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Evaluation of prognosticfactors in stage IIA breast

tumors and their correlationwith mortality risk

Rosa Da Lima YapeFitriany Dwiandari Putri

Nur Raihan


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Introduction Breast cancer is the most frequent malignant

neoplasm among women worldwide Higher e!ciency screening programs" #etter

diagnostic image de$nition and the appropriateuse of ad%u&ant drug therapies ha&e impro&edpatient sur&i&al in the last few decades'

( long term sur&i&al patient is de$ned as one

who is still li&ing ) years after $rst #eingdiagnosed with cancer' For #reast cancer" ) and *+ year sur&i&al rates

are ,,- and ..-" respecti&ely" #oth of which arequite good'


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Breast tumors classi$ed as stage II( are tumorspresenting with local or disseminated disease inthe homolateral a/illary lymph nodes'

(round ,+- of patients sur&i&e disease free after) years0 and 2+- will die within the same timeinter&al despite the good prognosis associatedwith these cases'

3olecular signature of in&asi&e ductalcarcinomas 4ID5s6 showed that the phenotypicdi&ersity in #reast tumors was associated withdi&ersity in gene e/pression'

7hese gene e/pression pro$les were calledluminal 4( and B6" H8R 2 o&ere/pression" #asaland similar to normal #reast'


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9ome molecular mar:ers of epithelialmesenchymal transition 48376 are correlatedwith sur&i&al'

7heir e/pression may #e associated with a moreaggressi&e phenotype" more mesenchymaldi;erentiation" and thus" decreased sur&i&al'

7he IH5 mar:ers that ha&e #een studied includeadhesion molecules < 8 cadherin" N cadherin andP cadherin6 and nitric o/ide synthase 2 4N=9 26'


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3aterials and 3ethods


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Study design, patients' characteristics and tissuesamples

7he study population consisted of ,2 patientsfemale with stage II( 47+N*3+" 7*N*3+ and

72N+3+6 In&asi&e Ductal 5arcinoma 4ID56 ' (naly>ed eight molecular mar:ers #y

immunohistochemistry on tissue microarrayscontaining #reast tumor specimens from patientswith ten years of follow up"

5lassi$ed each tumor according to its estrogenreceptor" progesterone receptor and H8R 2e/pression'


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9elected patients with a ) year minimum follow

up period 4?+ months6 and still ali&e' 7he ma/imum follow up period was *+ years

4*2+ months6" and we counted mortality at anytime during the follow up'

7he date of the $rst consultation as the startdate for clinical follow up and the date of the lastconsultation or death as the end date'

Patients did not return for consultation and didnot respond to telephone calls or telegraphs asloss to follow up'


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Immunohistochemistry of TMAs

7he immunohistochemistry 4IH56 study wasperformed with anti#odies that recogni>ed the

di;erent mar:ers used' For the IH5 reactions" speci$c standardi>ed

protocols from the manufacturers and pre&iousreports for each mar:er were followed'

(ll of the reactions included positi&e andnegati&e controls that were stained in parallelwith the slides from the study '


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Evaluation of I !

@sing light microscopy" percentage of stainedcells was e&aluated and classi$ed according to aspeci$c e/pression pattern for each anti#ody andthe num#er of positi&e cells'

For the nuclear mar:ers" when the percent ofstained nuclei was

› greater than *- < Positi&e› less than *- < Negati&e

For cytoplasmic and mem#ranous mar:ers"› more than *+- stained cells < Positi&e'


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8R 4estrogen receptor6 and PR 4progesterone

receptor6 status was determined on the #asis ofIH5 staining' 7umors were considered H8R 2 positi&e only if

they were scored as A #y IH5 or if they

wereHER-2

ampli$ed 4ratio C or 2'+6 on the#asis of Euorescence in situ hy#ridi>ation 4FI9H6' In the a#sence of positi&e FI9H data" tumors with

indeterminate IH5 scores 42 6 were considerednegati&e'


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Immunophenotypicalclassi"cation

Fi&e su# groups #ased on the IH5 e/pression of 8R"PR" H8R 2 and 5 )" ?" as follows<

#uminal A $ 8R " PR and H8R 2 G

#uminal % $ 8R " and or PR " and H8R 2 E& ( $ 8R G" PR G and H8R 2 Triple negative $ 8R G" PR G and H8R 2 G %asal pattern $ 8R G" PR G H8R 2 G and or

5 ) and ? '


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Statistical methods

5haracteri>ed sample < descripti&e statistics' aria#les analysis < chi square or FisherJs e/act

test' 7he $nal models were ad%usted for

chemotherapy completion" hormone therapy andage 4as a continuous &aria#le6 #ased on agreater potential for interference with theoutcome 4death6'

3ortality analysis < cross sectional' ( )- signi$cance le&el was used for all of the

tests'


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&ES)#TS


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7here were no signi$cant associations #etweenmortality and any of the clinical" demographic ortreatment related &aria#les'

(naly>ed the histopathologic &aria#les" weo#ser&ed that none of them was signi$cantlyassociated with mortality" e/cept for the nuclear

grade &aria#le0 the ma%ority of patients who diedhad grade A tumors 4P +'++,6


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For the #iomolecular &aria#les and mortality" we o#ser&ed that 8Re/pression was positi&e in signi$cantly more patients who did notdie than those that did die 4P +'+2*6


