Mechanisms of endocrine resistance.Introduction
Two-thirds of breast cancers are associated with oestrogen oes·tro·gen
Variant of estrogen.
see estrogen. receptor (ER) signalling, and hormonal manipulation was first shown to be a successful strategy against breast cancer over 100 years ago . Currently available endocrine strategies include targeting the ER itself with the selective ER modulator Modulator
Any device or circuit by means of which a desired signal is impressed upon a higher-frequency periodic wave known as a carrier. The process is called modulation. The modulator may vary the amplitude, frequency, or phase of the carrier. tamoxifen tamoxifen (təmŏk`sĭfĕn'), synthetic hormone used in the treatment of breast cancer. Introduced in 1978, tamoxifen is used to prevent recurrences of cancer in women who have already undergone surgery to remove their tumors. or the ER downregulator fulvestrant, as well as suppressing the amount of available ligand for the receptor with gonadal gonadal
pertaining to or arising from a gonad. See also testicular, ovarian.
cords formed by epithelial cells which migrate from the mesonephric tubules in the embryo to the gonadal ridge and establish the indifferent suppression in premenopausal pre·me·no·paus·al
Of or relating to the years or the stage of life immediately before the onset of menopause.
premenopausal adjective women or aromatase inhibitors (AIs) in postmenopausal post·men·o·paus·al
Of or occurring in the time following menopause.
postmenopausal Change of life Gynecology adjective Referring to the time in ♀ when menstrual periods stop for ≥ 1 yr women.
Among postmenopausal women with early ER-positive breast cancer, endocrine therapy has been shown to have a greater impact on reducing annual breast cancer death rate than adjuvant chemotherapy Adjuvant chemotherapy
Treatment of the tumor with drugs after surgery to kill as many of the remaining cancer cells as possible.
Mentioned in: Neuroblastoma (31% versus 20%) . Given their favourable side effect profile and their potential for significant anti-tumour activity, endocrine therapies represent an important tool in our armamentarium ar·ma·men·tar·i·um
n. pl. ar·ma·men·tar·i·ums or ar·ma·men·tar·i·a
The complete equipment of a physician or medical institution, including drugs, books, supplies, and instruments. against breast cancer. Unfortunately, despite documented levels of ERs, up to 50% of patients with metastatic Metastatic
The term used to describe a secondary cancer, or one that has spread from one area of the body to another.
Mentioned in: Coagulation Disorders
pertaining to or of the nature of a metastasis. disease do not respond to first-line endocrine treatment (de novo [Latin, Anew.] A second time; afresh. A trial or a hearing that is ordered by an appellate court that has reviewed the record of a hearing in a lower court and sent the matter back to the original court for a new trial, as if it had not been previously heard nor decided. resistance), while the remainder will eventually relapse (acquired resistance) . Understanding the various biological mechanisms responsible for the development of endocrine resistance can identify new strategies to enhance the efficacy of hormone receptor-positive breast cancer treatment This article or section recently underwent a major revision or rewrite and needs further review. You can help!
The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase .
A number of theories, supported by preclinical data, have been proposed to explain endocrine resistance. These vary according to the sustained dependence on ER-mediated signalling and a significant number implicate im·pli·cate
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.
2. growth factor-mediated mitogenic signalling (Table 1). Identifying which resistance mechanism(s) is (are) operational is of obvious clinical relevance in tailoring the most appropriate subsequent therapy (i.e. non-ER-targeted treatment, further endocrine manipulation, or a combination of both).
Normal ER function
The ER belongs to the steroid nuclear receptor family of ligand-dependent transcription factors (Figure 1A). The transcription of ER-regulated genes is regulated by two activating function (AF) domains. AF-2 is located at the C-terminus and requires binding of oestradiol Noun 1. oestradiol - the most powerful female hormone that occurs naturally; synthesized and used to treat estrogen deficiency and breast cancer
Loestrin - trade name for an oral contraceptive containing estradiol and norethindrone (E2) to the ligand-binding domain (LBD LBD Little Black Dress
LBD Ligand Binding Domain
LBD Lewy Body Dementia (aka Lewy Body Disease)
LBD Lesbian Bed Death
LBD London Beth Din
LBD Little Black Duck
LBD Laser Beam Detector
LBD Lost Bather Drill ) of the receptor, whereas AF-1 is located at the N-terminus and is hormone independent. E2 binding to the LBD induces a conformational change in the receptor, leading to the recruitment of nuclear co-activators (NCOAs) that increase ER interaction with DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. . The activated ER binds as a dimer dimer /di·mer/ (di´mer)
1. a compound formed by combination of two identical molecules.
