Background We compared docetaxel with vinorelbine for the adjuvanttreatment of early breast cancer. Women with tumors that overexpressedHER2/neu were also assigned to receive concomitant treatmentwith trastuzumab or no such treatment.
Methods We randomly assigned 1010 women with axillary-node–positiveor high-risk node-negative cancer to receive three cycles ofdocetaxel or vinorelbine, followed by (in both groups) threecycles of fluorouracil, epirubicin, and cyclophosphamide. The232 women whose tumors had an amplified HER2/neu gene were furtherassigned to receive or not to receive nine weekly trastuzumabinfusions. The primary end point was recurrence-free survival.
Results Recurrence-free survival at three years was better withdocetaxel than with vinorelbine (91 percent vs. 86 percent;hazard ratio for recurrence or death, 0.58; 95 percent confidenceinterval, 0.40 to 0.85; P=0.005), but overall survival did notdiffer between the groups (P=0.15). Within the subgroup of patientswho had HER2/neu-positive cancer, those who received trastuzumabhad better three-year recurrence-free survival than those whodid not receive the antibody (89 percent vs. 78 percent; hazardratio for recurrence or death, 0.42; 95 percent confidence interval,0.21 to 0.83; P=0.01). Docetaxel was associated with more adverseeffects than was vinorelbine. Trastuzumab was not associatedwith decreased left ventricular ejection fraction or cardiacfailure.
Conclusions Adjuvant treatment with docetaxel, as compared withvinorelbine, improves recurrence-free survival in women withearly breast cancer. A short course of trastuzumab administeredconcomitantly with docetaxel or vinorelbine is effective inwomen with breast cancer who have an amplified HER2/neu gene.(International Standard Randomised Controlled Trial number,ISRCTN76560285 [controlled-trials.com].)
Adjuvant (postoperative) treatment has markedly reduced ratesof death due to breast cancer.1,2 However, in 15 to 25 percentof breast carcinomas, there is amplification of the HER2/neu(ErbB2) gene, an excess of the HER2 protein in the cancer cells,3and a high risk of recurrence.4,5,6
Trastuzumab (Herceptin, Roche) is a humanized monoclonal antibodyagainst the HER2 protein. When administered with chemotherapy,it improves survival in advanced HER2-positive breast cancer.7,8When given concomitantly with paclitaxel or after chemotherapyfor 12 months as adjuvant treatment for early HER2-positivebreast cancer, trastuzumab reduces the risk of recurrence byapproximately 50 percent and the risk of death by approximately30 percent.9,10 In these studies, the principal adverse eventattributable to trastuzumab was heart failure, which occurredin 1.7 to 4.1 percent of women treated with the antibody; approximately10 percent of trastuzumab-treated participants had a substantialdecrease in the left ventricular ejection fraction. The riskof cardiac dysfunction with trastuzumab treatment increaseswith the use of anthracyclines.7,11 The long-term outcome oftrastuzumab-related heart failure is unknown, although symptomsusually subside with cessation of treatment with trastuzumaband management of the condition.10
Combining trastuzumab with docetaxel, vinorelbine, cisplatin,carboplatin, or paclitaxel has resulted in the highest pooledresponse rates to date in the treatment of breast cancer.12Data obtained in vitro suggest that such combinations kill breastcancer cells by synergistic effects.13,14 In the FinHer (FinlandHerceptin) study, we compared docetaxel with vinorelbine, administeredwith or without trastuzumab, as adjuvant treatment for earlybreast cancer. In this study, trastuzumab was administered beforeother cardiotoxic therapies and concomitantly with potentiallysynergistic chemotherapy for only nine weeks to test the hypothesisthat such a schedule would limit cardiotoxicity and maintainefficacy.
