Hormonal treatment of Breast Cancer

Moderator: Dr. S C SharmaHOD, Department of Radiotherapy, PGIMER

Background Henri François Le Dran (1685–1770) gave the hypothesis

that breast cancer spread was in a orderly fashion. The concept was carried to it’s logical conclusion by Halsted.

The Halstedian theory was based upon: Local and regional nodes were the first echelon of

metastatic spread They were effective barriers against further spread.

The concept was challenged by the Fisher brothers (Edward and Bernard), who showed in a series of trials conducted by the NSABP that:

Lymph nodes were not effective as barriers against systemic spread

Hematogenous dissemination was as important as lymphatic dissemination

Systemic therapy is therefore believed to be effective in this disease.

History

Schinzinger was the first person to propose that oophorectomy might be of benefit in breast cancer:

Post menopausal breast atrophy More virulent tumor growth in premenopausal

The first reported series of surgical oophorectomy for breast cancer was reported by Thomas Beatson (1896)

Showed significant tumor regression by castration Better sense of well being Regression of cutaneous metastasis Best above age of 40 No effect on osseous metastatsis

Time Line

1870

1st description of surgical oophorectomy

1940’s

Full range of ablative hormonal therapy developed

1950’s

Era of Additive hormonal therapy

1980’s

ER/PR detection and resurgence in interest in endocrine Rx

1990’s

Demonstration of the therapeutic efficacy of Tamoxifen

1970’s

Development of Tamoxifen

Endocrine pathways in cancer

Estrogen and Progesterone receptors

Several authors demonstrated the relationship of the cytosolic form ER to the efficacy of endocrine therapy.

The nuclear translocation and subsequent transcription are dependent on several co-repressors and activators.

The SRC co activator action is particularly important in this regard.

Recently ER-β has been identified.

Rationale for receptor based Rx Response rates to endocrine

manipulation in ER +ve patients was as high as 53% ( only 6% in ER –ve) – Whitliff et al.

Receptors correlate with other prognostic markers:

Cellular turnover rates, Nuclear grade, and Degree of histologic

differentiation Receptor positivity also

correlates with: Disease-free interval Decreasing tumor size

Prolongation of DFS is independent of menopausal status, tumor size, and nodal status.

78%

45%

34%

10%

0% 20% 40% 60% 80% 100%

ER+/PR+

ER-/PR+

ER+/PR-

ER-/PR-

Endocrine therapies

Selective Estrogen Receptor Modulators:

Tamoxifen Torimefene

Androgens Fluoxymesterone

Progestins Megestrol acetate Medroxyprogesterone

acetate High dose

Estrogens

Aromatase inhibitors: Letrozole Anastrazole Exemestane

Steroidal Antiestrogens: Fulvestrant

LHRH agonists Leuprolide Goserelin

Gland ablation Ovary Pituitary Adrenals

Mechanism of action

All endocrine therapies target the estrogen receptor at one level or other.

While the PR receptor doesn't act as a target directly it does indicate a functional ER pathway as it is a ER induced gene.

SERM The SERMs are chemically diverse compounds

that lack the steroid structure of estrogens but possess a tertiary structure that allows them to bind to the estrogen receptor.

Examples: Tamoxifen Raloxifen Tormifen

Selective modulation explained by: Differential estrogen-receptor expression in a given

target tissue Differential estrogen-receptor conformation on ligand

binding Differential expression and binding to the estrogen

receptor of coregulator proteins

Tamoxifen Chemically a triphenylethylene. The trans isomer is used as a citrate salt. MOA: Competitive binding to the estrogen

receptor resulting in reduction of transcription of estrogen regulated genes.

Dimethylaminoethoxy side chain and the trans configuration are crucial for the antiestrogenic activity of tamoxifen

The net result is a block in the G1 phase of the cell cycle and a slowing of cell proliferation.

Tamoxifen is thus, a cytostatic drug.

Pharmacokinetics

Long t1/2 : 7 -14 days. OD dose can be used Reduced bioavailability is not a cause for resistance. False negative receptor assays for several months

after stopping Rx in tumor tissue. Metabolism in liver and excretion in feces ►

Renal dysfunction not a contraindication. Metabolized by CYP 450 3A4 enzyme:

Can reduce warfarin metabolism. Careful INR monitoring needed in patients receiving

warfarin with tamoxifen.

Mechanisms of action Binding and inactivation of estrogen receptor in

cancerous cell : Predominant mode of action Other postulated mechanisms:

Initiation of apoptosis in malignant cells Reduction of serum IGF-1 and increase in IGF-1 binding

proteins are another potential mechanism of action. Other actions:

Increased sex hormone binding globulin ( ? Reduced estrogen bioavailability)

Increased TGF β ( ? Increased pulm fibrosis / breast fibrosis if used concurrently with RT)

Selective activation / inactivation of corepessors and coactivators responsible for selective agonist / antagonist activity

Toremifene Structure identical to that of

tamoxifen, except for a chorine atom

Less likely to form DNA adducts or induce liver tumors in animals

Prospective randomized clinical trials demonstrate that response rates, TTPs, OS, and toxicities of toremifene are equivalent to those of tamoxifen

One reported adjuvant trial did not indicate that toremifene is associated with a lower risk of endometrial cancer

Toremifene displays cross-resistance with tamoxifen and should not be used in tamoxifen-resistant disease

Aromatase Inhibitors Include a class of drugs which prevent peripheral

conversion of androgens to estrogen. Also cause selective impairment of gonadal

steroidogenesis. Thus are capable of selective estrogen

deprivation without impairment of adrenal androgen synthesis.

