Hormonal therapy for breast cancer

HORMONAL THERAPY FOR BREAST CANCER

MAYUR MAYANK

21.06.2013

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

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

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

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

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


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

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


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


1971 – Christie Hospital, Manchester

1st Clinical study of Tamoxifen in Advanced Breast Cancer


1973 – Queen Elizabeth Hospital, Birmingham


1973 – 1st work done on Aromatase Inhibitors in treatment of Breast cancer


TIMELINE OF DEVELOPMENT OF AGENTS IN BREAST CANCER

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

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

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

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

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


Selective Estrogen Receptor Modulators (SERM)

Tamoxifen

Raloxifen

Torimefene

Anti Estrogens

Fulvestrant

Aromatase Inhibitors

Letrozole

Anastrazole

Exemestane

LHRH Agonists

Leuprolide

Goserlin

Progestins

Megestrol acetate

Medroxyprogesterone acetate


SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Tamoxifen

Raloxifen

Torimefene


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


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

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

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

ANTI ESTROGENS(SELECTIVE ESTROGEN RECEPTOR DOWNREGULATOR)

Fulvestrant

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.

AROMATASE INHIBITORS

Letrozole

Anastrazole

Exemestane

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

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)

LHRH AGONISTS

Leuprolide

Goserelin

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.

PROGESTINS

Megestrol acetate

Medroxyprogesterone acetate

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


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

METASTATIC BREAST CANCER

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


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

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

Ref : New directions in hormone therapy for metastatic breast cancer ; M. Namer ; European Society for Medical Oncology

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


Ref : New directions in hormone therapy for metastatic breast cancer ; M. Namer ; European Society for Medical Oncology

Hormonal therapy shows response in : Bone metastasis Skin and soft tissue metastasis

No effect of hormonal therapy seen on Brain metastasis Visceral metastasis


In case of progression on Tamoxifen / Aromatase Inhibitors

Anti androgens – FULVESTRANT

Progestins

Other methods

Ovarian Suppression/Ablation : Medical/Surgical/Radiation Therapy

Adrenelectomy / Hypophysectomy


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


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


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


Ref : Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer; n engl j med 366;6 ; february 9, 2012


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

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


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

Ref : St Gallens Consensus guidelines 2003

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


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


Ref : Perez and Brady’s Principles and Practice of Radiation Oncology, 6th edition

Ref : Meta-Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus Tamoxifen; J Clin Oncol 28:509-518

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

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


Ref : A review of adjuvant hormonal therapy in breast cancer; Kellie L Jones and Aman U Buzdar; Endocrine-Related Cancer (2004) 11 391–406

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

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 ?



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

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


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



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

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

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


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

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

“

”Thank you !!!

Health & Medicine

Hormonal therapy for breast cancer