guideline concordant therapy prolongs survival in her2 ... · (cht) plus antihormone therapy (aht)...

Research ArticleGuideline Concordant Therapy Prolongs Survival inHER2-Positive Breast Cancer Patients: Results from a LargePopulation-Based Cohort of a Cancer Registry

E. C. Inwald,1 O. Ortmann,1 F. Zeman,2 M. Koller,2 F. Hofstädter,3

M. Gerstenhauer,4 and M. Klinkhammer-Schalke4

! Department of Gynecology andObstetrics, UniversityMedical Center Regensburg, Landshuter Straße "#, $%&#%Regensburg, Germany'Center for Clinical Studies, University Hospital Regensburg, $%&#% Regensburg, Germany% Institute of Pathology, University of Regensburg, $%&#% Regensburg, Germany(Tumor Center Regensburg e.V., University of Regensburg, $%&#% Regensburg, Germany

Correspondence should be addressed to E. C. Inwald; [email protected]

Received !" January #"!$; Accepted % February #"!$; Published #"March #"!$

Academic Editor: Peter A. Fasching

Copyright © #"!$ E. C. Inwald et al. &is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Even though randomized controlled clinical trials demonstrated improved survival by adjuvant trastuzumab treatment of HER#-positive breast cancer patients, data on its e'ect in clinical routine are scarce.&is study evaluated the use and e(cacy of trastuzumabin routine treatment of HER#-positive breast cancer patients. Data from the clinical cancer registry Regensburg (Germany) wereanalyzed. &e present study investigated %,))! female patients with primary invasive breast cancer. In premenopausal HER#-positive patients a considerable increase of trastuzumab therapy was observed from *+.!% in #""% to )".)% in #"!!, whereasin postmenopausal patients trastuzumab was rather used on a constant rate of $).!%. Best overall survival (OS) was found inHER#/steroid hormone receptor-positive patients receiving guideline concordant treatment with trastuzumab plus chemotherapy(CHT) plus antihormone therapy (AHT) with a ,-year OS rate of )%% compared to the non-trastuzumab group with a ,-yearOS rate of )#%. In multivariable analysis, HER#-positive patients treated with CHT or AHT who did not get trastuzumab, had aworse ,-year OS (%*%, ! = 0.006 versus ,)%, ! = 0.017) than the control groups.&is population-based study demonstrated thatguideline concordant use of adjuvant trastuzumab improves OS for HER#-positive breast cancer patients treated in routine clinicalcare.

1. Introduction

One of the pivotal advancements in breast cancer researchwas the identi-cation of HER# overexpression as a signi-cantpredictor of both disease-free survival (DFS) and overallsurvival (OS) in breast cancer patients by Slamon et al. in!)+, [!]. HER#, a member of the epidermal growth factorreceptor family of tyrosine kinases, is involved in cell growthand proliferation [#]. Overexpression and/or ampli-cation ofHER# occurs in !*–#*% of breast cancers and is associatedwith an unfavorable course of disease [!]. &e developmentof trastuzumab has improved treatment results of HER#-positive breast cancer. Trastuzumab is a recombinant human-ized monoclonal antibody directed against the extracellular

domain of the transmembrane HER# receptor [.]. Initially,the safety and e(cacy of trastuzumab were evaluated inpatients with HER#-positive metastatic breast cancer [$–+].Trastuzumab was FDA-approved for treatment of metastaticbreast cancer patients in !))+ [)] and in #""" it was approvedin Europe.

Later, -ve of six large phase III trials including morethan !$,""" patients with HER#-positive early breast cancerdemonstrated its e(cacy in the adjuvant setting [!"–!*].&ejoint analysis of the North American trials NSABP B-.!and NCCTG N)+.! found that the addition of trastuzumabto chemotherapy resulted in a signi-cant bene-t in termsof DFS and OS for women with HER#-positive breastcancer [!.]. A/er . years, the rate of DFS was +,.!% in

Hindawi Publishing Corporation

BioMed Research International

Volume 2014, Article ID 137304, 10 pages

http://dx.doi.org/10.1155/2014/137304

http://dx.doi.org/10.1155/2014/137304

# BioMed Research International

patients receiving trastuzumab plus chemotherapy comparedwith ,*.$% in patients in the standard chemotherapy arm(absolute di'erence !!.+ percentage points, HR ".$+, )*% CI"..)–".*); ! < 0.0001). Regarding OS, also a bene-t oftrastuzumab plus chemotherapy was shown ()$..% in thecombination therapy group versus )!.,% in the standardtherapy group, absolute di'erence #.* percentage points) [!.].In the Herceptin Adjuvant Trial (HERA), a/er a medianfollow-up of # years, a signi-cant absolute advantage in OSof #.,% in the trastuzumab group over the non-trastuzumabcontrol group was shown ()#.$% versus +).,%, HR ".%%, )*%CI ".$,–".)!; ! = 0.0115) [!!]. A second interim analysis ofthe BCIRG ""% study demonstrated superior DFS and OS inthe trastuzumab arms a/er a median follow-up of .%months[!%].&e DFS was +.% and the OS )#% in patients receivingdoxorubicin and cyclophosphamide followed by docetaxeland trastuzumab, in comparison with ,,% and +%% in thecontrol patients (HR ".%! for DFS; ! < 0.0001) [!%]. At amedian follow-up of .+months, the DFS in the FinHER trialwas longer with trastuzumab plus chemotherapy than withchemotherapy alone (+)% versus ,+%, HR ".$#, )*%CI ".#!–".+.; ! < 0.01) [!#]. Also OS was better in the trastuzumabgroup ()%..% versus +).,%), with a reduction of the risk ofdying (HR ".$!, )*% CI ".!%–!."+; ! = 0.07) [!#].

In summary, these studies showed that one year oftrastuzumab treatment in combination with or sequentiallya/er chemotherapy improved the relative risk for DFS byapproximately *"% andOS by ."% irrespective of tumor size,nodal status, and type of chemotherapy. As a consequence,in #""% trastuzumab was approved for adjuvant treatment ofbreast cancer in Europe.

Trastuzumab was the -rst FDA-approved monoclonalantibody targeting solid tumors [!,]. Commonly, trastuz-umab is well tolerated. Cardiac toxicity is considered to bethe most serious adverse e'ect, but in the large trials it wasalmost always reversible [!+, !)]. Meanwhile novel anti-HER#strategies are under development like the combination oftwo HER#-targeted agents with nonoverlapping mechanismsof action to optimize HER#-directed therapy [#"–##]. Onepotential approach is the combination of trastuzumab withthe HER# dimerization inhibitor pertuzumab [#., #$].

