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HORMONAL THERAPY IN
CARCINOMA BREAST
Dr. Ayush Garg
INTRODUCTION
 Around 60-70% patients diagnosed to have breast cancer
are Estrogen receptor-positive (65% of these are also
positive for Progesterone receptors)
 Patients with ER + tumors are candidates for hormonal
therapy
 Five-year survival - about 10 % better for women with ER+
than for those with ER- tumors
• The gold standard of treatment in the adjuvant setup is
tamoxifen.
• Adjuvant Tamoxifen has been used for treating breast
cancer since 1970s
• Some authors have attributed the 25% reduction in breast
cancer mortality in western countries over the past decade
to tamoxifen use.
• Issues that need to be answered are:
 Optimal duration and dose
 Patient selection criteria
 Combination with chemotherapy
 Risks of tamoxifen therapy
 Additional benefits of tamoxifen therapy
 Place of the newer agents like AIs
1966 – Dr Arthur L Walpole/Dr Dora Richardson
 Developed Tamoxifen
 Developed as a Contraceptive
“Morning After Pill”
HISTORY & EVALUATION
TIMELINE OF HORMONAL
AGENTS
Mechanism of action
 All endocrine therapies target the estrogen
receptor at one level or other.
 While the PR receptor doesn't act as a target
directly it does indicate a functional ER pathway
as it is a ER induced gene.
Endocrine pathways in
cancer
Ovary
Pituitary gland
LHRH
(hypothalamus)
Pre-/post-
menopausal
Premenopausal
Gonadotrophins
(FSH + LH)
ACTH
Adrenal
glands
Oestrogens
Progesterone
Progesterone
Androgens Oestrogens
Peripheral conversion
ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone;
LH, luteinising hormone; LHRH, LH releasing hormone
LHRHa
Aromatase Inhibitors
Hormones affecting the breast
Ovary
Rationale for receptor based
Rx
 Response rates to endocrine manipulation in
ER +ve patients was as high as 53% (only 6%
in ER –ve) – Whitliff et al.
 Receptors correlate with other prognostic
markers:
– Cellular turnover rates,
– Nuclear grade, and
– Degree of histologic differentiation
 Receptor positivity also correlates with:
– Disease-free interval
– Decreasing tumor size
 Prolongation of DFS is independent of
menopausal status, tumor size, and nodal
status.
78%
45%
34%
10%
0% 20% 40% 60% 80% 100%
ER+/PR+
ER-/PR+
ER+/PR-
ER-/PR-
ALLRED SCORE
0 (0%) 1 (<1%) 2 (1–10%) 3 (11–33%) 4 (34–66%) 5
(67–100%)
So the total scores for ER and PR are given as TS = PS
+ IS.
TS 0 and 2 are negative scores, and 3, 4, 5, 6, 7, and 8
are positive scores.
Classification
 Selective Estrogen Receptor Modulators (SERM):
– Tamoxifen
– Torimefene
 Aromatase inhibitors:
– Letrozole
– Anastrazole
– Exemestane
 Steroidal Antiestrogens (SERD):
– Fulvestrant
 Androgens
– Fluoxymesterone
Classification
 Progestins
– Megestrol acetate
– Medroxyprogesterone acetate
 LHRH agonists
– Leuprolide
– Goserelin
 Gland ablation
– Ovary, Pituitary, Adrenals
 High dose Estrogens
SERM
• The SERMs are chemically diverse compounds that lack the steroid
structure of estrogens but possess a tertiary structure that allows them to
bind to the estrogen receptor.
• Examples:
 Tamoxifen
 Raloxifen
 Tormifen
• Selective modulation explained by:
• 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
coregulator proteins
Tamoxifen
• Chemically a triphenylethylene.
• MOA: Competitive binding to the estrogen
receptor resulting in reduction of
transcription of estrogen regulated genes.
• Dimethylaminoethoxy side chain and the
trans configuration are crucial for the
antiestrogenic activity of tamoxifen
• The net result is a block in the G1 phase of
the cell cycle and a slowing of cell
proliferation.
• Tamoxifen is thus, a cytostatic drug.
Pharmacokinetics
• Long t1/2 : 7 -14 days.
• OD dose can be used
Metabolism in liver and excretion in feces
Renal dysfunction not a contraindication.
• Metabolized by CYP 450 3A4 enzyme:
• Can reduce warfarin metabolism.
• Careful INR monitoring needed in patients receiving
warfarin with tamoxifen.
Dose of tamoxifen
 20 mg once daily dose of tamoxifen is the
standard dose.
 Higher doses are not more effective
 Also lead to greater incidence of side effects.
Summary of Tamoxifen
Tab
Tamoxifen
20 mg OD
Take the pill daily at
the same time.
Don’t take double
dose in case of
missing dose
CBC/KFT every cycle
GYN examination every 6
monthly (including TVS)
Avoid alchohol
Tamoxifen in Elderly patients
 All meta-analyses have demonstrated a stastically significant benefit
for addition of Tamoxifen in patients aged > 70 yrs.
 ECOG evaluated the role of 2yr tamoxifen therapy vs placebo in 180
women aged > 65yrs
 Drug was well tolerated
 Significant reduction in recurrences
 Borderline significant reduction in risk of death
 Tamoxifen also reduced the incidence of contralateral breast
cancers
 Problems with adjuvant tamoxifen in elderly population:
 High risk of death for unrelated cancer (22% in ECOG trial)
 Poor adherence to prescribed treatment
 Risk of thromboembolism increases with age.
Tamoxifen and chemotherapy
Advantages of combining
CCT with Tmx include:
– Elimination of both
chemoresistant and tamoxifen
resistant cell populations.
– Tamoxifen and progestins inhibit
p-glycoprotein, an effect that
could enhance sensitivity to
drugs such as doxorubicin.
– The apoptosis inhibitor Bcl-2 is
down-regulated by tamoxifen,
possibly enhancing sensitivity to
drugs using this cell death
pathway.
