Her2 as Independent Prognostic Indicator in High Grade En Dome Trial CA

8/3/2019 Her2 as Independent Prognostic Indicator in High Grade En Dome Trial CA

1/11

HER-2 Is an Independent Prognostic Factor in EndometrialCancer: Association With Outcome in a Large Cohort ofSurgically Staged PatientsCarl Morrison, Vanna Zanagnolo, Nilsa Ramirez, David E. Cohn, Nicole Kelbick, Larry Copeland,Larry G. Maxwell, and Jeffrey M. Fowler

A B S T R A C T

PurposeTo evaluate HER-2 expression and amplification in a large cohort of endometrial cancer withcomplete surgical staging and outcome data.

Patients and MethodsA tissue microarray was constructed of 483 patients with endometrial cancer of diverse histologic

type and stage and tested for HER-2 expression and amplification using current standards ofpractice. There was outcome data for 83% of all patients and 81% with complete surgical staging.

ResultsBoth expression and amplification of HER-2 was associated with high-grade (P .0001) and highstage (P .0001) endometrial cancer. The highest rate of HER-2 expression and amplification wasseen in serous carcinoma (43% and 29%), while grade 1 endometrioid adenocarcinoma showedthe lowest levels (3% and 1%). For all histologic types, the rate of HER-2 expression andamplification was remarkably different (P .0001) for grade 3 cancers (31% and 15%) versusgrade 2 (7% and 3%) and grade 1 cancers (3% and 1%), with similar results for endometrioid type(P .0001). Both HER-2 expression and amplification correlated with disease-specific survival andprogression-free survival in univariate analyses. By multivariate analysis HER-2 expression in thepresence of amplification (P .012) correlated with overall survival, but not expression in theabsence of amplification. Overall survival was significantly shorter (P .0001) in patients whooverexpressed (median, 5.2 years) and/or showed amplification of HER-2 (median, 3.5 years)versus those that did not (median of all cases, 13 years).

ConclusionOur results would suggest that HER-2 is an important oncogene in high grade and stageendometrial cancer, but plays only a minor role in the much more common low grade and stagetumors that encompass the majority of clinical practice.

J Clin Oncol 24:2376-2385.

INTRODUCTION

An extensive body of literature exists regarding the

prognostic value and clinical utility of HER-2

(ERBB2; v-erb-b2 erythroblastic leukemia viral on-cogene homolog 2; alias NEU, HER-2) biomarker

expression for patients with breast cancer. In virtu-

ally all of these studies, HER-2overexpression in the

background of gene amplification, as opposed to

overexpression without gene amplification, appears

to have a stronger association with an adverse

outcome.1-5A recent meta-analysis6 of the literature

concerning HER-2 and breast cancer ( 27,000 pa-

tients)hasclearly shown thatHER-2 overexpression

with gene amplification is an independent prognos-

tic marker by multivariate analysisand strongly cor-

relates with other independent prognostic markers

in breast cancer including tumor grade and type.

HER-2 expression and amplification havebeen

studied in endometrial cancer,7-25 but there arecon-

flicting results in both the incidence and clinicalimportance of this finding. Many of these studies

have been limited by the methodology employed,as

well as the number of patients and histologic types

represented for analysis. With the exception of re-

cent reports,22-25 the previous studies evaluating

HER-2 expression evaluated an overabundance of

low grade and stage endometrial cancer. In this

study we have evaluated a broad spectrum of histo-

logic type, grade, and stage of endometrial cancer.

Analysis of a large numberof individual tumor

specimens is necessary to establish the prognostic

From the Department of Pathology,

Division of Gynecologic Oncology

Center for Biostatistics, The Arthur

James Cancer Hospital, and the Richard

Solove Research Institute, The Ohio

State University Medical School Colum-

bus, OH; and the Division of Gyneco-

logic Oncology, Walter Reed Army

Medical Center, Washington, DC.

Submitted August 2, 2005; accepted

March 1, 2006.

Supported by Grant No. BAA051 from

the Department of Defense Health

Systems/US Army Medical Research

and Material Command Gynecologic

Cancer Center for the Study of Racial

Disparities of the Uniformed Services

University of the Health Sciences.

Presented in part in abstract form at

the 36th Annual Meeting of the Society

of Gynecologic Oncologists, Miami, FL,

March 19-22, 2005.

Authors disclosures of potential con-

flicts of interest and author contribu-tions are found at the end of this

article.

Address reprint requests to Carl

Morrison, MD, DVM, Pathology Core

Facility, 418-M SL 320 W 10th Ave,

Columbus, OH 43210; e-mail:

[email protected].

0732-183X/06/2415-2376/$20.00

DOI: 10.1200/JCO.2005.03.4827

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

V OL UM E 2 4 N UM BE R 1 5 M A Y 2 0 2 0 0 6

2376

Downloaded from jco.ascopubs.org on January 17, 2012. For personal use only. No other uses without permission.Copyright 2006 American Society of Clinical Oncology. All rights reserved.


