HORMONE THERAPY IN EARLY AND LOCALLY

ADVANCED BREAST CANCER

DR. ASHUTOSH MUKHERJI

ASSISTANT PROFESSOR, RADIOTHERAPY

REGIONAL CANCER CENTRE, JIPMER

INTRODUCTION

• Endocrine manipulation in breast cancer 1st introduced by BEATSON in 1896 → Demonstrated objective regression of breast cancer after oophorectomy.

[Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet 2:104-107, 1896.]

• Hormone therapies now used : For palliative treatment of metastatic or very elderly hormone sensitive

breast cancer patients. Adjuvant therapy in hormone sensitive early breast cancer cases.

• Goal of hormone therapy is either to reduce synthesis of estrogen or blocking estrogen receptors in hormone dependent tumours.

RATIONALE FOR ENDOCRINE THERAPY

All estrogens 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).

Unconjugated estrogen crosses the cell membrane and binds to the ER, leading to various changes like dissociation from heat shock protein, homodimerization, phosphorylation and conformational change in activating factor (AF-2) domain.

This leads to production of mRNA and DNA sequences to with subsequent trancriptional and translational changes.

This leads to formation of specific protein sequences which bring about various actions.

ACTIVATION OF HORMONE RECEPTOR

MECHANISM OF HORMONE ACTION

Thus in breast cancers in post menopausal women, the small amount of estrogen produced by the breast tissue is still sufficient to promote tumour growth.

Hormonal therapy thus aims either in preventing the formation of hormones by blocking of the action of aromatase or to prevent upregulation of receptors by blocking the formation/release of regulatory hormones.

According to EBCTCG-1996; adjuvant ovarian ablation resulted in 18% reduction in risk of death in women less than 50 years age with early breast cancer.

SITE OF ACTION OF HORMONAL DRUGS

TYPES OF HORMONAL INTERVENTIONS

HORMONAL THERAPY

SURGICALRADIOTHERAPY

MEDICAL

SELECTIVE AROMATASE INHIBITORS

NON SELECTIVE AROMATASEINHIBITORS

LHRH ANALOGUES

SERMs/SERDs

SURGICAL OVARIAN FUNCTION SUPPRESSION

First report of surgical oophorectomy for the treatment of advanced breast cancer published by Dr. George Beatson in 1896 who saw a young lactating woman with advanced breast cancer and had tumor regression after removing both her ovaries.

Oophorectomy reliably and promptly reduces circulating estrogens to postmenopausal levels in nearly 100% of women, and has the advantage of simultaneously reducing ovarian cancer risk. It is also the most cost-effective method of ovarian ablation.

But oophorectomy may require hospitalization and carries potential operative and anesthesia-related morbidity and mortality. It also irreversibly induces premature menopause with sequelae including osteoporosis, an increased risk of coronary artery disease and permanent loss of fertility.

OVARIAN FUNCTION SUPPRESSION BY RADIATION

Ovarian ablation by radiation therapy has been used for over 50 years. The obvious advantage over oophorectomy is to avoid invasive surgery; however, radiation therapy may be less efficacious than surgery in permanently ablating ovarian function.

Ultrasound guidance to ascertain correct ovarian position for simulation has been utilized to improve the results of radiation ablation.

Doses range from a single 450 cGy fraction up to 1,000-2,000 cGy divided in five or six fractions.

TYPES OF DRUGS FOR MEDICAL OVARIAN

SUPPRESSION

LHRH ANALOGUES

NON SELECTIVEAROMATASE INHIBITORS

ESTROGENRECEPTOR

DOWNREGULATORS

SELECTIVE AROMATASE INHIBITORS

Example: Gosserelin,

Example:Anastrozole,

Letrozole, Exemustane,

Fadrozole

Example:Aminoglutethimide,

Formestane

Example:Tamoxifen, Toremifen

Fulvestrant,Arzoxifene HCl

HORMONE RECEPTOR STATUS AND PROBABILITY OF RESPONSE TO THERAPY

Estrogen Receptor Status

Progesterone Receptor Status

Response Probability

Positive Positive High (50-70%)

Positive Negative Intermediate (33%)

Negative Positive Intermediate (33%)

Negative Negative Low (Less than 10%)

ANTIESTROGENS

TAMOXIFEN Has been the standard of care in endocrine therapy for the last 35-40

years. Is recommended as 1st line therapy for metastatic breast cancer in

pre- and post-menopausal women and as adjuvant therapy in patients with node – positive or node – negative hormone receptor positive disease irrespective of menopausal status.