Disadvantages of
combined approach:
– Cytostatic nature of
tamoxifen may interfere with
chemotherapy by locking
cells in chemoresistant
phases of cell cycle.
– It also antagonizes
calmodulin and is an
effective Ca2+ channel
antagonist—effects that
could alter drug uptake.
Tamoxifen Toxicity
 Menopausal symptoms:
• 50% - 60% ( N.B. 40% - 50% in placebo)
• Most common 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.
Tamoxifen Toxicity
 Thromboembolism:
• Severe thromboembolism seen in ~ 1% patients in the
preventive setting.
• Risk up to 10 times that experienced by healthy women
• Complication more common in elderly patients with
metastatic breast cancer and who are receiving CCT
 Carcinogenesis:
• Increased risk of endometrial cancers
• Mostly low grade & stage I tumors.
 Other tumors:
• Hepatomas
• Clear cell sarcomas of ovary
Aromatase Inhibitors
• Capable of selective estrogen deprivation without
impairment of adrenal androgen synthesis.
• Two types exist:
• Type I : Enzyme inactivators (Steroidal)
• Type II : Competitive antagonists (Non steroidal)
3 generations exist:
• 1st generation: Aminoglutethemide
• 2nd generation: Formestane (Type I), Fadrazole
• 3rd generation: Exemestane (Type I), Anastrazole, Letrozole
3rd Generation AI
• These drugs inhibit the Aromatase enzyme
selectively by blocking the hememoiety of the
enzyme
• 3rd generation AIs are 3 times more potent than
aminoglutethemide.
• Dose:
• Letrozole (Femara) – 2.5 mg OD
• Anastrazole (Arimidex) – 1 mg OD
• Exemestane (Aromasin) – 25 mg OD
Summary of Anastrazole
Tab Anastrazole
1 mg
Dexa Scan at baseline and every
6 monthly
Zoledronic Acid 4mg 2monthly
for 2 years (Osteoporotic
patients)
Zoledronic Acid 4mg 6monthly
for 2 years (Non Osteoporotic
patients)
Calcium 500mg 1BD
Vitamin D Sachet
Bone Mineral Density
T-score
Z-score is the number of standard deviations
above or below what's normally expected for
someone’s age, sex, weight, and ethnic or
racial origin.
If Z-score is significantly higher or lower than
the average, it may suggest that something
other than aging is causing abnormal bone loss.
Toxicity of AIs vs Tamoxifen
MA -17 ATAC BIG IES
Vaginal Complications - 1.7% - 14% - 3.3% - 1.5% Tmx
poorer
Endometrial 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%
Since the absolute benefit of using a AI in adjuvant setting
over tamoxifen is ~ 2% reduction in recurrence rates and
1.5% reduction in mortality this excess toxicity needs to be
balanced against the bone damage produced by AIs in this
setting.
Fulvestrant
• Classified as a SERD.
• Considerably higher affinity for ER 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
• Developed for clinical use as a 250mg intramuscular
monthly depot injection
• Developed to counter the estrogenic effects of Tamoxifen on
uterus and the bone related effects of AIs.
Fulvestrant: unique mechanism of action
 A new type of oestrogen receptor (ER) antagonist with
no oestrogen agonist activity
 Removing cellular ER may impact the onset of hormone
resistance that occurs via cross-talk between growth
factor signalling pathways and the ER
Competitively
inhibits binding
of oestradiol to
the ER
Impaired
dimerisation,
destabilisation
and degradation
of the ER
 transcription
of ER-regulated
genes,
including the
PgR
1st treatment
2nd treatment
4th treatment
3rd treatment
Non-steroidal AI
Fulvestrant/Tamoxifen?
Exemestane?
Exemestane
Fulvestrant Tamoxifen
Tamoxifen Tamoxifen
Exemestane
or
Fulvestrant
Postmenopausal Patients with ER+ Advanced Breast
Cancer and hormonal options after Non-steroidal AI
Breast Cancer in Males
•Tamoxifen for 5-10 years
•If tamoxifen is contraindicated, a GnRH analog plus
an AI
•Single agent AI has been associated with inferior
outcomes compared to tamoxifen alone, likely due
to inadequate estradiol suppression and hence it is
not recommended
Endocrine therapy in the
adjuvant setting
Adjuvant Tamoxifen alone
 Several trials have demonstrated that tamoxifen adds
significantly to the DFS in the adjuvant setting.
 Two major trials have also demonstrated a OS benefit
Trial Dose Duration DFS OS
NATO 20 2 P < 0.05 P < 0.05
Christie 20 1 P < 0.05 NS
Stockholm 30 2 P < 0.05 NS
CRC 20 2 P < 0.01 NS
Scottish 20 5 P < 0.05 P < 0.05
Overall benefits of tamoxifen Rx
 While the patients are on tamoxifen:
 1 of every 2 recurrences and
 1 of every 3 deaths are avoided by the
tamoxifen therapy.
 Tamoxifen continues to demonstrate further
reductions in the odds of recurrence and death in
years 5 through 9.
 This is called the “carryover effect”
Optimal Duration of Tamoxifen Rx
Reduction in
recurrences
Reduction in
deaths
Tamoxifen ~ 1 yr 18% ± 3 11% ± 3
Tamoxifen ~ 2 yr 24% ± 2 14% ± 2
Tamoxifen ~ 5 yr 43% ± 3 23% ± 4
 In the EBCTCG 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.
AI in adjuvant setting
 7 trials have been reported all of which involve post
menopausal females with HR +ve disease.
 A theoretical priming benefit initial tamoxifen made
many trials use tamoxifen in initial 2-3 yrs prior to
switching over to tamoxifen.
