The evolution of tooth wear indices Tooth wear -- attrition , erosion and abrasion -- is perceived internationally as an ever-increasing problem . Clinical and epidemiological studies , however , are difficult to interpret and compare due to differences in terminology and the large number of indices that have been developed for diagnosing , grading and monitoring dental hard tissue loss . These indices have been designed to identify increasing severity and are usually numerical . Some record lesions on an aetiological basis -LRB- e.g. erosion indices -RRB- , others record lesions irrespective of aetiology -LRB- tooth wear indices -RRB- ; none have universal acceptance , complicating the evaluation of the true increase in prevalence reported . This article considers the ideal requirements for an erosion index . It reviews the literature to consider how current indices have evolved and discusses if these indices meet the clinical and research needs of the dental profession . Introduction There is both a clinical and a scientific need to be able to measure tooth wear , and the literature abounds with many methods which can be broadly divided into quantitative and qualitative in nature . Quantitative methods tend to rely on objective physical measurements , such as depth of groove , area of facet or height of crown . Qualitative methods , which rely on clinical descriptions , can be more subjective if appropriate training and calibration are not carried out but which , with correct safeguards , can be valuable epidemiological tools . In a clinical intra-oral examination , there will be an inclination towards descriptive assessment measures , such as mild , moderate or severe , rather than quantitative measurement , which is easier to perform reliably on a model or in the laboratory . Such methods tend to be more sensitive but do not lend themselves readily to clinical use -- especially in epidemiology , where fieldwork data collection is often carried out in an environment lacking sophisticated equipment . Quantitative and qualitative methods typically utilise grading or scoring systems designed to identify increasing severity or progression of a condition ; these are described as indices and are usually numerical . An ideal index should be simple to understand and use , clear in its scoring criteria and be demonstrably reproducible . Its application should be useful for research into the aetiology , prevention and monitoring of a condition , essentially being an epidemiological and clinical tool . Review of the literature reveals the fact that many different tooth wear indices have been developed for clinical and laboratory use all over the world . Unfortunately , the production of so many indices does not allow for ready comparison of results between different working groups , and this is especially important in epidemiology when trying to define the prevalence of a condition . Confusion is further generated in the literature as the majority of researchers , in their attempts to quantify the amount of tooth tissue loss due to tooth wear , have historically concentrated on one aetiology only , and these indices tend to be surface limited . Often , the wear patterns described do not appear to reflect the aetiology suggested , and this relates to lack of uniformity with tooth wear terminology and translation errors . Many diagnostic indices do not properly reflect the morphological defects , and there is little international standardisation . All of these factors complicate the comparison of data and evaluation of the efficacy of preventive and therapeutic measures . The literature identifies separate indices for use in clinical and laboratory situations and specific indices for attrition , abrasion , erosion and multifactorial tooth wear . There are common threads to all of the indices , such as descriptive diagnostic criteria and criteria for quantifying the amount of hard tissue loss . These generally consider the size of the affected area -- as a proportion of a sound surface and/or the depth of tissue loss -- often expressed as a degree of dentine exposure . The clinical measurement of erosion The earliest indices shared common , arbitrary criteria , relying on descriptive terms such as slight , mild , moderate , severe and extensive . Restarski et al. -LSB- 26 -RSB- developed a six-point grading system to evaluate the severity of erosive destruction observed on the lingual surfaces of rat and puppy molars , but concerns were raised with regards to reproducibility . With vague criteria definitions , variability in recording is expected . Each animal was allocated a total score , calculated by summing the mean molar quadrant scores . Whilst producing simple data for analysis , it is acknowledged that averaging scores in this manner leads to the loss of much data . If the number of teeth severely affected is small , the erosion score will be low ; but this could mask a significant , localised clinical problem -LSB- 27 -RSB- . Eccles -LSB- 9 -RSB- originally classified lesions broadly as early , small and advanced , with no strict criteria definitions , thus allowing wide interpretation . Later , the index was refined and expanded , with greater emphasis on the descriptive criteria -LSB- 10 -RSB- . It was presented as a comprehensive qualitative index , grading both severity and site of erosion due to non-industrial causes , and is considered as one of the cardinal indices from which others have evolved . In essence , it breaks down into three classes of erosion , denoting the type of lesion , assigned to four surfaces , representing the surface where erosion was detected -LRB- Table 1 -RRB- . Table 1Eccles index for dental erosion of non-industrial origin -LSB- 10 -RSB- ClassSurfaceCriteriaClass I Early stages of erosion , absence of developmental ridges , smooth , glazed surface occurring mainly on labial surfaces of maxillary incisors and caninesClass IIFacialDentine involved for less than one third surface ; two typesType 1 -LRB- commonest -RRB- : ovoid -- crescentic in outline , concave in cross section at cervical region of surface . Must differentiate from wedge shaped abrasion lesionsType 2 : irregular lesion entirely within crown . Punched out appearance , where enamel is absent from floorClass IIIaFacialMore extensive destruction of dentine , affecting anterior teeth particularly . Majority of lesions affect a large part of the surface , but some are localised and hollowed outClass IIIbLingual or palatalDentine eroded for more than one third of the surface area . Gingival and proximal enamel margins have white , etched appearance . Incisal edges translucent due to loss of dentine . Dentine is smooth and anteriorly is flat or hollowed out , often extending into secondary dentineClass IIIcIncisal or occlusalSurfaces involved into dentine , appearing flattened or with cupping . Incisal edges appear translucent due to undermined enamel ; restorations are raised above surrounding tooth surfaceClass IIIdAllSeverely affected teeth , where both labial and lingual surfaces are extensively involved . Proximal surfaces may be affected ; teeth are shortened Greater accuracy was introduced by Xhonga and Valdmanis -LSB- 33 -RSB- who divided erosions into four levels by measurement with a periodontal probe : none , minor -LRB- less than 2 mm -RRB- , moderate -LRB- up to 3 mm -RRB- and severe -LRB- greater than 3 mm -RRB- . They further differentiated types of erosion by morphological descriptions , such as wedge , saucer , groove and atypical . They did not address the problem of inter - or intra-examiner variability . The clinical measurement of tooth wear It is perhaps significant that the earliest index documented by Broca -LSB- 4 -RSB- and used as a foundation for the development of further indices graded horizontal or oblique patterns of occlusal wear without presupposing the aetiology . Smith and Knight -LSB- 30 -RSB- introduced the more general concept of measuring tooth wear per se , irrespective of the cause , and since then more recent indices have been developed or modified from Smith and Knight that do not rely on a prior diagnosis and are more clinically relevant . Most of these stress the importance of user training sessions and calibration exercises . Smith and Knight -LSB- 30 -RSB- took Eccles ' ideas a stage further , producing the tooth wear index -LRB- TWI -RRB- , a comprehensive system whereby all four visible surfaces -LRB- buccal , cervical , lingual and occlusal -- incisal -RRB- of all teeth present are scored for wear , irrespective of how it occurred -LRB- Table 2 -RRB- . This avoids the confusion associated with terminology and translation or differences in opinion for diagnosis of aetiology based on clinical findings . Guidelines for using the criteria were produced in a booklet by the authors to aid training and standardisation with other investigators ; in cases of doubt , the lowest score is given . Complete enamel loss -LRB- score 4 -RRB- may , however , be misleading , as there is almost always a rim of enamel at the worn surface margins -- the colloquial `` enamel halo . '' Table 2Smith and Knight tooth wear index -LSB- 30 -RSB- ScoreSurfaceCriteria0B/L/O / INo loss of enamel surface characteristicsCNo loss of contour1B/L/O / ILoss of enamel surface characteristicsCMinimal loss of contour2B/L/OLoss of enamel exposing dentine for less than one third of surfaceILoss of enamel just exposing dentineCDefect less than 1 mm deep3B/L/OLoss of enamel exposing dentine for more than one third of surfaceILoss of enamel and substantial loss of dentineCDefect less than 1 -- 2 mm deep4B/L/OComplete enamel loss -- pulp exposure -- secondary dentine exposureIPulp exposure or exposure of secondary dentineCDefect more than 2 mm deep -- pulp exposure -- secondary dentine exposure This index was the first one designed to measure and monitor multifactorial tooth wear ; a further pioneering feature was the ability to distinguish acceptable and pathological levels of wear , by comparison with threshold normal values for the age groups studied . Tooth wear was defined as pathological if the teeth became so worn that they do not function effectively or seriously mar the appearance -- before they are lost through other causes -- or the patient dies . Results from inter - and intra-reproducibility exercises were within a range regarded as acceptable for epidemiological purposes , and the index appears simple to use clinically -- intra-orally or from models and photographs . However , some problems have been identified with the TWI , including the time necessary to apply to a whole dentition , amount of data generated and the comparisons with threshold levels for each age group ; the thresholds proposed were high , erring towards understatement rather than exaggerations of pathological wear . Full use of the index as a research tool is not feasible without computer assistance . A sign of professional confidence in this index is its adopted use by a number of different investigators in the UK looking at tooth wear prevalence and severity -LSB- 3 , 20 , 25 , 27 -RSB- , aetiology and risk -LSB- 1 , 21 -RSB- . Other researchers have used it with modifications pertaining to the particular age group being studied . Millward et al. -LSB- 18 -RSB- made adjustments to study erosion in the primary and secondary dentitions , excluding cervical surfaces . Subjects were then grouped together to produce three classifications : no or mild erosion -- no score > 1 , moderate -- at least one tooth in dentition score 2 , severe -- at least one tooth in dentition score 3 or 4 . In a survey of elderly people , Steele et al. -LSB- 31 -RSB- combined low wear scores representing small losses of enamel and used the worst surface score per tooth as an overall tooth score . Donachie and Walls -LSB- 7 , 8 -RSB- outlined various flaws in the tooth wear index as an epidemiological tool in the ageing population and suggested a need to increase the sensitivity of TWI at extremes of tooth wear , to take account of the capacity of the elderly to have adequate function in cases of significant wear . They suggested altering threshold values , amplifying scoring criteria and creating a sixth point to distinguish between exposure of secondary dentine and frank pulp exposure . Development of indices Many other indices have been proposed for measuring erosive tooth wear -LSB- 2 , 14 , 15 , 17 , 23 -RSB- which have their roots in the indices of Eccles -LSB- 10 -RSB- and Smith and Knight -LSB- 30 -RSB- . Linkosalo and Markkanen -LSB- 15 -RSB- utilised a qualitative index with listed diagnostic criteria to confirm lesions as erosive and a four-scale grading of severity , relating to involvement of dentine . Their scoring system was modified by Lussi et al. -LSB- 17 -RSB- to create an erosive index that has been used widely by European workers to score the facial , lingual and occlusal surfaces of all teeth except the third molars -LRB- Table 3 -RRB- . Table 3Erosion index according to Lussi -LSB- 16 , 17 -RSB- SurfaceScoreCriteriaFacial0No erosion . Surface with a smooth , silky glazed appearance , possible absence of developmental ridges1Loss of surface enamel . Intact enamel cervical to the erosive lesion ; concavity on enamel where breadth clearly exceeds depth , thus distinguishing it from toothbrush abrasion . Undulating borders of the lesion are possible and dentine is not involved2Involvement of dentine for less than half of tooth surface3Involvement of dentine for more than half of tooth surfaceOcclusal/lingual0No erosion . Surface with a smooth , silky glazed appearance , possible absence of developmental ridges1Slight erosion , rounded cusps , edges of restorations rising above the level of adjacent tooth surface , grooves on occlusal aspects . Loss of surface enamel . Dentine is not involved2Severe erosions , more pronounced signs than in grade 1 . Dentine is involved O'Sullivan -LSB- 23 -RSB- proposed a new index for the measurement of erosion specifically in children . The index was qualitative with a broad attempt at quantification noting whether less or more than half of the surface was affected . Every tooth was examined and assigned a three-digit score relating to the site of erosion , severity -LRB- grade 0 -- 5 -RRB- and area of surface affected . O'Brien -LSB- 22 -RSB- reported the use of a partial recording system for measuring erosion in children in UK children 's dental health surveys , where only the facial and lingual surfaces of the primary and permanent maxillary incisor teeth were scored for erosion . Again , the criteria were mostly qualitative and descriptive , with a broad attempt made to quantify the area involved . Bardsley et al. -LSB- 2 -RSB- pioneered a new , simplified version of TWI -LSB- 30 -RSB- when carrying out epidemiological studies on large numbers of adolescents in North West England -LRB- Table 4 -RRB- . Tooth wear scoring was essentially dichotomised into the presence or absence of dentine , with even cupping of dentine scoring one . A partial recording system was used , collecting data from 40 surfaces including occlusal surfaces of the four first molar teeth and the labial , incisal and lingual -- palatal surfaces of the six upper and lower anterior teeth . Table 4Simplified scoring criteria for TWI -LSB- 2 -RSB- ScoreCriteria0No wear into dentine1Dentine just visible -LRB- including cupping -RRB- or dentine exposed for less than 1/3 of surface2Dentine exposure greater than 1/3 of surface3Exposure of pulp or secondary dentine However , despite calibration and training , difficulties were experienced diagnosing dentine exposure in the epidemiological field and there is some debate as to the significance of dentinal cupping when exposed dentine does not relate to significant amounts of tissue loss -LSB- 12 -RSB- . In a recent study of Ganss et al. -LSB- 12 -RSB- , teeth were visually and histologically examined for presence of exposed dentine , and the correlation in accuracy between the two examinations was poor . The diagnosis of exposed dentine is obviously important but may not be accurate from visual examination alone . Oilo et al. -LSB- 24 -RSB- concentrated on a different type of scoring system , with criteria based on treatment need . They criticised the use of indices that used a nonlinear scoring method , claiming calculated mean wear scores can be misleading . Their index was based on Ryge and Snyder 's -LSB- 28 -RSB- system for evaluating the quality of restorations and had five categories divided into two broad camps ; Romeo , Sierra and Mike were satisfactory , whilst Tango and Victor indicated unacceptable levels of wear requiring treatment . All groups except Romeo were subdivided according to degree of dentine exposed and clinical findings such as pain , sensitivity and fracture of restorations , giving the impression of a cumbersome system . Dahl et al. -LSB- 6 -RSB- modified it with the introduction of even more categories , with an aim to establish subjective dental criteria for present and future evaluations of tooth wear and the need for treatment . In practice , these indices require experience for reliable use ; individuals with differing clinical backgrounds will not get consistent , objective results . Indices that attempt to visualise , measure and monitor the amount of worn enamel or exposed dentine by difficult direct clinical interpretation -LSB- 13 -RSB- and indirectly on accurate , serial study casts which must be retained -LSB- 5 , 11 , 29 , 32 -RSB- have been described . Larsen et al. -LSB- 14 -RSB- recommended a new clinical index based on a combination of clinical examination , photographs and study casts , with complicated qualitative and quantitative criteria . Plaque-free teeth were clinically examined and photographed prior to taking silicone impressions for epoxy resin casts . They considered clinical and photographic data to be supplemental with final wear classification based on visual inspection of casts at × 10 magnification . Each tooth surface was scored , with six grades of erosion severity modelled from Smith and Knight -LSB- 30 -RSB- ; the index and its criteria are complicated and time consuming . Conclusion Review of the literature on indices for tooth wear -LRB- or erosion -RRB- is confusing ; there are too many indices proposed and used , with lack of standardisation in terminology . There are many epidemiological studies reported , but it is difficult to quantify the increases in prevalence reported internationally , as results are not easily comparable . It is doubtful whether any of the indices described are sensitive enough to monitor all but the most severe changes in tooth wear clinically and these can not be used to measure a rate of wear -LSB- 19 -RSB- . It is a challenge to try to develop a simple index that can be used clinically to assess progression of wear . To date , there is not one ideal index that can be used for epidemiological prevalence studies , clinical staging and monitoring , and it may be necessary to accept that one simple index does not yet exist to meet all requirements of both clinical and research teams . There should , however , be an aim for indices that can be relevant to both fields and can be used internationally in order to strengthen knowledge of dental erosion .