Also approved for chemoprevention of women at increased risk who have DCIS.

This drug is metabolized by demethylation and hydroxylation; and is a strong anti-estrogen and weak estrogen receptor agonist. In tumours that express Her-2, tamoxifen acts as weak agonist leading to poor response to treatment.

Response rates in pre-menopausal women with hormone responsive disease vary from 15-53%.

The benefits of adjuvant hormonal treatment with tamoxifen were first demonstrated in theNational SurgicalAdjuvant Breast and Bowel Project (NSABP) B-14 trial.

ANTIESTROGENS (contd)

TOREMIFENE Is a triphenylethylene analogue of tamoxifen. Is approved as 1st line therapy for metastatic breast cancer in ER

positive or unknown ER status tumours. Action and sequelae profile is similar to tamoxifen.

FULVESTRANT Is an ER downregulator and pure ER antagonist with affinity 50 times

that of tamoxifen. Administered as a monthly 250 mg IM injection. In randomized phase III trials it has been found to have similar efficacy

to Anastrozole (Howell et al 2005), and to Tamoxifen (Howell et al 2004).

Is presently FDA approved for post-menopausal hormone receptor positive breast cancer progressing on other anti-estrogen therapy.

Safety profile similar to tamoxifen.

AROMATASE INHIBITORS Two types of Aromatase inhibitors (AIs): Suicidal (type 1) or

irreversible inhibitors and Competitive inhibitors (type 2).

Type 1 or suicidal inhibitors are steroidal drugs (Aminoglutethimide or testolactone) 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. They had been used in metastatic breast cancer, but are now replaced by competitive blockers.

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.

FORMESTANE Was the 1st selective AI. Also has weak androgenic properties. Found to be superior to aminoglutethimide. Given as IM injection.

ANASTROZOLE This drug has rapid oral absorption with peak plasma levels within 2

hrs. Was found to be superior to tamoxifen in reducing recurrences at 5

yrs (ATAC). A higher fraction of women with ER positive tumours show benefit with anastrozole.

Is FDA approved for 1st or 2nd line therapy for post-menopausal women with hormone sensitive tumours.

Side effects includes arthralgias, increased risk of fractures, risk of ischaemic events; but decreased risk of vaginal bleeding/ hot flashes/ mood changes/ DVTs compared to tamoxifen.

Recommended dose is 1 mg/day for 3-5 years.

LETROZOLE Another selective AI which has been approved as 1st or 2nd line

therapy in post-menopausal women with hormone receptor positive disease.

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.

EXEMUSTANE Is a steroidal androgen derivative and a selective AI. It suppresses estradiol and estrone levels similar to those of

anastrozole and letrozole. Is presently FDA approved for 2nd line therapy of hormone sensitive metastatic breast cancer.

If given ih high doses (upto 200mg/day), may cause androgenic side effects like alopecia, hoarseness.

FADROZOLE Is a competitive inhibitor more selective than aminoglutethimide but

less than letrozole. No significant difference in response compared to megestrol acetate, but lesser incidence of weight gain and thrombo-embolic events.

LHRH AGONISTS

Used increasingly for ovarian ablation. Also called GnRH agonists. They reduce the release of estrogen by providing a constant high

level of pituitary-releasing hormones leading to stopping of gonadotropin release.

Chronic use results in estrogen levels similar to post oophorectomy patients.

Gosserelin approved for use in pre-menopausal women. Administration initially results in “Flare” symptoms due to initial rise

in gonadotropin levels.

