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