Trial Yrs Tmx N FU
(mo)
 DFS  OS
MA 17 (Let)* 5 5157 30 2.4% NA
ATAC (Ana) 0 6186 68 2.4% 0.3%
BIG 01-98 (Let) 0 8010 26 1.9% 0.7%
ABCSG/ARNO
(Ana)
2 3224 28 2.4% NA
ITA (Ana) 2 426 24 7.1% NA
IES (Exe) 2-3 4742 31 3.5% 0.6%
Endocrine therapy in
Metastatic Breast Cancer
Guidelines
 Endocrine therapy should be started in all hormone receptor
positive females with metastatic breast cancer.
 Hormone therapy may be suitable as a sole therapy in patients
with severe comorbid conditions or very old age.
 AI are standard 2nd line agents after tamoxifen therapy.
 Recently evidence has emerged which highlights the superiority
of AI in the 1st line setting too.
 In premenopausal females ovarian ablation may be another
alternative. It also allows use of AI in this population.
 Selection of the appropriate initial management depends on:
– Tempo of the disease (Slower progress, fewer symptoms)
– Vital organ involvement ( Bone & Soft tissue)
– General condition of the patient (Older age, poorer GC)
– Socio economic conditions.
Selection of patient & Rx
Premenopausal
Ovarian Ablation
Postmenopausal
Tamoxifen AIs
Resistance
Fulvestrant / Progestins
High dose Estrogen
??
In postmenopausal patients with
HR +ve advanced disease
Aromatase Inhibitors as first line
hormonal therapy have an overall
better therapeutic index than tamoxifen
Fulvestrant vs. Anastrozole: Trial Design
Postmenopausal women with advanced breast cancer receiving
prior endocrine treatment for early or advanced breast cancer
Trial 0020: International, randomised 1:1, open, parallel-group
Trial 0021: North American, randomised 1:1, double-blind, double-dummy,
parallel-group
Anastrozole 1mg daily orally
Trial 0020: (n=229)
Trial 0021: (n=194)
Fulvestrant 250mg i.m. once monthly
Trial 0020: 1 x 5ml (n=222)
Trial 0021: 2 x 2.5ml (n=206)
Analysis after 340 events
(progression or death prior to progression)
Trials 0020 and 0021: Recruitment between May 1997 and August 1999
Robertson JFR et al. Cancer 2003; 98: 229–238.
Hazard ratio (95.14% CI):
0.95 (0.82–1.10); p=0.48
Fulvestrant vs. Anastrozole:
Time to progression
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 6 12 18 24 30 36
Median follow-up 15.1 months
Time to progression (months)
Median TTP: Fulvestrant = 5.5 months
Anastrozole = 4.1 months
Fulvestrant 250 mg
Anastrozole 1 mg
Robertson JFR et al. Cancer 2003; 98: 229–238
Proportion not
progressed
Duration of response from randomisation
to progression (responding patients)
Median follow-up 22.1 months
0 6 12 18 24 30 36 42
Fulvestrant 250 mg
Anastrozole 1 mg
Duration of response (months)
0.0
0.2
0.4
0.6
0.8
1.0
Median DoR: Fulvestrant = 16.7 months
Anastrozole = 13.7 months
Proportion
responding
Robertson JFR et al. Cancer 2003; 98: 229–238
Duration of response –
without or with visceral metastases
Duration of objective response (days)
0 200 400 600 800 1000
Fulvestrant 250 mg (n=52)
Anastrozole 1 mg (n=45)
0.0
0.2
0.4
0.6
0.8
1.0
Without visceral metastases
Proportion
with
objective
response
0 200 400 600 800 1000
0.0
0.2
0.4
0.6
0.8
1.0
Fulvestrant 250 mg (n=30)
Anastrozole 1 mg (n=25)
With visceral metastases
Mauriac L et al. Eur J Cancer 2003; 39: 1228–1233
0 60 66
0.0
0.2
0.4
0.6
0.8
1.0
Overall survival (months)
Proportion
alive
Fulvestrant vs. Anastrozole:
Overall survival
54
48
42
36
30
24
18
12
6
Median survival: Fulvestrant = 27.4 months (n=428)
Anastrozole = 27.7 months (n=423)
Hazard ratio (95% CI):
0.98 (0.84–1.15); p=0.81
Median follow-up 27.0 months
Fulvestrant 250 mg
Anastrozole 1 mg
Howell, A et al. Cancer 2005; 104: 236–9.
Recent Evidence with Trastuzumab
(Herceptin) plus Anastrozole (Arimidex)
in Advanced Breast Cancer in
post-menopausal women:
TAnDEM Study
TrAstuzumab in Dual HER2-positive Metastatic breast cancer ESMO 2006
TAnDEM: Study Design
HER2-positive,
HR-positive MBC
(n=208)
R
Anastrozole 1 mg daily +
Trastuzumab 4 mg/kg loading dose
 2 mg/kg qw until
disease progression
Anastrozole
1 mg daily until
disease progression
ESMO 2006
PFS = time from randomisation to date of progressive disease or death
103 48 31 17 14 13 11 9 4 1 1 0 0
A + H
104 36 22 9 5 4 2 1 0 0 0 0 0
A
Probability 1.0
0.8
0.6
0.4
0.2
0 5 10 15 20 25 30 35 40 45 50 55 60
Months
95% CI
3.7, 7.0
2.0, 4.6
p value
0.0016
Median PFS
4.8 months
2.4 months
Events
87
99
0.0
No. at risk
TAnDEM: Progression-Free Survival
TAnDEM: Conclusions
 The combination of A+H in first-line treatment of
women with HER2-positive hormone-dependent MBC
leads to significant improvements in :
 PFS 4.8 vs. 2.4 months; p=0.0016
 CBR 42.7% vs. 27.9%; p=0.026
 ORR 20.3% vs. 6.8%; p=0.018
 OS was longer in the A+H arm (28.5 vs. 23.9 months,
p=0.325) despite crossover by patients in the A arm to
receive H upon PD.
