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HORMONAL THERAPY FOR BREAST CANCER
MAYUR MAYANK
21.06.2013
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OVERVIEW
INTRODUCTION
HISTORY AND EVOLUTION
MOLECULAR BASIS
AGENTS USED IN HORMONAL THERAPY
HORMONAL THERAPY IN METASTATIC SETTING
HORMONAL THERAPY IN ADJUVANT SETTING
HORMONAL THERAPY IN NEO ADJUVANT SETTING
HORMONAL THERAPY IN PREVENTION OF BREAST CANCER
CONCLUSIONS
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Breast cancer is the 2nd most common malignancy diagnosed throughout the world and is the 5th most common cause of cancer related death
In women throughout the world, it is the most common malignancy diagnosed and is the most common cause of death
Around 60-70% patients diagnosed to have breast cancer are Estrogen receptor-positive (65% of these are also positive for Progesterone receptors)
INTRODUCTION
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Patients with Estrogen receptor-Positive (ER+) tumors have a better survival than tumors with no Estrogen receptors (Estrogen receptor-negative ; ER-)
Five-year survival is about 10 percent better for women with ER+ breast cancer than for those with ER- tumors
Patients with ER + tumors are candidates for hormonal therapy
INTRODUCTION
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Study Study Populatio
n
Characteristics of
patients
Follow up
(Years)
ER + ER -
SEER 111,993 Stage I, II or III 8 Women younger than
40: 90%*Sig
Women 40-49:
94%*Sig
Women 50-59:
95%*Sig
Women 60-69:
95%*Sig
Women 70-74:
94%*Sig
Women younger than
40: 78%*Sig
Women 40-49:
81%*Sig
Women 50-59:
81%*Sig
Women 60-79:
81%*Sig
Women 70-74:
80%*Sig
5 YEAR OVERALL SURVIVAL
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Study Study Populatio
n
Characteristics of
patients
Follow up
(Years)
ER + ER -
Danish Breast Cancer
Cooperative Group
26,944 Grade I, II or III 5 85% 69%
Truong et al. 8,038 T1-2, M0Grade I, II, or III
4-6 Highersurvival
Sig
Lowersurvival
Sig
San Antonio Data Base
3,452 Stage I, II or III 3 84% 75%Sig
Crowe et al. 1,392 Stage I or II 10 82% 70%Sig
NSABP B-06 1,157 Node-negativeTumor smaller
than 4 cm
5 92% 82%Sig
Winstanley et al.
767 Stage I or II 11 69% 62%NS
Crowe et al. 501 Stage INode-negative
7 94% 80%Sig
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HISTORY AND EVOLUTION
1896 – Dr George Beaston
Surgical Oophorectomy for advanced breast cancer patients
Significant tumor regression
Sense of well being
Reduction in cutaneous metastases
No effect on osseous metastases
Best above age of 40 years
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1941 – Dr Charles Higgins
First discovery of hormonal therapy for treatment of cancers
Demonstrated that in men with prostate cancer, reducing androgen concentrations by orchiectomy or administering the female hormone Estrogen, appeared to restore the health of patients with widespread metastases
In his Nobel Prize Lecture on 13 December 1966, mentioned 8 cancers which were hormone responsive, breast cancer being one of them
HISTORY AND EVOLUTION
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1966 – Dr Arthur L Walpole/Dr Dora Richardson
Developed Tamoxifen (ICI-46474)
Developed as a Contraceptive “Morning After Pill”
Never proved useful in human contraception
HISTORY AND EVOLUTION
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1971 – Christie Hospital, Manchester
1st Clinical study of Tamoxifen in Advanced Breast Cancer
HISTORY AND EVOLUTION
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1973 – Queen Elizabeth Hospital, Birmingham
HISTORY AND EVOLUTION
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1973 – 1st work done on Aromatase Inhibitors in treatment of Breast cancer
HISTORY AND EVOLUTION
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TIMELINE OF DEVELOPMENT OF AGENTS IN BREAST CANCER
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MOLECULAR BASIS
Overexpression of Estrogen receptors is seen in a large number of breast cancer patients (~70%)
Estrogen :
Steroid hormone
Profound proliferative effect on normal human mammary epithelium through its activation of ER-alpha, a classic nuclear hormone receptor
Exerts its actions through both genomical and nongenomical mechanisms
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Genomic Mechanism :
Involves binding of hormones to their respective receptors, transcription of the specific genes, and protein synthesis
Sequence of events often takes hours to days
Non Genomic Mechanism :
Involves the modulation of neurotransmission unrelated to the transcription of genes
May occur within seconds to minutes
MOLECULAR BASIS
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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
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Non Genomic Mechanism :- 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
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Mechanism of action of Hormonal therapies :
All the hormonal therapies target either the Estrogen directly or the Estrogen receptor at one level or the other