2. a capsomer having two structural subunits.
1. to oestrogen response elements in the promoters of target genes and activates transcription. In contrast, AF-1 can be phosphorylated by growth factor receptors or other downstream effectors and can act both independently or synergistically syn·er·gis·tic
1. Of or relating to synergy: a synergistic effect.
2. Producing or capable of producing synergy: synergistic drugs.
3. with AF-2 to increase the efficiency of ER transcriptional activity .
[FIGURE 1 OMITTED]
Tamoxifen acts as a competitive inhibitor. Upon binding to the LBD, it induces a conformational change that inactivates AF-2, but has no effect on AF-1 transcriptional activity . Because ER activity in the breast is predominantly mediated via AF-2, tamoxifen has an overall antagonist effect in the breast, but can act as an agonist agonist /ag·o·nist/ (ag´ah-nist)
1. one involved in a struggle or competition.
2. agonistic muscle.
3. in other tissues primarily driven by AF-1, such as the uterus .
In addition, tamoxifen recruits co-repressors (NCORs) thereby further inhibiting transcription. Alterations in the relative contributions of AF-1/AF-2 to transcription, as well as the amounts of NCOAs/NCORs available, may shift the balance of tamoxifen activity towards agonism and have been implicated im·pli·cate
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.
2. in endocrine resistance. In addition to its role as a classical transcription factor, ER can also enhance transcription without direct DNA binding by participating in protein-protein interactions with other transcription factors (non-classical genomic activity). For example, ER can essentially act as a co-activator and increase the activity of the Jun/Fos activator protein 1 (AP-1) transcription complex  (Figure 1B).
Finally, in addition to these nuclear transcriptional functions, non-genomic actions have more recently been ascribed to the ER. Oestrogen-bound ER has been shown to interact directly with, and phosphorylate phos·pho·ryl·ate
tr.v. phos·pho·ryl·at·ed, phos·pho·ryl·at·ing, phos·pho·ryl·ates
To add a phosphate group to (an organic molecule).
phos , membrane-associated growth factor receptors [9,10] as well as downstream effectors such as the p85 subunit of phosphoinositide-3-kinase (PI3K PI3K Phosphatidylinositol-3-Kinase
PI3K Phosphoinositide 3-Kinase ) , resulting in further pro-survival and anti-apoptotic signalling (Figure 1C).
The degree to which these individual functions of the ER contribute to malignant proliferation may vary from one patient to another and evolve over time thereby contributing to the development of endocrine resistance.
Implication of growth factor receptor and downstream mitogenic signalling in endocrine resistance
Membrane growth factor receptors such as the epidermal growth factor receptor This article is about a cell suface receptor. For estimated measure of kidney function (eGFR), see Glomerular filtration rate.
The epidermal growth factor receptor (EGFR EGFR Epidermal Growth Factor Receptor (a kinase enzyme)
EGFR Estimated Glomerular Filtration Rate ), the human epidermal growth factor receptor 2 (HER2) or the insulin growth factor 1 receptor (IGF (Internet Governance Forum) An international organization of governments and U.N. agencies that was founded to discuss Internet issues such as security and spam. It was created at the United Nations Summit in 2005 after the U.S. 1R) have been implicated in endocrine resistance. Upregulation of HER2 occurs in approximately 15-20% of breast cancers and has been associated with poor prognosis and de novo resistance to tamoxifen in the neoadjuvant setting . Similarly, EGFR is overexpressed in a number of breast cancers and has also been associated with poor response to tamoxifen . It is important to note that cell models of acquired resistance to both tamoxifen and oestrogen deprivation (ED) have shown that the development of resistance is associated with adaptative upregulation of growth factor signalling pathways [13,14].
Activation of these membrane receptors stimulates two major intracellular kinase signalling cascades--the ras/mitogenic-activated protein kinase protein kinase /pro·tein ki·nase/ (pro´ten ki´nas) an enzyme that catalyzes the phosphorylation of serine, threonine, or tyrosine groups in enzymes or other proteins, using ATP as a phosphate donor. (MAPK MAPK Mitogen-Activated Protein Kinase
MAPK Map Kinase ) pathway and the PI3K/Akt pathway. These pathways activate downstream effectors leading to a cascade of signals involved in malignant growth and survival, and can be involved in endocrine resistance by a number of mechanisms including downregulation of ER expression, a switch to ER-independent growth, or bi-directional crosstalk between ER and mitogenic signalling.
