This document discusses hormonal therapy for breast cancer. It notes that around 60-70% of breast cancer patients are estrogen receptor positive. Estrogen receptor positive tumors have a better survival rate than estrogen receptor negative tumors. The document discusses the molecular basis of estrogen receptor signaling and the genomic and non-genomic mechanisms of estrogen action. It describes the different types of hormonal therapies used in breast cancer including selective estrogen receptor modulators, aromatase inhibitors, antiestrogens, LHRH agonists, and progestins. It discusses the application of hormonal therapy in the adjuvant setting for premenopausal and postmenopausal patients.
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Hormonal therapy breast mine
1.
2. • 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+) tumours have a better survival than (ER-)
tumours
• Patients with ER + tumours are candidates
for hormonal therapy
6. 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
7. 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
8. • 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
9.
10. • All estrogens are produced by action of AROMATASE enzyme.
• Aromatase present in high concentration in granulosa cells of ovaries of
pre-menopausal women; and produces 90% of plasma estrogens.
• In post-menopausal women who are devoid of ovarian aromatase
production, (only 10% of pre-menopausal levels), stromal and epithelial
cells of breast cancers contain measurable amount of aromatase.
• Virtually all breast cancers that respond to hormonal therapy express
significant levels of ESTROGEN RECEPTOR ALPHA (ER) which
increases with age (upto 80% ER positive above 65 yrs age).
11.
12. All the hormonal therapies target either the Estrogen
directly or the Estrogen receptor at one level or the
other
Mechanism of action of Hormonal
therapies
14. SELECTIVE ESTROGEN RECEPTOR
MODULATORS (SERMs)
Tamoxifen
Raloxifen
Torimefene
Mechanism of action :
• The SERMs lack the steroid structure of estrogens but possess a tertiary
structure that allows them to bind to the estrogen receptor.
• Competitive binding to the estrogen receptor resulting in reduction of
transcription of estrogen regulated genes
• Tamoxifen blocks the cell cycle in G1 phase
• Cytostatic drug
15. • Selective modulation
• Antagonist in breast and brain
No transcription
Cell growth
arrest/apoptosis
• Agonist in lung, liver, bone,
and uterus– promotes
Normal function
• Thus beneficial in
decreasing skeletal and
cardiovascular events
18. 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.
• Ocular toxicity:
Keratopathy, maculopathy & cataract
• 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
19. • Work by making less estrogen receptor available for estrogen binding
• Pure antagonists
• No agonist activity
• Fulvestrant (Faslodex)
ANTI ESTROGENS
(SELECTIVE ESTROGEN RECEPTOR
DOWNREGULATOR)
• 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
22. • Type 1 or suicidal inhibitors are steroidal drugs which bind to catalytic site of
aromatase enzyme and cause permanent blockage. They also block other enzymes
in CyP-450 family and alter other steroid hormone levels thereby causing side
effects.
• Type 2 or competitive inhibitors bind to the active enzyme site reversibly and their
continued activity depends on their serum levels. These drugs alter only estrogen
levels.
• These drugs can used only in women with no ovarian function; either in post-
menopausal women or pre-menopausal women having had ovarian ablation.
23. First generation :
• Aminoglutethimide (anticonvulsant), toxicity-adrenal insufficiency.
• It inhibit adrenal steroidogenesis so later redeveloped for use as
“medical adrenalectomy” against advanced breast cancer.
• Side effects -- drowsiness and rash, limited its use
Second Generation Aromatase Inhibitors :
• Formestane was the 1st selective AI. Also has weak androgenic properties.
Found to be superior to aminoglutethimide.
• Fadrozole is a competitive inhibitor more selective than aminoglutethimide
but less than letrozole.
• Main disadvantages are formestane requires intramuscular injection and
fadrozole causes aldostrene suppression
24. Third Generation Aromatase Inhibitors :
ANASTROZOLE
• This drug has rapid oral absorption with peak plasma levels within 2 hrs.
• Recommended dose is 1 mg/day for 3-5 years.
LETROZOLE
• It markedly suppresses estradiol, estrone levels within 2 weeks of start of therapy.
• Is associated with lower risk of thromboembolic events, vaginal bleeding or endometrial
cancer risk compared to tamoxifen; but has higher incidence of cardiac risk and
hyperlipidemia.