2/11

significance and potential therapeutic valueof a biologic marker, such

as HER-2, in endometrial carcinoma. The objective of this study was

to assess the prevalence of HER-2 expression and amplification and

compare that status to well-defined, traditional, clinicopathologic

prognostic factors in a large group of women diagnosed with endo-

metrial cancer where the great majority underwent surgical staging

and had clinical follow-up.

PATIENTS AND METHODS

PatientsAll of the patients in this study were diagnosed with uterine malignancy

and treated between January 1, 1980 and July 31, 2003 at the Arthur JamesCancer Hospital of the Ohio State University Medical School (OSU; Colum-bus, OH). The OSU institutional review board gave approval for this study.Morethan 81%of thepatients inthisstudyunderwentcomprehensive surgicalstaging including total abdominal hysterectomy bilateral salpingo-oophorectomy withpelvic and para-aortic lymph node dissection. Lymphad-enectomy was not performed in some patients who had either high surgicalrisk, gross intraperitoneal disease, or minimal risk intrauterine features at thetime of intraoperative frozen section analysis. Patients without lymphadenec-tomy and with no gross intraperitonealdisease were stagedby uterine factors.Platinum-based chemotherapy (with either doxorubicin or paclitaxel) was

given at the discretion of the attending physician to patients with advanceddisease.Alternatively, patients withadvanced disease or those at risk for pelvicfailure were given pelvic radiation (with or without coverage of the aortic

lymph nodes). A small subsetof patientswas treated with either concurrent orsequentialcisplatin-basedchemoradiotherapy.Two pathologists(C.M., N.R.)independently reviewed all cases for the evaluation of standard pathologicfactors including histologic type, grade, FIGO stage, and depth of myometrialinvasion. Cases for which there were discordant results were then reviewedconcurrently and a consensus agreement reached.

Immunohistochemistry and Fluorescent InSitu Hybridization

All of thepatients in this study were evaluated forHER-2 expression andamplification. HER-2 expression was performed using Pathway HER-2(Clone CB11) on the BenchMark XT automated system (Ventana MedicalSystems Inc, Tucson, AZ) per the manufacturers recommended protocol.Negative results were recorded for cases meeting one of the three followingcriteria: no staining, score 0; staining but without a membranous pattern,

score 0; or incomplete membranous staining or complete membranousstaining in less than 10% of the tumor cells, score 1. Positive results wererecorded for cases meeting one of the two following criteria: complete mem-branous staining in greater than 10%of thetumorcells of moderate intensity,score2,or completemembranousstaining ingreaterthan10% of the tumorcells of strong intensity, score 3.

Fluorescent in situ hybridization (FISH) for HER-2 amplification usingthe PathVysion HER-2 DNA Probe kit (Vysis, Dover, IL) was done in accor-dance with the manufacturers guidelines and performed manually. Speci-mens were evaluated with the Olympus BX51 microscope (Olympus OpticalCompany LTD, Tokyo, Japan) under oil immersion at100 magnificationusing the recommended filters. For each case the ratio of HER-2 to CEP17signals in at least 60 interphase nuclei with non-overlapping nuclei in thetumor cells was determined. Cells with no signals or with signals of only one

Fig 1. (A) Positive (3) immunohistochemistry with strong complete membra-

nous staining in more than 10% cells of case of serous carcinoma; (B) corre-

sponding FISH with high level of HER-2 gene amplification.

Table 1. Clinicopathologic Features of HER-2 Expression and Amplification

Patients

HER-2Positive

IHC

HER-2Positive

FISH

No. % No. % No. %

Race

White 446 91 58 13 26 6

Black 33 8 11 33 6 18Other 4 1 0 0 0 0

Stage

I 289 60 26 9 7 2

II 46 10 9 20 4 9

III 109 23 22 20 11 10

IV 39 8 13 33 9 23

Histologic Subtypes

Endometrioid grade 1 184 38 6 3 1 1



Mixed epithelial 27 6 7 26 2 7

MMT 26 5 3 12 1 4

Serous 58 12 25 43 17 29

Clear cell 9 2 3 33 2 22

OutcomeAlive without disease 309 64 26 8 5 2

Alive with disease 16 3 8 50 4 25

Died of disease 51 11 17 33 11 22

Died of other causes 24 5 5 21 2 8

No follow-up 83 17 14 17 9 11

Abbreviations: IHC, immunohistochemistry; FISH, fluorescent in situ hybrid-ization; MMT, malignant mixed tumor.