O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


Determination

of

myocardial

energetic

output

for

cardiac

rhythm

pacing

This

research

is

aimed

to

the

determination

of

the

changes

in

the

cardiac

energetic

output

for

three

different

modes

of

cardiac

rhythm

pacing

The

clinical

investigation

of

thirteen

patients

with

the

permanent

dual-chamber

pacemaker

implantation

was

carried

out

The

patients

were

taken

to

echocardiography

examination

conducted

by

way

of

three

pacing

modes

-LRB-

AAI

VVI

and

DDD

-RRB-

The

myocardial

energetic

parameters

the

stroke

work

index

-LRB-

SWI

-RRB-

and

the

myocardial

oxygen

consumption

-LRB-

-RRB-

are

not

directly

measurable

however

their

values

can

be

determined

using

the

numerical

model

of

the

human

cardiovascular

system

The

hemodynamical

model

-LRB-

pulsating

type

-RRB-

of

the

human

cardiovascular

system

was

used

for

the

numerical

simulation

of

the

changes

of

myocardial

workload

for

cardiac

rhythm

pacing

The

model

was

fitted

by

well-measurable

parameters

for

each

patient

The

calculated

parameters

were

compared

using

the

two-tailed

Student

's

test

The

differences

of

SWI

and

between

the

modes

AAI

and

VVI

and

the

modes

DDD

and

VVI

are

statistically

significant

-LRB-

P

-RRB-

On

the

other

hand

the

hemodynamic

effects

for

the

stimulation

modes

DDD

and

AAI

are

almost

identical

i.e.

