1

When all you have is a hammer…

Endocrine therapy Chemotherapy Targeted therapies Radiotherapy

Hormonal treatment of Breast Cancer

Time Line

1870

1st description of surgical oophorectomy

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-

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.

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

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 Toremifene

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.

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

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

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 + AI 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.

23

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.

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 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 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.

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

Tamoxifen 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

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.

Endocrine therapy in the neoadjuvant setup

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%)

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

??

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

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

41

Taxanes — Taxanes are among the most active agents for metastatic breast cancer – Docetaxel, Paclitaxel, NabPaclitaxel.

Anthracyclines – Doxorubicin, Epirubicin, Caelyx.

Capecitabine / 5 FU

Eribulin

Vinorelbine

Gemcitabine

Ixabepilone

Etoposide

Cyclophosphamide

Methotrexate

Platinum agents

Combination Chemotherapy

High Dose Chemotherapy and Stem Cell Transplant – no benefit.

Common Adjuvant Regimens

First Generation → Second

Generation → Third Generation

CMF*6 → CAF*6, CEF*6

CMF*6 → FAC*6 → TAC*6

CE(50)F*6 → CE(100)F*6 → FEC*3→D*3

AC*4 →AC*4→Txl*4

q3wk →Dose Dense (CA*4→Txl*4

q2wk)

AC*4 → TC*4

20% 20%

RANDOMIZE

Doxorubicin 60 mg/m2 IV Day 1

Cyclophosphamide 600 mg/m2 IV Day 1

Every 21 days x 4 cycles

Docetaxel 75 mg/m2 IV Day 1

Cyclophosphamide 600 mg/m2 IV Day 1

Every 21 days x 4 cycles

45

2nd Generation Adjuvant Chemo Trials

First Generation → Second

Generation → Third Generation

CMF*6 → CAF*6, CEF*6

CMF*6 → FAC*6 → TAC*6

CE(50)F*6 → CE(100)F*6 → FEC*3→D*3

AC*4 →AC*4→Txl*4

q3wk →Dose Dense (CA*4→Txl*4

q2wk)

AC*4 → TC*4

46

49

What’s the Goal?

• Select patients who will require systemic therapy

• Find predictive factors (either before or early in treatment) that allow for accurate tailoring of therapy

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

File:1911 Solvay conference.jpg

DCIS

Heterogeneous group of proliferative lesions & have diverse malignant potential

DCIS accounts for approx 21% of all new breast cancers diagnosed in the US.

Over 90 % of which are detected only on imaging studies.

ADJUVANT RADIOTHERAPY FOR INVASIVE BREAST CANCER

50 Gy / 25 # , 42.4 Gy / 16 # , 40.05 Gy / 15 #-Breast Conserving Surgery

-Post Mastectomy

( Absolute ) T3 / T4 / >=4 positive nodes / close or positive margins.

( Relative ) >2 cm tumor , LVI, Grade 3, Age < 50, 1 – 3 positive nodes, ENS, receptor negative tumors, lobular histology.

Boost – Age < 50 , close or positive margins.

16 Gy/8# , 10 Gy/5# , 9 Gy/3#

Early side effects Skin changesTirednessNausea.

Potential long-term side effects Cosmetic – telangectasia , pigmentation , scarring , painRestricted shoulder movementCardiac complications Pneumonitis , fibrosisEffect on the bonesLymphedemaBrachial plexopathyRadiation induced second malignancies.

MALE BREAST CANCER

Breast cancer is much less common in men than in women.

Men tend to present at an older age than women.

Invasive ductal breast cancers predominate in men (≥90 percent)

Breast cancers that arise in men are more often hormone receptor positive than female breast cancers, but they less often overexpress HER2.

Mammography is abnormal in 80 to 90 percent of cases, and can usually differentiate breast cancer from gynecomastia.

Biopsy is required to confirm the diagnosis and assay for hormone receptors and HER2 expression, both of which may influence the selection of treatment.

Any man with a diagnosis of breast cancer should be referred for genetic counseling and BRCA testing.

Treatment on lines very similar to female breast cancer

TREATMENT PATTERNS OF OLDER WOMEN — 

Often receive less than standard therapy worldwide.

In the largest study, which involved over 120,000 women, increasing age was associated with the following treatment trends

●Decreased surgical rates. ●Less frequent use of adjuvant radiation therapy (RT) following breast conservation surgery ●Increased use of primary endocrine therapy – Primary endocrine therapy (without surgical treatment) was administered in a higher proportion of women as age increased.

In addition, older women have generally not participated in clinical trials evaluating the treatment of breast cancer.

As a result, there is a lack of evidence-based guidelines to inform the treatment of breast cancer in this population.

Breast cancer is a major health concern in the geriatric population.

Patients with breast cancer over age 65 to 70 years should be screened for geriatric syndromes using a brief tool.

The treatment approach to medically fit older women with newly diagnosed non-metastatic breast cancer is similar to that of younger women.

For medically frail women with breast cancer who are not candidates for surgery (including those who decline surgery)-For patients with hormone receptor-positive breast cancer, we offer primary endocrine therapy rather than chemotherapy.)-For patients with hormone receptor-negative disease, we suggest single agent chemotherapy rather than combination chemotherapy -For patients with HER2-positive disease (regardless of hormone receptor-status), we suggest single agent HER2-directed therapy -An alternative option would be to add a HER2-directed agent to systemic therapy, provided patients are aware of the additional risks associated with combined treatment. -Supportive care and referral for palliative care services.

Gestational breast cancer - is commonly defined as breast cancer that is diagnosed during pregnancy, in the first postpartum year, or any time during lactation. ●In general, pregnant women with breast cancer should be treated according to guidelines for non-pregnant patients, with some modifications to protect the fetus.

●Either breast conserving surgery or mastectomy is a reasonable option in the pregnant woman with breast cancer. A choice between them is guided by tumor characteristics and patient preferences.

●Women with breast cancer during pregnancy should undergo an axillary node dissection. The safety of sentinel lymph node biopsy has not been established.

●For women who require adjuvant radiation therapy (RT), we recommend adjuvant RT be administered after delivery rather than during pregnancy

●For women in whom chemotherapy is recommended, we initiate treatment after the first trimester.

●We recommend against use of Herceptin during pregnancy due to fetal risks , and fetal death

Thank You