Independent Prognostic Factor in Endometrial Cancer

www.jco.org 2377



3/11

color weredisregarded. Tumors cells displaying at least two centromeric chro-mosome 17 signals and multipleHER-2 signals,witha HER-2/CEP17ratio2.2 were considered consistent with amplification of HER-2. Tumors cellsdisplaying at least two centromeric chromosome 17 signals and an equalnumber of HER-2 signals, with a HER-2/CEP17 ratio less than 2.2 wereconsidered consistent with no amplification of HER-2.

Tissue MicroarraysFour 1-millimeter tissue cores from formalin-fixed paraffin embedded

donor blocks were precisely arrayed into a new recipient paraffin block, in-cluding tumor specimens as well as controls.A previous study has shown thatthree to four cores from each sample give optimal statistical analysis in tissuemicroarrays (TMA), at least in other tumor types.26 As internal controls of

Table 2. Defined Subgroups for Comparison of HER-2 Expression and Amplification

Patients HER-2 Positive IHC HER-2 Positive FISH

No. % No. % P No. % P

Stage

Early (stage IA through IIB) 335 69 35 10 .0001 11 3 .0001

Advanced (stage IIIA through IVB) 148 31 35 24 21 14

Grade

Low to intermediate (endometrioid G1, G2) 297 61 13 4 .0001 4 1 .0001High (endometrioid G3, MMT, serous, clear cell, mixed epithelial) 186 39 57 31 27 15

Histologic type

Endometrioid 353 73 30 8 .0001 9 3 .0001

Nonendometrioid 130 27 40 31 23 18

Lymph-node status

Negative 359 82 39 11 .0002 15 4 .0107

Positive 79 18 21 27 9 11

Myometrial invasion

50% 301 62 29 10 .0001 9 3 .0002

50% 182 38 41 23 23 13

Abbreviations: IHC, immunohistochemistry; FISH, fluorescent in situ hybridization; G, grade; MMT, malignant mixed tumor.

Table 3. Univariate Analysis

Variable

Disease-Specific Survival Progression-Free Survival

Hazard

Ratio 95% CIP

Hazard

Ratio 95% CIP

Age, years

45 1.00 1.00

45 0.96 0.38 to 2.41 .9260 1.32 0.53 to 3.28 .5344

Lymph-node status

Negative 1.00 1.00

Positive 5.16 2.66 to 10.01 .0001 4.37 2.53 to 7.55 .0001

Grade

1 or 2 1.00 1.00

3 10.94 5.12 to 23.39 .0001 9.73 5.30 to 17.88 .0001

Myometrial invasion

50% 1.00 1.00

50% 3.76 2.00 to 7.07 .0001 3.88 2.27 to 6.63 .0001

Cervical involvement

No 1.00 1.00

Yes 2.85 1.59 to 5.12 .0005 2.42 1.46 to 4.00 .0011

Histology

Endometrioid 1.00 1.00

Nonendometrioid 5.63 3.22 to 9.85 .0001 6.47 3.98 to 10.51 .0001

Stage

I or II 1.00 1.00

III or IV 5.73 3.15 to 10.45 .0001 4.75 2.87 to 7.85 .0001

HER-2 IHC/HER-2 FISH

Negative/negative 1.00 1.00

Positive/negative 2.24 0.94 to 5.38 .0700 2.63 1.28 to 5.41 .0080

Positive/positive 6.86 3.45 to 13.63 .0001 5.29 2.89 to 9.67 .0001

Abbreviations: IHC, immunohistochemistry; FISH, fluorescent in situ hybridization.

Morrison et al

2378 JOURNAL OF CLINICAL ONCOLOGY



4/11

TMAadequacy we did immunohistochemistry (IHC) and FISH on completesections of five random cases scored as HER2 0, 1, 2 and 3 for a totalnumber of 20 cases that were included in the TMA. Specimens for controlswithin the TMA consisted of 50 secretory endometrium, 50 proliferativeendometrium, 50 normal cervix, and 50 normal ovaries, as well as multiplecores of normal tissue from10 different organs including heart, colon, kidney,adrenal, ovary, myometrium, brain, thyroid, lung, and prostate. For any casewithvariation ingrade or cytologicalatypia, TMAcores of the donor block wasalways taken from the areas of the highest grade tumor.

Statistical Analysis2 analysis was used for comparison of individual surgical-pathologic

variables and HER-2 expression and amplification. Both univariate and mul-tivariate logistic regression analysis were done to investigate relationshipsbetween surgical-pathologic variables and outcome. Kaplan-Meier survivalcurves for progression-free survival (PFS), overall survival (OS), and disease-specificsurvival (DSS)were evaluated witha log-ranktest. Deaths dueto causeother than disease were listed as censored events and not as adverse events forDSSor PFS. Forstatistical purposes, stage andgrade were each reduced to twocategories: stage I and II versus stage III and IV, grade 1 and 2 versus grade 3,respectively. HER-2 expression and amplification were consolidated into onevariable withthree categories: no expression and no amplification, expressionbut no amplification, and both expression and amplification.

