 or * Assuming all

commercially

5 yrs of Tamoxifen available AIs would have

similar efficacy and tolerability

Results – Best adjuvent therapy is switching to AI after 2.5 yrs of TAM

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

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.

Anastrazole 1st line…

North American Trial and TARGET trial (Tamoxifen and Anastrazole Randomised Group Efficacy and Tolerability)

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

NCCN, ASCO, ESMO & St Galen Expert Committee Recommendations

pre & perimenopausal ER+ Woman post menopausal ER+ woman

Tamoxifen Aromatase Inhibitor

“Role of Tamoxifen in receptor negative tumor needs further evaluation”

Early Breast Cancer Trialists Collaborative Group

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

Anastrazole as Neo-Adjuvant therapy

IMPACT(Immediate Pre-operative Anastrazole,Tamoxifen or Combined with

Tamoxifen) Trial

Comparison- A vs T vs Combination for 3 months

before surgery

BCS was possible Arm A-44%Arm T-31%

Hormone therapy with EBRTNode negetive ER positive breast ca with T 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 did TAM alone;

XRT and TAM resulted in a 63% lower rate than did XRT and placebo.

When compared with TAM alone, XRT plus TAM 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, and TAM 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

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- NSABP Trial- 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, IBCSG Trial IX

SEQUENCE- INTERGROUP 0100 Trial- sequential vs concurrent CT/HT- Improved 8 yr DFS in sequential group

Ovarian ablation & suppression

OA/OS

Ovarian ablation

Surgical oophorect

omy

Radiation induced

oophorectomy

Ovarian suppression

LHRH analogues

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.

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

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

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 of TAM.

Benefits of extended anastrozole adjuvant therapy ?

Long term side effects of AIs ? NACT converts 10 % receptor +ve tumours into

receptor – ve. Is it unidirectional ?

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. Can TAM may be given in Chemotherapy induced menopausal patients with unknown or –ve ER status ?

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

THANK YOU