&e positive results of controlled clinical trials notwith-standing, data on the e'ect of trastuzumab in clinical rou-tine are scarce [#*–#)]. &us, it is essential to ensure thattreatment strategies, which are recommended in currentnational and international guidelines, are implemented inroutine clinical care. As early as !)). a systematic reviewsuggested a positive impact of clinical guidelines on both theprocess and outcomes of care for several health conditions[."]. Nevertheless, it is di(cult to demonstrate e'ects oftreatment improvements on survival due to the lack of highquality clinical cancer registries with long term follow-up.&erefore, the intention of this population-based study wasto evaluate guideline concordant treatment of HER#-positivebreast cancer patients in the routine clinical adjuvant settingin a large cohort ofmore than %,"""patients by analyzing datafrom a population-based regional cancer registry.

complete data poolN = 10,152

(2000–2012)

N = 10,082

N = 9,245

N = 7,542

N = 7,104

N = 6,991

N = 6,164

male patientsN = 70

ductal carcinoma in situ(DCIS)

N = 837

distant metastases atprimary diagnosis/n.s.

N = 752/N = 951

neoadjuvant treatmentN = 438

distant metastases incourse of disease

N = 113

unknown HER2 statusN = 827

F01234 !: Scheme of data extraction.

2. Material and Methods

'.!. Database. Data from the Tumor Centre Regensburg(Bavaria,Germany), a high quality population-based regionalcancer registry covering a population of more than #.#million people of the districts of Upper Palatinate andLower Bavaria, were analyzed. &e clinical cancer registryRegensburg was founded in !))! and currently disposes thefollow-up of #$",%** patients. &is cancer registry achievesa cross-sectorial documentation of all breast cancer patientsin the area, following a rigorous prospective protocol. Doc-umentation includes diagnosis, course of disease, therapies,and long term follow-up. Patient data stem from *. regionalhospitals, the University Hospital Regensburg, and morethan !,""" practicing doctors. &e population-based datawere routinely analyzed in each case and documented in thecancer registry on the basis of medical reports, pathology,and follow-up records. Mortality data were obtained from allregional registry o(ces.

'.'. Inclusion and Exclusion Criteria. &e present analysisincludes all female patients of the registry with primary, non-metastatic (M") invasive breast cancer diagnosed betweenJanuary #""" and December #"!# (!. years). Patients werefollowed up until May #"!.. Exclusion criteria were malepatients, ductal carcinoma in situ (DCIS), neoadjuvant treat-ment, and distant metastases at primary diagnosis or duringthe course of disease (Figure !).

BioMed Research International .

T5674 !: Time dependent rates of HER# analyses.

Year of diagnosis Number of patients(") HER# status unknown

(", %)HER# status analyzed

(", %)HER# negative

(", %)HER# positive

(", %)#""" $." .%" (+..,%) ," (!%..%) $) (,"."%) #! (."."%)#""! $*% !., (."."%) .!) (,"."%) #.% (,$."%) +. (#%."%)#""# $** ,# (!*.+%) .+. (+$.#%) ."$ (,).$%) ,) (#".%%)#"". *!+ %+ (!..!%) $*" (+%.)%) .*! (,+."%) )) (##."%)#""$ *%+ *# ().#%) *!% ()".+%) $#! (+!.%%) )* (!+.$%)#""* *%) .$ (%."%) *.* ()$."%) $.+ (+!.)%) ), (!+.!%)#""% *#, + (!.*%) *!) ()+.*%) $") (,+.+%) !!" (#!.#%)#"", *," .$ (%."%) *.% ()$."%) $.) (+!.)%) ), (!+.!%)#""+ *%" $, (+.$%) *!. ()!.%%) $#. (+#.*%) )" (!,.*%)#"") %%% * (".+%) %%! ()).#%) *$$ (+#..%) !!, (!,.,%)#"!" *+) % (!."%) *+. ())."%) $%) (+".$%) !!$ (!).%%)#"!! *$. # (".$%) *$! ()).%%) $,% (++."%) %* (!#."%)#"!# *$" # (".$%) *.+ ()).%%) $,! (+,.*%) %, (!#.*%)Total %))! +#, (!!.+%) %!%$ (++.#%) *"." (+!.%%) !!.$ (!+.$%)

'.%. Analysis of HER' Expression. HER# testing was per-formed according to the German interdisciplinary S.Guide-lines for Diagnosis, Treatment and Follow-up Care ofBreast Cancer (registry number ".#-"$*OL of Associationof the Scienti-c Medical Societies, AWMF) [.!, .#] and toASCO/CAP recommendations [..]. HER#-protein overex-pression was analyzed by means of DAKO HercepTest, asemiquantitative immunohistochemical assay.

A total of six institutes of pathologywere involved in theseassessments. Consistency and quality control are ensuredthrough biannual quality assurance conferences and theparticipation in round robin tests [.$].

'.(. Primary Trastuzumab )erapy. In the trastuzumabgroup (! year of trastuzumab with . weeks intervals ofapplication) either concurrent or sequential administrationrelative to chemotherapy was performed. Di'erent typesof anthracycline- and taxane-based chemotherapy regimenswere used according to the previously reported large con-trolled clinical trials [!+].

'.#. Statistical Methods. Continuous data are expressed asmeans ± standard deviation (SD) and categorical data asfrequency counts (percentages). Baseline characteristics ofpatients were compared between HER# status by Student’s#-test for continuous variables and by Pearson’s chi-squaretests for categorical variables. OS was calculated from thedate of cancer diagnosis to the date of death from anycause. Patients who are not dead or patients without follow-up were classi-ed as censored. To assess the in8uenceof trastuzumab, chemotherapy (CHT), and antihormonetherapy (AHT) on OS in HER#-positive patients and ofCHT and AHT in HER#-negative patients, two multivariableCox regression models were calculated. Both models wereadjusted for the known confounding variables age, tumorsize, nodal status, grading, receptor status, andKi-%,. Kaplan-Meier plots were used for graphical illustrations. For all

combinations of trastuzumab, CHT, and AHT, odds ratiosand corresponding )*% con-dence intervals ()*% CI) werecalculated. All reported ! values are two-sided, and a ! valueof "."*was considered the threshold of statistical signi-cance.Calculations were made with the so/ware packages SPSS#!.".".! (Chicago, EUA) and R (version #.!$.#).