Two types exist: Type I : Enzyme inactivators (Steroidal) Type II : Competitive antagonists ( Non steroidal)

3 generations exist: 1st generation: Aminoglutethemide 2nd generation: Formestane (Type I) , Fadrazole 3rd generation: Exemestane (Type I) , Anastrazole ,

Letrozole, Vorozole

3rd generation AI

These drugs inhibit the Aromatase enzyme selectively by blocking the heme moiety of the enzyme.

Active sites of other steroidogenic enzymes remain free.

3rd generation AIs are 3 times more potent than aminoglutethemide.

Dose: Letrozole (Femara) – 2.5 mg OD Anastrazole (Arimidex) – 1 mg OD Exemestane (Aromasin) – 25 mg OD Letrozole

Anastrazole

Special Properties Anastrazole:

Less than 10% of the drug is cleared as unchanged drug because of its extensive metabolism.

Letrozole: Only 5% is excreted in the urine, letrozole can be

safely used in patients with renal insufficiency. Used with caution when patients have severe liver

impairment. Produces the greatest suppression of estrogen

synthesis Exemestane:

Weakly androgenic metabolite (17-hydroexemestane) that may ameliorate bone loss associated with estrogen deprivation

Fulvestrant Classified as a steroidal antiestrogen. Considerably higher affinity for ER

than tamoxifen Promotes accelerated ER turnover, Suppression of ER protein levels, Inhibition of ER dimerization, Reduced shuttling of the ER from the

cytoplasm to the nucleus Developed for clinical use as a 250-

mg intramuscular monthly depot injection

Developed to counter the estrogenic effects of Tamoxifen on uterus and the bone related effects of AIs.

Ovarian Ablation/ Suppression 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 oophorectomy

First series reported by Foveau de Courmelles in 1922

Radiation oophorectomy: 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.

Technique Position: Supine Field selection: Parallel opposing two field

technique Energy : Co60 or 6 MV LINAC Dose Schedules:

In a younger women 10 – 12 Gy in 5 -6 divided fractions is preferred.

In older women shorter course of radiation can give equivalent ovarian ablation.

Field borders: The volume of interest is the entire true pelvis 10 x 15 cm field is opened. Lower border is placed just below the superior border

of pubic symphysis.

Results

Treves in 1957 showed that following ovarian irradiation 10 yrs survival improved from 33.8% to 42.3%.

Benefit was greater in patients who had node negative disease as compared to patients with node positive disease.

Paterson and Russel (1959) also found that survival improved from 54.9% to 62.6% after addition of ovarian irradiation.

Endocrine therapy in the adjuvant setting

Background The gold standard of treatment in the adjuvant

setup is tamoxifen. Adjuvant Tamoxifen has been used for treating

breast cancer since 1970s Some authors have attributed the 25% reduction

in breast cancer mortality in western countries over the past decade to tamoxifen use.

Issues that need to be answered are:? Optimal duration and dose? Patient selection criteria? Combination with chemotherapy? Risks of tamoxifen therapy? Additional benefits of tamoxifen therapy? Place of the newer agents like AIs

Guidelines 5 yrs of tamoxifen is the standard therapy in all hormone

receptor +ve patients. 5 yrs of tamoxifen therapy is also standard in post

menopausal females. In females with unknown receptor status tamoxifen is

usually added specially if patient is post menopausal. Adjuvant endocrine Rx is of little benefit in ER -ve females. Except selected stage I patients without significant risk

factors all most all can be considered for adjuvant hormone therapy.

Present evidence doesn't support 1st line use of AI in adjuvant setting.

However it can be used after 3 -5 yrs of Tmx therapy after careful consideration of the cost benefit ratio.

Ca Breast for adjuvant therapy

Low risk*, node -ve High risk, node -ve Node +ve

Receptor - ve

Chemotherapy

Receptor - ve

No Rx

Receptor + ve Receptor + ve

Premenopausal PostmenopausalTamoxifen only

CCT + Tamoxifen CCT + Tamoxifen#

* Low risk defined as -ve axillary lymph nodes and tumor size ±1 cm, nuclear grade 1, special histologic type or 1-2 cm tumor with positive steroid receptor and special histologic type.

# Ovarian suppression may be considered in those who remain premenopausal after chemotherapy.

Adjuvant Tamoxifen alone

Several trials have demonstrated that tamoxifen adds significantly to the DFS in the adjuvant setting.

Two major trials have also demonstrated a OS benefit

Trial Dose Duration DFS OS

NATO 20 2 P < 0.05 P < 0.05

Christie 20 1 P < 0.05 NS

Stockholm 30 2 P < 0.05 NS

CRC 20 2 P < 0.01 NS

Scottish 20 5 P < 0.05 P < 0.05

Overall benefits of tamoxifen Rx

Reduction in Annual Odds ± SE

Years Recurrence Death

0–1 53 ± 5 22 ± 10

2–4 42 ± 5 29 ± 6

5–9 31 ± 6 29 ± 5

While the patients are on tamoxifen:

1 of every 2 recurrences and

1 of every 3 deaths are avoided by the tamoxifen therapy.

Tamoxifen continues to demonstrate further reductions in the odds of recurrence and death in years 5 through 9.