Methods
Study Population
Women eligible for the study were less than 66 years of age,had a World Health Organization performance status of 0 or 1,and had undergone breast surgery with axillary-node dissectionor sentinel-node biopsy for invasive breast carcinoma. We requireddetermination of steroid hormone–receptor status and HER2expression by immunohistochemistry, according to the guidelinesof each institution. When HER2 expression was scored 2+ or 3+(on a scale of 0, 1+, 2+, or 3+), the number of copies of theHER2/neu gene was determined by means of chromogenic in situhybridization in one of two reference laboratories.15
Participants were randomly assigned (centrally and with computer-assistedblinding) to a study group within 12 weeks after surgery. Eligiblepatients had either at least one positive axillary node (regardlessof the primary tumor size or its hormone-receptor expression)or a node-negative breast-cancer mass at least 20 mm in diameterand a negative test for progesterone receptors (usually definedas staining of <10 percent of the cancer cells). The stagingworkup included isotope bone scanning; chest radiography orcomputed tomography (CT); and CT or ultrasonography of the upperabdomen.
Criteria for exclusion were distant metastases, pregnancy, severehypertension, and cardiac disease (including cardiac failureof any degree, arrhythmia requiring regular medication, andmyocardial infarction within the previous 12 months). Patientswere ineligible if they had a serum bilirubin level above theupper limit of normal, an alanine or aspartate aminotransferaselevel greater than 1.5 times the upper limit of normal, an alkalinephosphatase level above 2.5 times the upper limit of normal,a blood leukocyte count below 3.0x109 per milliliter, a neutrophilcount below 1.5x109 per milliliter, or a platelet count below120x109 per milliliter.
An ethics committee at Helsinki University Central Hospitalapproved the study. Study participants provided written informedconsent.
Study Design
Figure 1 shows the design of the trial. Randomization was stratifiedaccording to HER2 status (positive vs. negative) and institutionin this phase 3, open-label, multicenter trial. Permuted blockswere used to randomly assign all participants to receive threecycles of either docetaxel or vinorelbine. Docetaxel (Taxotere,Sanofi-Aventis) was given at a dose of 100 mg per square meterof body-surface area as a one-hour intravenous infusion on day1 of each 21-day cycle. Vinorelbine (Navelbine, Pierre Fabre)was administered at a dose of 25 mg per square meter as a 5-to-10-minuteintravenous infusion on days 1, 8, and 15 of the 21-day cycles.After the completion of docetaxel or vinorelbine treatment,three cycles of a regimen consisting of intravenous fluorouracilat a dose of 600 mg per square meter, epirubicin at a dose of60 mg per square meter, and cyclophosphamide at a dose of 600mg per square meter, each administered on day 1 of a 21-daycycle (FEC), were given. The vinorelbine infusion on day 15was omitted from the third cycle to allow the initiation ofFEC at a full dose without delay. The duration of the chemotherapyregimen was 18 weeks.
CISH denotes chromogenic in situ hybridization, and FEC a regimen of fluorouracil, epirubicin, and cyclophosphamide.
Women who had verified HER2-positive cancer were randomly assignedto receive or not to receive trastuzumab. Nine trastuzumab infusionswere administered at one-week intervals; the first infusionwas given on day 1 of the first docetaxel or vinorelbine cycle.The first dose was 4 mg per kilogram of body weight and thesubsequent doses 2 mg per kilogram, administered over periodsof 90 and 30 minutes, respectively. Trastuzumab was infusedbefore docetaxel or vinorelbine. No trastuzumab was given duringFEC administration.
The primary end point was recurrence-free survival, definedas the time from the date of randomization to the date of detection(with histologic or cytologic confirmation or with radiologicevidence) of local, distant, or contralateral invasive breastcancer or death, whichever occurred first. Secondary end pointsincluded adverse effects, the effect of treatment on the leftventricular ejection fraction, the time to distant recurrence,and overall survival, defined as time from randomization todeath from any cause.
Study Procedures
Concomitant Therapy
Patients assigned to docetaxel received six 7.5-mg doses ofdexamethasone; the first two were given 12 hours and 1 hourbefore docetaxel infusion and the rest at 12-hour intervalsafter infusion. Use of prophylactic antibiotics or granulocytecolony-stimulating factors was not recommended unless one ormore episodes of febrile neutropenia or severe infection occurred.
Radiotherapy was given after the completion of chemotherapyaccording to each institution's guidelines, but it was requiredafter breast-conserving surgery. Tamoxifen at a dose of 20 mgper day was administered to patients with estrogen-receptor–positiveor progesterone-receptor–positive tumors; this treatmentwas to be continued for five years.
