Management of Hormonal Resistant Breast Cancer Ahmed Allam A.H. Mohammed.

Ass. Lecturer, Clinical oncology and Nuclear med. Depart. Assiut University

Hospitals

- Introduction 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.

Mechanism of action: 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.

( 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

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

Mechanisms of action:1- Tamoxifen:

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)

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

Mechanisms of action: 2- AIs

Cholesterol

Pregnenolone Androstenedione

TestesteroneProgesterone

Aldosterone Estrone Estradiol

Aromtase inhibitors

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

Mechanism of resistant:

Ras

Raf

MEK

MAPK

PI3K

AKT

mTOR

PTEN

4E-BP1

S6K1

cell growth, proliferation, and survival

Nuclear ER

Cytoplasmic ER

Estrogen

EGFR, HER2 & IGF1R, activated by growth factor

Types of hormonal resistance : - Denovo ( from the start) - Acquired : during the course, almost all the metastatic cases eventually develop endocrine resistance

Reversing resistance to endocrine therapy:

mTOR inhibitors Her2 blockade EGFR inhibitors PI3K inhibitors Hystone deactylase inhibitors Src inhibitors IGF-1R inhibitors

mTOR inhibitors Mammalian target of rapamycin

(mTOR) is a signal transduction kinase in the PI3K pathway that exists in two multiprotein complexes, mTOR complexes 1 and 2 (mTORC1 and mTORC2).

mTORC1 consists of mTOR that is associated with raptor (regulatory-associated protein of mTOR) and is downstream of AKT.

In contrast,mTORC2 is associated with rictor (rapamycin-insensitive companion of mTOR) and phosphorylates AKT

Everolimus is a rapamycin analog that inhibits mTORC1 kinase

PI3k

PTEN

AKT

mTOR

S6K14E-BP1

S6eIF-4E

Translation of DNA

raptor

mTORrictor

Everolimus

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 mg/day and 20 mg/day

respectively; n=54)

Tamoxifen alone (20 mg/day; n=57)

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.

TAMRAD study

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%

The phase III Breast Cancer Trial of Oral Everolimus 2 (BOLERO-2)

Randomly assigned 724 women with hormone receptor–positive metastatic breast cancer who previously progressed on nonsteroidal aromatase inhibitors

exemestane and a placebo exemestane 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)

HER-2 antagonists

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) 8 191–195Kurokawa 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.

207 Postmenopausal women with HER2/hormone receptor– copositive MBC were randomly assigned

anastrozole (1 mg/d orally) with trastuzumab (4 mg/kg intravenous

infusion on day 1, then 2 mg/kg every week) until progression.

anastrozole (1 mg/d orally)

Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4; months log-rank P .0016).

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.

219 Postmenopausal women with HR-positive MBC

Letrozole (2.5 mg/daily)+ Lapatinib

(1500mg/daily)

Letrozole (2.5mg daily)

ResultsIn HR-positive, HER2-positive patients (n 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-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.

EGFR inhibitors 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.

Postmenopausal women with hormone receptor–positive MBC during/after adjuvant tamoxifen were eligible

43 patients were randomized to

anastrozole plus gefitinib

50 patients were randomized

to anastrozole plus placebo

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)

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.

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

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