This is called the “carryover effect”

Optimal Duration of Tamoxifen Rx

Reduction in recurrences Reduction in deaths

Tamoxifen ~ 1 yr 18% ± 3 11% ± 3

Tamoxifen ~ 2 yr 24% ± 2 14% ± 2

Tamoxifen ~ 5 yr 43% ± 3 23% ± 4

In the EBCTSG meta-analysis 5 yr tamoxifen reduced the risk of recurrence and death twice as much as 2 yr tamoxifen therapy.

In two large European trials from Britain and Sweden, women treated with tamoxifen for 5 years, had fewer recurrences and deaths than those treated for only 2 years.

Longer Tamoxifen Rx 3 trials including one large NSABP trial have compared 5yrs

of Tamoxifen treatment with longer treatment: There is no convincing evidence that treatment lasting longer

than 5 years is beneficial. In two of these trials there was a trend, (statistically

significant in one), toward a detrimental effect with treatment for more than 5 years

Problems evaluating longer tamoxifen therapy: Significant carryover effect of tamoxifen beyond 5 yrs. A 1% increase in risk of endometrial cancer expected is

counterbalanced by 1% decrease in risk of contralateral breast cancer.

Trials evaluating these question now: ATLAS trial (Adjuvant Tamoxifen—Longer Against Shorter) aTTom trial (Adjuvant Tamoxifen Treatment Offer More?)

Dose of tamoxifen

20 mg once daily dose of tamoxifen is the standard dose.

Higher doses are not more effective Also lead to greater incidence of side

effects.

Tamoxifen & ER status ER receptor –ve tumors in tissue cultures are non

responsive to tamoxifen therapy. However problems interpreting the results of

tamoxifen therapy in ER –ve tumors are: Variable assay quality and reference values Variable assay sensitivity Possible paracrine loop action of tamoxifen (Few ER

+ve tumors affecting surrounding ER –ve tumors) Systemic effects of Tamoxifen (e.g. IGF -1

concentrations) The low response rates observed with tamoxifen

in ER -ve metastatic disease (5% to 10%) argue that these ancillary effects of tamoxifen are clinically unimportant

Tamoxifen & ER status

Reduction (SE) in Annual Odds

ER Level Recurrence Cancer Death Any Death

Poor (<10 fmol/mg) <4 (7%) <4 (8%) <3 (7%)

Positive (≥10, <100 fmol/mg) 36 (4%) 27 (5%) 22 (5%)

Positive (≥100 fmol/mg) 49 (5%) 45 (6%) 33 (5%)

Unknown 31 (7%) 20 (9%) 14 (8%)

Results of tamoxifen therapy for 5 years in patients with ER +ve or –ve tumors. Adapted from Tamoxifen for early breast cancer: an overview of the randomised trials Early Breast

Cancer Trialists’ Collaborative Group Lancet 1998; 351: 1451–67

Tamoxifen & ER status Most of the trials and meta-analyses have

demonstrated no benefit of adjuvant tamoxifen in ER poor / -ve tumors.

Three trials however showed some benefit: NATO study:

When 5 fmol/mg was taken as a cut off point beneficial effect of tamoxifen was equal in both ER +ve and –ve tumors.

Scottish trial: Showed that even in ER –ve tumors there was a increase in DFS over control group.

NSABP B-09 trial: some women aged 60 to 70 years received benefit from tamoxifen even if their tumor had an ER content of 0 to 9 fmol per mg protein

However in two recent prospective trials which compared tamoxifen alone in ER-ve, node negative patients no survival benefit could be demonstrated for 5 yrs tamoxifen therapy.

Tamoxifen & PR status

Effect of PR status: It is believed that in ER –ve patients PR +ve patients

may be more responsive to tamoxifen therapy. Results are interpolated from results in metastatic

disease. In a recent retrospective analysis patients who were

both ER and PR +ve, fared better than patients who were ER +ve and PR –ve

53% reduction* in risk of recurrence for patients who were ER & PR +ve.

In patients who were ER +ve only the risk was reduced* by 23% only.

The lesser benefit of Tamoxifen in patients with ER +ve but PR –ve tumors has also been confirmed in the ATAC trial recently.

Tamoxifen & Receptor status

Unresolved questions: Does addition of tamoxifen to ER –ve older

woman improve their outcome ? Impact of PR in patients who are ER –ve

tumors ? Is the reduction in contralateral breast cancer

in patients with ER –ve tumor worthwhile ? Impact of newer immunohistochemical

analytic techniques in the measurement of receptor levels – specially impact of false negative results.

Tamoxifen & Menopausal status

Initially believed to have lesser efficacy in premenopausal women.

Many trials gave tamoxifen for 2 years.

Greater proportion of premenopausal women have ER –ve tumors.

Recent trials have revealed a substantial benefit in terms of:

Long term survival Recurrence rates

Reduction of odds of

recurrence

Absolute reduction at 10 yrs

Age 0-4 yrs 5-9 yrs

<50 42% 22% 10.7%

50+ 49% 33% 14.6%

Reduction of odds of deaths

Absolute reduction at 10 yrsAge 0-4 yrs 5-9 yrs

<50 31% 28% 6.8%

50+ 32% 36% 8.2%

Tamoxifen in Elderly patients All meta-analyses have demonstrated a

stastically significant benefit for addition of Tamoxifen in patients aged > 70 yrs.