EVIDENCES ON ADJUVANT HORMONE THERAPY IN BREAST

CANCER

IN PRE-MENOPAUSAL WOMEN

Data from EBCTCG (2005) indicate that patients whose tumours are potentially responsive to endocrine therapy achieve a reduction in risk of relapse and death from breast cancer from treatment strategies that reduce the levels, or block the action, of circulating oestrogens.

In premenopausal women with oestrogen receptor alpha (ER) positive tumours, ovarian ablation or suppression is associated with a reduction in risk of relapse and death from breast cancer.

Whether younger women, not rendered menopausal as a consequence of adjuvant chemotherapy gain additional benefit from ovarian suppression remains a subject of continuing research.

Menopausal symptoms following ovarian ablation/suppression are worse than after chemotherapy.

In 2000, the National Institutes of Health (NIH) recommended that adjuvant chemotherapy should be offered to the majority of premenopausal women with early breast cancer, and that tamoxifen should be given to ER-positive patients for 5 years. The panel did not recommend the use of ovarian suppression in patients who were receiving both chemotherapy and tamoxifen for 5 years, but its use could be considered instead of tamoxifen in selected patients.

In contrast, the St. Gallen panel in 2003 highlighted the primacy of endocrine therapy in the management of premenopausal women and recommended the combination of tamoxifen for 5 years as an acceptable alternative to chemotherapy in ERpositive women

Ovarian ablation or suppression versus none: in premenopausal women with breast cancer that is ER-positive or with unknown ER status, ovarian ablation or suppression is beneficial compared to no ovarian treatment in terms of recurrence (respective rates 47% and 52%, p<0.0001) and breast cancer mortality (respective rates 40% and 44%, p<0.004), both assessed at 15 years follow-up (Early Breast Cancer Trialists' Collaborative Group, 2005).

Ovarian ablation and the role of chemotherapy: the most recent evidence from a meta-analysis of individual patient data suggests that ovarian ablation has benefit in terms of recurrence and survival over no ablation in premenopausal women, with or without chemotherapy (EBCTCG, 2005).

LHRHa versus no systemic therapy: Premenopausal women with operable breast cancer showed a 5 and 10 year disease-free survival and overall survival rates were significantly improved following adjuvant oophorectomy and tamoxifen (Love et al., 2008).

The ZEBRA trial showed that 2 years of Gosserelin treatment was equivalent to 6 cycles CMF chemotherapy for ER positive tumours at 6 years follow up.

ABCSG 05 trial showed that gosserelin plus tamoxifen was superior to CMF chemotherapy in increasing relapse free period.

Role of aromatase inhibitors is not indicated till complete ovarian ablation is achieved with use of LHRH agonists. In this subset of patients, AIs do not show benefit over tamoxifen.

Low levels of either ER or PR correlated with a shorter time to recurrence but hormone status did not predict the superiority of anastrazole over tamoxifen that had been found in a large multi-centre RCT (Dowsett et al., 2008).

Positive hormone receptor status (either estrogen or progesterone) was associated with significantly longer relapse-free survival compared with negative receptor expression whilst those with ER-ve status had a poorer relapse-free survival (Dowsett et al., 2006).

SIDE-EFFECTS Ovarian ablation, ovarian suppression and chemotherapy each

have adverse side effects and each can induce menopausal symptoms, including amenorrhoea (Brunt et al., 2004a; Groenvold et al., 2006; Schmid et al., 2007; Love et al., 1999; Sharma et al., 2007 and Celio et al., 2002).

A Cochrane Review cited trials which found that side effects are more severe following LHRHa plus tamoxifen compared to tamoxifen alone (Sharma et al., 2007).

Health-related quality of life tends to favour ovarian ablation or suppression over chemotherapy, wherein acute adverse effects appear to be worse following chemotherapy. In contrast, menopausal symptoms (for example hot flushes) appear to be worse following ablation or suppression, than after chemotherapy, and with earlier onset.