• Recommended dose is 2.5 mg / day for 3-5 years.
EXEMESTANE
• Is a steroidal androgen derivative and a selective AI.
• It suppresses estradiol and estrone levels similar to those of anastrozole and letrozole.
25. AI Contraindicated in women with functional
ovaries!!!!!
• AIs function through inhibition of the aromatase enzyme that converts
androgens into estrogens, resulting in profound estrogen depletion.
• In postmenopausal patients, where only nonovarian, baseline levels of
aromatase activity are present, AIs lower estrogen production by 90% to
nearly undetectable levels.
• AIs are not appropriate for premenopausal patients, as residual ovarian
function can lead to enhanced production of aromatase and thus overcome
the effects of AIs.
26. Toxicity – Aromatase Inhibitors
• 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
27. AI-associated musculoskeletal
syndrome (AIMSS)
• 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
2. Nonsteroidal antiinflammatory drugs
28. • 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
differentAI.
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).
29. LHRH AGONISTS
Leuprolide
Goserelin
Triptorelin
• Analoguest activate 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.)
• While this phase is reversible upon stopping the medication, it can be maintained
when GnRH agonists use is continued for a long time.
30. PROGESTINS
• Megestrol acetate
• Medroxyprogesterone acetate
• 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
32. Hormone Receptor Status and
Response to therapy
At 10 yrs:
The recurrence rates were reduced by 14% and 11% in node –ve and +ve
patients respectively.
Similarly, mortality reduced by 14.8% and 12% respectively.
33. Adjuvant endocrine therapy is recommended in
estrogen receptor- or progesterone receptor-positive
breast cancer
35. PREMENOPAUSAL
• Tamoxifen – standard drug of choice for all premenopausal
patients with Estrogen receptor positivity.
36. 2011 Early Breast Cancer Trialists' Collaborative
Group meta-analysis
• 60 trials with >80000 women
Tamoxifen administered for 5 yrs result in :
• 41% reduction in annual rate of breast cancer recurrence (HR-0.59).
• 34% reduction in annual death rate (HR-0.66)
The gains with tamoxifen are achieved independent of age or
menopausal status and are durable for even up to 15yrs of follow up
37. Relative Reduction at Yr 10: 32%
Meta-analysis of Tamoxifen Alone in
Premenopausal Women: Reduction at Yr 10
EBCTCG, et al. Lancet. 2011;378:771-784.
50
40
30
20
10
0
0 5 10 15
Recurrence,
%
Yrs
Recurrence
Entry age: younger than 45 yrs; ER+
2614 women Control
48.4%
35.8%
≈ 5 yrs of
tamoxifen
15-yr gain: 12.6% (SE: 2.3)
Log-rank 2P < .00001
20.2%
30.9%
31.7%
43.5%
% ± SE
Relative Reduction at Yr 10: 34%
50
40
30
20
10
0
0 5 10 15
Breast
Cancer
Mortality,
%
Yes
Breast Cancer Mortality
Entry age: younger than 45 yrs; ER+
2614 women
Control
35.9%
25.3%
≈ 5 yrs of
tamoxifen
15-yr gain: 10.6% (SE: 2.2)
Log-rank 2P = .00002
10.3%
21.0%
13.4%
28.0%
% ± SE
38. 14
Tamoxifen and Endometrial Cancer by Age:
Almost None if Premenopausal
EBCTCG, et al. Lancet. 2011;378:771-784.
50
40
30
20
10
0
0 5 10
Uterine
Cancer
as
First
Event,
Excluding
Cervical,
%
Yrs
Uterus (not Cervix)
Cancer Incidence
Entry age: younger than 45 yrs
5285 women
0.4%
Control
0.5%
≈ 5 yrs of
tamoxifen
10-yr loss: 0.1% (SE: 0.2)
Log-rank 2P = .72
0.4%
0.5%
0.1%
0.1%
% ± SE
50
40
30
20
10
0
0 5 10 15
Uterine
Cancer
as
First
Event,
Excluding
Cervical
Yrs
Uterus (not Cervix)
Cancer Incidence
Entry age: 55-69 yrs
8182 women
0.9%
Control
3.6%
≈ 5 yrs of
tamoxifen
15-yr loss: 2.7% (SE: 0.5)
Log-rank 2P < .00001
0.6%
2.2%
0.2%
0.9%
% ± SE
39. Moving Beyond Tamoxifen Alone as
Adj Therapy for Premenopausal ER+ EBC
• Postmenopausal women with ER+ EBC moved to the use of aromatase
inhibitors in 2002, but these agents are not useful for women in a
premenopausal state .