ECOG evaluated the role of 2yr tamoxifen therapy vs placebo in 180 women aged > 65yrs

Drug was well tolerated Significant reduction in recurrences Borderline significant reduction in risk of death Tamoxifen also reduced the incidence of contralateral

breast cancers Problems with adjuvant tamoxifen in elderly

population: High risk of death for unrelated cancer (22% in ECOG

trial) Poor adherence to prescribed treatment Risk of thromboembolism increases with age.

Tamoxifen & nodal status The NSABP – B14 protocol

outlined the following benefits of adjuvant tamoxifen in node –ve patients:

Fewer ipsilateral breast, local-regional, and distant recurrences.

Substantial reduction (~ 50%) in contralateral breast cancer.

These benefits persisted beyond 14 years of follow-up

Data from Early Breast Cancer Trialists’ Collaborative Group

Tamoxifen & nodal status

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%

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.

Tamoxifen alone vs XRT + Tmx Fisher et al (NSABP B21)

evaluated whether tamoxifen alone is as good as XRT followed by tamoxifen in node-negative women with invasive breast cancers of < 1 cm.

Overall 49% reduction in the hazard ratio for ipsilateral recurrence was seen when XRT was added w.r.t. tamoxifen alone.

Fyles et al also demonstrated that addition of XRT after lumpectomy significantly reduces the breast and axillary recurrences in women > 60yrs with early T1 / T2 leisons.

NSABP B 21 data ( N = 1009)

Tamoxifen and chemotherapy Advantages of combining

CCT with Tmx include: Elimination of both

chemoresistant and tamoxifen resistant cell populations.

Tamoxifen and progestins inhibit p-glycoprotein, an effect that could enhance sensitivity to drugs such as doxorubicin.

The apoptosis inhibitor Bcl-2 is down-regulated by tamoxifen, possibly enhancing sensitivity to drugs using this cell death pathway.

Disadvantages of combined approach:

Cytostatic nature of tamoxifen may interfere with chemotherapy by locking cells in chemoresistant phases of cell cycle.

It also antagonizes calmodulin and is an effective Ca2+ channel antagonist—effects that could alter drug uptake.

Chemoendocrine Rx - Premenopausal

Tmx has been evaluated against Tmx + CCT in a NSABP trial in ER +ve, node negative tumor

Women < 50 yrs who received concurrent CCT and tamoxifen compared with tamoxifen alone had a 35% reduction in annual odds of recurrence.

Initial trials had failed to show a benefit for addition of tamoxifen to chemotherapy in premenopausal women.

Addition of different CCT may explain the variable results as it is now known Tmx may inhibit the action of some CCT agents e.g. Melphalan (Used in NSABP B09 where premenopausal women had a poorer DFS and OS)

Chemoendocrine Rx - Premenopausal

The 1995 Oxford meta-analysis showed a significant reduction in recurrence rates and deaths.

Similar findings were seen in the 2000 overview also in premenopausal patients with ER +ve tumors.

Reduction in Annual Odds in % (SE)

Recurrence Cancer Mortality Any Death

CCT+tamoxifen 35 (± 7) 34 (± 9) 31 (± 9)

CCT alone 38 (± 4) 29 (± 5) 27 (± 4)

Chemoendocrine Rx - Postmenopausal

Benefits are less certain in this group. Apparently greatest benefit in:

Postmenopausal node positive disease patients who receive an anthracycline based CCT

Women in the age group of 50 - 60 yrs benefit greatest.

3 main trials have evaluated the impact of addition of CCT to tamoxifen in postmenopausal age group:

NSABP B20: Benefit greatest in women below 60 yrs age and DFS prolonged longest in women aged < 50 yr

SWOG 8814: 9% improvement in DFS after 5 yrs of Tmx after anthracycline (FAC) based CCT ( ER +ve , postmenopausal females)

IBCSG Trial IX: Improvement in outcome of postmenopausal females with ER –ve disease only (? Suboptimal CCT regimen – CMF x 3)

Chemoendocrine Rx - Postmenopausal

The findings of meta analysis are less clear as far as post menopausal females are concerned as:

Less number of females in the trials. Patients likely to receive less toxic combinations in less

dose intense fashion. Likely to experience more toxicity. Likely to die of unrelated causes in F/U period.

Reduction in Annual Odds in % (SE)

Recurrence Cancer Mortality Any Death

CCT+tamoxifen 16 ± 3 10 ± 3 10 ± 3

CCT alone 22 ± 4 13 ± 4 11 ± 4

Sequence of Tmx and CCT

Concurrent administration considered by some western observers as harmful due to cytostatic action of tamoxifen

Sequential vs Concurrent administration has been evaluated in a single trial till date.

Intergroup trail 0100: 8 yr DFS was 67% in patients receiving sequential vs 62% in patients receiving concurrent Tmx.

In the 2000 Oxford overview patients who had received sequential Tmx vs concurrent had a 7% reduction in the annual odds of recurrence.

AI in adjuvant setting 7 trials have been reported all of which involve post

menopausal females with HR +ve disease. A theoretical priming benefit initial tamoxifen made many

trials use tamoxifen in initial 2-3 yrs prior to witching over to tamoxifen.