RESULTS

PatientsForthe 483patients in this studythere wasan average patient age

of 62 years(range,17 to 89), with a total of42 patientsyounger than 45

years of age at the initial diagnosis of endometrial cancer. Just slightly

more than 90% of the patients were white, with the remainder of

patients consisting predominantly of black women. Follow-up was

available for 83% of all patients with a median follow-up time of 33

months (average, 41; range, 1 to 229). Seventy-five patient deaths

occurred, 51 related to endometrial cancer and 24 related to other

causes. Seventy adverse events were recorded, which included recur-

rent disease as well as deaths related to endometrial cancer. Ofpatients

who receivedfollow-up, 8% receivedexternal-beam radiation therapy

(EBRT)alone, 31% received chemotherapy alone, 9% received EBRT

plus chemotherapy, and 52% received no additional therapy beyond

surgical resection.

Rates of HER-2 Expression and Amplification

Uterine serous papillary carcinoma (Fig 1) showed the highest

rate of both expression and amplification (43% and 29%; Table 1).

Mixed epithelial cancers with serous differentiation compared with

uterine serous papillary carcinoma showed a lower but not signifi-

cantly different rate of HER-2 expression (26%; P .128), but a

significantly lower rate of amplification (7%; P .024). Grade 3

endometrioidcancersshowed a similar high rateof HER-2 expression

(29%), but a relatively lower rate of amplification (8%). HER-2 ex-

pression and amplification was uncommon in grade 1 (3% and 1%)

and grade 2 (7% and 4%) endometrioid endometrial cancer. For

stage there was a gradual increase in HER-2 expression and ampli-

fication from stage I (9% and 2%) to stage IV (33% and 23%;

P .0001). Both expression and amplification of HER-2 signifi-

cantly correlated with higher grade (P .0001) and stage (P

.0001), nonendometrioid histology type (P .0001), positive

lymph node status (P .0107), and greater than 50% myometrial

invasion (P .0002; Table 2). While there was definitely a trend for

a higher rate of HER-2 expression (33%) and amplification (18%)

amongblackpatients (Table1), thereweretoo fewof these patientsfora meaningful statisticalanalysisafter adjustingfor stage andgrade. The

results for IHC and FISH done for complete sections of five random

patients scored as HER2 0, 1, 2 and 3 for a total number of 20

patientsincludedin theTMA showed no changes in the overall results.

One case initially called no staining (negative result) by IHC was

reclassified as 1 staining (negative result), with no difference in the

remaining cases for IHC or FISH.

HER-2 Association With Standard Staging Parameters

and Survival

Univariate analyses involving Cox proportional hazards model

(Table 3) showed a number of standard histopathologic features

Table 4. Multivariate Analysis

Variable

Disease-Specific Survival Progression-Free Survival

HazardRatio 95% CI P

HazardRatio 95% CI P

Age, years

45 1.00 1.00

45 0.72 0.27 to 1.96 .530 0.97 0.37 to 2.52 .945

GradeEndometrioid G1 and G2 1.00 1.00

Endometrioid G3, serous, clear cell 8.17 3.27 to 20.46 .001 5.69 2.77 to 11.70 .001

Stage

I 1.00 1.00

II 2.07 0.75 to 5.70 .155 1.75 0.75 to 4.04 .194

III 2.90 1.36 to 6.19 .006 2.20 1.18 to 4.10 .013

IV 5.56 2.31 to 13.45 .001 5.24 2.55 to 10.79 .001

HER-2 IHC/HER-2 FISH

Negative/negative 1.00 1.00

Positive/negative 1.19 0.40 to 2.42 .976 1.53 0.76 to 3.08 .233

Positive/positive 2.30 1.25 to 5.32 .010 2.75 1.46 to 5.16 .002

Abbreviations: G, grade; IHC, immunohistochemistry; FISH, fluorescent in situ hybridization.


www.jco.org 2379



5/11

correlated withshorter DSS and PFS.Not unexpectedly these features

included high-grade (G3) histology, nonendometrioid histology, ad-

vanced stage (stage III and IV), positive nodal status, and more than

50% myometrial invasion (P .0001 for all). Likewise, DSS and PFS

showed statistically significant correlation with both HER-2 expres-sion(P .07 andP .008, respectively) and amplification (P .0001

for both). Multivariatemodels included age,grade, stage, and status of

HER-2 expression and amplification (Table 4). Stage III (P .009),

stage IV (P .001), and high grade (P .001) were associated with

DSS, as well as HER-2 expression in the presence of amplification

(P .010). HER-2 expression in the absence of amplification did not

showa statisticallysignificant correlation withDSS (P .976). Similar

results occurred for PFS, with a significant correlation for stage III

(P .013), stage IV (P .001), high grade (P .001), and HER-2

expression in the presence of amplification (P .002). As with DSS,

HER-2 expression in the absence of amplification did not show a statisti-

cally significant correlation with PFS by multivariate analysis(P .233).