the

differences

are

statistically

insignificant

-LRB-

P

-RRB-

Introduction

The

medical

management

of

cardiovascular

diseases

especially

of

arrhythmia

has

become

increasingly

reliant

upon

the

use

of

implanted

electronic

devices

for

the

treatment

of

bradycardia

or

tachycardia

-LRB-

Winters

et

al.

Gregoratos

et

al.

-RRB-

The

simple

pacemakers

of

the

gave

way

to

the

more

advanced

devices

capable

of

real-time

diagnosis

of

arrhythmia-related

disorders

and

their

treatment

The

pacemaker

technology

and

clinical

practice

permits

the

use

of

either

single-chamber

ventricular

pacemakers

or

dual-chamber

pacemakers

for

patients

who

require

cardiac

pacing

in

some

indications

The

single-chamber

ventricular

pacemakers

are

less

expensive

and

their

implantation

is

simpler

than

the

implantation

of

the

dual-chamber

pacemakers

Several

randomized

studies

comparing

the

dual-chamber

physiological

pacing

to

the

ventricular

pacing

-LRB-

Mattioli

et

al.

Connolly

et

al.

Lamas

et

al.

-RRB-

have

shown

that

the

physiological

pacing

was

more

beneficial

in

some

subgroup

of

patients

despite

the

fact

that

both

variants

caused

mortality

stroke

and

heart

failures

were

no

significant

differences

Clinical

studies

focusing

on

the

quality

of

life

with

respect

to

the

type

of

the

pacing

system

implantation

were

also

conducted

The

results

of

the

studies

confirmed

that

the

implantation

of

a

permanent

pacemaker

improves

health

and

quality

of

life

The

quality-of-life

benefits

associated

with

dual-chamber

pacing

as

compared

with

the

ventricular

pacing

were

observed

only

in

the

subgroup

of

patients

with

the

sinus-node

dysfunction

-LRB-

Lamas

et

al.

-RRB-

The

DAVID

trial

-LRB-

Dual

Chamber

and

VVI

Implantable

Defibrillator

-RRB-

demonstrated

increase

heart

failure

hospitalisation

and

mortality

in

patients

programmed

to

the

DDDR

mode

compared

to

ventricular

backup

pacing

The

Multicenter

Automatic

Defibrillator

Implantation

Trial

II

-LRB-

MADIT

II

-RRB-

evoke

the

question

of

minimising

the

unnecessary

right

ventricular

pacing

-LRB-

Wilkoff

et

al.

Moss

et

al.

Galley

et

al.

-RRB-

The

myocardial

energy

demands

during

the

cardiac

pacing

were

studied

experimentally

-LRB-

Montgomery

et

al.

Portman

and

Ning

-RRB-

The

clinical

data

demonstrating

the

energetic

changes

during

the

pacing

on

the

patients

with

dilated

cardiomyopathy

were

shown

by

Baller

et

al.

-LRB-

-RRB-

Kerckhoffs

et

al.

-LRB-

-RRB-

carried

out

mathematical

modelling

of

the

right

ventricular

pacing

and

comparison

with

spontaneous

depolarization

In

the

present

study

we

are

using

the

numerical

model

of

the

human

cardiovascular

system

developed

in

the

Institute

of

Thermomechanics

Czech

Academy

of

Sciences

-LRB-

Převorovská

and

Maršík

-RRB-

with

the

purpose

to

find

the

parameters

of

the

myocardial

energetics

during

the

cardiac

rhythm

pacing

Methods

and

materials

Patients

For

our

research

purposes

the

patients

were

designated

on

the

basis

of

selective

criteria

The

inclusion

criteria

were

established

sick

sinus

syndrome

and

pacemaker

implantation

lasting

more

than

months

The

exclusion

criteria

were

left

ventricle

dysfunction

clinical

significant

valvular

disease

and

other

pathological

structural

heart

changes

The

patients

with

other

than

sinus

rhythm

AV

block

under

beat/min

during

stimulation

or

bad

image

quality

from

echocardiography

examination

were

also

excluded

Our

research

finally

involved

thirteen

patients

with

the

sick

sinus

syndrome

-LRB-

eight

males

and

five

females

with

the

average

age

years

ranging

years

-RRB-

These

patients

with

permanent

dual-chamber

pacemaker

implantation

were

taken

to

echocardiography

examination

Study

protocol

The

numerical

model

of

cardiovascular

system

was

used

to

calculate

the

myocardial

energetic

parameters

such

as

the

stroke

work

index

and

the

myocardial

oxygen

consumption

for

three

types

of

pacing

The

stroke

work

index

SWI

-LRB-

-RRB-

is

used

as

a

measure

of

myocardial

contractility

or

work

performed

by

the

heart

at

every

contraction

The

work

performed

by

the

heart

can

be

simply

by

the

fluid

dynamic

formula

The

stroke

work

index

of

the

left

ventricle

LVSWI

is

then

determined

by

the

stroke

volume

SV

-LRB-

ml

-RRB-

by

the

difference

of

the

mean

arterial

pressure

MAP

-LRB-

mmHg

-RRB-

and

the

pulmonary

artery

occlusion

pressure

PAOP

-LRB-

mmHg

-RRB-

-LRB-

considered

to

be

the

indirect

measure

of

the

left

atrial

pressure

-RRB-

by

the

formula

-LRB-

-RRB-

the

constant

converts

the

units

mmHg

to

BSA

-LRB-

-RRB-

is

the

body

surface

area

given

by

the

DuBois

formula

-LRB-

Wang

et

al.

-RRB-

where

BW

-LRB-

kg

-RRB-

is

the

body

weight

and

BH

-LRB-

cm

-RRB-

is

the

body

height

The

myocardial

oxygen

consumption

-LRB-

ml

-RRB-

is

calculated

by

the

relationship

proposed

by

Suga

which

is

based

on

the

time-varying

elastance

model

of

the

ventricle

This

relationship

represents

linear

correlation

between

the

total

pressure-volume

area

PVA

-LRB-

J/beat

-RRB-

and

-LRB-

ml

J

-RRB-

where

a

is

the

slope

coefficient

and

b

is

unloaded

PVA

consists

of

the

external

mechanical

work

EW

-LRB-

J/beat

-RRB-

within

the

contraction

cycle

and

the

potential

energy

PE

-LRB-

J/beat

-RRB-

The

values

EW

-LRB-

representing

the

work

done

by

the

ventricle

to

eject

blood

-RRB-

and

PE

-LRB-

the

work

against

the

viscoelastic

properties

of

the

myocardium

-RRB-

can

be

estimated

using

the

pressure-volume

loops

-LRB-

see

Fig.

-RRB-

Fig.

pressure

volume

loopsThe

following

symbols

are

used

in

Eq

ppeakS

-LRB-

Pa

-RRB-

maximal

value

of

the

systolic

ventricular

pressureppED

-LRB-

Pa

-RRB-

end-diastolic

ventricular

pressureVED

-LRB-

-RRB-

end-diastolic

ventricular

volumeVES

-LRB-

-RRB-

end-systolic

ventricular

volumeVo

-LRB-

-RRB-

ventricular

volume

at

zero

pressure

-LRB-

point

of

intersection

on

the

volume

axis

see

Fig.

