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ER/PR Markers Predict Breast Cancer Endocrine Therapy Response
1.
2. ERs & PRs present frequently in breast
cancer, acting as predictive markers to the
endocrine therapy.
Around 60% of women with ER+ve Breast
cancer benefit from the endocrine
therapy, while only very tiny portion of ER/PR-ve
ptns may respond to endocrine therapy.
Most recent EBCTCG met-analysis of 194
randomized trails on adjuvant Tamxifen for 5
years reported decline in ½ of the recurrence
and 1/3 in the mortality.
New endocrine therapies have become
available like AIs & antiestrogen like Fulvestrant.
3. Estrogen influence gene expression and cellular
phenotypic changes by diffusing into the cell and binding
to ERs into the nucleus.*
The two isoforms (α,β) of ER belong to a super family of
nuclear hormone receptors. *
Recent data that ERα expression is the one correlated
with most prognostic factors in breast cancer and ERβ is
not a surrogate for ERα in breast cancer prognosis, and
the function of ERβ remains to be established. *
The binding activates these receptors by inducing
conformational changes followed by dimerization
promoting target genes to activate or repress
transcription through 2 pathways* (genomic and non-
genomic pathways)
* Osborne CK, Zhao H, Fuqua SA. Selective estrogen receptor modulators: structure, function, and clinical use. J Clin Oncol 2000;18:3172–86
.
4. ( Genomic pathway)After hormone binding and
dimerization, ERs bind to DNA with high affinity
through their DBD (DNA binding domain) at
specific DNA promoter regions known as
estrogen responsive elements (ERE), which
ultimately leads to transcription regulation of
genes involved in proliferation, inhibition of
apoptosis, and promotion of
angiogenesis, invasion, and metastasis *’**
( Non-genomic pathway) Besides this classical
mechanism of direct DNA binding, the ER can
influence cell proliferation and metastasis by
amplifying proliferative signals through non
genomic molecular cross talk involving tyrosine
receptor kinase growth factor receptors and
their downstream effector molecules. **
*Ogawa S, Inoue S, Watanabe T, et al. The complete primary structure of human estrogen receptor beta (hER-beta) and its heterodimerization with ER alpha in
vivo and in vitro. Biochem Biophys Res Commun 1998;243:122–6
**Kumar V, Chambon P. The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer. Cell 1988;55:145–56
5. P. Fedele et al. Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: Where are we now and where
are we going, Critical Reviews in Oncology/Hematology xxx (2012) xxx–xxx
6. Tamoxifen itself is a prodrug, with little affinity to ER.
It’s metabolized in the liver CYP into active
metabolites such as afimoxifen and
endoxidfen, which have 30-100 times more affinity
to ER than Tam.
These active metabolites compete with estrogen in
the body for binding to ER, in breast tissue
afimoxifene act as antagonist, so the transcription
of estrogen-responsive genes is inhibited.
Tamoxifen is known as SERM with antagonistic
effect on the breast cancer and agonist effect on
the endometrium.
Desta Z, et al 2004, compehensive evaluation of tamoxifen sequential biotransofrmation by human CYP 450 system, J Pharmacol Exp Ther 210 (3)
7. ER uses 2 independent functional
domains to bind co-activators proteins
required for transcriptions : activator
function 1&2(AF-1& AF-2).
In breast cancer Tamoxfein binds to ERα
the conformational changes prevent AF-
2 from bindings to coactivator.
In endomtrium AF-2 can bind to
coactivators and then ER bind to ERE in
DNA and start the transcriptions.
Kushner PJ, et al Estrogen receptor pathways to AP-1Steroid Biochem Biol 2000;74:311-317
10. Aromatase inhibitors block the conversion of
androstenedione to estrone and testosterone to
estradiol(Fig ).
Earlier aromatase inhibitors also affected adrenal
corticosteroidal metabolism, resulting in marked
toxicities.
Currently, three selective aromatase inhibitors are
available in the market that offer significant safety
advantages over their nonselective predecessors.
These new agents are divided into two categories:
steroidal/irreversible and nonsteroidal/ reversible
inhibitors of estrogen synthesis.