5 yrs vs 10 yrs Endocrine Therapy
• ATLAS
• 12894 women, Early Breast Ca
• 7.6 yrs FU
• Had completed 5 years of treatment with tamoxifen
were randomly allocated to continue tamoxifen to 10
years or stop at 5 years
• When ATLAS began in 1996, 2 years and 5 years of
tamoxifen were both standard treatment options
5 yrs vs 10 yrs Tamoxifen
Davies et al, Lancet 2012
 10 years tamoxifen reduced the risk of breast cancer
recurrence (617 vs 711 , p=0·002), reduced breast cancer
mortality (331 deaths vs 397 deaths, p=0·01), and reduced
overall mortality (639 deaths vs 722 deaths, p=0·01).
 10 years tamoxifen had a greater reduction in risk of
progression, possibly due to a “carryover effect.” The reduction
in risk of recurrence was 0.90 during 5 to 9 years of tamoxifen
treatment and 0.75 after 10 years of treatment.
 Results from ATLAS show that 10 years of endocrine therapy
will halve breast cancer mortality during years 10–14 after
diagnosis.
 After 10 years of tamoxifen treatment females were at an
increased risk for endometrial cancer and pulmonary embolism.
 The risk of recurrence during years 5 to 14 was
21.4% for women receiving tamoxifen versus 25.1%
for controls (absolute recurrence reduction 3.7%).
 There were also decreases in the incidence of
contralateral breast cancer.
 The results of the aTTom trial confirm the significant
reduction in recurrence and death from breast
cancer seen in the ATLAS trial with 10 versus 5
years of tamoxifen therapy.
 ATLAS
 ATTom
 E4181
 NSABP B 14
 Scottish Trial
 ATAC - Arimidex, Tamoxifen, Alone or in Combination
 ATAC, now known as LATTE (Long-term Anastrozole
versus Tamoxifen Treatment Effects)
 Anastrozole (1 mg) with tamoxifen (20 mg), both given
orally every day for 5 years, as adjuvant treatment for
postmenopausal women with early-stage breast cancer.
 Primary endpoint of disease-free survival
 Secondary endpoints of time to recurrence, time to distant
recurrence, incidence of new contralateral breast cancer,
overall survival, and death with or without recurrence
 Randomised patients (anastrozole n=3125, tamoxifen
n=3116) and hormone receptor-positive patients
(anastrozole n=2618, tamoxifen n=2598)
 Median follow up – 120 months
 Tamoxifen has shown a carryover benefit for recurrence in the first
5 years after treatment, but not after that.
 Carryover effect for recurrence was larger for anastrozole than for
tamoxifen in the present study and remained significant for the
entire 10-year follow-up period
 The additional benefit beyond that achieved with tamoxifen might
be waning after about 8 years, and further follow- up is needed to
see how long this effect will be maintained with anastrozole
 First trial to show that an aromatase inhibitor is more effective and
has fewer serious side- effects than tamoxifen in the adjuvant
setting
 Confirm the long-term superior efficacy and safety of anastrozole
over tamoxifen as initial adjuvant therapy for postmenopausal
women with hormone-sensitive early breast cancer.
Addition of Ovarian Function Suppression (OFS) to AIs –
SOFT & TEXTtrials
Adjuvant Ovarian Suppression in
Premenopausal Breast Cancer
Prudence A. Francis et al., N Engl J Med 2015;372:436-46
SOFT
Trial
Adjuvant Exemestane with Ovarian
Suppression in Premenopausal Breast Cancer
Olivia Pagani et al., N Engl J Med 2014;371:107-18
SOFT + TEXT Trial
Primary end point of
both RCT - DFS
SOFT Tamoxifen-OFS Tamoxifen P value
5-yr DFS 86.6% 84.7% 0.10
5-yr OS 96.7% 95.1% 0.13
TEXT-SOFT combined
analysis
Tamoxifen-
OFS
Exemestane-
OFS
P-value
5-yr DFS 87.3% 91.1% P<0.001
Freedom from recurrence
of breast cancer at a
distant site
92% 93.8% P=0.02
5-yr OS 95.9% 96.9% p=0.37
Selected adverse events
of Grade 3 or 4
29.4% 30.6%
NCCN Guidelines Version 1.2021
Breast Cancer
Suppression of ovarian estrogen production was achieved
with the use of the gonadotropin-releasing hormone agonist
triptorelin, oophorectomy, or ovarian irradiation.
Based on the results of the SOFT and TEXT trials, the NCCN
Panel has included ovarian suppression plus an aromatase
inhibitor for 5 years as an adjuvant endocrine therapy option
for premenopausal women with hormone-receptor–positive
breast cancer at higher risk of recurrence (eg, young age,
high-grade tumor, lymph-node involvement).
NCCN Guidelines Version 1.2021
Breast Cancer
BIG 1-98 is a randomized trial testing the use of
 tamoxifen alone for 5 years
 letrozole alone for 5 years
 tamoxifen for 2 years followed sequentially by letrozole for 3 years
 letrozole for 2 years followed sequentially by tamoxifen for 3 years.
 DFS was superior in the letrozole-treated women (P = .003).
 No difference in OS was observed.
 Grade 3 to 5 cardiac adverse events was significantly higher in
the letrozole arm, and both the overall incidence and incidence
of grade 3 to 5 TE events was significantly higher in the
tamoxifen arm.
 In addition, a higher incidence of bone fracture was observed for
women in the letrozole arm compared with those in the
tamoxifen arm (9.5% vs. 6.5%).
CONCLUSION
 Endocrine therapy is a safe and well tolerated targeted treatment
modality in majority of patients with breast cancer.
 In the adjuvant setting primary treatment with Tamoxifen should
be considered in all receptor positive pre menopausal females.
 Ovarian ablation may have additive benefits with Tamoxifen in
premenopausal females.
 Aromatase Inhibitors have a major role to play in hormone
positive post menopausal females.
