Transcript Chemo and endocrine

When all you have is a hammer…




Endocrine therapy
Chemotherapy
Targeted therapies
Radiotherapy
1
Hormonal treatment
of Breast Cancer
Time Line
1990’s
Demonstration
of the
therapeutic
efficacy of
Tamoxifen
1970’s
Development of
Tamoxifen
1870
1980’s
1st description of
surgical
oophorectomy
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:




20%
40%
60%
Disease-free interval
Decreasing tumor size
Prolongation of DFS is
independent of menopausal
status, tumor size, and nodal
status.
45%
ER-/PR+
34%
ER+/PR-
ER-/PR-
80%
100%
78%
ER+/PR+
Receptor positivity also
correlates with:



Cellular turnover rates,
Nuclear grade, and
Degree of histologic
differentiation
0%
10%
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:




Letrozole
 Anastrazole
 Exemestane

Fluoxymesterone
Progestins
Megestrol acetate
 Medroxyprogesterone
acetate
High dose Estrogens
Steroidal Antiestrogens:


Fulvestrant
LHRH agonists
Leuprolide
 Goserelin


Aromatase inhibitors:

Tamoxifen
Torimefene
Androgens




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
Anastrazole
Letrozole
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
Receptor + ve
Receptor - ve
Receptor + ve
No Rx
Node +ve
Receptor - ve
Chemotherapy
Tamoxifen only
Premenopausal
CCT + Tamoxifen#
Postmenopausal
CCT + AI
* 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

 1 of every 2
Reduction in Annual Odds ± SE
Years Recurrence
0–1
53 ± 5
recurrences and
 1 of every 3 deaths are
avoided by the
tamoxifen therapy.
Death
22 ± 10
2–4
42 ± 5
29 ± 6
5–9
31 ± 6
29 ± 5
While the patients are
on tamoxifen:


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 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.
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.
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%
Trial
* 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.

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.


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:

Ocular toxicity:

Thromboembolism:

Depression:



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
- 1.7%
- 14%
- 3.3%
- 1.5%
Endometrial Cancer
NA
- 0.6%
- 0.4%
NA
Thromboembolic events
NA
- 1.7%
- 1.2%
- .9%
Cardiac complications
0.5%
0%
0.4%
NA
Arthalgia /Myalgia
23%
7%
NA
6%
Osteoporotic fractures
2.3%
2.2%
1.7&
2%
6%
5%
4%
2%
Vaginal Complications
Hot flushes
Tmx
poorer
AI
poorer
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 hormonesensitive 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
Premenopausal
% 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%
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
Nabholtz et
al1
Ana
TARGET trail2
Ana
N
353
Tmx
668
Tmx
Mouridsen et
al5
Let
Tmx
907
RR
TTP (mo)
Comment
21%
11.1*
17.7%
5.6
32.9%
8.2
32.6%
8.3
Retrospective
analysis revealed
longer TTP with
Anastrazole after
combining these
two trials3,4
30%
9.4
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
20%
→
Second
Generation
CMF*6
→
CAF*6, CEF*6
CMF*6
→
CE(50)F*6
20%
→
Third
Generation
FAC*6
→
TAC*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
Doxorubicin
R
A
N
D
O
M
I
Z
E
Cyclophosphamide
60 mg/m2 IV Day 1
600 mg/m2 IV Day 1
Every 21 days x 4 cycles
Docetaxel
Cyclophosphamide
Every 21 days x 4 cycles
75 mg/m2 IV Day 1
600 mg/m2 IV Day 1
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
45
46
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
49
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 changes
Tiredness
Nausea.
Potential long-term side effects
Cosmetic – telangectasia , pigmentation , scarring , pain
Restricted shoulder movement
Cardiac complications
Pneumonitis , fibrosis
Effect on the bones
Lymphedema
Brachial plexopathy
Radiation 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 receptorstatus), 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