-RRB-

The

input

data

for

the

numerical

model

such

as

the

anthropometrical

data

of

the

patients

-LRB-

weight

height

-RRB-

or

the

heart

frequency

were

obtained

from

their

physical

examination

The

various

model

parameters

such

as

the

calcium

sodium

potassium

channel

's

conductance

were

fitted

to

obtain

the

stroke

volume

blood

pressure

and

pulmonary

artery

pressure

established

by

the

echocardiography

examination

which

was

performed

during

the

spontaneous

heart

rhythm

and

the

AAI

VVI

DDD

pacing

modes

Each

mode

was

examined

for

stimulation

frequencies

and

beat/min

Each

examination

was

performed

min

after

the

mode

change

to

ensure

steady

state

Standard

views

of

the

parasternal

long-axis

view

and

the

Doppler

outflow

tract

across

the

aortic

valve

were

taken

using

the

Agilent

Sonos

ultrasound

device

The

stroke

volume

was

determined

from

the

left

ventricular

outflow

-LRB-

aortic

valve

-RRB-

diameter

measured

on

the

parasternal

long-axis

view

and

from

the

outflow

velocity

on

the

aortic

valve

measured

from

the

apical

five-chamber

view

-LRB-

Huntsman

et

al.

Lewis

et

al.

-RRB-

by

the

Doppler

probe

The

blood

pressure

was

measured

by

the

sphyngomanometer

for

each

stimulation

mode

Then

the

pulmonary

pressure

was

measured

by

the

Doppler

echocardiography

on

tricuspid

valve

Medical

Ethical

Committees

of

the

University

Hospital

Královské

Vinohrady

Prague

approved

the

study

protocol

and

the

informed

consent

was

obtained

from

all

patients

Mathematical

model

For

the

modelling

purposes

the

real

cardiovascular

system

was

compartmentalised

-LRB-

see

Fig.

-RRB-

The

hemodynamical

model

-LRB-

pulsating

type

-RRB-

of

the

human

cardiovascular

system

imitating

the

electrochemical

and

mechanical

activity

of

the

heart

muscle

was

used

for

the

numerical

simulation

of

the

myocardial

workload

changes

during

the

cardiac

rhythm

pacing

Fig.

of

the

human

cardiovascular

system

applied

to

heart

workload

calculations

The

system

is

approximated

by

twenty-four

compartments

which

are

characterized

by

elasticity

resistivity

and

transfer

of

the

relevant

chemical

components

The

pulsating

heart

consists

of

the

following

compartments

RA

Right

Atrium

RV

Right

Ventricle

LA

Left

Atrium

LV

Left

Ventricle

The

pulmonary

circuit

includes

compartments

representing

the

pulmonary

artery

-LRB-

PA

-RRB-

arteries

-LRB-

Paa

-RRB-

capillaries

-LRB-

Pc

-RRB-

postcapillary

venules

-LRB-

Pvv

-RRB-

and

pulmonary

veins

-LRB-

PV

-RRB-

Systemic

circuit

connects

the

aorta

-LRB-

Ao

-RRB-

systemic

arteries

-LRB-

Saa

-RRB-

capillaries

-LRB-

Sc

-RRB-

head

arteries

-LRB-

HA

-RRB-

capillaries

-LRB-

Hc

-RRB-

and

head

veins

-LRB-

HV

-RRB-

In

addition

the

systemic

circuit

includes

the

coronary

circulation

with

coronary

arteries

-LRB-

CA

-RRB-

capillaries

-LRB-

Cc

-RRB-

veins

-LRB-

CV

-RRB-

shunt

-LRB-

CS

-RRB-

and

also

the

bronchial

circulation

with

bronchial

arteries

-LRB-

BA

-RRB-

left

bronchial

veins

-LRB-

BVL

-RRB-

capillaries

-LRB-

BRc

-RRB-

and

right

bronchial

veins

-LRB-

BVR

-RRB-

The

compartments

of

the

pulmonary

and

systemic

blood

circulation

are

connected

in

series

with

the

four

pulsating

heart

compartments

The

suggested

model

describes

the

one-dimensional

flow

of

incompressible

blood

through

the

network

of

elastic

blood

vessels

The

heart

compartments

are

considered

to

be

made

of

anisotropic

and

viscoelastic

incompressible

material

The

mathematical

formulation

describing

the

blood

flow

in

the

cardiovascular

system

is

based

on

the

mass

energy

and

momentum

balance

The

behaviour

of

the

cardiovascular

system

is

described

by

the

heart

rate

and

by

its

hemodynamical

variables

i.e.

blood

pressure

volume

and

flow

and

by

the

cardiovascular

parameters

such

as

the

compliances

and

resistances

in

the

corresponding

compartments

The

blood

inertia

and

physicochemical

variables

such

as

the

cardiac

action

potential

and

the

calcium

sodium

and

potassium

ion

concentrations

are

included

to

support

more

accurate

performance

of

the

cardiovascular

system

The

Beeler-Reuter

model

-LRB-

Beeler

and

Reuter

-RRB-

describes

the

behaviour

of

excitable

cardiac

cells

Discussion

and

conclusions

All

experimental

results

obtained

with

the

investigated

patients

and

simulated

values

resulting

from

the

applied

numerical

model

were

elaborated

by

the

following

statistical

analysis

We

use

the

hypothesis

to

demonstrate

the

agreement

or

discrepancy

between

the

values

of

the

myocardial

energetic

parameters

-LRB-

stroke

work

index

myocardial

oxygen

consumption

-RRB-

obtained

by

the

numerical

simulation

for

the

three

pacing

modes

All

comparisons

of

the

data

were

made

by

the

two-tailed

Student

's

test

The

statistical

analysis

was

performed

with

significance

level

and

the

degree

of

freedom

df

The

data

for

the

stroke

work

index

are

expressed

as

the

mean

value

standard

deviation

The

calculated

values

of

the

stroke

work

index

at

the

three

pacing

modes

are

shown

in

the

Fig.

It

was

shown

that

the

differences

in

the

compared

pacing

modes

AAI

and

VVI

and

the

modes

DDD

and

VVI

are

statistically

significant

-LRB-

P

-RRB-

The

comparison

of

the

stimulation

modes

DDD

and

AAI

shows

that

the

differences

are

statistically

insignificant

-LRB-

P

-RRB-

Fig.

work

index

calculated

by

the

numerical

model

of

cardiovascular

and

respiratory

system

The

calculated

values

of

the

myocardial

oxygen

consumption

for

three

pacing

modes

are

demonstrated

in

the

Fig.

The

myocardial

efficiency

which

is

an

important

factor

for

heart

performance

changes

according

to

the

stimulation

mode

The

changes

resulting

from

the

hemodynamical

model

fitting

by

the

well-measurable

data

i.e.

heart

rate

stroke

volume

systolic

pulmonary

artery

pressure

systolic

and

diastolic

aortic

pressure

The

conclusion

is

that

the

difference

between

the

modes

AAI

and

VVI

and

the

modes

DDD

and

VVI

is

statistically

significant

-LRB-

P

-RRB-

The

statistical

analysis

of

the

AAI

and

DDD

modes

indicates

that

the

compared

data

are

not

significantly

different

-LRB-

P

-RRB-

Fig.

oxygen

consumption

calculated

by

the

numerical

model

of

cardiovascular

system

in

various

pacemaker

modes

From

the

comparison

of

the

obtained

numerical

values

for

the

stroke

work

index

between

the

AAI

and

VVI

pacing

modes

and

between

DDD

and

VVI

modes

it

follows

that

the

differences

are

statistically

significant

-LRB-

P

-RRB-

The

results

are

consistent

with

the

published

data

-LRB-

Leclercq

et

al.

Nielsen

et

al.

-RRB-

The

results

of

the

statistical

analysis

for

the

AAI

and

DDD

stimulation

modes

show

that

the

differences

between

the

compared

groups

are

statistically

insignificant

-LRB-

P

-RRB-

These

results

are

consistent

with

the

clinical

observation

where

can

achieve

a

similar

clinical

outcome

in

AAI

and

DDD

modes

in

this

group

of

patients

-LRB-

Masumoto

et

al.