 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
 In the setting of metastatic breast cancer, hormone receptor
positivity gives a lot of options to be utilised in cases of failure on
one therapy or progression on one therapy
CONCLUSION
 In the setting of metastatic breast cancer, hormone receptor
positivity gives a lot of options to be utilised in cases of
failure on one therapy or progression on one therapy
 Hormonal therapies have also been found useful in chemo
prevention, however, sufficient data is lacking for routine
usage
 Adjuvant endocrine therapy is recommended for a minimum
of 5 years. A recent retrospective analysis by the Oxford
University studied risk of recurrence for years 5 through 20
after 5 years of endocrine therapy.
 Data has now emerged showing benefit of extended
endocrine therapy in improving DFS.
 ASCO adjuvant endocrine therapy Expert Panel
recommends extended duration with any one of
the following strategies:
 AI for up to a total of 10 years; or
 tamoxifen for 2 to 3 years followed by AI for 7 to 8
years; or
 tamoxifen for 5 years followed by AI for 5 years;
or
 tamoxifen for 10 years.
Thank you

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Hormonal therapy in breast cancer

  • 1. HORMONAL THERAPY IN CARCINOMA BREAST Dr. Ayush Garg
  • 2. INTRODUCTION  Around 60-70% patients diagnosed to have breast cancer are Estrogen receptor-positive (65% of these are also positive for Progesterone receptors)  Patients with ER + tumors are candidates for hormonal therapy  Five-year survival - about 10 % better for women with ER+ than for those with ER- tumors
  • 3. • The gold standard of treatment in the adjuvant setup is tamoxifen. • Adjuvant Tamoxifen has been used for treating breast cancer since 1970s • Some authors have attributed the 25% reduction in breast cancer mortality in western countries over the past decade to tamoxifen use. • Issues that need to be answered are:  Optimal duration and dose  Patient selection criteria  Combination with chemotherapy  Risks of tamoxifen therapy  Additional benefits of tamoxifen therapy  Place of the newer agents like AIs
  • 4. 1966 – Dr Arthur L Walpole/Dr Dora Richardson  Developed Tamoxifen  Developed as a Contraceptive “Morning After Pill” HISTORY & EVALUATION
  • 6. Mechanism of action  All endocrine therapies target the estrogen receptor at one level or other.  While the PR receptor doesn't act as a target directly it does indicate a functional ER pathway as it is a ER induced gene.
  • 8. Ovary Pituitary gland LHRH (hypothalamus) Pre-/post- menopausal Premenopausal Gonadotrophins (FSH + LH) ACTH Adrenal glands Oestrogens Progesterone Progesterone Androgens Oestrogens Peripheral conversion ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone; LH, luteinising hormone; LHRH, LH releasing hormone LHRHa Aromatase Inhibitors Hormones affecting the breast Ovary
  • 9. Rationale for receptor based Rx  Response rates to endocrine manipulation in ER +ve patients was as high as 53% (only 6% in ER –ve) – Whitliff et al.  Receptors correlate with other prognostic markers: – Cellular turnover rates, – Nuclear grade, and – Degree of histologic differentiation  Receptor positivity also correlates with: – Disease-free interval – Decreasing tumor size  Prolongation of DFS is independent of menopausal status, tumor size, and nodal status. 78% 45% 34% 10% 0% 20% 40% 60% 80% 100% ER+/PR+ ER-/PR+ ER+/PR- ER-/PR-
  • 10. ALLRED SCORE 0 (0%) 1 (<1%) 2 (1–10%) 3 (11–33%) 4 (34–66%) 5 (67–100%) So the total scores for ER and PR are given as TS = PS + IS. TS 0 and 2 are negative scores, and 3, 4, 5, 6, 7, and 8 are positive scores.
  • 11. Classification  Selective Estrogen Receptor Modulators (SERM): – Tamoxifen – Torimefene  Aromatase inhibitors: – Letrozole – Anastrazole – Exemestane  Steroidal Antiestrogens (SERD): – Fulvestrant  Androgens – Fluoxymesterone
  • 12. Classification  Progestins – Megestrol acetate – Medroxyprogesterone acetate  LHRH agonists – Leuprolide – Goserelin  Gland ablation – Ovary, Pituitary, Adrenals  High dose Estrogens
  • 13. SERM • The SERMs are chemically diverse compounds that lack the steroid structure of estrogens but possess a tertiary structure that allows them to bind to the estrogen receptor. • Examples:  Tamoxifen  Raloxifen  Tormifen • Selective modulation explained by: • 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 coregulator proteins
  • 14. Tamoxifen • Chemically a triphenylethylene. • MOA: Competitive binding to the estrogen receptor resulting in reduction of transcription of estrogen regulated genes. • Dimethylaminoethoxy side chain and the trans configuration are crucial for the antiestrogenic activity of tamoxifen • The net result is a block in the G1 phase of the cell cycle and a slowing of cell proliferation. • Tamoxifen is thus, a cytostatic drug.
  • 15. Pharmacokinetics • Long t1/2 : 7 -14 days. • OD dose can be used Metabolism in liver and excretion in feces Renal dysfunction not a contraindication. • Metabolized by CYP 450 3A4 enzyme: • Can reduce warfarin metabolism. • Careful INR monitoring needed in patients receiving warfarin with tamoxifen.
  • 16. Dose of tamoxifen  20 mg once daily dose of tamoxifen is the standard dose.  Higher doses are not more effective  Also lead to greater incidence of side effects.
  • 17. Summary of Tamoxifen Tab Tamoxifen 20 mg OD Take the pill daily at the same time. Don’t take double dose in case of missing dose CBC/KFT every cycle GYN examination every 6 monthly (including TVS) Avoid alchohol
  • 18. Tamoxifen in Elderly patients  All meta-analyses have demonstrated a stastically significant benefit for addition of Tamoxifen in patients aged > 70 yrs.  ECOG evaluated the role of 2yr tamoxifen therapy vs placebo in 180 women aged > 65yrs  Drug was well tolerated  Significant reduction in recurrences  Borderline significant reduction in risk of death  Tamoxifen also reduced the incidence of contralateral breast cancers  Problems with adjuvant tamoxifen in elderly population:  High risk of death for unrelated cancer (22% in ECOG trial)  Poor adherence to prescribed treatment  Risk of thromboembolism increases with age.