The nonsteroidal aromatase inhibitors ar
anastrozole and letrozole, and the steroidal
compound is exemestane
11. EGFR, HER2 & IGF1R, activated by growth factor
Estrogen
Types of hormonal resistance :
PI3K Ras
- Denovo ( from the start)
PTEN
- Acquired : during the course, almost all Cytoplasmic ER
AKT
the metastatic cases eventually developRaf
endocrine resistance
mTOR
S6K1 4E-BP1
MEK
MAPK
Nuclear ER
cell
growth, prolif
eration, and
13. Mammalian target of rapamycin
(mTOR) is a signal transduction
kinase in the PI3K pathway that
exists in two multiprotein PI3k
complexes, mTOR complexes 1 and
2 (mTORC1 and mTORC2). PTEN mTOR
mTORC1 consists of mTOR that is rictor
associated with raptor (regulatory- AKT
associated protein of mTOR) and is
downstream of AKT. raptor
mTOR
In contrast,mTORC2 is associated
with rictor (rapamycin-insensitive
S6K1 4E-BP1
companion of mTOR) and
phosphorylates AKT eIF-
S6
Everolimus is a rapamycin analog 4E
that inhibits mTORC1 kinase Translation of
DNA
14. TAMRAD study
Randomized trial of 111 patients with HR+/HER2- metastatic
breast cancer with prior exposure to AI treatment (in
adjuvant and/or metastatic setting)
Patients
randomized 1:1 to
receive
Everolimus plus
tamoxifen (10
Tamoxifen alone
mg/day and 20
(20 mg/day; n=57)
mg/day
respectively; n=54)
Bachelot, T. et. al. TAMRAD: A GINECO Randomized Phase II Trial of Everolimus in Combination With Tamoxifen Versus Tamoxifen Alone in Patients (pts) With Hormone-
Receptor Positive, HER2 Negative Metastatic Breast Cancer (MBC) With Prior Exposure To Aromatase Inhibitors (AI). 33rd San Antonio Breast Cancer Symposium. 2010.
15. Primary Objective : (CR+PR+SD) at six months in the
everolimus plus tamoxifen arm1
Secondary Objectives : To evaluate time to disease
progression, overall survival, objective response rate and
safety of everolimus in combination with tamoxifen.
Results:
- The study met its primary endpoint, showing that the
proportion of metastatic breast cancer patients without
tumor progression at six months was 61.1% in the everolimus
plus tamoxifen arm vs. 42.1% in patients treated with
tamoxifen alone
- Time to disease progression was delayed by a median of
8.6 months in patients treated with everolimus plus tamoxifen
vs. 4.5 months in patients treated with tamoxifen
alone, providing a statistically significant reduction in the risk
of disease progression by 47%
16. Randomly assigned 724 women with
hormone receptor–positive metastatic breast
cancer who previously progressed on
nonsteroidal aromatase inhibitors
exemestane exemestane
and a placebo and everolimus
Patients who received everolimus had a significantly longer PFS (median,
6.9 months v 2.8 months by investigator assessment, P<.001), as well as an
improved overall response rate.
Hortobagyi G: Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. San Antonio Breast Cancer
Symposium, San Antonio, TX, December 7, 2011 (abstr S3-7)
17. 9% of Breast cancer patients express both ER
and HER-2 postivity.*
Model systems indicate that forced
overexpression of HER-2 can leadto tamoxifen
resistance in ER positive breast cancer cells.*
The clinical data are less clear but overall
point to incomplete resistance resulting from
co-expression of HER-2 and ER.*
Trastuzumab, the monoclonal antibody against
HER2, reduces downstream MAPK/ERK
signaling, and at least partially reverses
tamoxifen resistance in vitro.**
M Dowsett , Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer, Endocrine-Related Cancer (2001) 8 191–195
Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Arteaga CL: Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen
action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 2000, 60:5887-5894.
