Hormonal treatment of Breast Cancer

Moderator: Dr. S C Sharma HOD, 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
1990’s 1940’s Full range of ablative hormonal therapy developed 1970’s Development of Tamoxifen Demonstration of the therapeutic efficacy of Tamoxifen

1870 1st description of surgical oophorectomy

1950’s Era of Additive hormonal therapy

1980’s ER/PR detection and resurgence in interest in endocrine Rx

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 corepressors 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:
  

0%

20%

40%

60%

80%

100%

ER+ /PR+

78%

Receptor positivity also correlates with:
 

Cellular turnover rates, Nuclear grade, and Degree of histologic differentiation Disease-free interval Decreasing tumor size

ER-/PR+

45%

ER+ /PR-

34%

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

ER-/PR-

10%

Endocrine therapies

Selective Estrogen Receptor Modulators:
 

Aromatase inhibitors:
Letrozole  Anastrazole  Exemestane

Tamoxifen Torimefene Fluoxymesterone Megestrol acetate Medroxyprogesterone acetate

Steroidal Antiestrogens:

Androgens

Fulvestrant

LHRH agonists
Leuprolide  Goserelin

Progestins
 

Gland ablation
Ovary  Pituitary  Adrenals

High dose Estrogens

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:
  

Selective modulation explained by:
  

Tamoxifen Raloxifen Tormifen

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:
 

Other actions:
 

Initiation of apoptosis in malignant cells Reduction of serum IGF-1 and increase in IGF-1 binding proteins are another potential mechanism of action.

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

Increased sex hormone binding globulin ( ? Reduced estrogen bioavailability) Increased TGF β ( ? Increased pulm fibrosis / breast fibrosis if used concurrently with RT)

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 crossresistance with tamoxifen and should not be used in tamoxifenresistant 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:
 

3 generations exist:
  

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

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:
  

Anastrazole

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

Letrozole

Special Properties

Anastrazole:

Less than 10% of the drug is cleared as unchanged drug because of its extensive metabolism. 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 Weakly androgenic metabolite (17-hydroexemestane) that may ameliorate bone loss associated with estrogen deprivation

Letrozole:
  

Exemestane:

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 250mg 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. 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.

Field borders:
  

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 No Rx

Receptor + ve

Receptor + ve

Receptor - ve Chemotherapy

Tamoxifen only

Premenopausal

Postmenopausal 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 NATO Christie Dose 20 20 30 20 20 Duration 2 1 2 2 5 DFS P < 0.05 P < 0.05 P < 0.05 P < 0.01 P < 0.05 OS P < 0.05 NS NS NS P < 0.05

Stockholm CRC Scottish

Overall benefits of tamoxifen Rx

While the patients are on tamoxifen:
 

Reduction in Annual Odds ± SE Years Recurrence 0–1 2–4 5–9 53 ± 5 42 ± 5 31 ± 6 Death 22 ± 10  29 ± 6 29 ± 5

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
Tamoxifen ~ 1 yr Tamoxifen ~ 2 yr Tamoxifen ~ 5 yr

Reduction in deaths 11% ± 3 14% ± 2 23% ± 4

18% ± 3 24% ± 2 43% ± 3

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 Poor (<10 fmol/mg) Positive (≥10, <100 fmol/mg) Positive (≥100 fmol/mg) Unknown Recurrence <4 (7%) 36 (4%) 49 (5%) 31 (7%) Cancer Death <4 (8%) 27 (5%) 45 (6%) 20 (9%) Any Death <3 (7%) 22 (5%) 33 (5%) 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:

 

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.

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

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

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.
 