Results for OS were similar to those for DSS and PFS (data not shown).

Kaplan-Meiersurvivalcurves forDSS,OS, andPFS for allgroups

of endometrial cancer patients were significantly different (log-rank

P .0001 for all) for cases that overexpressed and/or showedamplification of HER-2 (Fig 2). For 116 cases of high-stage (IIIA to

IVB) endometrial cancer there was a significant difference in PFS,

DSS, and OS (Fig 3) for cases that overexpressed and/or showed

amplification of HER-2 (log-rank P .05 for all). For 145 patients

with grade 3 endometrial cancer there was a significant difference in

PFS (log-rank P .0059) and OS (log-rank P .0271) for cases that

overexpressed and/or showed amplification of HER-2, with DSS

showing a similar trend but not quite reaching statistical significance

(log-rank P .1132; Fig 4).

Undoubtedly, the overall results of this study indicate that

HER-2 expression and amplification is much more common in

Fig 2. Kaplan-Meier survival curves for all cases of endometrial cancer (396 patients) for (A) disease-specific survival; (B) overall survival; and (C) progression-free survival. Five-year

survival data are presented as percentage (range). IHC, immunohistochemistry for HER-2; FISH, fluorescent in situ hybridization for HER-2; Pos, positive; Neg, negative.

Morrison et al




6/11

nonendometrioid than endometrioid endometrial cancer (EEC),

but the survival results are similar even at this lower rate of inci-

dence (Fig 5). For 315 cases of EEC with follow-up, there was a

significant difference in DSS (log-rank P .0002) and PFS (log-rankP .0001) for cases that overexpressed and/or showed amplification

of HER-2. For cases of EEC with stage IA and IB of any grade and

follow-up there were fewcaseswith HER-2expression and amplifica-

tion (224 patients;6% IHC, 1.3%amplified). Survivalcurvesforthis

group of patients (Fig 6) showed a significant difference in DSS (log-

rank P .00001) and PFS (log-rank P .00001) that overexpressed

and/or showed amplification of HER-2, although these results should

be viewed with caution due to the limited number of total events.

HER-2 Association With Treatment

In regard to potential interactions of HER-2 and EBRT and

chemotherapy, the overall number of patients treated with the

former was too small for a meaningful analysis. Of the 160 patients

(40%) of all patients given chemotherapy with follow-up (123

patients received chemotherapy alone,37 patients received chemo-

therapy plus EBRT), there was a statistically significant differencebetween those patients alive with no disease or who died due to

another cause versus those patients either alive with disease or who

died of disease (P .0000024). For the 120 patients alive with no

disease or who died due to another cause, there was a 11.7% rate of

HER-2 expression, versus a 46.3% rate for those patients either

alive with disease or who died of disease. This finding is con-

founded by the fact that those patients with an adverse outcome

related to disease showed a statistically significant difference com-

pared with the other group for all the standard staging parameters,

including high grade and stage, nonendometrioid type, and posi-

tive lymph node status (all Pvalues .01).

Fig 3. Kaplan-Meier survival curves for stage III and IV endometrial cancer (116 patients) for (A) disease-specific survival; (B) overall survival; and (C) progression-free

survival. Five-year survival data are presented as percentage (range). IHC, immunohistochemistry for HER-2; FISH, fluorescent in situ hybridization for HER-2; Pos,

positive; Neg, negative.


www.jco.org 2381



7/11

DISCUSSION

There have been few prior studies of this size to address HER-2 over-

expression and gene amplification in endometrial cancer. Our overall

results would suggest that HER-2 is an independent prognostic

marker for survival by multivariate analysis and important in a smallsubset of patients. In this study HER-2 overexpression without gene

amplification wasnot found to be an independent prognostic marker

for survival by multivariate analysis. Undoubtedly other studies are

needed to confirm and refine these results.

It is not that surprising that HER-2 overexpression with or with-

out gene amplification is strongly correlated with other independent

prognostic markers, including tumor grade and stage, based on our

knowledge of this biomarker in breast cancer. This association with

other known prognostic clinicopathologic markers complicates the

issue of response to chemotherapy in HER-2 positive endometrial

cancer. It should also be noted that the survival curves for both high-

stage and high-grade endometrial cancersshowed a decline in survival

for cases with HER-2 overexpression, irrespective of the presence or

absence of amplification. This would suggest that 2 levels of staining

without increased copy numbers of the HER-2 genes is a group that

needs additional study.