3. Results

%.!. Patient Characteristics and Histopathological Parameters.From the total data pool of breast tumor patients, %,))!female patients with invasive early breast cancer accordingto the ICD-!" classi-cation (C*") were extracted for furtheranalysis (Figure !). In ++.#% (%,!%$ patients) the HER# statuswas available. In !!.+% (+#, patients) the HER# status wasnot available owing to missing information in the medicalreports or no assessment. In the year #""", the HER# statuswas analyzed only in !%..% of patients (,"/$.").&is numberincreased to +$.#% of patients (.+./$**) in #""# right up to)).%% of patients (*.+/*$") in #"!# (Table !).

Only patients with known HER status were consid-ered for further evaluation. &us, a total of %,!%$ patientswith invasive breast cancer were taken into considerationfor subsequent statistical analyses. Of these, !,.+, patients(##.*%) were premenopausal and $,,,, patients (,,.*%)were postmenopausal. &e mean age was %! years (median:%# years, range: #!–), years). *,"." patients (+!.%%) wereHER# negative, whereas !,!.$ patients (!+.$%) were HER#positive (overexpression and/or ampli-cation). High gradetumors were more likely to be HER# positive than low gradetumors. $$.!% ($ = 500) of HER#-positive patients hadpoorly di'erentiated tumors, whereas only %.#% ($ = 70)were low grade. Estrogen receptor (ER) and progesteronereceptor (PR) negative tumors were more likely to be HER#-positive than ER-positive and PR-positive tumors (#..)%versus *+.,%). Vice versa, in HER#-negative tumors ,).#%were ER and PR positive whereas only !".,%were ER and PR

$ BioMed Research International

T5674 #: Rate of adjuvant trastuzumab therapy in HER#-positive patients.

Year of diagnosis Total number of HER#-positive patients (") Trastuzumab receivedTotal Premenopausal Postmenopausal

#""" #! "/#! ("%) "/!" ("%) "/!! ("%)#""! +. !/+. (!%) "/!) ("%) !/%$ (#%)#""# ,) #/,) (.%) #/## ()%) "/*, ("%)#"". )) #/)) (#%) !/#+ ($%) !/,! (!%)#""$ )* #/)* (#%) "/#% ("%) #/%) (.%)#""* ), .$/), (.*%) !!/#. ($+%) #./,$ (.!%)#""% !!" $#/!!" (.+%) !+/.! (*+%) #$/,) (."%)#"", ), *,/), (*)%) !*/!) (,)%) $#/,+ (*$%)#""+ )" *./)" (*)%) !*/!) (,)%) .+/,! (*$%)#"") !!, %$/!!, (**%) #!/.. (%$%) $./+$ (*!%)#"!" !!$ %*/!!$ (*,%) !)/#) (%%%) $%/+* (*$%)#"!! %* $./%* (%%%) #"/## ()!%) #./$. (*$%)#"!# %, #$/%, (.%%) !!/#$ ($%%) !./$. (."%)Total !!.$ .+)/!!.$ (.$%) !../."* ($$%) #*%/+#) (.!%)

T5674 .: Concomitant diseases in HER#-positive patients without adjuvant trastuzumab treatment.

Premenopausal Postmenopausal All patientsConcomitant diseases, $ (%) !" (#$.%%) &'& (%".&%) &!( (#''.'%)

Cardiopulmonary !#/.* (.$..%) !#%/#"# (%#.$%) !.+/#., (*+.#%)Gastrointestinal/hepatic/renal — !"/#"# (*."%) !"/#., ($.#%)Metabolic ,/.* (#"."%) ##/#"# (!".)%) #)/#., (!#.#%)Mental %/.* (!,.!%) !*/#"# (,.$%) #!/#., (+.)%)Others !"/.* (#+.%%) #)/#"# (!$.$%) .)/#., (!%.*%)

negative. In HER#-positive tumors, lymphatic and vascularinvasion was more frequent than in HER#-negative tumors(.,.)% and +.*% versus #%.%% and *.#%). Low Ki-%, values% !*% were predominant in HER#-negative tumors ($*.+%)whereas higher Ki-%, categories (Ki-%, >#*%) were found inHER#-positive patients.

%.'. HER' Overexpression and Trastuzumab )erapy. Upto #""$, trastuzumab therapy was hardly administered inadjuvant treatment. Only about #%ofHER#-positive patientsreceived trastuzumab from #""" to #""$. Since trastuzumabapproval for adjuvant therapy, the number of HER#-positivepatients receiving the antibody continuously increased from.+.#% in #""% to %%.#% in #"!!. &e analyses of age-relatedsubcategories (pre- and postmenopausal patients) showedthat nonuse of trastuzumab was found predominantly inpostmenopausal women. Di'erences in trastuzumab therapybetween premenopausal and postmenopausal patients werefurther analyzed (Table #).&ere was a considerable increaseof trastuzumab therapy in premenopausal patients from*+.!% in #""% to )".)% in #"!!.&e decrease of trastuzumabuse in #"!# can be explained by incomplete documentation.In contrast, in postmenopausal patients trastuzumab wasrather used on a constant rate of $).!% from #""% to #"!!a/er a -rst augmentation from .".$% in #""% to *..+% in#"",. In the total population of HER#-positive patients, whowere diagnosed between #""% and #"!# ($ = 660), only

*#.,% (.$+ patients) received the appropriate treatment withtrastuzumab. Among these, more premenopausal HER#-positive patients received trastuzumab in comparison topostmenopausal patients (%,.#% ($ = 119) premenopausalpatients versus $,.$% ($ = 229) postmenopausal patients).

To elucidate reasons for the insu(cient application oftrastuzumab, we further analyzed HER#-positive patientswho did not receive trastuzumab between #""% and #"!#with respect to their concomitant diseases. .!#HER#-positivepatients did not receive trastuzumab. Out of these, #.,patients (,%."%) had at least one serious concomitant disease.#! patients (%.,%) had no comorbidity and in *$ patients(!,..%) concomitant diseases were not documented. &emajority of patients (*+.#%) su'ered from cardiopulmonarydisease. Others had metabolic (!#.#%), mental (+.)%), andgastrointestinal/hepatic/renal ($.#%) disorders (Table .).

Furthermore, combinations of systemic therapies wereanalyzed since #""%, also contemplating CHT and AHT(Table $). .$..% ($ = 221) of HER#-positive patients weretreated with trastuzumab plus CHT plus AHT. !,.$% ($ =112) received trastuzumab plus CHT; #!.$% ($ = 138)received only AHT. A considerable number of HER#-positivepatients (!*."%, $ = 97) received neither trastuzumab norCHT nor AHT.

%.%. Survival Analyses. Since patients received a number ofdi'erent systemic treatments, analyses of trastuzumab e'ects

BioMed Research International *

T5674 $: Di'erent systemic therapies in HER#-positive patients.