18. 207 Postmenopausal
women with
Patients in the trastuzumab plus anastrozole arm
HER2/hormone
experienced significant improvements in PFS
receptor– copositive
MBC were randomly
compared with patients receiving anastrozole
assigned
alone (hazard ratio 0.63; 95% CI, 0.47 to 0.84;
median PFS, 4.8 v 2.4; months log-rank P .0016).
anastrozole (1 mg/d
orally) with trastuzumab
(4 mg/kg intravenous anastrozole (1 mg/d
infusion on day 1, then 2 orally)
mg/kg every week) until
progression.
19. Lapatinib is an oral tyrosine kinase inhibitor of
both EGFR and HER2. As a dual inhibitor it may
have the potential for greater anti-tumor effect
than strategies targeting a single receptor
In vitro data have demonstrated that estrogen
deprivation significantly enhances the
antiproliferative effects of lapatinib in HER2
amplified breast cancer cell lines*
A phase I study has shown that the
combination with letrozole is well
tolerated, with toxicities consisting mainly of
grade 1-2 diarrhea, nausea, rash and fatigue**
*Leary AF, Martin LA, Lykkesfeldt AE, Dowsett M, Johnston SRD: Enhancing endocrine responsiveness using the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib in cell models
of endocrine resistance. Breast Cancer Res Treat 2006, 100(Suppl 1):Abstract 303 .
**Chu Q, Cianfrocca ME, Murray N, Oslund M, Nelson LM, Rowinsky E, Schwartz G, Goldstein LJ, Loftiss JI, Paul E, Koch KM, Pandite L: A phase I, open-label study of the
safety, tolerability and pharmacokinetics of lapatinib (GW572016) in combination with letrozole in cancer patients. Breast Cancer Res Treat 2004, 88(Suppl 1):Abstract 6044.
20. 219
Results Postmenopausal
In HR-positive, HER2-positive patientswith HR- addition of lapatinib to
women (n 219),
letrozole significantly reduced positive MBC progression versus letrozole-
the risk of disease
placebo (hazard ratio [HR] 0.71; 95% CI, 0.53 to 0.96; P .019); median PFS
was 8.2 v 3.0 months, respectively.
Letrozole (2.5
mg/daily)+ Letrozole (2.5mg
Lapatinib daily)
(1500mg/daily)
21. EGFR is a transmembrane growth factor receptor
tyrosine kinase (TK) commonly expressed in epithelial
tumors. In breast cancer, EGFR plays a major role in
promoting cell proliferation and malignant growth.
Binding of EGF-related growth factors results in
receptor homo and/or heterodimer- ization and
stimulation of the intrinsic TK activity. And activation of
MAPK and PI3K pathways
An inverse relationship between ER activity and EGFR
expression has been reported in breast cancer, with
overexpression of these TK receptors associated with
decreased sensitivity to endocrine therapy and poorer
prognosis *
Gefitinib is a small molecule that reversibly inhibits EGFR
TK autophosphorylation and inhibits downstream
signaling.
Nicholson RI, McClelland RA, Gee JMW, et al. Epidermal growth factor receptor expression in breast cancer: association with response to endocrine therapy. Breast
Cancer Res Treat 2000;29:117–25.
22. Postmenopausal women with hormone receptor–positive MBC
during/after adjuvant tamoxifen were eligible
patients receiving the combination of anastrozole and gefitinib
showed a longer PFS, which was the primary end point of this
study, compared with those receiving anastrozole plus placebo
(HR gefitinib/placebo, 0.55; 95% CI, 0.32–0.94; median PFS, 14.7
vs. 8.4 months) 50 patients were
43 patients were
randomized to randomized
anastrozole plus to anastrozole
gefitinib plus placebo
Cristofanilli M, Valero V, Mangalik A, et al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone
receptor-positive metastatic breast cancer. J Clin Cancer Res 2010;16(March (6)):1904–14.
23. Neratinib (HKI-272) is an orally
administered irreversible pan-ErbB
receptor tyrosine kinase inhibitor
In Phase 1 trail the safety and toxicity of
combening Neratinib and Trastuzumab,
was well tolerated with no significant or
unexpected toxicities and demonstrated
clinical activity.
R. F. Swaby et al, Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase 1/2 study, JCO :2009
24. “The roots of education are bitter, but the
fruit is sweet”-Aristotle