ER and HER2 expression are frequently described as inversely related. ER-positive cell lines stably transfected with full-length HER2 demonstrate downregulation of ER, while quantitative measurements of ER levels in tumour samples show consistently lower levels of the receptor among patients with HER2-amplified breast cancer .
There is some evidence that hyperactive growth factor signalling can suppress ER expression, and may eventually lead to complete loss of ER . Conversely, interruption of hyperactive MAPK or EGFR has been shown to re-induce ER expression in cell lines and xenograft xenograft /xeno·graft/ (zen´o-graft) a graft of tissue transplanted between animals of different species; it may be concordant, models [17,18]. In fact, in a small study of 10 patients with ER-negative/HER2-positive breast cancer receiving trastuzumab, three patients acquired ER expression with treatment . Studies with the dual EGFR/HER2 inhibitor lapatinib have shown that long-term treatment with this agent was associated with adaptive increase in ER signalling . The degree to which complete loss of ERs secondary to mitogenic signalling may contribute to acquired resistance needs further confirmation as serial clinical samples from women who have relapsed on endocrine therapy suggest that this is a rare event (10-15%) [21,22]. However, this 'yin and yang' dynamic interaction between ER and growth factor signalling would support using ER- and growth factor-targeted therapies in combination, or in fact in sequence, as one may sensitise Verb 1. sensitise - cause to sense; make sensitive; "She sensitized me with respect to gender differences in this traditional male-dominated society"; "My tongue became sensitized to good wine"
sensitize to the other.
Switch to ER-independent growth
Other mechanisms are likely to account for endocrine resistance in HER2-amplified breast cancer, as measurable levels of ERs are expressed in 50% of cases. Another possible mode of escape from the inhibitory effects of endocrine therapy is an adaptive switch to ER-independent growth, where the ER is still present but no longer driving proliferation. A cell model for acquired resistance to fulvestrant has shown that cells adapt to long-term treatment with the ER downregulator by pronounced upregulation of multiple growth-stimulatory pathways, resulting in oestrogen-independent autocrine-regulated proliferation . This would imply pan-endocrine resistance and support the use of non-ER-targeted therapies.
Endocrine resistance is usually associated with a functional ER
Most in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. and clinical observations would suggest that even following the development of endocrine resistance, ER signalling continues to play an important role in the proliferation of breast cancer. Biopsies of tumours from breast cancer patients who have relapsed while receiving treatment with an anti-oestrogen agent show a functional ER , while women who have become refractory to tamoxifen or non-steroidal AIs actually respond to further endocrine manipulation with the ER[alpha] downregulator fulvestrant [24,25], indicating that ER-mediated signalling remains functional. There is increasing evidence that crosstalk with growth factor and downstream mitogenic pathways can augment the genomic and non-genomic functions of ERs.
Synergistic interaction between ER and mitogenic signalling resulting in enhanced genomic and non-genomic functions of ER
Increase in classical transcription via AF-1
Growth factor-mediated activation of MAPK or Akt can potentiate po·ten·ti·ate
1. To make potent or powerful.
2. To enhance or increase the effect of a drug.
3. To promote or strengthen a biochemical or physiological action or effect. E2-mediated ER classical transcriptional activity by directly phosphorylating AF-1 . Of note, both MAPK and Akt have been shown to phosphorylate ER within AF-1 (at serine serine (sĕr`ēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer appears in mammalian protein. 118 and serine 167, respectively) in the absence of E2, thereby contributing to ligand-independent ER transactivation Transactivation is an increased rate of gene expression triggered either by endogenous cellular or viral proteins - transactivators. These protein factors act in trans (i.e., intermolecularly). [27,28]. Other downstream effectors of peptide growth factor receptors have also been shown to activate ERs, such as protein kinase A and the cyclin cy·clin
A class of proteins that fluctuate in concentration at specific points during the cell cycle and that regulate the cycle by binding to a kinase. E-cdk-2 complex .
An increase in AF-1 transcription may predict for differential sensitivity to endocrine agents. Tamoxifen may efficiently block AF-2-mediated transcription; however, in tumours that exhibit high levels of AF-1 activity driven by mitogenic signalling, tamoxifen may act as an agonist . This is supported by the high rate of primary tamoxifen resistance observed in neoadjuvant trials of HER2-amplified breast cancer . There are some data to suggest that E2 deprivation using an AI, or ER downregulation using fulvestrant, may therefore be a more effective anti-cancer strategy in EGFR-positive/HER2-positive breast cancer [12,30,31].