HER#-positive patients (year of diagnosis: #""%–#"!#)Trastuzumab + CHT + AHT Trastuzumab + CHT CHT + AHT CHT AHT No adjuvant therapy Total

#""% #, (#$.+%) !$ (!#.+%) ) (+..%) ) (+..%) $" (.%.,%) !" ().#%) !") (!""%)#"", ." (.#.%%) ## (#..)%) % (%.*%) ! (!.!%) #! (##.+%) !# (!.."%) )# (!""%)#""+ .! (.$.+%) #! (#..%%) % (%.,%) $ ($.*%) !% (!+."%) !! (!#.$%) +) (!""%)#"") $* ($".#%) !$ (!#.*%) ) (+."%) $ (..%%) #$ (#!.$%) !% (!$..%) !!# (!""%)#"!" $$ (.)..%) !) (!,."%) ) (+."%) . (#.,%) !+ (!%.!%) !) (!,."%) !!# (!""%)#"!! #) ($*..%) !. (#"..%) $ (%.#%) . ($.,%) !" (!*.%%) * (,.+%) %$ (!""%)#"!# !* (##.$%) ) (!..$%) ! (!.*%) ) (!..$%) ) (!..$%) #$ (.*.+%) %, (!""%)Total ##! (.$..%) !!# (!,.$%) $$ (%.+%) .. (*.!%) !.+ (#!.$%) ), (!*."%) %$* (!""%)

T5674 *: Overall survival rates categorized by HER# status and adjuvant therapy.

.-year OS *-year OS %-year OS ,-year OSHER# positive

Trastuzumab + CHT+ AHT ),% )%% )%% )%%CHT + AHT )+% )+% )#% )#%Trastuzumab + CHT )*% )#% )#% +%%CHT +#% %*% %*% %*%AHT )!% +.% ,)% ,)%No adjuvant therapy ,*% %.% **% **%

HER# negativeCHT + AHT )+% )*% ).% )#%CHT +)% +%% +.% +.%AHT )*% )"% ++% ++%No adjuvant therapy +!% ,*% ,.% %$%

were performed by comparing survival data obtained fromthese treatment groups (Table *). HER#-positive patientswho did not receive trastuzumab had a worse OS in allof the compared groups. Kaplan-Meier curves (Figures #and .) show that guideline concordant therapy—that is,trastuzumab in HER#-positive, CHT in risk factor positive(high grade, large, nodal positive tumors, etc.), and AHTin ER/PR-positive patients—resulted in best survival rates.Deviation from guideline concordance reduced OS signi--cantly. Best OS was found in HER#/ER/PR-positive patientsreceiving trastuzumab plus CHT plus AHT with a ,-yearOS rate of )%%. Depriving HER#/ER/PR-positive patients oftrastuzumab, ,-year OS rate deteriorated to )#%. Similarly,the nonuse of trastuzumab inHER#-positive/ER/PR-negativepatients decreased ,-year OS rates from +%% to %*%. &eworst OS of all patients was found in HER#-positive patientswho received neither trastuzumab nor CHT nor AHT witha ,-year OS rate of **%. Similarly, the impact of guidelineconcordant therapy was seen in HER#-negative patientswhereas the e'ects were not that distinct. Consequently, anappreciable bene-t of following guidelineswas demonstrated.Remarkably, the addition of trastuzumab overcame the pri-marily worse outcome of HER#-positive patients indicatingits e(cacy. A particularly striking e'ect was found whencomparing HER#-positive patients receiving no adjuvanttherapy with triple-negative breast cancer patients receivingno adjuvant therapy at all. HER#-positive patients had an

even worse survival (**%) than triple-negative breast cancerpatients (%$%).

By using Cox regression models (Tables %(a) and %(b)),it was demonstrated that HER#-positive patients ($ = 516,*. events) without trastuzumab/CHT/AHT therapy ($ =80, #! events) showed the worst OS of all patients (HR =10.44, )*% CI .."#–.%."%, ! < 0.001) compared to patientsreceiving trastuzumab/CHT/AHT therapy (reference group).Also patients without trastuzumab therapy but only CHT(HR = 9.50, )*%-CI !.)"–$,.$., ! = 0.006) or AHT (HR =4.28, )*%-CI !.."–!$."*, ! = 0.017), respectively, had worsesurvival than the control groups (Table %(a)). In the HER#-negative group ($ = 2,,#,, #!) events) patients receivingonly AHT (HR = 2.33, )*%-CI !.$"–..+,, ! = 0.001) oronly CHT (HR = 3.15, )*%-CI !.%!–%.!%, ! = 0.001) orno adjuvant therapy at all (HR = 4.91, )*% CI #.+!–+.*),! < 0.001) showed a highly signi-cant decrease in OScompared to patients with both CHT and AHT (referencegroup) (Table %(b)).

4. Discussion

National oncological guidelines are essential for optimaltreatment of cancer patients. In Germany, the majority ofbreast cancer patients are treated in specialized breast cancercenters which have to follow current guidelines for diagnosisand treatment of breast cancer [.#, .*]. Determination of

% BioMed Research International

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7Years a!er cancer diagnosis

Prob

abili

ty o

f ove

rall

surv

ival

Strata

221(0)44(0)

112(0)138(0)33(0)97(0)

221(0)43(0)

109(1)132(2)27(0)

74(10)

192(1)41(0)96(4)

118(9)21(1)

55(18)

157(6)37(1)77(5)

103(12)17(4)

42(20)

112(6)22(1)62(6)

82(18)12(6)

27(24)

73(7)18(1)45(7)

58(19)10(7)

19(25)

45(7)10(2)22(7)

40(22)6(7)

9(27)

19(7)6(2)9(8)

23(22)4(7)

6(27)Numbers at risk (cumulative events)

AHTCHTNo adjuvant therapy

Trastuzumab + CHT + AHTCHT + AHTTrastuzumab + CHT

AHTCHT

No adjuvant therapy

Trastuzumab + CHT + AHTCHT + AHT

Trastuzumab + CHT

F01234 #: Kaplan-Meier plot of overall survival in years of HER#-positive patients based on adjuvant therapy.

HER# status is required in all patients with invasive breastcancer according to national [.#] and international guidelines[.%]. In HER#-positive early breast cancer, adjuvant CHT incombination with trastuzumab is indicated. Using data froma high-quality population-based regional cancer registry wewere able to analyze guideline concordant patient care.