MOLECULAR BASIS
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AGENTS USED IN HORMONAL THERAPY
Selective Estrogen Receptor Modulators (SERM)
Tamoxifen
Raloxifen
Torimefene
Anti Estrogens
Fulvestrant
Aromatase Inhibitors
Letrozole
Anastrazole
Exemestane
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LHRH Agonists
Leuprolide
Goserlin
Progestins
Megestrol acetate
Medroxyprogesterone acetate
AGENTS USED IN HORMONAL THERAPY
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SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)
Tamoxifen
Raloxifen
Torimefene
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SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)
The SERMs lack the steroid structure of estrogens but possess a tertiary structure that allows them to bind to the estrogen receptor
Selective modulation 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 co regulator
proteins
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SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)
TAMOXIFEN
1st hormonal drug approved by the FDA for usage in Breast Cancer
Chemically : Triphenylethylene
Mechanism of action : Competitive binding to the estrogen receptor resulting in reduction of transcription of estrogen regulated genes
Blocks the cell cycle in G1 phase
Cytostatic drug
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Ancillary benefits of Tamoxifen
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
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Toxicity of Tamoxifen
Menopausal symptoms: 50% - 60% ( N.B. 40% - 50% in placebo) MC in premenopausal Vaginal dryness and discharge may occur
in excess. Depression:
Maybe seen in as high as 10% of patients. But no randomized comparisons
available. Ocular toxicity:
Keratopathy, maculopathy & cataract Reported with high doses However NSABP studies have found no
increase in vision threatening ocular toxicity.
Thromboembolism: Severe thromboembolism seen in ~ 1%
patients 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
(hazard rate of 1.7 per 1000 – NSABP B 14 data)
Mostly low grade & stage I tumors. Other tumors:
Hepatomas Clear cell sarcomas of ovary
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ANTI ESTROGENS(SELECTIVE ESTROGEN RECEPTOR DOWNREGULATOR)
Fulvestrant
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ANTI ESTROGENS
FULVESTRANT Steroidal antiestrogen. Considerably higher affinity for Estrogen receptor than tamoxifen
Promotes accelerated ER turnover, Suppression of ER protein levels, Inhibition of ER dimerization, Reduced shuttling of the ER from the cytoplasm to the nucleus
Developed for clinical use as a 250-mg intramuscular monthly depot injection
Developed to counter the estrogenic effects of Tamoxifen on uterus and the bone related effects of AIs.
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AROMATASE INHIBITORS
Letrozole
Anastrazole
Exemestane
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AROMATASE INHIBITORS
Work by inhibiting the action of the enzyme aromatase
Peripheral conversion of androgens into estrogens by a process called aromatization
2 types available (3rd Generation)
Steroidal Inhibitors : Exemestane
Irreversible Inhibition
Permanent and deactivating bond with the aromatase enzyme
Non steroidal Inhibitors : Letrozole, Anastrazole
Reversible Inhibition
inhibit the synthesis of estrogen via reversible competition for the aromatase enzyme
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Toxicity management
Hot Flushes: Usually self limiting and respond well to placebos. HRT/ SSRIs are not recommended Best managed by life style changes.
Vaginal Bleeding: Routine work up indicated. Watch out for an endometrial CA in post menopausal females.
Myalgia / Arthalgia: More common with AI Switching to Tamoxifen may be required.
Osteoporosis: Calcium supplements, Vitamin D and bisphosphonates HRT / Raloxifen not recommended (Raloxifen with AI – may limit efficacy)
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LHRH AGONISTS
Leuprolide
Goserelin
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LHRH ANALOGUES
Analogue that activates the GnRH receptor resulting in increased secretion of FSH and LH
After their initial stimulating action – termed a “flare” effect - eventually causes a paradoxical and sustained drop in gonadotropin secretion
This second effect is termed “downregulation” and can be 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.
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PROGESTINS
Megestrol acetate
Medroxyprogesterone acetate
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PROGESTINS
Powerful antiandrogenic and antiestrogenic effects
Significantly lowers the expression of the androgen receptor (AR) and the Estrogen receptor (ER) in the body
The antineoplastic action of progestins on carcinoma of the breast is effected by
modifying the action of other steroid hormones and
by exerting a direct cytotoxic effect on tumor cells
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HORMONAL THERAPY IN METASTATIC SETTING
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.