Trial Yrs Tmx N FU (mo) DFS OS

MA 17 (Let)* 5 5157 30 2.4% NA

ATAC (Ana) 0 6186 68 2.4% 0.3%

BIG 01-98 (Let) 0 8010 26 1.9% 0.7%

ABCSG/ARNO (Ana) 2 3224 28 2.4% NA

ITA (Ana) 2 426 24 7.1% NA

IES (Exe) 2-3 4742 31 3.5% 0.6%

* Placebo controlled

AI in adjuvant setting Data about the use of AI as 1st line adjuvant therapy is not

mature enough to support routine use of AI. Results have shown that:

No advantage in use of AI over tamoxifen in first 2-3 yrs No survival benefit over Tmx in first 5 yrs Clinical impact of long term AI toxicity not known Tamoxifen “priming” may be important for control of disease

as well as prevention of bone damage due to Tmx However timing and duration of switch remain to be

established. Use in premenopausal women not recommended

(hypophyseal feedback is presumably strong enough to overcome AI induced ovarian estrogen blockade).

Data for specific subgroups not available. Use of Tmx with AI may impair the efficacy of AI as seen in

the ATAC trial.

Adjuvant Ovarian ablation 60% of premenopausal women are receptor +ve at

diagnosis. Poorer prognosis of premenopausal women < 35 yrs age:

More poorly diff. & higher grade Greater vascular invasion ~ 10% reduction in 10 yr DFS & OS (Aebi et al) Paradoxically poorer survival in ER +ve patients compared to

ER –ve patients who received CCT only. Greater proportional benefits of CCT in the

premenopausal (vis a vis postmenopausal) may be secondary to the endocrine effects of CCT in this population.

Despite drug induced amenorrhea in 30% women CCT induced hormonal effects not sufficient to prolong DFS/OS in hormone sensitive patients.

Results : 2004 EBCTSG review

Reduction (SE) in annual odds

Age group Recurrence % Cancer death % Any death %

Ovarian ablation vs nil

<40 30 ± 17 29 ± 16 22 ± 16

40–49 33 ± 8 32 ± 9 30 ± 8

LHRH agonist vs nil

<40 33 ± 12 45 ± 17 35 ± 17

40–49 16 ± 9 15 ± 13 13 ± 13

Ablation or LHRH agonist vs nil

<40 42 ± 10 32 ± 12 28 ± 12

40–49 25 ± 6 26 ± 7 25 ± 7

Ovarian ablation + CCT vs CCT alone

<40 7 ± 10 <1 ± 11 <1 ± 11

40–49 7 ± 7 <2 ± 8 <3 ± 8

Ovarian ablation vs CCT

Two trials have evaluated ovarian suppression vs ablation:

Scottish trial: Ovarian ablation was equally effective as adjuvant CCT

with CMF In ER +ve women a trend towards better survival was

found with ovarian ablation ZEBRA trial:

Goserelin ( x 2yrs) was as effective as CMF ( x 6 cycles) in ER +ve, stage II & node +ve patients.

In the ER –ve subgroup CMF had better OS and DFS.

Thus at best, ovarian ablation is as good as CMF based CCT ( but not better) in the ER +ve premenopausal females with early stage disease.

Tamoxifen with ovarian ablation

Author Design Comments

ABCSG Jakesz

CMF x 6 CMF < G +Tam for DFS [HR = 1.40; P = .017]G x 3 years + Tam x 5 years

ZIPP Rutqvist

G x 2 yrs G > no G ( HR 0.9; p= 0.001)Tam x 2 yrs

G + Tam x 2yrs

INT - 0101 Davidson

FAC FAC + G = FAC alone (HR = 0.93 , p = 0.25)FAC + G x 5 yrsFAC + G + Tam > FAC + G (HR = 0.73 , p = 0.01)

FAC + G + Tam x 5 yrs

A recent SOFT trial is evaluating the question whether the addition of ovarian ablation to tamoxifen is better than tamoxifen in premenopausal females after CCT who are hormone receptor +ve.

Conclusions Ovarian ablation or suppression by LHRH agonists are

equally good at preventing cancer related deaths. In the premenopausal age group a significant reduction in

the mortality and recurrence seen with either modality compared to no adjuvant therapy.

Ovarian irradiation or surgery are equally effective as ablative modalities.

Addition of tamoxifen provides an additional benefit in terms of DFS.

Caveat: The duration of treatment with LHRH agonists is not well

defined (most trial use 2 -3 yrs treatment). The impact of resumption of ovarian function after stoppage

of these agents on risk of recurrence remains to be seen. The exact benefit of addition of ovarian ablation in receptor

+ve females already receiving tamoxifen after CCT remains to be ascertained.

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 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

Tamoxifen toxicity

The excess incidence of serious adverse events for patients receiving tamoxifen therapy was approximately 5 per 1000 woman years in NSABP P1 trial.

Serious side effects occur in approximately 1 in 200 patients annually

In large randomized trial ~ 5% patients withdrew from therapy due to toxicity.

Relative to the toxicities of chemotherapy, these side effects are tolerable.