• Trials testing oophorectomy as an adjuvant therapy have had mixed results
• To address this, the SOFT and TEXT trials were designed
– Step 1, SOFT: is tamoxifen plus ovarian suppression superior to
tamoxifen alone?
– Step 2, TEXT (combined with elements of SOFT): is exemestane plus
ovarian suppression superior to tamoxifen plus ovarian suppression?
Pagani O, et al. N Engl J Med. 2014;371:107-118.
40. Methods Of Ovarian Function Suppression
• GnRH analogs : Goserelin, Leuprolide, or Triptorelin.
• Oophorectomy results in reliable and prompt reduction in the levels of
circulating estrogens but carries the risks associated with anesthesia and
surgery
• Ovarian irradiation can be used to ablate ovarian function. This requires
cumulative doses over 12 Gy, as lower doses are associated with decreased
efficacy. Because of the side effects of radiotherapy, this approach is rarely
used in contemporary practice.
42. SOFT RESULTS
• In the primary analysis, tamoxifen plus ovarian suppression was not
superior to tamoxifen alone for DFS.
No difference in DFS and freedom from breast cancer at 5 years
43. • At 8 yrs , Compared with tamoxifen alone, tamoxifen plus OFS improved
eight-year disease-free survival (DFS) rate (83 versus 79 percent; hazard
ratio [HR] 0.76, 95% CI 0.62-0.93), as did exemestane plus OFS (86 versus
79 percent; HR 0.65, 95% CI 0.53-0.81).
44. • Tamoxifen plus OFS also modestly improved survival compared with tamoxifen
alone (93.3 versus 91.5 percent; HR 0.67, 95% CI 0.48-0.92), though the OS
was similar between OFS plus exemestane (92.1 percent) and the other groups
(HR compared with tamoxifen 0.85, 95% CI 0.62-1.15).
• However, freedom from distant recurrence at eight years was similar between
patients receiving tamoxifen plus OFS versus tamoxifen alone (89 versus 88
percent; HR 0.86, 95% CI 0.66-1.13), and it was only modestly improved for
those receiving exemestane plus OFS (91 percent; HR versus tamoxifen 0.73,
95% CI 0.55-0.96).
• Tamoxifen plus ovarian suppression resulted in a 24% lower relative risk of
recurrence, a second invasive cancer, or death than tamoxifen alone (P = 0.009).
45. Subgroup analysis
• In a subgroup analysis, women at high risk of recurrence, who received
prior chemotherapy, had improved outcomes with ovarian suppression.
• Freedom from distant recurrence at 8 years in patients with previous
chemotherapy was 80 percent for those receiving tamoxifen only, 82
percent among those receiving tamoxifen and OFS, and 85 percent for
those receiving exemestane and OFS (HR for tamoxifen and OFS versus
tamoxifen 0.84, 95% CI 0.64-1.12; HR for exemestane and OFS versus
tamoxifen 0.74, 95% CI 0.56-0.99
• In the subgroup of women with no prior chemotherapy, no meaningful
benefit was seen from ovarian suppression, as women who received
tamoxifen alone demonstrated a 95% chance of remaining disease-free for
5 years.
48. • 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.
• Pathologically involved lymph nodes
• Large tumor size
• High risk of recurrence based on a genomic assay, or
other high-risk features for which the patient received
chemotherapy
• Age <35yrs
49. Timing Of Adjuvant Hormonal
Therapy
• 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.
• Timing of endocrine therapy doesn’t impact overall survival given either
sequential or concurrently.
• With chemotherapy , it is preferred to give sequentially as intergroup trial
has shown a trend towards improvement in DFS compared with concurrent
treatment (HR 0.84, 95% CI 0.70- 1.01)
• With radiotherapy, sequential treatment is given to avoid treatment
complications.
50. 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.
51.