-RRB-

The

increase

of

the

stroke

work

index

in

AAI

or

DDD

modes

was

caused

by

saving

the

AV

synchrony

in

the

patient

with

the

normal

left

ventricle

systolic

function

During

the

AAI

pacing

mode

the

implantation

of

the

pacemaker

is

easier

This

fact

supports

the

clinical

superiority

of

the

AAI

mode

against

the

DDD

mode

in

the

sick-sinus

group

patients

with

preserved

left

ventricular

function

The

results

of

the

comparison

of

the

obtained

numerical

values

for

the

myocardial

oxygen

consumption

between

the

AAI

and

VVI

and

between

DDD

and

VVI

modes

show

that

the

difference

between

the

modes

is

statistically

significant

-LRB-

P

-RRB-

The

increase

of

the

myocardial

oxygen

consumption

corresponds

to

the

increase

of

the

stroke

work

index

From

the

comparison

of

AAI

and

DDD

modes

we

can

see

that

the

difference

is

statistically

insignificant

-LRB-

P

-RRB-

The

insufficient

number

of

the

designated

subjects

gives

the

limitation

of

our

research

study

because

very

strict

exclusion

criteria

exist

for

the

concomitant

disease

Many

pacemaker

patients

were

not

eligible

for

echocardiography

examination

because

they

had

hypertension

left

ventricle

dysfunction

or

valvular

disease

We

conclude

that

mathematical

modelling

of

the

cardiovascular

system

is

a

recommended

method

for

the

estimation

of

the

myocardial

energy

demand

in

patients

with

heart

diseases

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O 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Femara ® and the future : tailoring treatment and combination therapies with Femara Long-term estrogen deprivation treatment for breast cancer can , in some patients , lead to the activation of alternate cellular pathways , resulting in the re-emergence of the disease . This is a distressing scenario for oncologists and patients , but recent intensive molecular and biochemical studies are beginning to unravel these pathways , revealing opportunities for new targeted treatments . Far from making present therapies redundant , these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance . Letrozole , one of the most potent aromatase inhibitors , is the ideal candidate for combination therapy ; indeed , it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting . Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments . Microarray gene profiling studies , designed to detect letrozole-responsive targets , are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs . Introduction The proliferative , invasive , and metastatic potential of breast tumors may be largely predetermined at an early stage in the course of disease , whereas genetic alterations that accumulate during progression from in situ to metastatic disease are unpredictable and result in specific phenotypic changes and loss of sensitivity to treatments -LSB- 1 -RSB- ; for example , although the estrogen receptor-positive -LRB- ER + -RRB- phenotype may be largely stable over time -LSB- 2 -RSB- , hormone therapy-sensitive breast tumors may develop resistance and progress to a hormone-independent state -LSB- 3 -RSB- . In addition , progression to hormone independence may be associated with alterations in the expression of other regulatory genes , such as human epidermal growth factor receptor 2 -LRB- HER2 -RRB- -LSB- 4 -RSB- . In the clinical setting , a quantitative decrease in ER expression was found in over 900 patients with primary breast cancer when HER2 was amplified -LSB- 5 -RSB- . Recent advances in translational research studies have highlighted the complexity of ER signaling , including differential roles for the ERα and ERβ subtypes -LSB- 6 -RSB- , and multiple regulatory interactions between steroid hormone , growth factor , and other tyrosine kinase signaling pathways -LSB- 7 -- 10 -RSB- . Greater understanding of tumor biology is beginning to help physicians to individualize treatment selection based on clinical , pathologic , molecular , and genetic profiling , and to rationally design novel combinations to improve efficacy and safety . This article reviews novel approaches with the more potent third-generation aromatase inhibitor -LRB- AI -RRB- letrozole -LRB- Femara ® ; Novartis Pharmaceuticals -RRB- in combination strategies with agents targeting other growth factor pathways . The review explores the hypothesis that combining letrozole with specifically targeted therapies may delay or overcome endocrine therapy resistance in postmenopausal women with hormone receptor-positive -LRB- HR + -RRB- breast cancer . Endocrine therapy resistance It is well established that breast cancer cells can adapt to low concentrations of estrogen by becoming hypersensitive to estradiol -LSB- 11 -RSB- . Long-term exposure to tamoxifen induces hypersensitivity to estradiol -LSB- 12 -RSB- and this adaptive change can result in resistance to endocrine therapy -LSB- 13 -RSB- . It has been postulated that tamoxifen is more susceptible than AIs to this phenomenon because of its intrinsic agonist properties -LSB- 12 -RSB- . Moreover , it has been suggested that highly potent AIs are required to block estrogen synthesis when breast cancer tumors are hypersensitive to small amounts of estradiol -LSB- 13 -RSB- . Recent research has provided a compelling explanation for the development of resistance -LSB- 13 , 14 -RSB- . Experiments using MCF-7 and other breast cancer model systems have identified alternative intracellular signaling pathways used by breast tumors to enhance and activate ER signaling , thus allowing cells to escape from the inhibitory effects of endocrine therapies -LSB- 15 , 16 -RSB- . It has been shown that long-term estrogen deprivation upregulates ERα and growth factor signaling pathways such as mitogen-activated protein kinase -LRB- MAPK -RRB- , phosphatidylinositol 3-kinase -LRB- PI3K -RRB- , and the mammalian target of rapamycin -LRB- mTOR -RRB- pathways -LSB- 14 -- 19 -RSB- . Of note , Jeng et al. -LSB- 15 -RSB- reported that a specific inhibitor of MAPK -LRB- PD98059 -RRB- could block the elevation of activated MAPK observed in MCF-7 cells exposed to long-term estrogen deprivation . Furthermore , studies in both wild-type and long-term estrogen-deprived MCF-7 cells suggested that mTOR has a key role in breast cancer cell proliferation and showed that mTOR inhibition by farnesylthiosalicylic acid -LRB- FTS -RRB- can reduce proliferation and induce apoptosis -LSB- 19 -RSB- . Growth factor pathways The role of nongenomic pathways has been highlighted in resistance to antiestrogen therapy -LSB- 20 -RSB- . Classically , estrogens bind to nuclear ER to enhance transcription of genes important in breast cancer proliferation and survival -LRB- genomic pathway -RRB- -LSB- 21 -RSB- ; however , estrogen may also act through ER located in or near the cell membrane -LSB- 22 -RSB- . Nongenomic actions include activation of various growth signaling pathways , including MAPK -LSB- 15 -RSB- . In addition , ER may indirectly activate epidermal growth factor receptors -LRB- EGFR -RRB- via coactivators , including src , leading to activation of EGFR -LSB- 23 -- 25 -RSB- . Subsequently , dimerization of activated EGFR with other HER family receptors , particularly HER2 , activates intracellular signaling pathways , which in turn may enhance nuclear ER signaling -LSB- 4 -RSB- , thus completing a vicious cycle of events . Cross-talk between ER and HER2 pathways has been implicated in clinical resistance to tamoxifen -LSB- 4 , 7 -RSB- . Shou et al. -LSB- 4 -RSB- reported that tamoxifen behaves as an agonist in MCF-7 breast cancer cells that express high levels of the coactivator AIB1 -LRB- src3 -RRB- and HER2 , resulting in de novo resistance . Interestingly , addition of an anti-EGFR tyrsosine kinase inhibitor eliminated cross-talk and restored tamoxifen 's antitumor activity -LSB- 4 -RSB- . It has been postulated that AIs may be more effective than selective estrogen-receptor modulators -LRB- SERMs -RRB- -LSB- 26 -RSB- because they can block genomic and nongenomic activities of ER -LSB- 27 -RSB- . Elucidation of ER biology and interactions with growth factor signaling pathways will help to identify potential therapeutic targets for HR + breast cancer -LSB- 4 , 28 -RSB- . Combination therapy Several strategies to inhibit growth factor signaling and signal transduction in breast cancer have been tested in the preclinical setting -LRB- see Fig. 1 -RRB- . The humanized monoclonal antibody