  • 19. Tamoxifen and chemotherapy Advantages of combining CCT with Tmx include: – Elimination of both chemoresistant and tamoxifen resistant cell populations. – Tamoxifen and progestins inhibit p-glycoprotein, an effect that could enhance sensitivity to drugs such as doxorubicin. – The apoptosis inhibitor Bcl-2 is down-regulated by tamoxifen, possibly enhancing sensitivity to drugs using this cell death pathway. Disadvantages of combined approach: – Cytostatic nature of tamoxifen may interfere with chemotherapy by locking cells in chemoresistant phases of cell cycle. – It also antagonizes calmodulin and is an effective Ca2+ channel antagonist—effects that could alter drug uptake.
  • 20. Tamoxifen Toxicity  Menopausal symptoms: • 50% - 60% ( N.B. 40% - 50% in placebo) • Most common 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.
  • 21. Tamoxifen Toxicity  Thromboembolism: • Severe thromboembolism seen in ~ 1% patients in the preventive setting. • Risk up to 10 times that experienced by healthy women • Complication more common in elderly patients with metastatic breast cancer and who are receiving CCT  Carcinogenesis: • Increased risk of endometrial cancers • Mostly low grade & stage I tumors.  Other tumors: • Hepatomas • Clear cell sarcomas of ovary
  • 22. Aromatase Inhibitors • Capable of selective estrogen deprivation without impairment of adrenal androgen synthesis. • Two types exist: • Type I : Enzyme inactivators (Steroidal) • Type II : Competitive antagonists (Non steroidal) 3 generations exist: • 1st generation: Aminoglutethemide • 2nd generation: Formestane (Type I), Fadrazole • 3rd generation: Exemestane (Type I), Anastrazole, Letrozole
  • 23. 3rd Generation AI • These drugs inhibit the Aromatase enzyme selectively by blocking the hememoiety of the enzyme • 3rd generation AIs are 3 times more potent than aminoglutethemide. • Dose: • Letrozole (Femara) – 2.5 mg OD • Anastrazole (Arimidex) – 1 mg OD • Exemestane (Aromasin) – 25 mg OD
  • 24. Summary of Anastrazole Tab Anastrazole 1 mg Dexa Scan at baseline and every 6 monthly Zoledronic Acid 4mg 2monthly for 2 years (Osteoporotic patients) Zoledronic Acid 4mg 6monthly for 2 years (Non Osteoporotic patients) Calcium 500mg 1BD Vitamin D Sachet
  • 26.
  • 27. Z-score is the number of standard deviations above or below what's normally expected for someone’s age, sex, weight, and ethnic or racial origin. If Z-score is significantly higher or lower than the average, it may suggest that something other than aging is causing abnormal bone loss.
  • 28. Toxicity of AIs vs Tamoxifen MA -17 ATAC BIG IES Vaginal Complications - 1.7% - 14% - 3.3% - 1.5% Tmx poorer Endometrial 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% Since the absolute benefit of using a AI in adjuvant setting over tamoxifen is ~ 2% reduction in recurrence rates and 1.5% reduction in mortality this excess toxicity needs to be balanced against the bone damage produced by AIs in this setting.
  • 29. Fulvestrant • Classified as a SERD. • Considerably higher affinity for ER 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 • Developed for clinical use as a 250mg intramuscular monthly depot injection • Developed to counter the estrogenic effects of Tamoxifen on uterus and the bone related effects of AIs.
  • 30. Fulvestrant: unique mechanism of action  A new type of oestrogen receptor (ER) antagonist with no oestrogen agonist activity  Removing cellular ER may impact the onset of hormone resistance that occurs via cross-talk between growth factor signalling pathways and the ER Competitively inhibits binding of oestradiol to the ER Impaired dimerisation, destabilisation and degradation of the ER  transcription of ER-regulated genes, including the PgR
  • 31. 1st treatment 2nd treatment 4th treatment 3rd treatment Non-steroidal AI Fulvestrant/Tamoxifen? Exemestane? Exemestane Fulvestrant Tamoxifen Tamoxifen Tamoxifen Exemestane or Fulvestrant Postmenopausal Patients with ER+ Advanced Breast Cancer and hormonal options after Non-steroidal AI
  • 32. Breast Cancer in Males •Tamoxifen for 5-10 years •If tamoxifen is contraindicated, a GnRH analog plus an AI •Single agent AI has been associated with inferior outcomes compared to tamoxifen alone, likely due to inadequate estradiol suppression and hence it is not recommended
  • 33. Endocrine therapy in the adjuvant setting
  • 34. Adjuvant Tamoxifen alone  Several trials have demonstrated that tamoxifen adds significantly to the DFS in the adjuvant setting.  Two major trials have also demonstrated a OS benefit Trial Dose Duration DFS OS NATO 20 2 P < 0.05 P < 0.05 Christie 20 1 P < 0.05 NS Stockholm 30 2 P < 0.05 NS CRC 20 2 P < 0.01 NS Scottish 20 5 P < 0.05 P < 0.05
  • 35. Overall benefits of tamoxifen Rx  While the patients are on tamoxifen:  1 of every 2 recurrences and  1 of every 3 deaths are avoided by the tamoxifen therapy.  Tamoxifen continues to demonstrate further reductions in the odds of recurrence and death in years 5 through 9.  This is called the “carryover effect”
  • 36. Optimal Duration of Tamoxifen Rx Reduction in recurrences Reduction in deaths Tamoxifen ~ 1 yr 18% ± 3 11% ± 3 Tamoxifen ~ 2 yr 24% ± 2 14% ± 2 Tamoxifen ~ 5 yr 43% ± 3 23% ± 4  In the EBCTCG 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.