Dose Modifications
Chemotherapy doses were reduced by 20 percent in cases of persistenthematologic toxic effects or grade 3 or 4 nonhematologic toxiceffects, defined according to the National Cancer InstituteCommon Toxicity Criteria (version 2.0). When either docetaxelor vinorelbine was discontinued because of adverse effects,the cycles not given were replaced by an equal number of cyclesof FEC. Trastuzumab was administered at full doses regardlessof blood-cell counts, but infusions were deferred whenever vinorelbineor docetaxel infusions were postponed because of adverse effects.
Evaluations
Adverse effects of therapy were recorded on protocol-specifiedforms on day 21 of each chemotherapy cycle and 12 and 36 monthsafter chemotherapy. Patients were scheduled for follow-up fora minimum of five years. Mammography was performed at one-to-two-yearintervals, but otherwise follow-up was carried out accordingto each institution's guidelines. In the group of patients assignedto trastuzumab treatment, the left ventricular ejection fractionwas measured by either echocardiography or isotope cardiographybefore chemotherapy, after the last FEC cycle, and 12 and 36months after chemotherapy.
Statistical Analysis
The study was designed to have a power of 0.80 to detect anincrease in five-year recurrence-free survival from 70 percentto 80 percent in the docetaxel-plus-FEC group as compared withthe vinorelbine-plus-FEC group (with use of a two-sided testat a significance level of 0.05); approximately 150 events wererequired for this purpose. We estimated that 30 percent of theparticipants would have breast cancer with HER2/neu amplificationand that the study would be able to detect a difference in theirfive-year recurrence-free survival of 50 percent to 67 percentat a power of 0.80 when approximately 1000 patients were enrolled.
Protocol-defined safety analyses took place in March 2001, September2001, and December 2002.16 The current protocol specified thatsafety and early efficacy analyses were to be carried out whenthe median follow-up time exceeded three years; this point wasreached in May 2005. The final analyses will be performed when150 events have occurred or the median follow-up time exceedsfive years. For the primary variable, a P value of less than0.029 was considered to indicate significance, in order to maintainan overall type 1 error of 0.05 for the interim and final analysis.17
Frequency tables were analyzed with use of the chi-square test.Survival between groups was compared with use of the Kaplan–Meierlife-table method and the Cox proportional-hazards model; thelog-rank test was used to confirm the robustness of the analysis.Efficacy analyses were based on the intention-to-treat principle.The effects of treatment, time, the method of assessment, andtheir interactions with the left ventricular ejection fractionwere analyzed in a repeated-measures analysis of covariance(ANCOVA) model; pretreatment measurement of the ejection fractionwas used as a covariate and the ejection fractions measuredlater as response variables. All P values are two-sided andwere not adjusted for multiple testing.
Dr. Joensuu drafted the study design. The investigators initiatedthe study, and collected, analyzed, and maintained the data.The sponsor (the Finnish Breast Cancer Group) received grantsfrom Sanofi-Aventis, Pierre Fabre, and Pharmacia; Roche supportedthe HER2/neu analyses. Trastuzumab was purchased from fundsprovided in the state budget of Finland; other study drugs werepurchased by the participating institutions. The manuscriptwas drafted by Dr. Joensuu and modified by the coauthors. Theauthors determined the content of the manuscript and vouch forits accuracy and completeness.
Results
Patients
From October 2000 to September 2003, 1010 women (approximately40 percent of the eligible women in Finland who received a diagnosisof breast cancer within this period, according to the FinnishCancer Registry and other sources [www.cancer.fi])18 were randomlyassigned to receive either docetaxel (502 women) or vinorelbine(508). Of these 1010 women, 232 who had an amplified HER2/neugene were further randomly assigned to receive trastuzumab (116women) or not to receive it (116). The median follow-up timeswere 36 and 35 months in the docetaxel and vinorelbine groups,respectively, and 37 and 35 months in the trastuzumab and no-trastuzumab(control) groups, respectively, at the time of analysis (May19, 2005). No patient was lost to follow-up. Two women who didnot receive the study treatments because of abnormal resultson liver-function tests were excluded from the safety analyses,and one woman (who had been assigned to the vinorelbine groupand had HER2/neu-positive cancer) with overt distant metastasesat randomization was excluded from the survival analyses. Onewoman with HER2/neu amplification did not participate in randomizationwith respect to trastuzumab, and seven women were ineligible.The baseline characteristics of the groups were balanced, exceptthat larger tumors were more common in the docetaxel group thanin the vinorelbine group and axillary nodal metastases tendedto be more frequent in the trastuzumab group than in the groupthat did not receive the antibody (Table 1).