Contraindications to Tmx Rx Absolute:

Retinal macular edema or degeneration History of benign or malignant liver tumor secondary

to oral contraceptives Pregnancy Other hormonal therapy (estrogens, oral

contraceptives) Relative:

History of thrombophlebitis, particularly hormone related

History of depression, particularly hormone related Cataract Drugs: Chlorpromazine, chloroquine, thioridazine,

amiodarone, other Severe vasomotor symptoms Polycystic ovaries

Toxicity of AIs vs Tamoxifen

MA -17 ATAC BIG IES

Vaginal Complications - 1.7% - 14% - 3.3% - 1.5% Tmx poorerEndometrial Cancer NA - 0.6% - 0.4% NA

Thromboembolic events NA - 1.7% - 1.2% - .9%

Cardiac complications 0.5% 0% 0.4% NA AI poorerArthalgia /Myalgia 23% 7% NA 6%

Osteoporotic fractures 2.3% 2.2% 1.7& 2%

Hot flushes 6% 5% 4% 2%

Since the absolute benefit of using a AI in adjuvant setting over tamoxifen is ~ 2% reduction in recurrence rates and 1.5% reduction in mortality this excess

toxicity needs to be balanced against the bone damage produced by AIs in this setting.

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 Tmx may be required.

Osteoporosis: Calcium supplements, Vitamin D and bisphosphonates HRT / Raloxifen not recommended (Raloxifen with AI –

may limit efficacy)

Endocrine therapy in the neoadjuvant setup

Background Limited experience Data derived from trials comparing endocrine therapy vs

surgery in older women ( >70 yrs) stage I/ II disease with ER +ve status

A multicenter Italian trial (GRETA) compared surgery followed by tamoxifen with tamoxifen alone in 473 patients

No difference was seen in disease-free or overall survival Local control was inferior in the tamoxifen arm, with a 25%

chance of local recurrence (vs. 6% in Sx arm) Response rates (CR & PR) = 43% to 78% in patients not

selected for hormone receptor status. Now a days in absence of serious comorbidities &/or limited

life expectancy endocrine therapy should not be used solely in the treatment of such patients.

Use of hormone therapy

Best suited for a hormone receptor positive, postmenopausal woman

Presence of +ve HR strongly influences response to preoperative endocrine therapy

Complete and partial response rates of the order of 40 - 70%

Majority of patients will have evidence of tumor shrinkage by 3 months.

Progression of disease is uncommon in hormone-sensitive patients receiving preoperative therapy (<5%)

Studies Eirmann et al conducted a RCT comparing 4 months of

Tmx vs Letrozole: 337 postmenopausal woman with ER/PR +ve, T2 to T4a-c

breast cancer Overall clinical response rates are 36% for tamoxifen and

55% for letrozole (p < .001) Conservative surgery was possible in 45% of patients treated

with letrozole versus 35% with tamoxifen (P=0.022) Both treatments well tolerated

PROACT trial: Preoperative Tmx vs. Anastrazole vs. the combination in ER

+ve, postmenopausal patients with tumors >2 cm No difference in clinical response between the treatment

arms (36%-T, 37%-A, 39%-C) Women who were initially thought to require a mastectomy

were more likely to undergo breast-conserving surgery if they were randomized to the Anastrazole alone arm (46%-A vs. 22%-C, p = .03)

Summary

The strategy of preoperative endocrine therapy will require more studies.

Exciting area for further translational research: The therapeutic target is known and can, therefore, be

measured The biologic pathways arising from the therapeutic

target have been extensively studied Slower response to therapy gives a greater window of

opportunity for assessing changes in tumor tissue. Caution: 2nd generation taxane based CCT

regimes have clinical response rates ranging from 80 -90%.

Endocrine therapy in Metastatic Breast Cancer

Guidelines Endocrine therapy should be started in all hormone

receptor positive females with metastatic breast cancer. Hormone therapy may be suitable as a sole therapy in

patients with severe comorbid conditions or very old age. AI are standard 2nd line agents after tamoxifen therapy. Recently evidence has emerged which highlights the

superiority of AI in the 1st line setting too. In premenopausal females ovarian ablation may be another

alternative. It also allows use of AI in this population. Selection of the appropriate initial management depends

on: Tempo of the disease (Slower progress, fewer symptoms) Vital organ involvement ( Bone & Soft tissue) General condition of the patient (Older age, poorer GC) Socio economic conditions.

Selection of patient & Rx

Site % OR

Local recurrence 12%

Opposite breast 10%

Opposite axilla 10%

Bone (osteolytic) 40%

Bone (osteoblastic) 30%

Lung 15%

Liver 11%

Brain 2%

Soft tissue 15%

Neck nodes 13%

Premenopausal

Ovarian Ablation

Postmenopausal

Tamoxifen AIs

Resistance

Fulvestrant / Progestins

High dose Estrogen

??

Overall effect of endocrine Rx Bone Mets:

Significant and quick relief of pain Increased bone calcification and sclerosis Reduced hypercalcemia and calcium loss. Better benefit in osteolytic (osteoclastic) leisons.

Skin / soft tissue mets: Nodular leisons respond better than lymphangitic leisons. Edema is rarely reduced.

Choroidal metastasis: Regression and vision recovery may be seen in 10 - 20%

Pleuropulmonary leisons: Significant number of patients have reduction in size of leisons and

effusions. Systemic effects:

Increased feeling of well being Reduced incapacitation due to pain

Metastatic leisons that don’t respond: Hepatic Cerebral

Endocrine Rx in Metastatic CA

Tamoxifen remains the gold standard. Been in use since 1970s Began to be used instead of high dose estrogens

which were due to highly favourable side effect profile.

Response rates range from 16% to 56% (Median 30%) – same as ovarian ablative techniques.