&e steady increase in HER# determination from #"""(!%..%) up to #"!# ()).%%) illustrates the implementationof guidelines in routine clinical practice. &e -rst Germaninterdisciplinary S. Guidelines for Diagnosis, Treatment andFollow-up Care of Breast Cancer were published in #""$and -rst updated in #""+ [.!]. Concerning HER# status,the number of HER#-positive tumors declined over time. In#""", ."."% of tumors were HER# positive, whereas over theyears, the percentage of HER#-positive tumors continuouslydecreased to !#.*% in #"!#. &e decrease of HER# positivitymight be due to false positivity because of short -xation timeand revised cuto' de-nition in CISH and FISH in course ofthe investigated period [.., .,].

All common histopathological parameters showed highlystatistically signi-cant di'erences between HER#-negativeand HER#-positive patients as shown in previous studies[.+, .)]. For instance, HER# overexpression has been foundto correlate with several adverse prognostic parameters such

as large tumor size, high grade, and steroid hormone receptornegativity [.), $"].

As expected, up to #""$, trastuzumab therapy was hardlyadministered in primary therapy. In Europe, trastuzumabwas approved for adjuvant therapy in #""%. Consequently,since #""%, the number of HER#-positive patients receivingtrastuzumab continuously increased from .+.#% to %%.#% in#"!!. In a cohort study from the National ComprehensiveCancer Network (NCCN) overall $$% of HER#-positivebreast cancer patients received neoadjuvant or adjuvanttrastuzumab with increasing proportions over time (+% ofpatients diagnosed in #""", %%% of patients diagnosed in#""*, and ,,% of patients diagnosed in #"",) [#*]. Anotherstudy that investigated the management of HER#-positivebreast cancer patients in routine clinical setting reported arate of *$.*%of patients receiving adjuvant trastuzumab [#%].

Besides analyzing the fact of guideline conform diag-nostics and therapies, we demonstrated the consequencesof guideline adherence on survival of patients. Guideline-conform treatment led to similar OS of HER#-positivepatients compared to HER#-negative patients. &is has alsobeen shown in previous studies [#,, $!, $#]. A retrospec-tive population-based analysis of adjuvant trastuzumab useamong ,". HER#-positive Canadian women, of whom $+"

BioMed Research International ,

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7Years a!er cancer diagnosis

Prob

abili

ty o

f ove

rall

surv

ival

808(0)1626(0)331(0)461(3)

795(5)1542(17)287(10)348(32)

691(9)1285(45)227(23)241(54)

556(13)1036(70)183(29)182(66)

394(22)789(97)148(31)133(72)

282(26)501(112)100(34)80(76)

163(30)321(120)

55(37)49(77)

57(32)98(121)18(37)16(81)

Numbers at risk (cumulative events)

Strata

AHTCHTNo adjuvant therapy

CHT + AHT

AHTCHT

No adjuvant therapy

CHT + AHT

F01234 .: Kaplan-Meier plot of overall survival in years of HER#-negative patients based on adjuvant therapy.

(%+%) received trastuzumab, demonstrated highly favorableoutcomes at a #-year follow-up [#+]. In patients receivingtrastuzumab, the #-year DFS was )%.!% ()*% CI: )..%% to),.,%) and the OS was ))..% ()*% CI ),.)% to )).+%).Among node-negative and node-positive patients, the #-yearDFS was ),.+% and )$.+% (! = 0.09) for the trastuzumab-treated group and )".)% and ,,..% (! = 0.01) for the groupnot receiving trastuzumab ($ = 223) [#+]. Similar to ourresults, their population had better survival outcomes thanthose reported in the large adjuvant clinical trials. So far, onlya few healthcare research studies have analyzed the impact ofguideline-adherent therapies on clinical outcomes in breastcancer patients [$.–$*]. Overall, several prior studies con--rmed that there appears to be a strong association betweenguideline-adherent treatment and improved survival [$*–$+]. Nevertheless, a study from the Netherlands CancerRegistry showed that adherence to treatment guidelines wasa'ected by age at diagnosis but was not associated with OSin either age group [$)]. Remarkably, a considerable numberof patients did not receive guideline concordant therapy bothin our study and previous studies, which demonstrates thedi(culty of implementing guideline recommendations inroutine clinical care. &e reasons for this are multifactorial.Indicated therapy either never had been started or wasdiscontinued prematurely [*"]. A potential explanation for

noninitiation is the preference of patients who are not willingto receive indicated therapy from the start or discontinuein the course of treatment [*!]. In particular older patientsmay be less willing to trade current quality of life for survival[*#]. Nevertheless, an observational retrospectivemulticenterItalian study showed that trastuzumab treatment was feasibleand well tolerated in routine clinical practice [#)].

Moreover, there might be a percentage of patientswith small HER#-positive tumors with no CHT indication.&e large international, adjuvant, randomized clinical trialshave demonstrated signi-cant improvements in DFS andOS with trastuzumab-based CHT in node-positive and/orgreater than ! cm HER#-positive tumors [!$, !*, *., *$].Node-negative patients with smaller tumors were generallyexcluded [**]. Current guidelines from the NCCN rec-ommend trastuzumab-based CHT for women with node-positive breast cancer, and women with node-negativetumors that are &".% cm.

Several other factors were assumed to in8uence guidelineadherence in breast cancer patients in prior studies such aseducation, access to medical resources, health care servicesthemselves, and an urban versus rural location [*%]. However,these e'ects could not be replicated in the present analysessince these variables are not part of the data set.

+ BioMed Research International

T5674 %: Multivariable Cox regression models.

(a) Multivariable Cox regression models in HER#-positive patients since#""%

Characteristic Overall survival ($ = 516, events = *.)HR )*% CI ! value

Trastuzumab + CHT + AHT($ = 180, events = $) Reference — —

CHT + AHT($ = 35, events = #) #..$ ".$.; !...+ "..#

Trastuzumab + CHT($ = 91, events = %) ..+" ".+,; !%.*) "."+

AHT($ = 106, events = !,) $.#+ !.."; !$."* '.'#(

CHT($ = 24, events = .) ).*" !.)"; $,.$. '.'')

No adjuvant therapy($ = 80, events = #!) !".$$ .."#; .%."% <'.''#Model is controlled for age, Ki%, categories, tumor size, nodal status,grading, and receptor status; HR: hazard ratio; )*% CI: )*% con-denceinterval.(b) Multivariable Cox regression model in HER#-negative patients since#""%

Characteristic Overall survival ($ = 2727, events = #!))HR )*% CI ! value

CHT + AHT($ = 671, events = #.) Reference — —

AHT($ = 1392, events = !"$) #... !.$"; ..+, '.''#

CHT($ = 279, events = #+) ..!* !.%!; %.!% '.''#

No adjuvant therapy($ = 385, events = %$) $.)! #.+!; +.*) <'.''#Model is controlled for age, Ki%, categories, tumor size, nodal status,grading, and receptor status; HR: hazard ratio; )*% CI: )*% con-denceinterval.