52. • Women 60yrs and older
• Women < 60yrs with one of the following :
Prior bilateral oopherectomy
They have 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.
They are amenorrheic on tamoxifen, and follicle-stimulating hormone (FSH)
and serum estradiol are in the postmenopausal range.
Menopause
Postmenopausal
FSH – 24-156 mIU/ml
Estradiol – 10-15pg/ml
53. • The AIs have consistently been shown to improve outcomes
for postmenopausal women with hormone receptor-positive
breast cancer compared with tamoxifen, both during and after
treatment.
• Therefore, an AI is the preferred adjuvant treatment of
postmenopausal women, although tamoxifen is an acceptable
alternative for women who are intolerant of AI’s.
54. • AIs suppress plasma estrogen levels by inhibiting or
inactivating aromatase, the enzyme responsible for the
peripheral conversion of androgens to estrogens
• AIs are inactive in women with intact ovarian function,
including those who experienced therapy-induced amenorrhea,
and hence ovarian suppression/ablation must be used in
premenopausal women receiving AIs.
55. Early Breast Cancer Trialists' Collaborative Group
(EBCTCG)-2015 METAANALYSIS
AI versus tamoxifen
• Aromatase inhibitors reduce recurrence rates by about 30%
(proportionately) compared with tamoxifen while treatments
differ, but not thereafter.
• 5 years of an aromatase inhibitor reduces 10-year breast cancer
mortality rates by about 15% compared with 5 years of
tamoxifen, hence by about 40% (proportionately) compared
with no endocrine treatment.
56. AI versus tamoxifen
In trials where women (n = 9885) were randomly assigned to treatment with a
five-year course of an AI or tamoxifen, treatment with an AI resulted in:
• Reduced breast cancer recurrence, particularly during years 0 to 1 (relative
risk [RR] 0.64, 95% CI 0.52-0.78) and years 2 to 4 (RR 0.80, 95% CI 0.68-
0.93). There was no further impact on recurrence rates after the 5-year
treatment period.
• Lower 10-year breast cancer mortality (RR 0.85, 95% CI 0.75-0.96).
58. ATAC Results
• With a median of 100 months follow-up, results in 5216 postmenopausal
women with HR-positive, early-stage breast cancer enrolled in the ATAC
trial demonstrated fewer recurrences (HR for DFS, 0.85; 95% CI, 0.76–
0.94; P = .003) with anastrozole compared with tamoxifen.
• No difference in survival has been observed (HR, 0.90; 95% CI, 0.75–1.07;
P = .2).
• Patients in the combined tamoxifen and anastrozole group gained no
benefit over those in the tamoxifen group, suggesting a possible deleterious
effect from the weak estrogenic effect of tamoxifen in patients with near
complete elimination of endogenous estrogen levels.
59. Tamoxifen alone versus a short course of
tamoxifen followed by an AI
• In trials where women (n = 11,798) were randomly assigned to
a continuous five-year course of tamoxifen versus two or three
years of tamoxifen followed by an AI for five years of total
endocrine therapy, switch to an AI resulted in:
– Reduced breast cancer recurrence during years 2 to 4 (RR 0.56, 95% CI
0.46-0.67), with no further effect on recurrence beyond the treatment
period.
– Fewer deaths from breast cancer (RR 0.84, 95% CI 0.72-0.96).
60. AI alone versus a short course of tamoxifen
followed by an AI
• In trials where women (n = 12,799) were randomly assigned to five years
of an AI versus two or three years of tamoxifen followed by an AI for five
years of total endocrine therapy, treatment with an AI alone resulted in:
– Lower recurrence rates during years 0 to 1, before the switch had occurred (RR
0.74, 95% CI 0.62-0.89).
– Similar recurrence rates during years 2 to 4, when both groups were treated
with an AI (RR 0.99, 95% CI 0.85-1.15), and beyond year 5.
– A trend toward reduced breast cancer mortality, which did not reach
statistical significance (RR 0.89, 95% CI 0.78-1.03).
62. • An early analysis compared tamoxifen alone versus letrozole alone,
including those patients in the sequential arms during their first 2 years of
treatment only.
• With 8010 women included in the analysis, DFS was superior in the
letrozole-treated women (HR, 0.81; 95% CI, 0.70–0.93; log rank P = .003).