  • 37. AI in adjuvant setting  7 trials have been reported all of which involve post menopausal females with HR +ve disease.  A theoretical priming benefit initial tamoxifen made many trials use tamoxifen in initial 2-3 yrs prior to switching over to tamoxifen. Trial Yrs Tmx N FU (mo)  DFS  OS MA 17 (Let)* 5 5157 30 2.4% NA ATAC (Ana) 0 6186 68 2.4% 0.3% BIG 01-98 (Let) 0 8010 26 1.9% 0.7% ABCSG/ARNO (Ana) 2 3224 28 2.4% NA ITA (Ana) 2 426 24 7.1% NA IES (Exe) 2-3 4742 31 3.5% 0.6%
  • 39. Guidelines  Endocrine therapy should be started in all hormone receptor positive females with metastatic breast cancer.  Hormone therapy may be suitable as a sole therapy in patients with severe comorbid conditions or very old age.  AI are standard 2nd line agents after tamoxifen therapy.  Recently evidence has emerged which highlights the superiority of AI in the 1st line setting too.  In premenopausal females ovarian ablation may be another alternative. It also allows use of AI in this population.  Selection of the appropriate initial management depends on: – Tempo of the disease (Slower progress, fewer symptoms) – Vital organ involvement ( Bone & Soft tissue) – General condition of the patient (Older age, poorer GC) – Socio economic conditions.
  • 40. Selection of patient & Rx Premenopausal Ovarian Ablation Postmenopausal Tamoxifen AIs Resistance Fulvestrant / Progestins High dose Estrogen ??
  • 41. In postmenopausal patients with HR +ve advanced disease Aromatase Inhibitors as first line hormonal therapy have an overall better therapeutic index than tamoxifen
  • 42. Fulvestrant vs. Anastrozole: Trial Design Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer Trial 0020: International, randomised 1:1, open, parallel-group Trial 0021: North American, randomised 1:1, double-blind, double-dummy, parallel-group Anastrozole 1mg daily orally Trial 0020: (n=229) Trial 0021: (n=194) Fulvestrant 250mg i.m. once monthly Trial 0020: 1 x 5ml (n=222) Trial 0021: 2 x 2.5ml (n=206) Analysis after 340 events (progression or death prior to progression) Trials 0020 and 0021: Recruitment between May 1997 and August 1999 Robertson JFR et al. Cancer 2003; 98: 229–238.
  • 43. Hazard ratio (95.14% CI): 0.95 (0.82–1.10); p=0.48 Fulvestrant vs. Anastrozole: Time to progression 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 6 12 18 24 30 36 Median follow-up 15.1 months Time to progression (months) Median TTP: Fulvestrant = 5.5 months Anastrozole = 4.1 months Fulvestrant 250 mg Anastrozole 1 mg Robertson JFR et al. Cancer 2003; 98: 229–238 Proportion not progressed
  • 44. Duration of response from randomisation to progression (responding patients) Median follow-up 22.1 months 0 6 12 18 24 30 36 42 Fulvestrant 250 mg Anastrozole 1 mg Duration of response (months) 0.0 0.2 0.4 0.6 0.8 1.0 Median DoR: Fulvestrant = 16.7 months Anastrozole = 13.7 months Proportion responding Robertson JFR et al. Cancer 2003; 98: 229–238
  • 45. Duration of response – without or with visceral metastases Duration of objective response (days) 0 200 400 600 800 1000 Fulvestrant 250 mg (n=52) Anastrozole 1 mg (n=45) 0.0 0.2 0.4 0.6 0.8 1.0 Without visceral metastases Proportion with objective response 0 200 400 600 800 1000 0.0 0.2 0.4 0.6 0.8 1.0 Fulvestrant 250 mg (n=30) Anastrozole 1 mg (n=25) With visceral metastases Mauriac L et al. Eur J Cancer 2003; 39: 1228–1233
  • 46. 0 60 66 0.0 0.2 0.4 0.6 0.8 1.0 Overall survival (months) Proportion alive Fulvestrant vs. Anastrozole: Overall survival 54 48 42 36 30 24 18 12 6 Median survival: Fulvestrant = 27.4 months (n=428) Anastrozole = 27.7 months (n=423) Hazard ratio (95% CI): 0.98 (0.84–1.15); p=0.81 Median follow-up 27.0 months Fulvestrant 250 mg Anastrozole 1 mg Howell, A et al. Cancer 2005; 104: 236–9.
  • 47. Recent Evidence with Trastuzumab (Herceptin) plus Anastrozole (Arimidex) in Advanced Breast Cancer in post-menopausal women: TAnDEM Study TrAstuzumab in Dual HER2-positive Metastatic breast cancer ESMO 2006
  • 48. TAnDEM: Study Design HER2-positive, HR-positive MBC (n=208) R Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose  2 mg/kg qw until disease progression Anastrozole 1 mg daily until disease progression ESMO 2006
  • 49. PFS = time from randomisation to date of progressive disease or death 103 48 31 17 14 13 11 9 4 1 1 0 0 A + H 104 36 22 9 5 4 2 1 0 0 0 0 0 A Probability 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 35 40 45 50 55 60 Months 95% CI 3.7, 7.0 2.0, 4.6 p value 0.0016 Median PFS 4.8 months 2.4 months Events 87 99 0.0 No. at risk TAnDEM: Progression-Free Survival
  • 50. TAnDEM: Conclusions  The combination of A+H in first-line treatment of women with HER2-positive hormone-dependent MBC leads to significant improvements in :  PFS 4.8 vs. 2.4 months; p=0.0016  CBR 42.7% vs. 27.9%; p=0.026  ORR 20.3% vs. 6.8%; p=0.018  OS was longer in the A+H arm (28.5 vs. 23.9 months, p=0.325) despite crossover by patients in the A arm to receive H upon PD.