A main cause for nonadherence to guideline recom-mendations may be the existence of comorbidities of whichelderly patients are more o/en a'ected than younger ones.Comorbidities, especially cardiovascular diseases, may alsobe the cause of reduction of OS. &ese data have to beincluded in a systematic way in the update of documentationof cancer registries and will then allow systematic analyses.A retrospective study on diagnosis and treatment accordingto national guidelines in the Netherlands demonstrated thatdeviation from guidelines in elderly breast cancer patientsmainly occurs due to a deliberate adjustment to patients’comorbidity and preference. Similar to our results cardiovas-cular disease was the most frequently observed comorbidity(*.% versus *+% in our study) [$$]. Moreover, a *-yearmulticenter cohort study of .,),% patients by Wockel et al.also concluded that advanced age at initial diagnosis wasassociated with a reduction in guideline adherence [$.].An observational study from Schwentner et al. found lowerguideline adherence in triple-negative breast cancer (TNBC)patients compared to non-triple-negative subtypes. &ese

lower rates of guideline adherence were observed in allage groups and were most pronounced in the >%*-year-oldsubgroup (<*" (#".)% versus $#."%), *"–%$ (#*.!% versus*!.!%), and >%* (.+.$% versus ,$.%%)). ##.)% of their TNBCsubgroup did not receive any CHT which is comparable toour results [*!].&us, several studies have shown that patientswith comorbidities are less likely to be treated according toguidelines than patients without comorbidities [*#, *,, *+].

5. Conclusions

In conclusion, this population-based study was able todemonstrate that guideline adherent use of adjuvanttrastuzumab improves OS for patients with HER#-positivebreast cancer treated in routine clinical care. &is extendsour knowledge on the e(cacy of such treatment. However, aconsiderable proportion of HER#-positive postmenopausalbreast cancer patients did not get the appropriate therapy. It isthereforemandatory to analyze the reasons for nonadherenceand to develop means to improve guideline adherence.

Conflict of Interests

&e authors declare that they have no con8ict of interests.

Authors’ Contribution

E. C. Inwald and O. Ortmann contributed equally to thispaper.

References

[!] D. J. Slamon, G. M. Clark, S. G. Wong, W. J. Levin, A.Ullrich, andW. L. McGuire, “Human breast cancer: correlationof relapse and survival with ampli-cation of the HER-#/neuoncogene,” Science, vol. #.*, no. $,+*, pp. !,,–!+#, !)+,.

[#] H. Tsuda, “Prognostic and predictive value of c-erbB-# (HER-#/neu) gene ampli-cation in human breast cancer,” BreastCancer, vol. +, no. !, pp. .+–$$, #""!.

[.] S. A. Hurvitz, Y. Hu, N. O’Brien, and R. S. Finn, “Currentapproaches and future directions in the treatment of HER#-positive breast cancer,” Cancer Treatment Reviews, vol. .), no.., pp. ##)–#!), #"!..

[$] D. J. Slamon, B. Leyland-Jones, S. Shak et al., “Use of chemother-apy plus a monoclonal antibody against HER# for metastaticbreast cancer that overexpresses HER#,” )e New EnglandJournal of Medicine, vol. .$$, no. !!, pp. ,+.–,)#, #""!.

[*] E. A. Eisenhauer, “From the molecule to the clinic—inhibitingHER# to treat breast cancer,” )e New England Journal ofMedicine, vol. .$$, no. !!, pp. +$!–+$#, #""!.

[%] M. A. Cobleigh, C. L. Vogel, D. Tripathy et al., “Multinationalstudy of the e(cacy and safety of humanized anti-HER#mon-oclonal antibody in women who have HER#-overexpressingmetastatic breast cancer that has progressed a/er chemotherapyfor metastatic disease,” Journal of Clinical Oncology, vol. !,, no.), pp. #%.)–#%$+, !))).

[,] M.Marty, F. Cognetti, D.Maraninchi et al., “Randomized phaseII trial of the e(cacy and safety of trastuzumab combinedwith docetaxel in patients with human epidermal growth factor

BioMed Research International )

receptor #-positive metastatic breast cancer administered as-rst-line treatment: theM,,""! study group,” Journal of ClinicalOncology, vol. #., no. !), pp. $#%*–$#,$, #""*.

[+] G. Gasparini, M. Gion, L. Mariani et al., “Randomized phase IItrial of weekly paclitaxel alone versus trastuzumab plus weeklypaclitaxel as -rst-line therapy of patients with Her-# positiveadvanced breast cancer,” Breast Cancer Research and Treatment,vol. !"!, no. ., pp. .**–.%*, #"",.

[)] T. L. Brenner and V. R. Adams, “First MAb approved fortreatment of metastatic breast cancer,” Journal of the AmericanPharmaceutical Association, vol. .), no. #, pp. #.%–#.+, !))).

[!"] M. J. Piccart-Gebhart, M. Procter, B. Leyland-Jones et al.,“Trastuzumab a/er adjuvant chemotherapy in HER#-positivebreast cancer,” )e New England Journal of Medicine, vol. .*.,no. !%, pp. !%*)–!%,#, #""*.

[!!] I. Smith, M. Procter, R. D. Gelber et al., “#-year follow-upof trastuzumab a/er adjuvant chemotherapy in HER#-positivebreast cancer: a randomised controlled trial,” )e Lancet, vol..%), no. )***, pp. #)–.%, #"",.

[!#] H. Joensuu, P.-L. Kellokumpu-Lehtinen, P. Bono et al., “Adju-vant docetaxel or vinorelbine with or without trastuzumab forbreast cancer,” )e New England Journal of Medicine, vol. .*$,no. +, pp. +")–+#", #""%.

[!.] E. H. Romond, E. A. Perez, J. Bryant et al., “Trastuzumabplus adjuvant chemotherapy for operable HER#-positive breastcancer,” )e New England Journal of Medicine, vol. .*., no. !%,pp. !%,.–!%+$, #""*.

[!$] D. Slamon, W. Eiermann, N. Robert et al., “Adjuvant trastuz-umab inHER#-positive breast cancer,”)eNewEngland journalof medicine, vol. .%*, no. !$, pp. !#,.–!#+., #"!!.

[!*] M. Spielmann, H. Roche, T. Delozier et al., “Trastuzumab forpatients with axillary-node-positive breast cancer: results of theFNCLCC-PACS "$ trial,” Journal of Clinical Oncology, vol. #,,no. .%, pp. %!#)–%!.$, #"").