Potentiation potentiation /po·ten·ti·a·tion/ (po-ten?she-a´shun)
1. enhancement of one agent by another so that the combined effect is greater than the sum of the effects of each one alone.
2. posttetanic p. of genomic activity by altering the balance of co-regulators
ER transcription is tightly regulated by the balance of NCOAs/NCORs. Mitogenic signalling can alter the expression of some of these co-regulators thereby enhancing classical and non-classical ER transcription. The co-activator NCOA NCOA National Change Of Address (USPS)
NCOA National Council On the Aging
NCOA Nuclear Receptor Coactivator
NCOA National Corvette Owners Association
NCoA New Care-Of Address
NCOA Non-Commissioned Officer Academy 3, also known as amplified in breast cancer-1 (AIB AIB n abbr (BRIT) (= Accident Investigation Bureau) → oficina de investigación de accidentes
AIB n abbr (Brit) (= Accident Investigation Bureau) → 1) is overexpressed in 50% of breast cancers and amplified in 5% . Among untreated patients with ER-positive breast cancer it is associated with improved survival. In contrast, AIB1 has been associated with poor outcome on tamoxifen in HER2-amplified breast cancer because HER2 activates AIB1 and enhances the agonist effects of tamoxifen [33,34]. Similarly, decreased levels of NCORs have been shown to enhance tamoxifen agonism by shifting the balance towards ER transcriptional activity .
Cyclin D1 is overexpressed in 50% and amplified in 25% of breast cancers. As a transducer transducer, device that accepts an input of energy in one form and produces an output of energy in some other form, with a known, fixed relationship between the input and output. of both ER and growth factor-mediated cell cycle progression, cyclin D1 emerged as a potentially useful target in endocrine-resistant breast cancer. In addition, more recent data suggested that cyclin D1 could interact directly with ERs via recruitment of members of the steroid receptor co-activators (Src) family of NCOAs in the absence of endogenous ligand . However, there are conflicting clinical data regarding the causal relationship between cyclin D1 and endocrine responsiveness [37,38].
In addition to binding directly to DNA and increasing transcription of ER-dependent genes (classical), ligand-bound ER can also complex with other transcriptional factors, such as Jun/Fos via AP-1 (non-classical genomic activity). Acquired tamoxifen resistance in tumour samples has been associated with increased AP-1 activity presumably pre·sum·a·ble
That can be presumed or taken for granted; reasonable as a supposition: presumable causes of the disaster. via tamoxifen-liganded ER agonist activity . The stress-activated kinase p38 MAPK is a major upstream modulator of AP-1 transcriptional activity and may potentiate the agonist effects of tamoxifen at AP-1 .
There are data to suggest that mitogenic signalling can alter the ratio of NCOAs/NCORs and result in a hypersensitive response of ERs to E2, or an agonist effect of tamoxifen-bound ERs. Whether profiling tumours by measuring the levels of various transcription co-regulators may offer useful predictive information regarding endocrine responsiveness has not been clearly established.
Enhanced non-genomic functions of ER
Conversely, as detailed in Figure 1, in addition to its effects on transcription, oestrogen-bound ER has also been shown to result in non-genomic effects via rapid activation of EGFR , IGF1R , HER2  or the cleavage of membrane-bound growth factor receptor ligands such as epidermal growth factor Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation and differentiation. Human EGF is a 6045 Da protein with 53 amino acid residues and three intramolecular disulfide bonds. or transforming growth factor [alpha] . This bi-directional interaction between ERs and growth factor pathways creates a self-reinforcing synergistic loop that potentiates pro-survival signals and may allow breast cancer to escape normal endocrine responsiveness. Furthermore, the extranuclear extranuclear /ex·tra·nu·cle·ar/ (-noo´kle-er) situated or occurring outside a cell nucleus. functions of ERs appear to require a ligand, and both E2 and tamoxifen can act as agonists .
It is important to note that this crosstalk does not seem to be operational in hormone-sensitive ER-positive MCF7 cells; its relevance appears to be limited to HER2-amplified cell lines or those with acquired endocrine resistance . Unfortunately, while supported by extensive in vitro models, the clinical relevance of the non-genomic actions of the ERs remains controversial as membrane and/or cytoplasmic cytoplasmic
pertaining to or included in cytoplasm.
include secretory inclusions (enzymes, acids, proteins, mucosubstances), nutritive inclusions (glycogen, lipids), pigment granules (melanin, lipofuscin, ERs have yet to be conclusively demonstrated in clinical samples.