Prognostic implications of HER-2 expression and amplificationin endometrial cancer are controversial. Part of the confusion regard-

ing the incidenceof HER-2 protein expression and geneamplification

in endometrial cancer can be explained in part by the methodologies

of prior studies, which used no standardized method of scoring

results7-18 and the predominance of type I low-stage tumors.19-21 The

current standard of practice for positive scoring of HER-2 expression

in breast cancer is based on membranous staining that must be com-

pletely circumferential in at least 10% of the tumor cells and with a

disregard for cytoplasmic staining. Whether a patient is scored as 2

(moderately positive and possibly amplified)or 3 (strongly positive

and usually amplified) are based on the intensity of this particular

Fig 4. Kaplan-Meier survival curves for grade3 endometrial cancer (145patients)for (A) disease-specific survival; (B) overall survival;and (C) progression-freesurvival.Five-yearsurvival

data are presented as percentage (range). IHC, immunohistochemistry for HER-2; FISH, fluorescent in situ hybridization for HER-2; Pos, positive; Neg, negative.

Morrison et al




8/11

pattern of membranous staining. In this study we scored HER-2

expression by the criteria that currently exists for breast cancer andused a reasonable proportion of type II and high-stage tumors.

The highest level of HER-2 expression, particularly that associ-

ated with gene amplification, in this study was seen in the group of

uterine serous papillary carcinoma. Two recent papers have looked at

HER-2 in this group of tumors with discordant results.22,24,26 One of

these studies22 included cases of mixed epithelial type with serous

differentiation,althoughSlomovitz etal22didnotdisclosethe percent-

age of such cases. In our study, we divided such cases and included

only cases with essentially 100% serous differentiation as uterine se-

rous papillary carcinoma. Our cases of mixed epithelial type with

serous differentiation showed a similar rate of HER-2 expression, but

a significantly lower rateof amplification thanuterine serous papillary

carcinoma. This most likely explains some of the recent discrepanciesconcerning HER-2 in uterine serous papillary carcinoma and under-

scores the need for ancillary techniques in the classification of endo-

metrial cancer as we move toward specific gene targeted therapies.

Considering thebody of literature thatcurrentlyexists, it is safeto

say there are no current accepted guidelines for HER-2 testing in

endometrial cancer. For breast cancer the guidelines are simpleall

cases of invasive carcinoma irrespective of type, grade, or stage are

tested for HER-2 expression by immunohistochemical staining with

subsequent FISHanalysisfor intermediateexpressing (2) cases.Our

results would suggest that grade 3 endometrial cancer, regardless of

stage, and all patients with stage greater than IIIA should be tested for

Fig 5. Kaplan-Meier survival curves for all cases of endometrioid endometrial

cancer (315 patients) for (A) disease-specific survival and (B) progression-free

survival. Five-year survival data are presented as percentage (range). () No

survivors at 5 years. IHC, immunohistochemistry for HER-2; FISH, fluorescent in

situ hybridization for HER-2; Pos, positive; Neg, negative.

Fig 6. Kaplan-Meier survival curves for stage IA and IB endometrioid endometrial

cancer (224 patients) for (A) disease-specific survival and (B) progression-free

survival. Five-year survival data are presented as percentage (range). () No

survivors at 5 years. IHC, immunohistochemistry for HER-2; FISH, fluorescent in

situ hybridization for HER-2; Pos, positive; Neg, negative.


www.jco.org 2383



9/11

HER-2 expression andamplification.For bothof these groups,HER-2

expression (2 or greater) would identify almost 50% of the adverse

events in a prospective fashion. This apparent enthusiasm for HER-2

testingin highgrade andstage endometrialcancer should be tempered

by the relatively low incidence of these types of cases. For the vast

majority of endometrial cancer, which are endometrioid in type and

stage IC or less, the low incidence of HER-2 expression and/or gene

amplification in this group wouldsuggestthatglobal testing asdone in

breast cancer would not be warranted.

Trastuzumab (Herceptin; Genentech, San Francisco, CA) is

now standard therapy for appropriately selected patients with

breastcancer. It is logical to assume that targeted therapies directed

against HER-2 would be effectivein a segment of the populationof

patients with endometrial cancer; however, little information ex-

ists in theliterature. The Gynecologic Oncology Group reported its

experience with trastuzumab given to 23 patients with recurrent

disease with 2 or 3 staining or amplification by FISH.27 Unfor-

tunately, no objective response was observed. While this study did

not rule out the use of trastuzumab in endometrial cancer, it did

illustrate the importance of defining a population where targeted

therapies are considered as only 13% of the patients in this study

were documented to have tumors positive for amplification by

FISH analysis. An additional clinical trial (Gynecologic Oncology

Group 229D) involving GW572016 (lapatinib, GlaxoSmithKline,

Parsippany, NJ),a dual inhibitor of epidermal growth factorrecep-

tor and HER-2, is currently accruing patients with endometrial

cancer, but no results are currently available. At this time it might

be appropriate to state that continued investigation of HER-2

inhibition in high grade or stage endometrial cancer is appropriate

before discounting the use of HER-2 blocking agents in endome-

trial cancer.