trastuzumab specifically targets the extracellular domain of HER2 -LSB- 29 , 30 -RSB- . Amplification of HER2 occurs in approximately 25 % of breast tumors and is associated with more aggressive disease and a poor prognosis -LSB- 31 -RSB- . Trastuzumab has been shown to restore sensitivity to estrogen and tamoxifen in estrogen-independent HER2-transduced MCF-7 cells -LSB- 32 -RSB- . Furthermore , trastuzumab blocked HER2 heterodimer formation and phosphorylation , reduced ERK1/2 activity , and strongly inhibited cell growth in MCF-7 cells overexpressing EGFR and HER2 and resistant to tamoxifen -LSB- 18 -RSB- . Of note , synergistic inhibition of the BT474 breast cancer cell line was observed with trastuzumab and the HER dimerization inhibitor pertuzumab -LSB- 33 -RSB- , which targets a different domain of HER2 -LSB- 34 -RSB- . The combination of tamoxifen and trastuzumab in ER + , HER2 + BT-474 cells resulted in synergistic growth inhibition due to the enhancement of cell accumulation in the G0 -- G1 phase of the cell cycle , and a decreased number of cells in S phase -LSB- 35 -RSB- . Fig. 1Cross-talk between signal transduction pathways and ER signaling in endocrine resistant breast cancer , with opportunities for targeted intervention . Estrogen -LRB- E2 -RRB- - liganded ER activates E2-regulated genes in classical pathway -LRB- thick black arrow -RRB- , but following long-term tamoxifen therapy resistance can develop with bidirectional cross-talk -LRB- gray arrows -RRB- between ER and growth factor receptors , with association of membrane bound ER with growth factor receptors , and/or IGFR or EGFR/HER2 activation of ER phosphorylation . Stars show various targeted therapies . AI aromatase inhibitor , SERD selective estrogen receptor down-regulator , MoAb monoclonal antibodies , TKI tyrosine kinase inhibitor , FTI farnesyltransferase inhibitor , CCI cell cycle inhibitor . Reprinted from -LSB- 28 -RSB- with permission from the American Association for Cancer Research HER signaling pathways can also be targeted by inhibiting receptor phosphorylation by intracellular tyrosine kinases -LSB- 36 -RSB- . Gefitinib and erlotinib both specifically inhibit the EGFR tyrosine kinase and have demonstrated inhibitory activity in models of hormone-resistant breast cancer -LSB- 37 , 38 -RSB- . Interestingly , pretreatment of HER2 + , hormone-resistant MCF-7 cells with gefitinib eliminated the agonist effects of tamoxifen and restored its antitumor activity -LSB- 4 -RSB- . In ER + breast tumors , targeted therapy with single-agent gefitinib was found to be less effective than endocrine therapy -LSB- 39 -RSB- ; however , tamoxifen plus gefitinib had greater activity than tamoxifen alone in vivo in hormone-sensitive cells -LSB- 39 -RSB- . Data also support the use of EGFR tyrosine kinase inhibitors in combination with HER2 antibodies , such as trastuzumab , against breast tumors that express EGFR and high levels of HER2 -LSB- 37 -RSB- . Alternatively , the tyrosine kinase inhibitor lapatinib provides single-agent targeting of both EGFR and HER2 -LSB- 40 , 41 -RSB- . Using a panel of 31 human breast tumors , Konecny et al. -LSB- 41 -RSB- showed that response to lapatinib was significantly correlated with HER2 expression and its ability to inhibit HER2 , Raf , Akt , and ERK phosphorylation . In vivo studies showed that lapatinib had a sustained antitumor effect that was further prolonged by combination with trastuzumab -LSB- 41 -RSB- . Another study showed that the combination of AEE788 -LRB- an EGFR/HER2 tyrosine kinase inhibitor -RRB- with letrozole enhanced antiproliferative effects of these agents by 20 -- 30 % in MCF-7 and ZR75 .1 cell lines and by 60 -- 70 % in the BT474 cell line -LSB- 42 -RSB- . In a model system of acquired resistance to letrozole , AEE788 partially restored sensitivity to letrozole , whereas rapamycin was not effective , suggesting that letrozole resistance and mTOR activation may not be connected in this model -LSB- 43 -RSB- . The authors concluded that inhibition of both HER2-mediated signaling and mTOR-dependent translation may restore responsiveness to letrozole in breast cancer refractory to this AI -LSB- 43 -RSB- . Strategies to inhibit downstream signal pathways have also been developed . Farnesyl transferase inhibitors block the first and most important step in the activation of Ras signaling pathways -LSB- 44 -RSB- . Aberrant function of the Ras signal transduction pathway is common in breast cancer as a result of upstream activation via HER2 or EGFR -LSB- 45 -RSB- . The farnesyl transferase inhibitor R11577 -LRB- tipifarnib -RRB- was found to have antitumor activity against MCF-7 xenografts -LSB- 44 -RSB- . Another interesting therapeutic target is mTOR , a central regulator of G1 cell cycle protein synthesis , that precedes commitment to normal cellular replication -LSB- 46 -RSB- . Treatment of MCF-7 Arom-1 cells with letrozole and the mTOR inhibitor RAD001 resulted in a further 50 % reduction in proliferation compared with letrozole alone -LSB- 47 -RSB- . Another set of experiments , developed to test the hypothesis that Akt kinase confers resistance to endocrine therapy through suppression of ASK1/JNK pathway , showed that combining RAD001 with letrozole restored activation of the ASK/JNK pathway and increased the sensitivity of MCF-7 cells with constitutively active Akt to endocrine therapy -LSB- 48 -RSB- . Studies have also targeted the selective estrogen receptor down-regulator -LRB- SERD -RRB- fulvestrant , which indirectly inhibits growth factor pathways by down-regulating ER -LSB- 3 -RSB- . In MCF-7Ca xenografts , combined treatment with fulvestrant and letrozole prevented increases in HER2 and activation of MAPK and inhibited tumor growth -LSB- 49 -RSB- . These preclinical models -LRB- see Table 1 -RRB- suggest that treatments to reduce growth factor signaling pathways may be useful in the treatment of human breast cancer -LSB- 52 -RSB- . Specifically , novel combination strategies may be developed to prevent or delay the development of endocrine therapy resistance -LSB- 3 , 39 -RSB- , to restore sensitivity to endocrine therapy -LSB- 53 -RSB- , and to treat hormone-resistant tumors -LSB- 18 , 46 -RSB- . Anti-vascular endothelial growth factor -LRB- VEGF -RRB- therapy with bevacizumab may be able to overcome resistance to endocrine therapy and improve efficacy in HR + metastatic breast cancer -LSB- 54 -RSB- , and preclinical models have shown that the estrogen-induced increase in VEGF expression may be counteracted by aromatase inhibition . Inhibition of growth factor signaling and angiogenesis pathways may be rationally combined with conventional endocrine strategies for breast cancer -LSB- 4 , 35 , 50 , 55 , 56 -RSB- . Table 1Summary of letrozole in combination with growth factor signaling inhibitors in preclinical modelsTarget for growth factor inhibitorCombination regimenSummary of key findingsReferencesEGFR/HER2Letrozole + AEE78Combination enhanced antiproliferative effects in MCF-7 -LRB- ER + HER2 − -RRB- , ZR75 .1 -LRB- ER + HER2 + -RRB- , and BT474 -LRB- ER + HER2 + -RRB- cell lines -LSB- 42 -RSB- Partial restoration of growth inhibitory effects of letrozole in refractory cell lines -LRB- LTLT-Ca ; long-term letrozole treated -RRB- -LSB- 43 -RSB- mTORLetrozole + RAD001 -LRB- everolimus -RRB- Letrozole + RAD001 significantly increased apoptosis compared with either agent alone -LSB- 50 -RSB- Co-treatment increased sensitivity to letrozole in resistant MCF-7 cells with constitutively active Akt -LSB- 48 -RSB- RAD001 increased antiproliferative effects of letrozole in MCF-7 Arom 1 cell line -LSB- 47 -RSB- IGFBPLetrozole + rhIGFBP-3rhIGFBP-3 Enhanced letrozole activity in MCF-7-Ca cells in vitro and in vivo -LSB- 51 -RSB- rhIGFBP recombinant human insulin-like growth factor binding protein The activity of inhibitors of growth factor signaling depends on the presence of specific cellular aberrations , such as overexpression of HER2 -LSB- 57 -RSB- or mutations of EGFR -LSB- 58 -RSB- . Consequently , targeted therapies may have limitations as single agents because the target is active in a restricted subset of patients , and breast tumors may undergo adaptive changes to render the target redundant . Since tamoxifen exhibits agonist effects on breast cancer cells exposed to long-term estrogen deprivation -LSB- 12 -RSB- , it may be better to combine AIs with inhibitors of growth factor signaling . Letrozole is one of the most potent AIs and is one of the most extensively studied AIs in combination with new agents -LRB- see Table 1 -RRB- . Clinical trials of letrozole in combination with inhibitors of growth factor signaling pathways Based on results from preclinical studies , several clinical trials of novel combinations are under way , with the aim of improving efficacy and safety of endocrine therapy with letrozole -LRB- see Table 2 -RRB- . Many of these trials are being conducted in patients with locally advanced or metastatic breast cancer who have failed prior tamoxifen or have a suboptimal response to letrozole . This represents a high-risk , difficult-to-treat population who are candidates for cytotoxic chemotherapy . Preliminary results have shown that letrozole can be safely combined with trastuzumab , lapatinib , everolimus , tipifarnib , bevacizumab , and imatinib . It is too early , however , to make definitive conclusions about efficacy and clinical benefits with these novel combinations . Table 2Clinical studies of letrozole and inhibitors of growth factor signaling pathwaysTarget for growth factor inhibitorCombination regimenStudy type and patient populationSummary of key findingsReferencesHER2Letrozole + trastuzumabPhase IIMetastatic BC , postmenopausal , ER + and/or PR + , HER2 + -LRB- n = 31 -RRB- ORR 26 % ; median TTP 5.8 months -LSB- 59 -RSB- EGFR/HER2Letrozole + lapatinibPhase IAdvanced BC -LRB- ER + or PR + -RRB- or other tumors -LRB- n = 36 -RRB- Letrozole + lapatinib safely combined at recommended single agent doses -LSB- 60 -RSB- Phase IIIAdvanced/metastatic BC -LRB- n = 1,200 target accrual -RRB- Ongoing trial ; primary end point TTP -LSB- 61 -RSB- mTORLetrozole + RAD-001 -LRB- everolimus -RRB- Phase IbAdvanced BC pts with suboptimal response to letrozole -LRB- n = 6 -RRB- RAD001 pharmacokinetics not altered by letrozole -LSB- 62 -RSB- Phase IIPresurgical therapy in patients with newly diagnosed ER + BC -LRB- n = 255 planned -RRB- Ongoing trial of efficacy and biomarkers -LSB- 63 -RSB- Letrozole + CCI-779 -LRB- temsirolimus -RRB- Phase IIAdvanced or metastatic BC -LRB- n = 92 -RRB- No difference in ORR , but trend to longer PFS with letrozole + temsirolimus -LRB- 30 mg -RRB- -LSB- 64 -RSB- Phase IIIAdvanced or metastatic breast cancer -LRB- n = 1,236 planned -RRB- Terminated -LSB- 65 -RSB- Farnesyl transferaseLetrozole + tipifarnib Randomized phase IIAdvanced or metastatic BC that has progressed on tamoxifen -LRB- n = 121 -RRB- ORR 38 % for letrozole and 26 % for letrozole + tipifarnib -LRB- NS -RRB- -LSB- 66 -RSB- Randomized , placebo-controlled phase IIAdvanced or metastatic BC that has progressed on antiestrogen therapy -LRB- n = 120 -RRB- No longer recruiting -LSB- 67 -RSB- VEGFLetrozole + bevacizumab -LRB- anti-VEGF monoclonal antibody -RRB- Phase IIMetastatic BC , postmenopausal , candidates for AI -LRB- n = 28 -RRB- Letrozole + bevacizumab is well-tolerated -LSB- 54 -RSB- Endocrine therapy -LRB- tamoxifen or aromatase inhibitor -RRB- + bevacizumabPhase III placebo-controlledFirst-line therapy in ER + / PR + Metastatic BC -LRB- n = TBC -RRB- Planned trialPlanned CALGB trial -LSB- 54 -RSB- Bcr-ablLetrozole + imatinibPhase IIMetastatic BC , postmenopausal ER + and/or PR + -LRB- n = 15 -RRB- Letrozole + imatinib is feasible -LSB- 68 -RSB- BC breast cancer , ORR overall response rate , TTP time to progression , PFS progression-free survival , AI aromatase inhibitor , TBC to be confirmed In a clinical trial -LSB- 69 -RSB- designed to test whether combination therapy with letrozole and bevacizumab was possible , patients with ER + or progesterone receptor-positive -LRB- PR + -RRB- metastatic or locally advanced breast cancer were treated with letrozole -LRB- 2.5 mg daily -RRB- and bevacizumab -LRB- 15 mg/kg IV every 3 weeks -RRB- -LSB- 54 -RSB- . The majority of patients had received prior therapy with a nonsteroidal AI . The combination of bevacizumab and letrozole was found to be well-tolerated . Common drug-related toxicities reported were hypertension , fatigue , headache , and joint pain . Median progression-free survival was reported to be 10 months , and this compares favorably with the published data on median time to progression with first-line letrozole -LRB- 9.4 months -RRB- -LSB- 70 -RSB- . However , analysis of efficacy and biomarker data was confounded by the long duration of prestudy aromatase inhibition -LSB- 54 , 71 -RSB- . Nevertheless , when the data were corrected for duration of previous AI therapy , the study did determine that changes in circulating endothelial cell -LRB- CEC -RRB- levels may be a biomarker of response or progression on anti-angiogenic therapy -LSB- 71 -RSB- . Based on these findings , a randomized , double-blind , placebo-controlled trial of bevacizumab combined with endocrine therapy in patients with ER + or PR + metastatic breast cancer has been initiated by the Cancer and Leukemia Group B -LRB- CALGB -RRB- -LRB- see Fig. 2 -RRB- -LSB- 54 -RSB- . The primary end point of the trial is progression-free survival . Fig. 2Planned CALGB trial of first-line endocrine therapy -LRB- tamoxifen or aromatase inhibitor -RRB- with or without bevacizumab Letrozole plus trastuzumab produced durable responses in about one in four patients with ER/PR + , HER2 + metastatic breast cancer , but early progression occurred in one in two patients -LSB- 59 -RSB- . This suggests that common resistance pathways may be responsible for relapse -LSB- 59 -RSB- . Targeting multiple pathways may reduce the risk of resistance . The combination of letrozole and the dual EGFR/HER2 inhibitor lapatinib was found to be feasible and well-tolerated in a phase I study -LSB- 60 -RSB- , and this regimen is currently being compared with letrozole plus placebo in a phase III study in women with ER/PR + advanced or metastatic breast cancer -LSB- 61 -RSB- -LRB- see Fig. 3 -RRB- . Future studies will focus on finding the right combination or sequence of agents for different patients in specific treatment settings . Furthermore , studies in the neoadjuvant setting in patients with locally advanced breast cancer will allow correlative biomarker assessment , such as the proliferation marker Ki-67 , to determine the efficacy of combination therapies . For example , everolimus and letrozole are being studied as preoperative therapy of primary breast cancer in postmenopausal women -LSB- 63 -RSB- . In this phase II trial , patients are randomized to receive letrozole in combination with everolimus or placebo , an adaptive design strategy , so that identification of biomarkers can be used to optimize patient selection for a future phase III trial of first-line combination therapy in patients with advanced breast cancer . Even if a biomarker is not identified , the trial is adequately powered to demonstrate a statistically significant difference in treatment effect of the combination in the overall population . Fig. 3Letrozole and lapatinib phase III trial design . Target recruitment : 1,280 patients Combination strategies may also change the conventional approach for treatment selection based on HR status . Interestingly , it has been suggested that treatment of HER2 + , ER − metastatic breast cancer with trastuzumab may transform the tumor phenotype to become hormone responsive -LSB- 72 -RSB- . The hypothesis-generating study found that three of ten patients demonstrated ER overexpression at 9 , 12 , and 37 weeks , respectively , following the initiation of trastuzumab . Two of these patients were subsequently treated with endocrine therapy alone and one received letrozole for 3 years without evidence of progression . Further trials of letrozole used in combination with trastuzumab or sequentially in patients with HER2 + , ER − tumors appear warranted . Microarray/gene profiling studies and optimization of treatment with letrozole The growing importance of biomarkers in oncology has been reflected in the US Food and Drug Administration -LRB- FDA -RRB- , the National Cancer Institute -LRB- NCI -RRB- , and the Centers for Medicare and Medicaid Services -LRB- CMS -RRB- Oncology Biomarker Qualification Initiative -LRB- OBQI -RRB- , designed to improve the development of cancer therapies and the outcomes for cancer patients through biomarker development and evaluation -LSB- 73 -RSB- . Not only are biomarkers potentially useful as prognostic and predictive factors but they also serve as surrogate end points for long-term outcomes . For example , Dowsett et al. found that changes in Ki-67 in the neoadjuvant setting may be used to predict likely benefit -LRB- improved disease-free and overall survival -RRB- of AIs in the adjuvant setting -LSB- 74 -RSB- , potentially expediting clinical