Amenorhoea can be longer lasting following chemotherapy compared with LHRHa (Brunt et al., 2004a; Groenvold et al., 2006; Sharma et al. 2007 and Schmid et al. 2007).

POST-MENOPAUSAL PATIENTS

The aromatase inhibitors (anastrozole, exemestane and letrozole), are alternative options to tamoxifen for ER-positive invasive breast cancer in postmenopausal women. (ATAC, BIG-98, ITA, ARNO-95 trials)

The risk of disease recurrence is significantly reduced with anastrozole and is reported to be independent of nodal status, tumour size or prior chemotherapy. All ER-positive patients showed a benefit but there was no statistical difference between the progesterone receptor (PR)-positive or PR-negative subgroup ( Buzdar et al., 2006; Dowsett et al., 2005; and Kaufmann et al., 2007b).

When patients who were disease-free at the end of receiving 5 years of adjuvant tamoxifen were randomly assigned to receive either 3 years of anastrozole or no further treatment; the disease-free survival was statistically improved with significantly fewer recurrences.

The risk of contralateral breast cancer is significantly reduced only if anastrozole is given as first line adjuvant treatment; it is not significantly different if given after tamoxifen.

In the BIG-98 trial letrozole when compared to tamoxifen showed improved DFS than with tamoxifen alone.

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.

Hence the recommendations were to shift to aromatase inhibitors after 2-3 years of tamoxifen.

EXTENDED ADJUVANT HORMONAL THERAPY

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

Letrozole significantly improved DFS in all patients, irrespective of nodal status.

Letrozole significantly improved OS in patients with node-positive tumors (hazard ratio = 0.61; 95% CI 0.38, 0.98; P = 0.04)

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.

On the basis of this trial, letrozole was approved as extended adjuvant therapy, and it is currently the only AI approved for this indication

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.

NEOADJUVANT HORMONE THERAPY Two trials (IMPACT and PROACT) evaluated Anastrozole and

tamoxifen in post-menopausal women with locally advanced inoperable tumours. A comparative analysis (Smith et al 2004) showed better response with anastrozole but no statistically significant difference.

P024 trial (Eiermann 2001) evaluated Letrozole and found that Letrozole made breast conserving surgery more possible than tamoxifen.

Exemustane also been evaluated and results are promising.

Optimal neoadjuvant hormone therapy recommendations are awaited.

RECOMMENDATIONS

• Hormone therapy results in disease palliation in 50-60% of hormone sensitive tumors.

• Alone or with chemotherapy, it significantly reduces disease recurrence.

• Tamoxifen is standard adjuvant endocrine therapy in pre-menopausal women.

• Aromatase inhibitors now recommended in adjuvant treatment of post-menopausal hormone sensitive breast cancers.

Do not offer adjuvant ovarian ablation/suppression to premenopausal women with ER-positive early invasive breast cancer who are being treated with tamoxifen and, if indicated, chemotherapy.

Offer adjuvant ovarian ablation/suppression in addition to tamoxifen to premenopausal women with ER-positive early invasive breast cancer who have been offered chemotherapy but have chosen not to have it.

Postmenopausal women with ER-positive early invasive breast cancer who are not considered to be at low risk should be offered an aromatase inhibitor, either anastrozole or letrozole, as their initial adjuvant therapy. Offer tamoxifen if an aromatase inhibitor is not tolerated or contraindicated.

Offer an aromatase inhibitor, either exemestane or anastrozole instead of tamoxifen to postmenopausal women with ER-positive early invasive breast cancer who are not low-risk and who have been treated with tamoxifen for 2–3 years.

Offer additional treatment with the aromatase inhibitor letrozole for 2–3 years to postmenopausal women with lymph node-positive ER-positive early invasive breast cancer who have been treated with tamoxifen for 5 years.

Following drugs were recommended:

a) Anastrozole for primary adjuvant therapy

b) Exemestane for adjuvant therapy following 2–3 years of adjuvant tamoxifen therapy

c) Letrozole for primary adjuvant therapy and extended adjuvant therapy following standard tamoxifen therapy.