  • 51. 5 yrs vs 10 yrs Endocrine Therapy
  • 52. • ATLAS • 12894 women, Early Breast Ca • 7.6 yrs FU • Had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years • When ATLAS began in 1996, 2 years and 5 years of tamoxifen were both standard treatment options 5 yrs vs 10 yrs Tamoxifen Davies et al, Lancet 2012
  • 53.  10 years tamoxifen reduced the risk of breast cancer recurrence (617 vs 711 , p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01).  10 years tamoxifen had a greater reduction in risk of progression, possibly due to a “carryover effect.” The reduction in risk of recurrence was 0.90 during 5 to 9 years of tamoxifen treatment and 0.75 after 10 years of treatment.  Results from ATLAS show that 10 years of endocrine therapy will halve breast cancer mortality during years 10–14 after diagnosis.  After 10 years of tamoxifen treatment females were at an increased risk for endometrial cancer and pulmonary embolism.
  • 54.  The risk of recurrence during years 5 to 14 was 21.4% for women receiving tamoxifen versus 25.1% for controls (absolute recurrence reduction 3.7%).  There were also decreases in the incidence of contralateral breast cancer.  The results of the aTTom trial confirm the significant reduction in recurrence and death from breast cancer seen in the ATLAS trial with 10 versus 5 years of tamoxifen therapy.
  • 55.  ATLAS  ATTom  E4181  NSABP B 14  Scottish Trial
  • 56.  ATAC - Arimidex, Tamoxifen, Alone or in Combination  ATAC, now known as LATTE (Long-term Anastrozole versus Tamoxifen Treatment Effects)
  • 57.  Anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer.  Primary endpoint of disease-free survival  Secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence  Randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone receptor-positive patients (anastrozole n=2618, tamoxifen n=2598)  Median follow up – 120 months
  • 58.  Tamoxifen has shown a carryover benefit for recurrence in the first 5 years after treatment, but not after that.  Carryover effect for recurrence was larger for anastrozole than for tamoxifen in the present study and remained significant for the entire 10-year follow-up period  The additional benefit beyond that achieved with tamoxifen might be waning after about 8 years, and further follow- up is needed to see how long this effect will be maintained with anastrozole  First trial to show that an aromatase inhibitor is more effective and has fewer serious side- effects than tamoxifen in the adjuvant setting  Confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.
  • 59. Addition of Ovarian Function Suppression (OFS) to AIs – SOFT & TEXTtrials Adjuvant Ovarian Suppression in Premenopausal Breast Cancer Prudence A. Francis et al., N Engl J Med 2015;372:436-46 SOFT Trial Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer Olivia Pagani et al., N Engl J Med 2014;371:107-18 SOFT + TEXT Trial
  • 60. Primary end point of both RCT - DFS
  • 61. SOFT Tamoxifen-OFS Tamoxifen P value 5-yr DFS 86.6% 84.7% 0.10 5-yr OS 96.7% 95.1% 0.13 TEXT-SOFT combined analysis Tamoxifen- OFS Exemestane- OFS P-value 5-yr DFS 87.3% 91.1% P<0.001 Freedom from recurrence of breast cancer at a distant site 92% 93.8% P=0.02 5-yr OS 95.9% 96.9% p=0.37 Selected adverse events of Grade 3 or 4 29.4% 30.6%
  • 62. NCCN Guidelines Version 1.2021 Breast Cancer Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing hormone agonist triptorelin, oophorectomy, or ovarian irradiation. Based on the results of the SOFT and TEXT trials, the NCCN Panel has included ovarian suppression plus an aromatase inhibitor for 5 years as an adjuvant endocrine therapy option for premenopausal women with hormone-receptor–positive breast cancer at higher risk of recurrence (eg, young age, high-grade tumor, lymph-node involvement).
  • 63. NCCN Guidelines Version 1.2021 Breast Cancer BIG 1-98 is a randomized trial testing the use of  tamoxifen alone for 5 years  letrozole alone for 5 years  tamoxifen for 2 years followed sequentially by letrozole for 3 years  letrozole for 2 years followed sequentially by tamoxifen for 3 years.  DFS was superior in the letrozole-treated women (P = .003).  No difference in OS was observed.  Grade 3 to 5 cardiac adverse events was significantly higher in the letrozole arm, and both the overall incidence and incidence of grade 3 to 5 TE events was significantly higher in the tamoxifen arm.  In addition, a higher incidence of bone fracture was observed for women in the letrozole arm compared with those in the tamoxifen arm (9.5% vs. 6.5%).
  • 64.
  • 65. CONCLUSION  Endocrine therapy is a safe and well tolerated targeted treatment modality in majority of patients with breast cancer.  In the adjuvant setting primary treatment with Tamoxifen should be considered in all receptor positive pre menopausal females.  Ovarian ablation may have additive benefits with Tamoxifen in premenopausal females.  Aromatase Inhibitors have a major role to play in hormone positive post menopausal females.  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  In the setting of metastatic breast cancer, hormone receptor positivity gives a lot of options to be utilised in cases of failure on one therapy or progression on one therapy
  • 66. CONCLUSION  In the setting of metastatic breast cancer, hormone receptor positivity gives a lot of options to be utilised in cases of failure on one therapy or progression on one therapy  Hormonal therapies have also been found useful in chemo prevention, however, sufficient data is lacking for routine usage  Adjuvant endocrine therapy is recommended for a minimum of 5 years. A recent retrospective analysis by the Oxford University studied risk of recurrence for years 5 through 20 after 5 years of endocrine therapy.  Data has now emerged showing benefit of extended endocrine therapy in improving DFS.
  • 67.  ASCO adjuvant endocrine therapy Expert Panel recommends extended duration with any one of the following strategies:  AI for up to a total of 10 years; or  tamoxifen for 2 to 3 years followed by AI for 7 to 8 years; or  tamoxifen for 5 years followed by AI for 5 years; or  tamoxifen for 10 years.