1 When all you have is a hammer… Endocrine therapy Chemotherapy Targeted therapies Radiotherapy
Dec 19, 2015
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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.
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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
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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
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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
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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
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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