Growth factor signalling has been extensively implicated in endocrine resistance. In some cases the interaction between ER and mitogenic pathways can be described as a dynamic inverse relationship, where inhibition of one results in a compensatory increase in the other. This is supported by pre-clinical and clinical data which show that growth factor inhibition may increase ER expression or function and re-sensitise breast cancer cells to endocrine therapy, and which would support combination, or in fact sequential treatment.
Alternatively, growth factor signalling can interact synergistically with the ER and augment both genomic and non-genomic functions of the receptor. This would provide a strong rationale for simultaneous blockade of both ERs and mitogenic pathways. Given this body of evidence, a number of trials have been completed exploring the benefit of various inhibitors of growth factor receptors or downstream effectors [e.g. mammalian target of rapamycin The mammalian target of rapamycin, commonly known as mTOR, is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. (mTOR)] in modulating endocrine resistance (for reviews see [43,44]). As shown in Table 2, despite strong pre-clinical evidence, some of these studies have yielded disappointing results, which may be in part attributable to a poor selection of patients. It is unlikely that patients will respond to a combination of specific inhibitors unless the intended target is a significant driver of endocrine-resistant growth. Conversely, while significant overexpression of HER2 is a known requirement for benefit from trastuzumab, further studies are needed to determine whether more moderate receptor expression or activation may be relevant in the setting of endocrine resistance. Most ongoing studies are therefore including parallel biological studies in an effort to define the subset of patients most likely to benefit from specific combinations (Table 3).
Other mechanisms implicated in endocrine resistance
Loss of ER expression due to promoter Hypermethylation
ER expression is an obligate obligate /ob·li·gate/ (ob´li-gat) pertaining to or characterized by the ability to survive only in a particular environment or to assume only a particular role, as an obligate anaerobe. , albeit insufficient, requirement for sensitivity to endocrine therapy, and loss of ERs with progressive disease due to clonal selection could account for acquired endocrine resistance. ER silencing as a result of promoter hypermethylation has been documented in a proportion of breast cancers . It is important to note that this process has been shown to be reversible. Demethylating agents or histone deacetylase (HDAC HDAC Histone Deacetylase (biochemistry)
HDAC Heavy Duty Air Cylinder ) inhibitors can re-activate expression of a functional ER in cell lines with ER silencing due to promoter methylation methylation,
n a phase-II detoxification pathway in the liver; methyl groups combine with toxins to rid the body of various substances.
(meth´ [46,47]. These observations are provocative and have obvious clinical implications for a proportion of patients with ER-negative tumours who may benefit from endocrine therapy if ER expression could be reactivated using a demethylating agent. A trial of tamoxifen in combination with an HDAC inhibitor in patients who have relapsed after endocrine therapy is ongoing to investigate whether the HDAC inhibitor may restore endocrine sensitivity by enhancing ER expression.
Adaptive increase in ER and E2 hypersensitivity hypersensitivity, heightened response in a body tissue to an antigen or foreign substance. The body normally responds to an antigen by producing specific antibodies against it. The antibodies impart immunity for any later exposure to that antigen.
The biological mechanisms contributing resistance to ED using AIs or gonadal suppression are less well defined than those underpinning tamoxifen resistance and may in fact be quite distinct. Long-term ED can be associated with adaptive aberrant mitogenic signalling as previously described. However, as ED strategies do not involve direct interaction with ERs, none of the paradoxical agonist activities of tamoxifen would be expected. In addition, whereas acquired tamoxifen resistance has been frequently associated with relative decrease in ER expression, adaptation to ED may lead to upregulation of ERs. In vitro models of long-term ED have shown that part of the adaptive process involves an increase in ER expression and E2 hypersensitivity to very low levels of residual oestrogen . This is supported by a recent clinical trial showing that women who have relapsed on an AI respond to more potent endocrine manipulation using the irreversible AI exemestane, or ER downregulation with fulvestrant . If part of the adaptive process to AIs involves E2 hypersensitivity, then there may be a rationale for continued ED in combination with a novel agent, rather than switching to it. The current Study of Faslodex, Exemestane and Arimidex (SOFEA SOFEA Study of Faslodex, Exemestane and Arimidex (drug trial) ) trial will address this question. In this trial, women who have relapsed on a non-steroidal AI (anastrozole or letrozole) are randomly assigned to the irreversible steroidal AI exemestane, fulvestrant or fulvestrant in combination with anastrozole.