Table 1. Characteristics of the Patients and the Tumors at Baseline.
Most (84.3 percent) of the cancers with strong (3+) HER2-proteinexpression on immunohistochemical analysis contained amplifiedHER2/neu. Of the cancers that stained moderately positively(2+), 26.2 percent contained amplified HER2/neu.
Treatment
In February 2002, an independent study-monitoring committeerecommended that the dose of docetaxel be reduced because 36.9percent of the women treated with this agent had received adiagnosis of neutropenic fever. Therefore, 206 of the 502 patientstreated with docetaxel (41.0 percent) received 100 mg per squaremeter and 296 (59.0 percent) received 80 mg per square meteras the starting dose. Three docetaxel cycles were completedby 472 patients (94.0 percent), and three vinorelbine cycleswere completed by 483 patients (95.1 percent). Docetaxel (100mg per square meter), docetaxel (80 mg per square meter), andvinorelbine were given at the protocol-specified dose in 64.7,83.9, and 82.4 percent of cycles, respectively. The most commonreasons for a reduction in the dose of docetaxel were neutropeniaand neutropenic infections, and the most common reason for areduction in the dose of vinorelbine was neutropenia. The fulldose of trastuzumab was administered in 99.1 percent of cycles,and 93.6 and 96.6 percent of the protocol-specified trastuzumabinfusions were delivered to women in the docetaxel and vinorelbinegroups, respectively.
Three or more FEC cycles were administered to 98.6 and 98.0percent of the women assigned to docetaxel and vinorelbine,respectively, and 91.2 and 93.1 percent received FEC at theprotocol-specified dose. Adjuvant radiotherapy was given to97.0 and 97.6 percent of the patients, respectively, and tamoxifento 71.1 and 73.8 percent.
Within the subgroup of women with HER2/neu-positive cancer,54 of the women assigned to receive trastuzumab (46.6 percent)and 58 of those who did not receive trastuzumab (50.0 percent)were in the docetaxel group (P=0.60). The protocol-specified100-mg dose of docetaxel was administered in 61.1 percent and64.4 percent of the cycles in the trastuzumab and control groups,respectively; the protocol-specified 80-mg dose of docetaxelin 83.3 percent and 81.6 percent of the cycles, respectively;the protocol-specified dose of vinorelbine in 80.3 percent and71.9 percent of the cycles, respectively; and the protocol-specifieddose of epirubicin in 94.0 percent and 92.0 percent of the cycles,respectively.
Efficacy
Recurrence of breast cancer or death without recurrence wasless common among women treated with docetaxel plus FEC thanamong those treated with vinorelbine plus FEC (42 of 502 vs.71 of 507; hazard ratio for recurrence or death, 0.58; 95 percentconfidence interval, 0.40 to 0.85; P=0.005) (Figure 2A). Thedevelopment of distant metastases also was less common in thedocetaxel group (33, vs. 58 in the vinorelbine group; hazardratio, 0.56; 95 percent confidence interval, 0.37 to 0.86; P=0.008).The hazard ratios for recurrence or death in the docetaxel group,as compared with the vinorelbine group, remained similar whenadjusted according to center (0.58; 95 percent confidence interval,0.40 to 0.85) or according to the number of positive nodes (0.57;95 percent confidence interval, 0.39 to 0.83). Overall survivalwas not significantly different between the groups (20 patientsin the docetaxel group vs. 30 in the vinorelbine group died;hazard ratio for death in the docetaxel group, as compared withthe vinorelbine group, 0.66; 95 percent confidence interval,0.38 to 1.17; P=0.15) (Figure 2B).
Figure 2. Effects of Single-Agent Docetaxel or Vinorelbine and of Trastuzumab on the Kaplan–Meier Estimates of Recurrence-free Survival (Panels A and C) and Overall Survival (Panels B and D) among Women with Breast Cancer.