• No interaction between PR expression and benefit was observed.
• No difference in OS was observed.
• A comparison of the cardiovascular side effects in the tamoxifen and
letrozole arms of the BIG 1-98 trial showed that the overall incidence of
cardiac adverse events was similar (letrozole, 4.8%; tamoxifen, 4.7%).
63. • However, the incidence of grade 3 to 5 cardiac adverse events and bone
fractures was significantly higher in the letrozole arm.
• The grade 3 to 5 thromboembolic events was significantly higher in the
tamoxifen arm.
• After a longer follow-up (median 71 months) no significant improvement
in DFS was noted with either tamoxifen followed by letrozole or the
reverse sequence as compared with letrozole alone (HR for tamoxifen
followed by letrozole, 1.05; 99% CI, 0.84–1.32; HR for letrozole followed
by tamoxifen, 0.96; 99% CI, 0.76–1.21)
64. • The breast cancer outcomes were better for letrozole compared with
tamoxifen monotherapy.
• There was no significant difference in either disease-free or overall survival
between the sequential therapies and letrozole monotherapy.
• Moreover, efficacy of monotherapy with letrozole versus tamoxifen for
contralateral breast cancer varied over time (0 to 5-, 5 to 10-, and >10-year
hazard ratios [HRs] 0.62, 0.47, and 1.35, respectively)
65.
66. • The highest risk for recurrence is within the first few years after initial
diagnosis, and that the more effective treatment strategy, aromatase
inhibition, is preferable to tamoxifen during that time.
• However, once patients have remained disease free for a few years,
switching to tamoxifen is similarly effective to continuation of AI
treatment, and there may be a longer carry-over effect with tamoxifen than
an AI in terms of protection against contralateral breast cancer.
67. Comparison between AIs
• Evidence suggests similar clinical outcomes and tolerability between the
aromatase inhibitors (AIs).
• (NCIC-CTG) MA.27 study – Exemestane Vs Anastrozole With a median
follow-up of four years, there was no difference in the event-free or overall
survival rate.
• FACE Trial : Letrozole versus anastrozole –
Both were found to have similar five-year DFS rates (85 versus 83 percent;
HR 0.93, 95% CI 0.80-1.07) and comparable side effect profiles
68. FATA-GIM3 trial
• 1800 women were randomly assigned to oral anastrozole (1 mg per day),
exemestane (25 mg per day), or letrozole (2.5 mg per day) for five years .
• Five-year disease-free survival (DFS) was 90 percent with anastrozole
(95% CI 87.9-91.7), 88 percent with exemestane (95% CI 85.8-89.9), and
89 percent with letrozole (95% CI 87.3-91.1).
• Gastrointestinal side effects were more common with exemestane
• Hypercholesterolemia was more frequent with anastrozole and letrozole
than with exemestane.
• All other side effects were similar between the agents.
69. EBCTCG - 2015
• Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the
bone and improve breast cancer survival, but there is definite benefit only in
women who were postmenopausal when treatment began..
• With bisphosphonate therapy, the greatest improvement was seen in bone
recurrence (RR=0.83, P = .004) and bone fractures (RR=0.85, P = .02).
• No effect was seen on distant recurrence outside bone (RR =0.98, P =0.69).
• No differences were seen in non-breast cancer mortality.
• In premenopausal patients, bisphosphonate therapy did not seem to have a
significant effect on bone recurrence.
NCCN Recommendation :
Adjuvant bisphosphonate therapy for postmenopausal (natural or induced) women
receiving adjuvant endocrine therapy.
70. • Initially, patients with hormone receptor-positive (HR+) breast tumors have
a lower risk of recurrence than those with HR− tumors, but with longer
follow-up, the opposite may be the case .
• The Oxford meta-analysis found that more than half of breast cancer
recurrences and two thirds of breast cancer deaths occur after 5 years of
adjuvant tamoxifen
• These data clearly indicate the need for continuous hormonal treatment for
women with HR+ tumors.
EXTENDED ADJUVANT HORMONAL THERAPY
73. Significant reduction in the risk of recurrence and breast cancer mortality with 10yr
of tamoxifen compared with a five-year treatment course.
RECURRENCE MORTALITY
74. • 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%).