A single activating mutation in the ER gene has been identified and shown to result in constitutive constitutive /con·sti·tu·tive/ (kon-stich´u-tiv) produced constantly or in fixed amounts, regardless of environmental conditions or demand. ER transactivation . However, screening of clinical samples has revealed that mutations occur in fewer than 1% of breast cancers and most are silent [3,49]. In addition, a significant number of naturally occurring mRNA splice variants encoding truncated ER have been identified; however, these have not been shown to modulate endocrine responsiveness in the clinical setting .
Altered drug metabolism Drug Metabolism/Interactions Definition
Drug metabolism is the process by which the body breaks down and converts medication into active chemical substances.
Drugs can interact with other drugs, foods, and beverages. and cellular clearance
Measurements of intratumoral levels of tamoxifen have shown that women with acquired resistance to tamoxifen have lower levels than sensitive controls . Whether low intracellular levels of tamoxifen are attributable to decreased influx of the drug or increased efflux efflux Medtalk That which flows outward via a membrane pump such as p-glycoprotein has not been established. However, this mechanism is likely to be a minor contributor to tamoxifen resistance as clinical samples have consistently demonstrated that tamoxifen saturates ERs with greater than 99.9% occupancy . The cytochrome cytochrome (sī`təkrōm'), protein containing heme (see coenzyme) that participates in the phase of biochemical respiration called oxidative phosphorylation. P450 2D6 enzyme is required to convert tamoxifen to its more potent metabolite metabolite, organic compound that is a starting material in, an intermediate in, or an end product of metabolism. Starting materials are substances, usually small and of simple structure, absorbed by the organism as food. , endoxifen. CYP CYP
In currencies, this is the abbreviation for the Cyprus Pound.
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion. 2D6 variants have been identified and bi-allelic polymorphism polymorphism, of minerals, property of crystallizing in two or more distinct forms. Calcium carbonate is dimorphous (two forms), crystallizing as calcite or aragonite. Titanium dioxide is trimorphous; its three forms are brookite, anatase (or octahedrite), and rutile. results in decreased levels of circulating endoxifen, fewer hot flushes and an increased risk of relapse among women treated with tamoxifen . Similarly, CYP2D6 inhibitors, such as the selective serotonin reuptake inhibitor selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor (SSRI)
A class of antidepressants that work by blocking the reabsorption of serotonin in the brain, raising the levels of antidepressants Antidepressants
Medications prescribed to relieve major depression. Classes of antidepressants include selective serotonin reuptake inhibitors (fluoxetine/Prozac, sertraline/Zoloft), tricyclics (amitriptyline/ Elavil), MAOIs (phenelzine/Nardil), and heterocyclics , which are frequently used to treat postmenopausal hot flushes, also decrease endoxifen levels leading some to suggest that these agents should be avoided in women treated with tamoxifen [52,53]. Whether women with homozygous ho·mo·zy·gous
Having the same alleles at one or more gene loci on homologous chromosome segments.
Identical genes controlling a specified inherited trait. CYP2D6 variants would benefit from higher doses of tamoxifen or an alternative endocrine therapy has not been investigated.
Alterations in aromatase expression or function
In postmenopausal women, the only source of E2 is from the aromatisation of adrenal adrenal /ad·re·nal/ (ah-dre´n'l)
2. adrenal gland.
3. pertaining to an adrenal gland.
1. androgens Androgens
Male sex hormones produced by the adrenal glands and testes, the male sex glands.
Mentioned in: Acne, Congenital Adrenal Hyperplasia, Finasteride, Homocysteine, Polycystic Ovary Syndrome, Salpingo-Oophorectomy
. While peripheral conversion in adipose tissue adipose tissue (ăd`əpōs'): see connective tissue.
or fatty tissue
Connective tissue consisting mainly of fat cells, specialized to synthesize and contain large globules of fat, within a contributes to measurable levels of circulating E2, local production via tumoural aromatase activity results in 10- to 20-fold higher E2 concentrations in the tumour than in plasma . Variations in tumour aromatase levels could therefore contribute to responsiveness to AIs. A small study suggested that the level of intratumoral aromatase activity could predict for response to the first-generation AI aminoglutethemide . However, more recent studies have shown no correlation between aromatase mRNA levels and response to AIs . A number of single-nucleotide polymorphisms (SNPs) have been identified in the aromatase gene (CYP19); however, most do not translate into a clinically significant variation in circulating E2 levels . One SNP SNP Scottish National Party
Noun 1. SNP - (genetics) genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is altered; SNPs are usually considered to be point mutations that have been evolutionarily has been shown in vitro to reduce affinity of the aromatase enzyme for exemestane ; however, there is no clinical evidence to date that genetic variations in CYP19 lead to resistance to aromatase inhibition in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body.