In summary, to date this studythe largest study of HER-2 in

endometrial cancersuggests that HER-2 is an importantfactor in at

least a small subset of cases, particularly high-risk tumors. Unfortu-

nately the role that HER-2 plays in the vast majority of endometrial

cancermay bediminishedin comparisonwithbreastcancerdue tothe

relatively low incidence of expression and/or amplification in low

grade and stage endometrial cancer.

REFERENCES

1. Slamon DJ, Godolphin W, Jones LA, et al:

Studies of the HER-2/neu proto-oncogene in human

breast and ovarian cancer. Science 244:707-712,

1989

2. Borg A, Tandon AK, Sigurdsson H, et al:

HER-2/neu amplification predicts poor survival in

node-positive breast cancer. Cancer Res 50:4332-

4337, 1990

3. Wright C, Angus B, Nicholson S, et al: Expres-

sion of c-erbB-2 oncoprotein: A prognostic indicator

in human breast cancer. Cancer Res 49:2087-2090,

1989

4. Hayes DF, Thor AD: C-erbB-2 in breast can-

cer: Development of a clinically useful marker. Se-

min Oncol 29:231-245, 20025. Andrulis IL, Bull SB, Blackstein ME, et al:

Neu/erbB-2 amplification identifies a poor-prognosis

group of women with node-negative breast cancer:

Toronto Breast Cancer Study Group. J Clin Oncol

16:1340-1349, 1998

6. Ross JS, Fletcher JA, Linette GP, et al: The

Her-2/neu gene and protein in breast cancer 2003:

Biomarker and target of therapy. Oncologist 8:307-

325, 2003

7. Hetzel DJ, Wilson TO, Keeney GL, et al:

HER-2/neu expression: A major prognostic factor in

endometrial cancer. Gynecol Oncol 47:179-185,

1992

8. Khalifa MA, Mannel RS, Haraway SD, et al:

Expression of EGFR, HER-2/neu, P53, and PCNA in

endometrioid, serous papillary, and clear cell endo-metrial adenocarcinomas. Gynecol Oncol 53:84-92,

1994

9. Lukes AS, Kohler MF, Pieper CF, et al: Multi-

variable analysis of DNA ploidy, p53, and HER-2/neu

as prognostic factors in endometrial cancer. Cancer

73:2380-2385, 1994

10. Pisani AL, Barbuto DA, Chen D, et al: HER-2/

neu, p53, and DNA analyses as prognosticators for

survival in endometrial carcinoma. Obstet Gynecol

85:729-734, 1995

11. Nazeer T, Ballouk F, Malfetano JH, et al:

Multivariate survival analysis of clinicopathologic

features in surgical stage I endometrioid carcinoma

including analysis of HER-2/neu expression. Am J

Obstet Gynecol 173:1829-1834, 1995

12. Kohlberger P, Loesch A, Koelbl H, et al: Prog-

nostic value of immunohistochemically detected

HER-2/neu oncoprotein in endometrial cancer. Can-

cer Lett 98:151-155, 1996

13. Backe J, Gassel AM, Krebs S, et al: Immuno-

histochemically detected HER-2/neu-expression and

prognosis in endometrial carcinoma. Arch Gynecol

Obstet 259:189-195, 199714. Rasty G, Murray R, Lu L, et al: Expression of

HER-2/neu oncogene in normal, hyperplastic, and

malignant endometrium. Ann Clin Lab Sci 28:138-

143, 1998

15. Mariani A, Sebo TJ, Webb MJ, et al: Molecu-

lar and histopathologic predictors of distant failure in

endometrial cancer. Cancer Detect Prev 27:434-

441, 2003

16. Macwhinnie N, Monaghan H: The use of P53,

PTEN, and C-erbB-2 to differentiate uterine serous

papillary carcinoma from endometrioid endometrial

carcinoma. Int J Gynecol Cancer 14:938-946, 2004

17. Saffari B, Jones LA, el-Naggar A, et al: Ampli-

fication and overexpression of HER-2/neu (c-erbB2)

in endometrial cancers: Correlation with overall sur-

vival. Cancer Res 55:5693-5698, 199518. Riben MW, Malfetano JH, Nazeer T, et al:

Identification of HER-2/neu oncogene amplification

by fluorescence in situ hybridization in stage I endo-

metrial carcinoma. Mod Pathol 10:823-831, 1997

19. Rolitsky CD, Theil KS, McGaughy VR, et al:

HER-2/neu amplification and overexpression in en-

dometrial carcinoma. Int J Gynecol Pathol 18:138-

143, 1999

20. Cianciulli AM, Guadagni F, Marzano R, et al:

HER-2/neu oncogene amplification and chromo-

some 17 aneusomy in endometrial carcinoma: Cor-

relation with oncoprotein expression and

conventional pathological parameters. J Exp Clin

Cancer Res 22:265-271, 2003

21. Konopka B, Janiec-Jankowska A, Paszko Z, et

al: The coexistence of ERBB2, INT2, and CMYC

oncogene amplifications and PTEN gene mutations

in endometrial carcinoma. J Cancer Res Clin Oncol

130:114-121, 2004

22. Slomovitz BM, Broaddus RR, Burke TW, et al:

Her-2/neu overexpression and amplification in uter-

ine papillary serous carcinoma. J Clin Oncol 22:

3126-3132, 200423. Amant F, Vloeberghs V, Woestenborghs H, et

al: ERBB-2 gene overexpression and amplification in

uterine sarcomas. Gynecol Oncol 95:583-587, 2004

24. Santin AD, Bellone S, Siegel ER, et al: Racial

differences in the overexpression of epidermal

growth factor type II receptor (HER2/neu): A major

prognostic indicator in uterine serous papillary can-

cer. Am J Obstet Gynecol 192:813-818, 2005

25. Santin AD, Bellone S, Van Stedum S, et al:

Determination of HER2/neu status in uterine serous

papillary carcinoma: Comparative analysis of immu-

nohistochemistry and fluorescence in situ hybridiza-

tion. Gynecol Oncol 98:24-30, 2005

26. Rubin MA, Dunn R, Strawderman M, et al:

Tissue microarray sampling strategy for prostate

cancer biomarker analysis. Am J Surg Pathol 26:312-319, 2002

27. Fleming GF, Sill MA, Thigpen JT, et al: Phase

II evaluation of trastuzumab in patients with ad-

vanced or recurrent endometrial carcinoma: A report

on GOG 181B. Proc Am Soc Clin Oncol 22:453,

2003 (abstr 1821)

Morrison et al




10/11

Authors Disclosures of Potential Conflicts of InterestThe authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Carl Morrison, Nicole Kelbick, Larry G. Maxwell, Jeffrey M. Fowler

Financial support: Carl Morrison, Jeffrey M. Fowler

Administrative support: Carl Morrison, Jeffrey M. Fowler

Provision of study materials or patients: Carl Morrison, Jeffrey M. Fowler

Collection and assembly of data: Carl Morrison, Vanna Zanagnolo, David E. Cohn, Jeffrey M. FowlerData analysis and interpretation: Carl Morrison, David E. Cohn, Nicole Kelbick, Larry G. Maxwell, Jeffrey M. Fowler

Manuscript writing: Carl Morrison, Vanna Zanagnolo, David E. Cohn, Nicole Kelbick, Larry Copeland, Larry G. Maxwell, Jeffrey M. Fowler

Final approval of manuscript: Carl Morrison, Larry Copeland, Larry G. Maxwell, Jeffrey M. Fowler


www.jco.org 2385



11/11

ERRATA

The February 1, 2006, article by Liu et al entitled, [18F]Fluorodeoxyglucose PositronEmission Tomography Is More Sensitive Than Skeletal Scintigraphy for Detecting Bone

Metastasis in Endemic Nasopharyngeal Carcinoma at Initial Staging (J Clin Oncol24:599-604, 2006) contained an error in the spelling of Shu-Hang Ng. It was originally

published as Shu-Kung Ng and should have been Shu-Hang Ng.

DOI: 10.1200/JCO.2006.06.004

The April 20, 2006, article by Hurley et al, entitled Docetaxel, Cisplatin, and Trastu-

zumab As Primary Systemic Therapy for Human Epidermal Growth Factor Receptor2Positive Locally Advanced Breast Cancer (J Clin Oncol 24:1831-1838, 2006) contained

an error. Jodeen E. Powell (Department of Surgery, University of Miami, Miami, FL) wasinadvertently omitted from the author list. In the Author Contributions section,Dr Powell

should have been acknowledged for Provision of study materials or patients. There is no

change to the Authors Disclosure of Potential Conflicts of Interest section. The correctedauthor list is reprinted below in its entirety.

Judith Hurley, Philomena Doliny, Isildinha Reis, Orlando Silva, Carmen Gomez-

Fernandez, Pedro Velez, Giovanni Pauletti, Jodeen E. Powell, Mark D. Pegram, and

Dennis J. SlamonThe online version has been corrected in departure from the print.

DOI: 10.1200/JCO.2006.06.002

The May 20, 2006, article by Morrison et al entitled, HER-2 Is an IndependentPrognostic Factor in Endometrial Cancer:Association With Outcome in a Large Cohort of

Surgically Staged Patients (J Clin Oncol 24:2376-2385, 2006) contained an error in thespelling of G. Larry Maxwell. It was originally published as Larry G. Maxwell and should

have been G. Larry Maxwell.

DOI: 10.1200/JCO.2006.06.003

3515


Documents

Her2 as Independent Prognostic Indicator in High Grade En Dome Trial CA