Reduction of odds of recurrence Age <50 50+ 0-4 yrs 42% 49% 5-9 yrs 22% 33%

Absolute reduction at 10 yrs 10.7% 14.6%

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:
 

Reduction of odds of deaths Age <50 50+ 0-4 yrs 31% 32% 5-9 yrs 28% 36%

Absolute reduction at 10 yrs 6.8% 8.2%

Long term survival Recurrence rates

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
   

Problems with adjuvant tamoxifen in elderly population:
  

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

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 0 – 4 yrs 5 + yrs 0 – 4 yrs 5 + yrs  48% 35% 41% 20% Cancer Deaths Any Deaths 33% 30% 40% 38% 25% 21% 29% 36% Node negative

Node Positive

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 nodenegative 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 pglycoprotein, 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 CCT+tamoxifen CCT alone 35 (± 7) 38 (± 4) Cancer Mortality 34 (± 9) 29 (± 5) Any Death 31 (± 9) 27 (± 4)

Chemoendocrine Rx - Postmenopausal
 

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

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

Postmenopausal node positive disease patients who receive an anthracycline based CCT Women in the age group of 50 - 60 yrs benefit greatest.

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 10 ± 3 13 ± 4 Any Death 10 ± 3 11 ± 4

CCT+tamoxifen CCT alone

16 ± 3 22 ± 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 5 0 0 2 2 2-3 N 5157 6186 8010 3224 426 4742 FU (mo) 30 68 26 28 24 31  DFS 2.4% 2.4% 1.9% 2.4% 7.1% 3.5%
* Placebo controlled

 OS NA 0.3% 0.7% NA NA 0.6%

MA 17 (Let)* ATAC (Ana) BIG 01-98 (Let) ABCSG/ARNO (Ana) ITA (Ana) IES (Exe)

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 <40 40–49 <40 40–49 <40 40–49 <40 40–49 Recurrence % 30 ± 17 33 ± 8 33 ± 12 16 ± 9 42 ± 10 25 ± 6 7 ± 10 7±7 Cancer death % 29 ± 16 32 ± 9 45 ± 17 15 ± 13 32 ± 12 26 ± 7 <1 ± 11 <2 ± 8 Any death % 22 ± 16 30 ± 8 35 ± 17 13 ± 13 28 ± 12 25 ± 7 <1 ± 11 <3 ± 8 Ovarian ablation vs nil

LHRH agonist vs nil

Ablation or LHRH agonist vs nil

Ovarian ablation + CCT vs CCT alone

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 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.

ZEBRA trial:

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 ABCSG Jakesz ZIPP Rutqvist Design CMF x 6 G x 3 years + Tam x 5 years G x 2 yrs Tam x 2 yrs G + Tam x 2yrs INT - 0101 FAC Davidson FAC + G x 5 yrs FAC + G + Tam x 5 yrs FAC + G = FAC alone (HR = 0.93 , p = 0.25) FAC + G + Tam > FAC + G (HR = 0.73 , p = 0.01) Comments CMF < G +Tam for DFS [HR = 1.40; P = .017] G > no G ( HR 0.9; p= 0.001)

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. Significant reduction in incidence of fractures of weight bearing bones. Estrogen agonist action on BMD

Skeletal:
 

Prevention of contralateral breast cancer

Toxicity

Menopausal symptoms:
  

Depression:
 

50% - 60% ( N.B. 40% 50% in placebo) MC in premenopausal Vaginal dryness and discharge may occur in excess. Maybe seen in as high as 10% of patients. But no randomized comparisons available. Keratopathy, maculopathy & cataract Reported with high doses However NSABP studies have found no increase in vision threatening ocular toxicity.

Thromboembolism:

Carcinogenesis:

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 Increased risk of endometrial cancers (hazard rate of 1.7 per 1000 – NSABP B 14 data) Mostly low grade & stage I tumors. Hepatomas Clear cell sarcomas of ovary

Ocular toxicity:
  

Other tumors:
 

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:
   

Relative:
     

Retinal macular edema or degeneration History of benign or malignant liver tumor secondary to oral contraceptives Pregnancy Other hormonal therapy (estrogens, oral contraceptives) 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
Vaginal Complications Endometrial Cancer Thromboembolic events Cardiac complications Arthalgia /Myalgia Osteoporotic fractures Hot flushes

ATAC - 14% - 0.6% - 1.7% 0% 7% 2.2% 5%

BIG - 3.3% - 0.4% - 1.2% 0.4% NA 1.7& 4%

IES - 1.5% NA - .9% NA 6% 2% 2% AI poorer Tmx poorer

- 1.7% NA NA 0.5% 23% 2.3% 6%

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:
  

Vaginal Bleeding:
 