development . Therefore , identifying biomarkers that predict endocrine resistance is essential for the optimal use of letrozole . In addition , biomarker studies that help to delineate the oncogenic pathways may be particularly useful for the development of novel combination therapies with letrozole . Gene expression analysis of tumors represents a novel approach for biomarker development that promises to increase the understanding of breast cancer heterogeneity and facilitate the development of individualized treatment strategies . Microarray analysis , such as the Affymetrix Human Genome Gene Chips , is an exciting development in breast cancer diagnostics that allows the expression of genes in tumors to be quantified using RNA retrieved from breast cancer biopsies . Using cDNA microarray and unsupervised clustering analysis , ER + breast cancer can be subdivided into at least two subtypes , luminal A and luminal B , with distinct gene expression patterns and clinical outcomes -LSB- 75 -- 77 -RSB- . Supervised analysis , comparing gene expression patterns between tumors that relapsed and those that did not , generated a `` gene signature '' as an independent prognostic parameter for lymph-node negative disease -LSB- 78 , 79 -RSB- . The National Surgical Adjuvant Breast and Bowel Project -LRB- NSABP -RRB- has developed a multigene profiling assay , using reverse transcriptase polymerase chain reaction -LRB- RT-PCR -RRB- to quantify the expression of 21 genes -LSB- 80 -RSB- . The 21-gene assay -LRB- Oncotype DX , Genomic Health -RRB- can predict risk of recurrence in patients with HR + early breast cancer receiving tamoxifen -LSB- 80 , 81 -RSB- or chemotherapy -LSB- 82 -RSB- . Naderi et al. -LSB- 83 -RSB- have also reported validation of gene expression signatures that may have predictive value in the clinic . Furthermore , newly identified interactions between ER and other signaling pathways have been studied using microarray analysis -LSB- 84 , 85 -RSB- . For example , Bex1 and Bex2 genes have been identified as novel breast cancer-related genes and identify a subtype of ER + tumors associated with estrogen response and nuclear factor kappa B -LRB- NF-κB -RRB- pathways -LSB- 84 -RSB- . Advances in gene profiling will provide further insights into tumor biology and improve prediction of likely response to specific therapies in the clinic . Microarray analysis has shown to be valuable in predicting response to neoadjuvant endocrine therapy and was used in a study of neoadjuvant letrozole 2.5 mg/day administered to postmenopausal women with large operable or locally advanced breast cancers for 3 months -LSB- 86 , 87 -RSB- . Changes in patterns of gene expression were assessed from tissue samples taken at diagnosis , 14 days , and 3 months -LRB- N = 58 -RRB- . Changes in gene expression level with treatment were identified as early as 14 days and involved classical markers of estrogen action -LRB- trefoil factors 1 and 3 , LIV-1 , KIAA0101 -RRB- as well as tumor proliferation -LRB- cyclin D1 , cyclin B2 , CSK2 , cell division cycle 2 -RRB- . The objective clinical response to neoadjuvant letrozole was 71 % -LRB- N = 52 assessable -RRB- . Of note , the observed changes in gene expression , when clustered , were predictive of response in all cases except one , whereas classical markers of estrogen action were not predictive -LSB- 87 -RSB- . In another study , postmenopausal women with primary operable breast cancer were randomized to 2 weeks of presurgical treatment with letrozole 2.5 mg/day or anastrozole 1 mg/day -LSB- 88 -RSB- . Microarray gene expression profiling -LRB- Breakthrough Centre cDNA chips -RRB- of biopsies taken before and during treatment identified differences in gene expression patterns between the two AIs , although the clinical significance of these preliminary findings remains to be clarified . Itoh et al. -LSB- 89 -RSB- also found differences between letrozole , anastrozole , and tamoxifen using microarray analysis on MCF-7 cells stably transfected with the aromatase gene -LRB- MCF-7Aro -RRB- . Gene expression patterns revealed a high correlation between the AIs -LRB- letrozole and anastrozole -RRB- and a clear difference between AIs and tamoxifen -LSB- 89 -RSB- . Emerging data therefore suggest that estrogen-responsive genes are candidate biomarkers -LSB- 90 -RSB- and may be useful in the clinic as predictive factors of benefit from AI treatment -LSB- 89 -RSB- . The value of gene expression profiling is now being evaluated in prospective studies . MINDACT -LRB- Microarray In Node negative Disease may Avoid ChemoTherapy -RRB- , an ongoing three-part randomized trial of 6,000 patients with node-negative breast cancer , is comparing the efficacy of selection of breast cancer patients for adjuvant chemotherapy based on either clinical criteria or the 70-gene microarray prognosis profile -LSB- 91 -RSB- . In one part of the trial , 3,500 node-negative , HR + positive patients will be randomized to receive either 7 years of letrozole or 2 years of tamoxifen followed by 5 years of letrozole . In the US , the TAILORx Trial -LSB- 92 -RSB- is comparing hormone therapy with or without combination chemotherapy as adjuvant therapy for node-negative , ER + breast cancer . The objective of this randomized phase III trial is to determine the best individual therapy using Oncotype DX gene profiling . One of the more recent advances in transcriptional profiling addresses its potential application as an identification tool for `` oncogenic pathway signatures '' that could be used to guide targeted therapy . Oncogenic pathway signatures , developed in cell-line models , have been shown to predict sensitivity to therapeutic agents in vitro -LSB- 93 -RSB- . This offers an opportunity to identify pathway-specific drugs in endocrine therapy-resistant tumors and creates an opportunity for the rational design of combination therapy with letrozole . In addition to the RNA-based gene expression profiling approach , high throughput analysis at the DNA level , such as genome-wide microarray comparative genomic hybridization -LRB- aCGH -RRB- and DNA sequencing , has made it possible to decipher the genetic anomalies that drive a particular tumor phenotype . The use of these molecular approaches for biomarker development is still in its infancy but is now feasible with recent advances in genomic technologies . Conclusions Hormone-sensitive breast cancer can be regarded as a chronic disease with a persistent risk of escape from effective endocrine control . Activation of growth factor signaling pathways has been implicated in progression of HR + breast cancer to an estrogen-independent phenotype and the development of resistance to endocrine therapy , particularly tamoxifen . It has been hypothesized that combining endocrine therapy with targeted signal transduction inhibitors may circumvent hormone-independent signaling pathways , so that patients may experience prolonged disease control . Letrozole is one of the most potent AIs . As such , it may be more effective than tamoxifen for patients with tumor profiles associated with a high risk of developing hormone resistance -LRB- e.g. , tumors with HER2 gene amplification -RRB- and represents an ideal combination partner for agents that inhibit growth signaling pathways implicated in hormone resistance . The efficacy of letrozole is currently being investigated with a variety of signal transduction inhibitors with different mechanisms of action , including monoclonal antibodies against HER family receptors , receptor tyrosine kinase inhibitors , and downstream signaling pathway inhibitors . Gene expression profiling has been validated as a useful new tool to predict risk of relapse in patients treated with hormone therapy and chemotherapy . This approach will help physicians to identify which patient will likely benefit from specific therapies , such as letrozole . Tailoring therapy to individual patient profiles -LRB- clinical , histologic , pathologic , and genetic -RRB- will become more sophisticated in the future , helping to maximize the benefits of endocrine therapy throughout the breast cancer continuum ; letrozole will undoubtedly become an integral part of the next generation of tailored combination regimens for the treatment of breast cancer .

O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B I O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B I O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O B I O

adjuvant therapy
aromatase inhibitors
breast cancer
combination therapy
letrozole
postmenopausal