Within a living organism.
in vivo adv. .
A number of theories involving ER mutations or drug metabolism and clearance have been proposed to contribute to endocrine responsiveness. However, there is an increasing body of evidence implicating im·pli·cate
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.
2. growth factor receptor and downstream kinases in both de novo and acquired endocrine resistance. The nature of the interaction between ER and mitogenic signalling probably varies over time and from one patient to another. In some models, activated growth factor-mediated signalling suppresses expression of ERs and function, raising the intriguing possibility that growth factor-targeted therapy may, over time, restore endocrine responsiveness. In other cases, ERs and growth factor signalling may interact synergistically providing the basis for combination strategies. Importantly, a significant proportion of endocrine-resistant breast cancer still depends on a functional ER. Acquired resistance can be attributed to tamoxifen agonism due to AF-1-driven transcription, or an increase in non-genomic ER activity. Degrading the receptor with fulvestrant might provide an effective strategy in this setting, while ED would be expected to abrogate abrogate v. to annul or repeal a law or pass legislation that contradicts the prior law. Abrogate also applies to revoking or withdrawing conditions of a contract. (See: repeal) ligand-dependent non-genomic activity. Comparatively little is known about the mechanisms underpinning resistance to ED; however, as more postmenopausal women are receiving first-line adjuvant adjuvant /ad·ju·vant/ (aj?dbobr-vant) (a-joo´vant)
1. assisting or aiding.
2. a substance that aids another, such as an auxiliary remedy.
3. treatment with AIs, this question has become increasingly relevant. Both growth factor signalling and E2 hypersensitivity have been shown to contribute and would suggest that continued ED with an AI might be a superior approach to growth factor targeting alone. A huge number of trials (Table 3) are currently exploring the benefit of various targeted agents in combination or in sequence with endocrine therapy and include biological analyses that may shed further light on the clinically relevant mechanisms of endocrine resistance.
[1.] Beaston GT. On the treatment of inoperable inoperable /in·op·er·a·ble/ (in-op´er-ah-b'l) not susceptible to treatment by surgery.
Unsuitable for a surgical procedure. cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet, 1896, ii, 104-107.
[2.] Early Breast Cancer Trialists' Collaborative Group (EBCTCG EBCTCG Early Breast Cancer Trialists Collaborative Group ). Effects of chemotherapy and hormonal therapy Hormonal therapy
Use of hormone medications to inhibit menstruation and relieve the symptoms of endometriosis.
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irregular - contrary to rule or accepted order or general practice; "irregular hiring practices" trials. Lancet, 2005, 365, 1687-1717.
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The cellular molecules DNA and RNA that act as coded instructions for the production of proteins and are copied for transmission of inherited traits. Res, 1992, 20, 2813-2817.
[7.] Tzukerman MT, Esty A, Santiso-Mere D et al. Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular in·tra·mo·lec·u·lar
Within a molecule.