• Patients who received tamoxifen for 10 years had a greater reduction in risk of
progression, possibly due to a “carryover effect.”
• The reduction in risk of recurrence was 0.90 (95% CI, 0.79–1.02) during 5 to 9 years
of tamoxifen treatment and 0.75 (0.62–0.90) after 10 years of treatment.
• There were also decreases in the incidence of contralateral breast cancer.
• Furthermore, reduced mortality was also apparent after completion of 10 years of
treatment with tamoxifen.
75. aTTom and ATLAS: Endometrial
Cancers With 5 vs 10 Yrs of Tamoxifen
Absolute hazard: 0.5%
Event 10-Yr Tam,
n (%)
5-Yr Tam,
n (%)
Rate Ratio
(95% CI)
P Value
Endometrial cancer 102 (2.9) 45 (1.3) 2.20
(1.31-2.34)
< .0001
Endometrial cancer death 37 (1.1) 20 (0.6) 1.83
(1.09-3.09)
.02
Gray RG, et al. ASCO 2013. Abstract 5.
• Despite a doubling in the risk of endometrial cancer (76 vs 35) with 10yrs
tamoxifen, there was no increase in deaths from endometrial cancer (10 vs
12) or from any other non-breast cancer cause.
76. 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 .
Duration ??
• Earlier 5 years of Tamoxifen was the recommendation
• Both the ATLAS and aTTom trials have confirmed benefits
of giving the drug for 10 years in high risk patients
77. • MA.17 was a phase III, randomized, double-blind, placebo controlled trial
of letrozole as extended adjuvant therapy in postmenopausal women with
primary breast cancer who had completed approximately 5 years of
adjuvant tamoxifen therapy .
• For women who complete a five-year course of AI after any duration of
prior tamoxifen, this trial demonstrated that an additional five years of
letrozole improved DFS but not OS .
• Letrozole significantly improved OS in patients with node-positive tumors
(hazard ratio = 0.61; 95% CI 0.38, 0.98; P = 0.04)
MA.17
78. • Letrozole for an additional 5 years improved 5-year DFS relative to those
who received placebo (95 percent [95% CI 93-96 percent] versus 91 percent
[95% CI 89-93 percent]).
79. • The annual rate of contralateral breast cancer was reduced with letrozole
(0.21 versus 0.49 percent; HR 0.42, 95% CI 0.22-0.81).
• Bone-related toxic effects were more frequent among those receiving
letrozole, including bone pain (18 versus 14 percent), fractures (14 versus 9
percent), and new-onset osteoporosis (11 versus 6 percent).
• Most patient- reported quality of life outcome measures were similar
between the two groups.
81. • Improvement was seen in five-year DFS in those receiving letrozole
compared to those who received placebo (95% [95% CI 93 - 96%] vs. 91%
[95% CI 89 -93%]).
• The annual rate of contralateral breast cancer reported was lower with
letrozole (0.49% vs. 0.21%; HR 0.42, 95% CI 0.22-0.81%).
• However, longer duration of AI resulted in more frequent bone-related
adverse effects compared with those who received placebo and no
improvement was observed with respect to OS.
• Bone-related adverse effects included bone pain (18% vs. 14%), fractures
(14% vs. 9%), and new-onset osteoporosis (11% vs. 6%).
82. NSAPB B-42: Study Design
0 5 10
Tamoxif
en
AI
Aromatase
Inhibitor (AI)
R
Letrazole 2.5
mg
Placebo
Mamounas EP P et al. SABCS 2016
2-3
83. NSAPB B-42: Results
Mamounas EP P et al. SABCS 2016
Didn’t reach Statistical
Significance for DFS
??? Cumulative incidence
for DR Benefit
84. IDEAL* & DATA**
0 2 3 5 10
Tamoxifen
Aromatase Inhibitor
(AI)
Tamoxifen AI
R
Letrazole 2.5
mg
Letrazole
2.5 mg
*Blok EJ J et al. SABCS 2016
**Tjan-Heijnen VC C et al. SABCS 2016
0 2 3 5 10
Tamoxife
n
R
Anastrazole 1
mg
Anastrazole
1 mg
IDEAL* DATA**
These findings do not yet support the use of extended
adjuvant AI prescription after 5 years of sequential
endocrine therapy for postmenopausal patients with
hormone receptor-positive breast cancer
85. • Thus the results from NSABP-B42, the DATA trial, and the IDEAL trial have
not confirmed the benefit on recurrence-free survival seen in MA.17R .