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7he distri#ution of the cases according to their phenotypic pro$le" weo#ser&ed a larger proportion of luminal ( patients among the patientswho did not die than those that did die 4P +'++?6 and a larger proportionof patients who died in the triple negati&e 4P +'+*?6 and #asal su#groups 4P +'+*,6


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@sing logistic regression" we indi&idually tested theluminal (" triple negati&e and #asal phenotype &aria#les4models6 ad%usted for age" chemotherapy completionand hormone therapy" in clinical stage II( tumors'

Khen e&aluating the mortality ris: within *2+ months"

we o#ser&ed that the patients with a phenotypic patternother than luminal ( had an increased ris: of dying43odel (" =R ?'A" )- 5I *'. 22'?" P +'++)6'

=#ser&ed that patients with the triple negati&e and#asal patterns had an increased ris: of dying"

respecti&ely 43odel B" =R **"," )- 5I 2'+ .+'A" P +'++.6 and 43odel 5" =R *,'M" )- 5I *', *,M"."P +'+*A6" independent of the e;ect of hormonetherapy" ad%u&ant chemotherapy or age


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*IS!)SSI+


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In this study" analy>ed stage II( #reast tumors"ta:ing into account the &aria#les of age" race"num#er of pregnancies" hormonal status andfamily history' Did not $nd any statisticallysigni$cant correlation with mortality ris: withinthe *2+ month follow up period'

(ccording to the literature" one important factor

in determining long term sur&i&al is age' Younger patients 4A+ A) years6 ha&e a worse

sur&i&al rate as compared with patients aged .+or older' Did not $nd any statistically

signi$cant correlation #etween age and sur&i&alduring the *2+ months'


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5onsidering the histopathologic&aria#les" nuclear grade &aria#le was

the only one associated with mortality' 7he histological grade also has a

signi$cant impact on the selection ofpatients who will undergo systemicad%u&ant treatment' 7he histologicalgrade ta:es into consideration tu#ularformation" nuclear grade and mitotic

inde/'


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7he patients who were 8R positi&e had a reducedmortality rate within the *2+ month follow up period

4P +'+2*6' Pre&ious $ndings ha&e demonstratedthat 8R positi&ity confers a #etter prognosis for thepatients" independent of su# group" which allows forthe use of speci$c anti hormonal medication'

Luminal ( tumors are characteri>ed #y their positi&e8R e/pression and or positi&e PR e/pression andnegati&e H8R 2 e/pression pro$le'

tumors in the luminal ( su# group are more oftenassociated with 8R positi&ity" a larger percentage of

patients in stages I and II and moderatelydi;erentiated tumors' the presence of hormonereceptors de$nes a su# group with more fa&ora#lemorphological characteristics'


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multi&ariate analysis showed that the patients with a phenotypicpattern other than luminal ( had an increased ris: of dying 4?'Atimes6 within *2+ months" independent of the e;ects of hormonetherapy" chemotherapy and age'

increased ris: in the triple negati&e pattern 4**', times6 and the#asal pattern 4*,'M times6' (lthough this result should #einterpreted with caution" the #asal pattern may nonethelessrepresent a ris: factor for death'

In general" the literature indicates that patients with a #asal ortriple negati&e #reast tumor pattern ha&e a worse prognosis' when a tumor #elonged to the #asal su# group" it was associated

with a worse prognosis in #oth early and ad&anced stages inaddition to #eing more frequently associated with &isceraldissemination'

patients with #asal su# group tumors had an a&erage disease freesur&i&al of 2, months and an o&erall sur&i&al of A? months" ofwhich only )+- were disease free' Basal su# group tumors alsoappear to #e more common among young women' In oure/perience" more than )+- of the cases in this population ha&e a#asal phenotype' A2


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7his association #etween decreased sur&i&al and non luminal (tumors can also #e analy>ed in relation to the e/pression of 837mar:ers' 7he progression of #reast cancer is a result of a processin&ol&ing a loss of epithelial characteristics and the acquisition of

mesenchymal properties" which results in a more aggressi&e tumorphenotype'

in&asi&e #reast carcinoma" tumor 8 cadherin protein e/pressionmay #e related to o&erall #reast cancer sur&i&al' In our study" wedid not o#ser&e a relationship #etween the phenotypic pro$les andthe e/pression of 837 mar:ers in stage II( tumors #y IH5'

the e/pression of these 837 mar:ers in #reast tumors depends onthe degree of transformation of epithelial cells into mesenchymalcells and that the entire process occurs &ia speci$c and comple/regulation'

In conclusion" none of the 837 mar:ers or N=9 2 was related with

mortality ris: for stage II( #reast cancer' 7he mortality ris: wasassociated with the tumor not #elonging to the luminal ( su# group#ut instead #elonging to the #asal or triple negati&e su#group'

no correlations #etween the studied IH5 mar:ers and sur&i&al' 7hus"ro#ust population #ased studies with appropriate patientpopulations are important to de$ne these prognostic factors'


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