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Alexandra Leary and Stephen Johnston
Royal Marsden Hospital, London, UK
Correspondence to: Alexandra Leary, Department of Medicine, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK (email: email@example.com)
Table 1: Postulated mechanisms of endocrine resistance and potential avenues for therapy Biological mechanism Therapeutic options / comments Growth factor driven Downregulation of ER expression Sequential growth factor--ER- and/or function targeted therapy Switch to ER-independent Non-ER-targeted therapy proliferation Enhanced genomic and non-genomic Dual ER and growth factor functions of ER targeting Other ER silencing due to promoter Demethylating agents or HDAC hypermethylation inhibitors E2 hypersensitivity Continued ED plus ER downregulator or growth factor inhibitor ER mutations Rare Altered tamoxifen metabolism and Higher tamoxifen doses in selected cellular clearance patients? Aromatase expression and function Relevance unknown ER, oestrogen receptor; E2, oestradiol; HDAC, histone deacetylase; ED, oestrogen deprivation. Table 2: Combinations of endocrine therapies with inhibitors of membrane receptors or downstream effectors: selected completed trials (data from ). Clinical Clinical setting Phase Intervention endpoints Reference Combinations with EGFR inhibitor gefitinib (GEF) MBC II ANA + GEF PR=0 SD=0  Endocrine ORR=61% vs  resistant 48%, P=0.067 Neoadjuvant II RCT ANA vs ANA + ORR=50% vs 54% PBC GEF x 16  weeks Preoperative II RT GEF vs GEF + PBC ANA EGFR+ only x 4-6 Combinations with trastuzumab (TRAS) HER2+ MBC II TRAS + LET PR=26% SD=26%  HER2 MBC (all III RCT ANA vs ANA + PFS=2.4 mo vs  pts were IHC TRAS 4.8 mo, 3+ or FISH+) P=0.0016 OS=23.9 mo vs 28.5 mo, P=0.325 mTor inhibitors: everolimus (EVE) or temsirolimus (TEM) MBC Ib n=9 LET+EVE 1, 5 No grade 3/4  stable or or 10 mg toxicities slowly daily at 5 mg progressing (6 pts) or on letrozole 10 mg (3 pts) MBC II n=92 Let vs LET+TEM ORR=45% vs 33%  10 mg daily vs 40% vs LET+TEM PFS=11.6 mo 30 mg vs 11.5 mo intermittent vs 13.2 mo MBC III RCT LET vs ORR=24% vs 24%  n=992 letrozole+ SD=19% vs TEM 16% PFS=9.2 intermittent mo vs 9.2 mo EGFR, epidermal growth factor receptor; MBC, metastatic breast cancer; PBC, primary breast cancer; RCT, randomised controlled trial; RT, randomised trial; PR, partial response; SD, stable disease; ORR, objective response rate (PR+CR); ANA, anastrozole; LET, letrozole; mTOR, mammalian target of rapamycin; PFS, progression-free survival; OS, overall survival; vs, versus; +, positive; mo, months; pts, patients; IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation. Table 3. Endocrine combinations: selected ongoing or recently closed trials. NCT Clinical Trial Biological protocol setting phase Intervention endpoints number Endocrine combinations MBC III FUL vs EXEM vs Serum hormone 00253422 Previously FUL+ANA levels treated with AI MBC III ANA vs ANA + Not available 00256698 1st line FUL With EGFR inhibitors: gefitinib (GEF) or erlotinib (ERL) Neoadjuvant II GEF x 2 wks Tumour biomarker 00206492 PBC followed by analysis at (HER2+ only) GEF+TAM weeks 1, 2 and 6, and surgery Neoadjuvant II ANA + FUL + GEF Tumour biomarker 00206414 PBC analysis pre- and post-treatment MBC II RCT TAM [+ or -] Correlate RR to 00069290 GEF HER2/A1B1 status and other biomarker studies MBC II RCT ANA [+ or -] biomarker study 00077025 GEF MBC II RCT ANA [+ or -] None specified 00066378 GEF MBC II FUL + GEF None specified 00234403 MBC II RT ANA + GEF vs Identify 00057941 FUL + GEF biologic predictors MBC II LET + ERL Correlation of 00179296 EGFR, HER2 and pERSer118 to benefit MBC II RT GEF [+ or -] Correlate early 00080743 TAM resistant TAM changes on PET and in plasma DNA to response With trastuzumab (TRAS) HER2+ MBC II TRAS Correlate 00238290 AI-resistant monotherapy benefit with until PD HER2 ECD at followed by baseline and TRAS + LET after treatment HER2+ MBC III RCT ANA [+ or -] None specified 00022672 TRAS HER2+ MBC IV LET + TRAS None specified 00171847 TRAS-naive With lapatinib (LAP) MBC II LAP + TAM None specified 00118157 TAM resistant MBC III RCT LET [+ or -] Biomarker and 00073528 LAP genetic variant analysis With mTOR inhibitors: everolimus (EVE) and temsirolimus (TEM) Neoadjuvant II RCT LET [+ or -] None specified 00107016 PBC EVE MBC II RCT LET [+ or -] None specified 00061971 TEM Combination with HDAC inhibitor SAHA MBC II TAM+SAHA Pre-and post 00365599 treatment ER expression and histone acetylation PBC, primary breast cancer; MBC, metastatic breast cancer; RCT, randomised controlled trial; RT, randomised trial; RR, response rate; ECD, extracellular domain: ANA, anastrozole; FUL, fulvestrant; EXEM, exemestane; LET, letrozole; TAM, tamoxifen; SAHA, suberoylanalide hydroxamic acid; PET, positron emission tomography.