• The difference in results between these trials may be due to a difference in how
they defined recurrence-free survival; for example, MA.17R included only
recurrences of the original breast cancer or a new breast cancer, and NSABP-
B42 also included new nonbreast primary cancer and death from any cause.
• In both studies, the breast cancer-free interval was similarly defined and showed
a small but statistically significant improvement with extended endocrine
therapy.
• No trial has demonstrated an OS benefit to extended treatment among those
who had already received a five-year course of an AI
86. “Extended Endocrine Therapy Beyond 5
years”
• Treatment Pros/Cons
• Benefits include: lower distant recurrences & secondary prophylaxis
• Side Effects include: ongoing familiar side effects & bone health risks
• Extended adjuvant endocrine therapy can be considered in :
• Women with Stage 3
• Women with stage 2 at higher risks especial node positive
• Women who had tolerated and willing to continue!
• Women had started with Tamoxifen!!
87.
88. HORMONAL THERAPY IN NEO ADJUVANTSETTING
• Limited data
• Mostly used in patients with locally advanced breast
cancer who are deemed unfit for systemic
chemotherapy
• Complete and partial response rates -40-70%
• Responses are slower than neo adjuvant
chemotherapy
89. 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.
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
Estrogen promotes the growth of breast cancer by binding to and activating the Estrogen Receptor (ER)
Progesterone Receptor is a ER induced gene
3 possible ways to interrupt this process
▫ Cardiovascular: ◦ Fewer non cancer related deaths due to cardiovascular events.
◦ Fewer hospitalizations for cardiac events ◦ Serum LDL / cholesterol reduced. ◦ Actual magnitude of benefit still unclear.
◦ Skeletal: ◦ Significant reduction in incidence of fractures of weight bearing bones. ◦ Estrogen agonist action on BMD
◦ Prevention of contralateral breast cancer
LHRH agonist therapy downregulates pituitary
Decreased production of LH and FSH
Suppression of ovulation and estrogen production.
Potentially reversible; most commonly utilized
Progestins
Megestrol acetate Medroxyprogesterone acetate
They had been used in metastatic breast cancer, but are now replaced by competitive blockers.
ER, estrogen receptor; SE, standard error.
This analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) study demonstrated the effectiveness of tamoxifen in premenopausal women who are younger than 45 years of age. The effects on recurrence highlight the importance of long-term follow-up; the benefit of 5 years of tamoxifen on recurrence is strongest during the first 5 years (during treatment, with the curves strongly diverging) and between Years 5-10 (the “carryover effect”). After Year 10, the curves no longer diverge further, but the substantial difference in recurrence rate persists.
The effects on breast cancer mortality are different, at least in part because mortality occurs years after recurrence, particularly in patients with hormone receptor–positive disease. The effects on mortality are seen within the first 5 years, but the curves continue to diverge beyond 10 years of follow-up.
SE, standard error.
Of interest, one of the main concerns with tamoxifen—endometrial cancer—is not an issue in premenopausal women (those younger than 45 years of age). In this population, the rates of endometrial cancer are low, and there is very little effect of tamoxifen on endometrial cancer incidence. By contrast, tamoxifen does strikingly increase endometrial cancers in postmenopausal women. After the endometrium ceases to undergo cyclic sloughing and regeneration, a drug like tamoxifen can induce endometrial cancer through estrogen-like effects on the endometrium. These data highlight that certain concerns emphasized to postmenopausal patients about a drug like tamoxifen, such as the increased risk for endometrial cancer, do not need to be emphasized to premenopausal patients.
BC, breast cancer; EBC, early breast cancer; ER, estrogen receptor.
Aromatase inhibitors, an additional class of hormonal agent different from antiestrogens like tamoxifen, were introduced use as an adjuvant therapy approximately 10 years ago. Aromatase inhibitors suppress estrogen levels in postmenopausal women but not in the presence of fully functional ovaries in premenopausal women.