[!%] D. Slamon, W. Eiermann, N. Robert et al., “BCIRG ""%:#nd interim analysis phase III randomized trial comparingdoxorubicin and cyclophosphamide followed by docetaxel(AC'T) with doxorubicin and cyclophosphamide followedby docetaxel and trastuzumab (AC'TH) with docetaxel,carboplatin and trastuzumab (TCH) in HER# positive earlybreast cancer patients,” Breast Cancer Research and Treatment,vol. !"", supplement !, #""%.

[!,] M. Harris, “Monoclonal antibodies as therapeutic agents forcancer,”)e Lancet Oncology, vol. *, no. *, pp. #)#–."#, #""$.

[!+] G. A. Viani, S. L. Afonso, E. J. Stefano, L. I. de Fendi, andF. V. Soares, “Adjuvant trastuzumab in the treatment of her-#-positive early breast cancer: a meta-analysis of publishedrandomized trials,” BMC Cancer, vol. ,, article !*., #"",.

[!)] G. Fried, T. Regev, and M. Moskovitz, “Trastuzumab-relatedcardiac events in the treatment of early breast cancer,” BreastCancer Research and Treatment, vol. !$#, no. !, pp. !–,, #"!..

[#"] G. E. Konecny, “Emerging strategies for the dual inhibition ofHER#-positive breast cancer,” Current Opinion in Obstetrics &Gynecology, vol. #*, no. !, pp. **–%*, #"!..

[#!] C. Melcher, C. Scholz, B. Jager, C. Hagenbeck, B. Rack, andW. Janni, “Breast cancer: state of the art and new -ndings,”Geburtsh Frauenheilk, vol. ,#, no. ., pp. #!*–##$, #"!#.

[##] D. Lu/ner,M. Lux, N.Maass et al., “Advances in breast cancer—looking back over the year,”Geburtsh Frauenheilk, vol. ,#, no. !#,pp. !!!,–!!#), #"!#.

[#.] M. Hubalek, C. Brantner, and C. Marth, “Role of pertuzumabin the treatment of HER#-positive breast cancer,” Breast Cancer:Targets and)erapy, vol. #"!#, pp. %*–,., #"!#.

[#$] H. Kolberg, D. Lu/ner, M. Lux et al., “Breast cancer #"!#—newaspects,” Geburtsh Frauenheilk, vol. ,#, no. ,, pp. %"#–%!*, #"!#.

[#*] I. Vaz-Luis, R. A. Ottesen, M. E. Hughes et al., “Impact ofhormone receptor status on patterns of recurrence and clin-ical outcomes among patients with human epidermal growthfactor-#-positive breast cancer in the National ComprehensiveCancer Network: a prospective cohort study,” Breast CancerResearch, vol. !$, no. *, article R!#), #"!#.

[#%] C. Palmieri, D. Shah, J. Krell et al., “Management and outcomeof HER#-positive early breast cancer treated with or withouttrastuzumab in the adjuvant trastuzumab era,” Clinical BreastCancer, vol. !!, no. #, pp. ).–!"#, #"!!.

[#,] S.Dawood,K. Broglio, A.U. Buzdar,G.N.Hortobagyi, and S.H.Giordano, “Prognosis of women with metastatic breast cancerby HER# status and trastuzumab treatment: an institutional-based review,” Journal of Clinical Oncology, vol. #+, no. !, pp.)#–)+, #"!".

[#+] M. D. Seal, C. H. Speers, S. O’Reilly, K. A. Gelmon, S. L. Ellard,and S. K. Chia, “Outcomes of women with early-stage breastcancer receiving adjuvant trastuzumab,” Current Oncology, vol.!), no. $, pp. !),–#"!, #"!#.

[#)] M. Campiglio, R. Bufalino, M. Sasso et al., “E'ect of adjuvanttrastuzumab treatment in conventional clinical setting: anobservational retrospective multicenter Italian study,” BreastCancer Research and Treatment, vol. !$!, no. !, pp. !"!–!!", #"!..

[."] J.M. Grimshaw and I. T. Russell, “E'ect of clinical guidelines onmedical practice: a systematic review of rigorous evaluations,”)e Lancet, vol. .$#, no. +++., pp. !.!,–!.##, !))..

[.!] R. Kreienberg, I. Kopp, U. Albert et al., Interdisciplinary S%Guideline for Diagnosis and)erapy of Breast Cancer inWomen,German Cancer Society, Berlin, Germany, #""+.

[.#] R. Kreienberg, U. Albert, M. Follmann, I. Kopp, T. Kuhn,and A. Wockel, “Interdisciplinary GoR level III guidelines forthe diagnosis, therapy and follow-up care of breast cancer,”Geburtsh Frauenheilk, vol. ,., no. %, pp. **%–*+., #"!..

[..] A. C. Wol', M. E. H. Hammond, J. N. Schwartz et al.,“American Society of Clinical Oncology/College of AmericanPathologists guideline recommendations for human epidermalgrowth factor receptor # testing in breast cancer,” Journal ofClinical Oncology, vol. #*, no. !, pp. !!+–!$*, #"",.

[.$] E. C. Inwald,M.Klinkhammer-Schalke, F.Hofstadter et al., “Ki-%, is a prognostic parameter in breast cancer patients: resultsof a large population-based cohort of a cancer registry,” BreastCancer Research and Treatment, vol. !.), no. #, pp. *.)–**#,#"!..

[.*] N. Eisemann, A. Waldmann, and A. Katalinic, “Epidemiologyof breast cancer—current -gures and trends,” Geburtsh Frauen-heilk, vol. ,., no. #, pp. !."–!.*, #"!..

[.%] A. C.Wol',M. E.H.Hammond,D.G.Hicks et al., “Recommen-dations for human epidermal growth factor receptor # testing inbreast cancer: American Society of Clinical Oncology/Collegeof American Pathologists clinical practice guideline update,”Journal of Clinical Oncology, vol. .!, no. .!, pp. .)),–$"!., #"!..

[.,] L. C. Tong, N. Nelson, J. Tsourigiannis, and A. M. Mulligan,“&e e'ect of prolonged -xation on the immunohistochemicalevaluation of estrogen receptor, progesterone receptor, andHER# expression in invasive breast cancer: a prospective study,”)e American Journal of Surgical Pathology, vol. .*, no. $, pp.*$*–**#, #"!!.

!" BioMed Research International

[.+] M. Ferrero-Pous, K. Hacene, C. Bouchet, V. le Doussal, M.Tubiana-Hulin, and F. Spyratos, “Relationship between c-erbB-# and other tumor characteristics in breast cancer prognosis,”Clinical Cancer Research, vol. %, no. !#, pp. $,$*–$,*$, #""".