Tamoxifen is the gold standard 1st choice agent for Metastatic Breast Cancer
Hormonal therapy depends on the patients menopausal state
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METASTATIC BREAST CANCER
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Pre menopausal :
Tamoxifen is the drug of choice
Response rates range from 16% to 56% (Median 30%) – same as ovarian ablative techniques.
Overall mean Time to progression for patients with metastatic disease treated with Tamoxifen is about 6 months
Duration of response is between 12 and 18 months
Tamoxifen plus castration has been shown to have better results in a meta analysis
HORMONAL THERAPY IN METASTATIC SETTING
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Ref : Facts and Controversies in Systemic Treatment of Metastatic Breast Cancer ; CHANTAL BERNARD-MARTY, FATIMA CARDOSO, MARTINE J. PICCART ; The Oncologist 2004;9:617-632
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Ref : Facts and Controversies in Systemic Treatment of Metastatic Breast Cancer ; CHANTAL BERNARD-MARTY, FATIMA CARDOSO, MARTINE J. PICCART ; The Oncologist 2004;9:617-632
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Ref : New directions in hormone therapy for metastatic breast cancer ; M. Namer ; European Society for Medical Oncology
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Post Menopausal 4 major phase III trials have directly compared Tamoxifen against Aromatase
Inhibitors (AI)
All have shown an improvement in time to progression The impact on Overall survival not clear however. In the trial comparing Letrozole to Tamoxifen it was shown that OS improved
in the first 2 yrs. However no benefit exists at 5yrs. Crossing over to Tamoxifen after initial AI therapy may be theoretically
unwise as: Estrogen deprived cancer cells may be become paradoxically sensitive to
tamoxifen
HORMONAL THERAPY IN METASTATIC SETTING
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Ref : New directions in hormone therapy for metastatic breast cancer ; M. Namer ; European Society for Medical Oncology
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Hormonal therapy shows response in : Bone metastasis Skin and soft tissue metastasis
No effect of hormonal therapy seen on Brain metastasis Visceral metastasis
HORMONAL THERAPY IN METASTATIC SETTING
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In case of progression on Tamoxifen / Aromatase Inhibitors
Anti androgens – FULVESTRANT
Progestins
Other methods
Ovarian Suppression/Ablation : Medical/Surgical/Radiation Therapy
Adrenelectomy / Hypophysectomy
HORMONAL THERAPY IN METASTATIC SETTING
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Ovarian Suppression/Ablation Ovarian ablation classically includes techniques that cause
permanent cessation of menstruation. Techniques:
Surgical oophorectomy Radiation induced oophorectomy
Ovarian suppression on the other hand refers to the suppression of ovarian function through the use of LHRH analogues.
Uses: Treatment of breast cancer:
Adjuvant setting Metastatic cancer
Prevention of hereditary breast cancer syndromes
HORMONAL THERAPY IN METASTATIC SETTING
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Radiation Oopherectomy
First series reported by Foveau de Courmelles in 1922
Non invasive and cheap procedure.
Low dose carries little additional morbidity.
However takes time for effect to appear usually 2-3 months
For such reason best avoided when prompt relief is needed.
Also best reserved for the patient with slow progression of disease
Dose : 4.5 Gy in single fraction to 10-20 Gy in 5-6 fractions
HORMONAL THERAPY IN METASTATIC SETTING
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BOLERO 2 Trial :
Randomized controlled Phase III trial
Compared everolimus and exemestane versus exemestane and placebo in hormone-receptor–positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both)
Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor–positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors
HORMONAL THERAPY IN METASTATIC SETTING
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Ref : Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer; n engl j med 366;6 ; february 9, 2012
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HORMONAL THERAPY IN ADJUVANT SETTING
Tamoxifen is the agent of choice for all pre menopausal patients with Estrogen receptor positivity
5 years of adjuvant Tamoxifen reduced the risk of breast cancer recurrence and death at 15 years
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Several trials have demonstrated that Tamoxifen adds significantly to the DFS in the adjuvant setting.