Overall mean TTP for patients with metastatic disease treated with tamoxifen is about 6 months

Duration of response is between 12 and 18 months

Tamoxifen resistance

Mechanism: Tamoxifen agonism: AI still produce effects on

breast cancer through estrogen deprivation. ER β phenotype and ER βα hetrodimer

formation ER mutations. HER -2 receptor mediated ER downregualtion

(through MAP kinase pathway)

Tumor Flare

Tumor Flare: Incidence:

4% to 7% with high-dose estrogen 3% to 13% with tamoxifen

Dramatic in bone pain, an in size & number of metastatic skin nodules, and erythema.

Within days to several weeks after starting treatment Hypercalcemia in 5% Tumor regression may occur as the flare reaction

subsides Look for objective evidence of disease progression if

the patient's symptoms have not resolved by 4 to 6 weeks as flare is transient

Withdrawal response Secondary response after discontinuation of

treatment resulting from disease progression 25% to 35% of patients on high-dose estrogen

therapy Seen in patients who experience an initial

response, followed by subsequent recurrence of tumor

Patients may experience disease stability for more than 6 months

Withdrawal therapy trial is therefore appropriate for patients who responded well to prior tamoxifen therapy and whose symptoms are minimal at the time of disease progression

AI : 2nd Line therapy

Initially used instead of high dose steroid in tamoxifen resistant patients.

Showed a small but significant benefit in 5 RCTs in terms of survival and better side effect profile

However overall the response rates were in the 10% to 20% range

Significant clinical benefit from Aromatase inhibitors often occurs in the absence of dramatic disease regression.

Therefore now the standard 2nd line endocrine therapy in tamoxifen resistant metastatic breast cancer.

Results: AIs as 2nd line Rx

Trial Drug N RR TTP (mo) OS (mo)

Anastrazole vs Megestrol acetate

Ana (10 mg) 764 8.9 < 21 25.5

Ana (1 mg) 10.3 26.7 *

Meg (40 mg) 7.9 22.5

Letrozole vs Megestrol acetate

Let (2.5 mg) 551 24 5.6* 25.3*

Let (0.5 mg) 13 5.1 21.5

Meg (40 mg) 16 5.5 21.5

Letrozole vs Megestrol acetate

Let (2.5 mg) 602 16 3 29

Let (0.5 mg) 21 6* 33*

Meg (40 mg) 15 3 26

AI : 1st line therapy 3 major pahse III trials have directly compared tamoxifen

against AI. All have shown an improvement in time to progression

(TTP) The study by the International Letrozole Breast Cancer

Group is the largest in the series.

Trial Drug N RR TTP (mo) Comment

Nabholtz et al1

Ana 353 21% 11.1* Retrospective analysis revealed longer TTP with Anastrazole after combining these

two trials3,4

Tmx 17.7% 5.6

TARGET trail2 Ana 668 32.9% 8.2

Tmx 32.6% 8.3

Mouridsen et al5

Let 907 30% 9.4

Tmx 20% 6.0

AI : 1st line therapy Several trials have shown that the TTP is

significantly improved in metastatic breast cancer when AI are used as 1st line therapy instead of tamoxifen.

The impact on OS not clear however. In the trail comparing Letrozole to Tamoxifen it

was shown that OS improved in the first 2 yrs. However no benefit exists at 5yrs. However due to crossing over a significant impact

on OS may have been lost. Crossing over to Tamoxifen after initial AI therapy

may be theoretically unwise as: Estrogen deprived cancer cells may be become

paradoxically sensitive to tamoxifen.

AI : 1st line therapy

Toxicity: Patients on AI therapy have experienced significantly

lesser thromboembolic phenomenon. However the incidence of hot flashes is increased.

There have been no trials which showed a benefit of one AI over another.

One trial comparing Letrozole vs Anastrozole failed to show a difference in TTP or other parameters.

Because intratumoral Aromatase inhibition is most important so it s unlikely any particular AI will be more beneficial over the other.

Treatment after progression on AI

Progression after 1st line AI therapy is difficult to tackle.

A retrospective analysis has shown that objective response after tamoxifen therapy is of the order of 10% after AI failure.

Another phase II trial has shown that Exemestane may be associated with a response rate of 6.6% after Letrozole / Anastrazole therapy.

No endocrine therapy is thus available that can give promising results after AI failure.

Fulvestrant A potent inhibitor of estrogen-dependent transcription. In preclinical models, Fulvestrant was found to be effective

against tamoxifen-resistant MCF7 cell xenografts. In a trial comparing 1st line tamoxifen vs fulvestrant, no

advantage was obtained in TTP or overall response over tamoxifen.

Given easier use of AI / Tamoxifen place in therapy remains questionable.

Trial NResponse Rates (%)

Stable Disease ≥ 24

wk (%)

Time to Progression

(mo)

Osborne et al

An400

17.5 18.6 3.4

Ful 17.5 24.8 5.4

Howell et al

Ana451

15.7 45 5.1

Ful 20.7 44.6 5.4

Ovarian Ablation In a 2001 meta analysis by Klijn

et al comparing adjuvant Tamoxifen + LHRH agonist vs LHRH agonist alone in advanced breast cancer:

22% reduction in the hazard of death for the combined treatment group

30% reduction in the hazard of progression/death for the combined treatment group.