[.)] S. Menard, A. Balsari, E. Tagliabue et al., “Biology, prognosisand response to therapy of breast carcinomas according toHER# score,” Annals of Oncology, vol. !), no. !", pp. !,"%–!,!#,#""+.

[$"] G. Konecny, G. Pauletti, M. Pegram et al., “Quantitative asso-ciation between HER-#/neu and steroid hormone receptors inhormone receptor-positive primary breast cancer,” Journal ofthe National Cancer Institute, vol. )*, no. #, pp. !$#–!*., #""..

[$!] S. Goel, J. Chirgwin, P. Francis et al., “Rational use of trastuz-umab in metastatic and locally advanced breast cancer: impli-cations of recent research,”Breast, vol. #", no. #, pp. !"!–!!", #"!!.

[$#] M. Schmidt, P. Fasching, M. Beckmann, and H. Kolbl, “Bio-markers in breast cancer—an update,” Geburtsh Frauenheilk,vol. ,#, no. ), pp. +!)–+.#, #"!#.

[$.] A. Wockel, C. Kurzeder, V. Geyer et al., “E'ects of guidelineadherence in primary breast cancer—a *-year multi-centercohort study of .),% patients,”)e Breast, vol. !), no. #, pp. !#"–!#,, #"!".

[$$] M. E. Hamaker, W. H. Schreurs, J. M. Uppelschoten, and C. H.Smorenburg, “Breast cancer in the elderly: retrospective studyon diagnosis and treatment according to national guidelines,”)e Breast Journal, vol. !*, no. !, pp. #%–.., #"").

[$*] N. Hebert-Croteau, J. Brisson, J. Latreille, M. Rivard, N.Abdelaziz, and G. Martin, “Compliance with consensus recom-mendations for systemic therapy is associated with improvedsurvival of women with node-negative breast cancer,” Journal ofClinical Oncology, vol. ##, no. !+, pp. .%+*–.%)., #""$.

[$%] K.Hancke,M.D.Denkinger, J. Konig et al., “Standard treatmentof female patients with breast cancer decreases substantiallyfor women aged ," years and older: a German clinical cohortstudy,” Annals of Oncology, vol. #!, no. $, pp. ,$+–,*., #"").

[$,] L. Schwentner, R.Wolters,M.Wischnewsky, R. Kreienberg, andA. Wockel, “Survival of patients with bilateral versus unilateralbreast cancer and impact of guideline adherent adjuvant treat-ment: a multi-centre cohort study of *#)# patients,”)e Breast,vol. #!, no. #, pp. !,!–!,,, #"!#.

[$+] L. Schwentner, R. van Ewijk, C. Kurzeder et al., “Participation inadjuvant clinical breast cancer trials: does study participationimprove survival compared to guideline adherent adjuvanttreatment? A retrospective multi-centre cohort study of ), $..patients,” European Journal of Cancer, vol. $), no. ., pp. **.–*%.,#"!..

[$)] W. van de Water, E. Bastiaannet, O. M. Dekkers et al., “Adher-ence to treatment guidelines and survival in patients withearly-stage breast cancer by age at diagnosis,” British Journal ofSurgery, vol. )), no. %, pp. +!.–+#", #"!#.

[*"] C. R. Friese, T. M. Pini, Y. Li et al., “Adjuvant endocrine therapyinitiation and persistence in a diverse sample of patients withbreast cancer,” Breast Cancer Research and Treatment, vol. !.+,no. ., pp. ).!–).), #"!..

[*!] L. Schwentner, A. Wockel, J. Konig et al., “Adherence to treat-ment guidelines and survival in triple-negative breast cancer:a retrospective multi-center cohort study with )!*% patients,”BMC Cancer, vol. !., no. !, article $+,, #"!..

[*#] S. B. Yellen, D. F. Cella, and W. T. Leslie, “Age and clinicaldecision making in oncology patients,” Journal of the NationalCancer Institute, vol. +%, no. #., pp. !,%%–!,,", !))$.

[*.] L. Gianni, U. Dafni, R. D. Gelber et al., “Treatment withtrastuzumab for ! year a/er adjuvant chemotherapy in patientswith HER#-positive early breast cancer: a $-year follow-up of arandomised controlled trial,” )e Lancet Oncology, vol. !#, no.., pp. #.%–#$$, #"!!.

[*$] H. Joensuu, P. Bono, V. Kataja et al., “Fluorouracil, epirubicin,and cyclophosphamide with either docetaxel or vinorelbine,with or without trastuzumab, as adjuvant treatments of breastcancer: -nal results of the FinHer trial,” Journal of ClinicalOncology, vol. #,, no. .$, pp. *%+*–*%)#, #"").

[**] A. Templeton, A. Ocana, B. Seruga et al., “Management of smallHER# overexpressing tumours,” Breast Cancer Research andTreatment, vol. !.%, no. !, pp. #+)–#)., #"!#.

[*%] P. S. Cra/, J.M. Buckingham, J. E. Dahlstrom et al., “Variation inthe management of early breast cancer in rural and metropoli-tan centres: implications for the organisation of rural cancerservices,”)e Breast, vol. !), no. *, pp. .)%–$"!, #"!".

[*,] S. Houterman, M. L. G. Janssen-Heijnen, C. D. G. W. Verheijet al., “Comorbidity has negligible impact on treatment andcomplications but in8uences survival in breast cancer patients,”British Journal of Cancer, vol. )", no. !#, pp. #..#–#..,, #""$.

[*+] W. J. Louwman, M. L. G. Janssen-Heijnen, S. Houterman et al.,“Less extensive treatment and inferior prognosis for breastcancer patient with comorbidity: a population-based study,”European Journal of Cancer, vol. $!, no. *, pp. ,,)–,+*, #""*.

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 201


MEDIATORSINFLAMMATION

of


Behavioural Neurology

,QWHUQDWLRQDO�-RXUQDO�RI

(QGRFULQRORJ\+LQGDZL�3XEOLVKLQJ�&RUSRUDWLRQKWWS��ZZZ�KLQGDZL�FRP

9ROXPH��


Disease Markers

BioMed Research International

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 201H

OncologyJournal of



Oxidative Medicine and Cellular Longevity

PPARRe sea rch

Hindawi Publishing Corporationhttp://www.hindawi.com Volume ��

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 201

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice

Parkinson’s DiseaseHindawi Publishing Corporationhttp://www.hindawi.com Volume 201

Evidence-Based Complementary and Alternative Medicine

Volume 201Hindawi Publishing Corporationhttp://www.hindawi.com

guideline concordant therapy prolongs survival in her2 ... · (cht) plus antihormone therapy (aht)...

Documents