Usually self limiting and respond well to placebos. HRT/ SSRIs are not recommended Best managed by life style changes. Routine work up indicated. Watch out for an endometrial CA in post menopausal females. More common with AI Switching to Tmx may be required. Calcium supplements, Vitamin D and bisphosphonates HRT / Raloxifen not recommended (Raloxifen with AI – may limit efficacy)

Myalgia / Arthalgia:
 

Osteoporosis:
 

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 hormonesensitive patients receiving preoperative therapy (<5%)

Studies

Eirmann et al conducted a RCT comparing 4 months of Tmx vs Letrozole:

PROACT trial:

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 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:
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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 Local recurrence Opposite breast Opposite axilla Bone (osteolytic) Bone (osteoblastic) Lung Liver Brain Soft tissue Neck nodes % OR 12% 10% 10% 40% 30% 15% 11% 2% 15% 13% Fulvestrant / Progestins ?? High dose Estrogen Tamoxifen Resistance AIs Postmenopausal Premenopausal Ovarian Ablation

Overall effect of endocrine Rx

Bone Mets:
   

Skin / soft tissue mets:
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Significant and quick relief of pain Increased bone calcification and sclerosis Reduced hypercalcemia and calcium loss. Better benefit in osteolytic (osteoclastic) leisons. Nodular leisons respond better than lymphangitic leisons. Edema is rarely reduced. Regression and vision recovery may be seen in 10 - 20% Significant number of patients have reduction in size of leisons and effusions. Increased feeling of well being Reduced incapacitation due to pain Hepatic Cerebral

 

Choroidal metastasis:
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Pleuropulmonary leisons: Systemic effects:
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Metastatic leisons that don’t respond:
 

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
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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 Anastrazole vs Megestrol acetate Letrozole vs Megestrol acetate Letrozole vs Megestrol acetate Drug Ana (10 mg) Ana (1 mg) Meg (40 mg) Let (2.5 mg) Let (0.5 mg) Meg (40 mg) Let (2.5 mg) Let (0.5 mg) Meg (40 mg) 602 551 N 764 RR 8.9 10.3 7.9 24 13 16 16 21 15 TTP (mo) < 21 26.7 * 22.5 5.6* 5.1 5.5 3 6* 3 25.3* 21.5 21.5 29 33* 26 OS (mo) 25.5

AI : 1st line therapy
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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 Ana Tmx Ana Tmx Let Tmx 668 907 N 353 RR 21% 17.7% 32.9% 32.6% 30% 20% TTP (mo) 11.1* 5.6 8.2 8.3 9.4 6.0 Comment
Retrospective analysis revealed longer TTP with Anastrazole after combining these two trials3,4

Nabholtz et al1 TARGET trail2 Mouridsen et al5

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:
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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
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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.
Stable Time to Disease ≥ 24 Progression wk (%) (mo) 18.6 24.8 45 44.6 3.4 5.4 5.1 5.4

Trial Osborne et al Howell et al An Ful Ana Ful

N 400 451

Response Rates (%) 17.5 17.5 15.7 20.7

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

TMX alone LHRH + Tmx LHRH alone

Klijn, J. G. M. et al. J Natl Cancer Inst 2000;92:903-911

High Dose Estrogens

Considered only in postmenopausal women as ineffective before the menopause

Activation of the FAS cell death receptor  therapeutic response
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 

Reasonable alternative to chemotherapy in setting of failure to initial hormonal therapy (old age / poor GC) Doses: Contraindication:

Reduction in serum IGF -1 and 2 levels.

Estrogen deprivation  upregulation of FAS receptor Estrogen  FAS ligand expression

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

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

DVT  Cardiac problems

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. 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.

Hypophysectomy:
  

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
ECOG (1993)

Tamoxifen
1 (90) 18 (711) 8 (661) 13 (1318)

Placebo
3(91) 32 (696) 14 (651 ) 29 (1326)

Comment
Post meno Post meno Pre / post meno Pre / post meno

Stockholm (1989) Scottish (1987) NSABP (1989)

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:
  

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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.

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

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

Use in DCIS:
  

Male Breast Cancer:
 

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.

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