Median duration of response in patients receiving combined treatment was 602 days, compared with a median of 350 days in those receiving LHRH agonist alone Klijn, J. G. M. et al. J Natl Cancer Inst

2000;92:903-911

LHRH alone

LHRH +

Tmx

TMX alone

High Dose Estrogens Considered only in postmenopausal women as ineffective

before the menopause Activation of the FAS cell death receptor therapeutic

response Estrogen deprivation upregulation of FAS receptor Estrogen FAS ligand expression

Reduction in serum IGF -1 and 2 levels. Reasonable alternative to chemotherapy in setting of failure

to initial hormonal therapy (old age / poor GC) Doses:

DES – 5 mg TDS Ethinyl Estradiaol: 30 mg in 3 – 4 divided doses

Contraindication: DVT Cardiac problems

Can produce objective responses in ~ 30 – 40% patients who have received endocrine therapy.

Progestins

Useful in some selected patients who have developed resistance to SERM and AIs

Megestrol acetate is used (160 mg /d) C/I include:

Thromboembolic events Diabetes

Needs evaluation in phase II trials for usefulness as 3rd line agent.

MOA: ? Aromatase inhibition ? Estrogen turnover increased (Estrogen deprivation) ? Separate action through PRs.

Other ablative procedures

Adrenalectomy: Adrenals are source of estrogen in PM female. In large series ( 1950s – 60s) objective response rates

varied from 28% - 59% (Mean 42%) Duration of benefit varied from 12 – 36 months. Necessity for life long hormone replacement and high

operative mortality obsolescence. Hypophysectomy:

Another ablative procedure associated with response rates ranging from 40% - 50%

Response duration ~ 18 months Better tolerance than adrenalectomy made this

procedure a better choice.

Radiation Hypophysectomy

Modalities: Interstitial Brachytherapy Proton Rx

Need to deliver doses in range of 100 Gy – 200 Gy to bring pituitary ablation.

Investigators in the Berkley university have used proton beam therapy ( 50 Gy x 6 # = 300 Gy)

This dose ablated 90% of the pituitary glands with minimal morbidity.

Growth Hormone Thyroid hormones Gonadotropin Estrogen and Progesterone Corticosteroid.

Interstitial Brachytherapy

Yttrium 90 most commonly used. Pure β emitter with one of the highest energies

( 0.9 MeV) A circumscribed ring of necrosis is produced – 4.0

mm in diameters. Short t1/2 61 hrs. (Using Sr90 can overcome the

problems of handling due to this short t1/2) Easily packed in small spherules. Objective:

Deliver 1000 Gy to pituitary Deliver 50 Gy or less to neighboring nervous tissue.

Technique and results

Circumscribed necrosis

Methods to overcome Tmx resistance

HER 2 targeted therapy (Trastuzumab) Franesyl Transferase inhibitors Rapamycin analogues COX 2 inhibitors.

Endocrine therapy in Preventive & other settings

Rationale: Preventive setting

Prevention : Reduction in cancer mortality via reduction in incidence.

There is a discreet, multistep progression of leisons that lead to cancer over a long period of time.

Premalignant change progresses via this route:Ductal Hyperplasia Atypical ductal hyperplasia

Ductal carcinoma in situ Invasive cancer Chemoprevention based strategies are now being

tried to interrupt this process.

Hypothesis generation Women with early disease benefit more from adjuvant

therapy Benefit in DFS and OS in most trials with adjuvant

tamoxifen Several trials have demonstrated a reduction in the

incidence of contralateral breast cancer in women receiving tamoxifen.

Preclinical studies have demonstrated a preventive effect in animal populations.

Trial Tamoxifen Placebo Comment

ECOG (1993) 1 (90) 3(91) Post meno

Stockholm (1989) 18 (711) 32 (696) Post meno

Scottish (1987) 8 (661) 14 (651 ) Pre / post meno

NSABP (1989) 13 (1318) 29 (1326) Pre / post meno

Results 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.

Ongoing STAR trial evaluating role of Raloxifen in prevention.

Criticisms 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

Application in face of other high risk factors not validated Duration of follow up is too limited (5 yrs) Duration of tamoxifen therapy not known Duration of beneficial effect not known Optimal time at which to start tamoxifen in high risk patients is

not known Questions remain on the long term effect on cancer related

mortality. The benefits have not been reciprocated in two European trials. Finally who all should be screened for high risk factors not known Without proper public health backup chemoprevention not suited

in the Indian setup.

Hereditary Breast Cancer Prevention

Kauff et al showed a statistically significant reduction in 5 yr breast cancer free rates in patients who are BRCA 1 or 2 +ve ( ~ 24% improvement) after prophylactic oophorectomy.

Further reduction in risk of ovarian cancers and diagnosis of some ovarian cancers during surgery itself.

Rebbeck et al found in a series of 241 women, a 53% breast cancer risk reduction.

Most benefit in breast cancer risk reduction was observed in women who had prophylactic oophorectomy by age 50 years.

Other uses of Endocrine Rx

Risk reduction in LCIS: NSABP P1 trial: Risk reduction for invasive breast

cancer was 56% in those receiving tamoxifen. Use in DCIS:

NSABP B24 and UK DCIS trial ( n = 3374) Significant reduction in Local recurrence and incidence

of contralateral breast cancers. Systemic Rx may be a safe, well tolerated option in

these females. Male Breast Cancer:

Prognosis poorer Treatment same as that for females – tamoxifen is DOC

for endocrine therapy.

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 females.

Ovarian ablation may have additive benefits with tamoxifen in premenopausal females.

While AIs are a better option in metastatic breast cancer in postmenopausal females, use in adjuvant setting should be tempered with caution as long term F/U data is lacking.

Thank You