Two major trials have also demonstrated a overall survival 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
HORMONAL THERAPY IN ADJUVANT SETTING
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Reduction in Annual Odds*
Recurrence Cancer Deaths Any Deaths
Node negative
0 – 4 yrs 48% 33% 25%
5 + yrs 35% 30% 21%
Node Positive
0 – 4 yrs 41% 40% 29%
5 + yrs 20% 38% 36%
TAMOXIFEN AND NODAL STATUS
Ref : Tamoxifen for early breast cancer: an overview of the randomised trials Early Breast Cancer Trialists’ Collaborative Group Lancet 1998; 351: 1451–67
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Ref : St Gallens Consensus guidelines 2003
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Duration of therapy :
Earlier 5 years of Tamoxifen was the recommendation
2 trials : ATLAS and aTTom have been done to see the advantage of giving Tamoxifen for more than 5 years
Both the trials have confirmed benefits of giving the drug for 10 years in high risk paients
ASCO 2014 Update on adjuvant Hormonal therapy in Breast Cancer recommends the use of Tamoxifen for 10 years in pre and peri menopausal females with Estrogen receptor positivity
HORMONAL THERAPY IN ADJUVANT SETTING
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Aromatase Inhibitors
Have been proven beneficial in Post menopausal setting
No benefit seen in Pre menopausal setting
Presently considered the 1st line hormonal therapy in Post menopausal setting
HORMONAL THERAPY IN ADJUVANT SETTING
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Ref : Perez and Brady’s Principles and Practice of Radiation Oncology, 6th edition
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Ref : Meta-Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus Tamoxifen; J Clin Oncol 28:509-518
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MA -17 ATAC BIG IES
Vaginal Complications - 1.7% - 14% - 3.3% - 1.5% Tamoxifen 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%
TOXICITY OF AROMATASE INHIBITORS VERSUS TAMOXIFEN
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LHRH Agonists in Early breast Cancer
Several trials have been done which have evaluated the role of LHRH agonists either alone or in combination with Tamoxifen or chemotherapy in adjuvant setting for Early breast cancer
ZEBRA
ABCSG 05 Trial
GROTA 02 Trial
ZIPP Trial
INT 0101 Trial
HORMONAL THERAPY IN ADJUVANT SETTING
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Ref : A review of adjuvant hormonal therapy in breast cancer; Kellie L Jones and Aman U Buzdar; Endocrine-Related Cancer (2004) 11 391–406
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PRIMARY OUTCOMES OF INT-0101 TRIAL (CHEMOHORMONAL THERAPY)
Ref : A review of adjuvant hormonal therapy in breast cancer; Kellie L Jones and Aman U Buzdar; Endocrine-Related Cancer (2004) 11 391–406
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Whom to start on Hormonal Therapy ?
Who should be started on what Hormonal Therapy ?
What is the correct sequencing of Hormonal Therapy ?
What is the ideal duration of Hormonal Therapy ?
How should hormonal therapies be switched ?
HORMONAL THERAPY IN ADJUVANT SETTING
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HORMONAL THERAPY IN NEO ADJUVANT SETTING
Limited data
Mostly used in patients with locally advanced breast cancer who are deemed unfit for systemic chemotherapy
Responses are slower than neo adjuvant chemotherapy
Rates of pathological complete response (pCR) are also less than neo adjuvant chemotherapy
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IMPACT Trial :
Immediate Pre operative Anastrazole, Tamoxifen or Combined with Tamoxifen Trial
330 Estrogen receptor positive post menopausal females randomised to 1:1:1
Response rates of 36% to 39%
Only 1% to 3% achieving a clinical complete response
Rates of breast conservation after 3 months of neo adjuvant hormone treatment were highest in the anastrozole-alone arm
HORMONAL THERAPY IN NEO ADJUVANT SETTING
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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
HORMONAL THERAPY IN NEO ADJUVANT SETTING
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HORMONAL THERAPY IN PREVENTION OF BREAST CANCER
The BCPT trial (NSABP P1) was designed to evaluate the efficacy of Tamoxifen given for 5yrs in high risk population
49% reduction in invasive breast cancer
50% reduction in non invasive cancers
ER +ve tumors were much less frequent in women receiving tamoxifen
Incidence of ER –ve tumors remained same
Reduction in rates of occurrence of tumors of all sizes The FDA has now approved the use of tamoxifen in high risk women to
reduce breast cancer incidence. STAR trial evaluated role of Raloxifen in prevention of breast cancer
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Ref : Effects of Tamoxifen vs Raloxifene on theRisk of Developing Invasive Breast Cancerand Other Disease OutcomesTheNSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial ; JAMA, June 21, 2006—Vol 295, No. 23
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Validated approach for only selected high risk females: Women more than 35 yrs, who have completed family with high risk as
defined by the Gail model (5 yr risk > 1.66%) Age > 60 yrs ( intrinsic risk > 1.66%) Presence of LCIS
Duration of follow up is too limited (5 yrs)
Duration of beneficial effect not known
Optimal time at which to start tamoxifen in high risk patients is not known
Finally who all should be screened for high risk factors not known
HORMONAL THERAPY IN PREVENTION OF BREAST CANCER
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CONCLUSIONS
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
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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
Hormonal therapies have also been found useful in chemo prevention, however, sufficient data is lacking for routine usage
CONCLUSIONS
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“
”Thank you !!!