For premenopausal women, the question of whether combining OFS with either tamoxifen or aromatase inhibitors had not been conclusively answered. To address these questions, 2 very large trials were designed: the SOFT and TEXT trials. The SOFT trial was designed to answer the question of whether OFS adds to tamoxifen. The TEXT trial was designed to determine whether dual therapy should combine OFS with either tamoxifen as the oral agent or with an aromatase inhibitor, in this case exemestane.
Ovarian function can be suppressed with GnRHa or by permanent methods, such as oophorectomy or irradiation. Any of these strategies is appropriate, depending on patient preferences, although we often start with a GnRHa and proceed to oophorectomy if OFS is tolerated
In the SOFT trial,281 premenopausal women with hormone-receptor breast cancer were randomized to tamoxifen alone, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression for 5 years
281 The OS data from these trials is still pending because the overall follow-up is relatively short in the context of endocrine-sensitive disease.
After 67 months of median follow-up, the DFS rate at 5 years was 86.6% in the tamoxifen– ovarian suppression group and 84.7% in the tamoxifen alone group (HR 0.83; 95% CI, 0.66–1.04; P = .10).
Their chance of remaining disease-free at 5 years was 78% with tamoxifen alone, 82.5% with tamoxifen and ovarian suppression, and 85.7% with exemestane and ovarian suppression.
Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT).
Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen–ovarian suppression group, and 32.3% of the exemestane–ovarian suppression group.
In the SOFT trial, eight-year DFS among those receiving chemotherapy was 71 percent for those receiving tamoxifen only, 77 percent among those receiving tamoxifen and OFS, and 80 percent for those receiving exemestane and OFS (HR for tamoxifen and OFS versus tamoxifen 0.76, 95% CI 0.60-0.97; HR for exemestane and OFS versus tamoxifen 0.68, 95% CI 0.53-0.88) [7].
EBCTCG meta-analysis similar reductions in the rate of recurrence (RR 0.62 and RR 0.71, respectively)
In women premenopausal at the beginning of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status as ovarian function may still be intact or resume despite anovulation/amenorrhea after chemotherapy. For these women with therapy- induced amenorrhea, oophorectomy or serial measurement of FSH and/or estradiol are needed to ensure postmenopausal status if the use of aromatase inhibitors is considered as a component of endocrine therapy.
However, in postmenopausal patients, zoledronic acid significantly reduced bone recurrence (3.4% vs. 4.5%, RR=0.73, 99% CI 0.53 to 1.00); the difference in breast cancer mortality was not statistically significant (7.1% vs. 7.9%, RR=0.88, 99% CI 0.69 to 1.11)
The use of extended tamoxifen substantially increases the risk of endometrial cancer. In this analysis, with 10 years of tamoxifen treatment, 2.9% of patients developed endometrial cancer vs 1.3% at with 5 years of treatment (P < .0001). A caveat to remember for this analysis is that most of these patients (~ 90%) were postmenopausal, which may increase the risk of endometrial cancer with tamoxifen treatment.
Tam, tamoxifen.
The risk of disease recurrence increased over time in the placebo group, whereas in patients receiving letrozole, risk appeared to peak at around 2 years of treatment and decrease thereafter.
MA.17 demonstrated that extended adjuvant therapy with letrozole provides women further protection against relapse after the completion of tamoxifen. Also women in all risk categories benefited in terms of reduced risk for recurrence of their cancer.
This could mean that distant micrometastases that have survived 5 years of tamoxifen therapy remain highly estrogen-sensitive and responsive to extended adjuvant letrozole treatment.
Extended therapy with adjuvant letrozole should therefore be considered for all women completing tamoxifen.
On the basis of this trial, letrozole was approved as extended adjuvant therapy, and it is currently the only AI approved for this indication
In women initially treated with an AI, a randomized phase III trial (MA17.R) evaluated the effects of extending adjuvant AI therapy from 5 to 10 years.314
In the IES trial, exemustane after 2-3 years of tamoxifen showed improved DFS with lower incidence of side effects.
In the ARNO trial anastrozole after 2-3 years of tamoxifen improved relapse free intervals.
Late Recurrences are real accounting for > 50% of events
Baseline Stage, grade, and other prognostic markers……….
ITA & ARNO/ABCSG Trials support the benifits of switching from Tamoxifen to Anastrazole