One-, two-, and three-year survival data are shown. Hazard ratios are for recurrence or death (Panel A) or for death (Panel B) in the docetaxel group as compared with the vinorelbine group and, among women with HER2/neu-positive cancer, for recurrence or death (Panel C) or for death (Panel D) in the group that received trastuzumab as compared with the group that did not receive trastuzumab. FEC denotes a regimen of fluorouracil, epirubicin, and cyclophosphamide, and CI confidence interval.
Of the 115 patients in the trastuzumab group who were includedin the analysis of efficacy, 12 had a recurrence of breast canceror died without recurrence, whereas in the control group (116patients), there were 27 such cases (hazard ratio for recurrenceor death in the trastuzumab group, as compared with the controlgroup, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01)(Figure 2C). The hazard ratio remained similar when adjustmentwas made according to the type of chemotherapy given (0.41;95 percent confidence interval, 0.21 to 0.82), center (0.42;95 percent confidence interval, 0.21 to 0.83), or the numberof positive nodes (0.39; 95 percent confidence interval, 0.20to 0.77). Women who received trastuzumab had fewer distant recurrencesof cancer than did women who did not receive the antibody (8vs. 26; hazard ratio, 0.29; 95 percent confidence interval,0.13 to 0.64; P=0.002) (Figure 3). In addition, their overallsurvival tended to be better (6 vs. 14 patients died; hazardratio for death, 0.41; 95 percent confidence interval, 0.16to 1.08; P=0.07) (Figure 2D).
Figure 3. Effect of HER2/neu Amplification and Trastuzumab on the Kaplan–Meier Estimates of Survival Free of a First Distant Recurrence of Breast Cancer.
CI denotes confidence interval.
Adverse Effects
Docetaxel was more commonly associated with neutropenic fever,stomatitis, alopecia, nail problems, toxic effects on the skin,allergic reactions, neuropathy, and edema than was vinorelbine,which more frequently caused peripheral-vein phlebitis and elevationin the serum aspartate aminotransferase level. After the doseof docetaxel was reduced from 100 mg per square meter to 80mg per square meter, the frequency of neutropenic fever decreasedto 14.9 percent (P<0.001). Trastuzumab did not significantlyincrease the frequency of adverse events related to vinorelbineor docetaxel (Table 2).
Table 2. Influence of Trastuzumab on Adverse Events Related to Docetaxel and Vinorelbine Treatment.
One patient had cardiac infarction and three had cardiac failure;none of these four patients had received trastuzumab. Left ventricularejection fractions were preserved in women who received trastuzumab(Table 3). Trastuzumab-treated women had slightly better ejectionfractions than those who did not receive trastuzumab; in anANCOVA model, the estimated difference 12 months after the completionof chemotherapy was 1.7 percentage points (95 percent confidenceinterval, –0.1 to 3.5 percentage points; P=0.06), andat 36 months it was 3.0 percentage points (0.7 to 5.4 percentagepoints, P=0.01). In this model, vinorelbine and docetaxel hadsimilar estimated effects on the ejection fraction at both times(P=0.50). Four women treated with trastuzumab (3.5 percent)and seven who were not (6.0 percent) had one or more measurementsof ejection fraction more than 15 percentage points less thanthe pretreatment value. A decrease by more than 10 percentagepoints, resulting in an ejection fraction of less than 50 percent,occurred in three patients (none of whom had received trastuzumab).
Table 3. Left Ventricular Ejection Fraction (LVEF) during Follow-up among Study Participants Who Had Breast Cancer with HER2/neu Amplification.
Discussion
Adjuvant docetaxel, as compared with vinorelbine, improved recurrence-freesurvival in women with breast cancer. However, docetaxel wasmore toxic, and the scheduled starting dose was reduced duringthe study because of adverse effects. The use of granulocytecolony-stimulating factors or prophylactic antibiotics mighthave reduced the severity of neutropenia. Different doses ofdocetaxel have not been compared in the adjuvant setting. Inthis trial, women treated with 100 mg of docetaxel per squaremeter and those treated with 80 mg per square meter had similaroutcomes (data not shown), but this unplanned analysis may havebeen underpowered.
A short course of adjuvant trastuzumab given concomitantly withchemotherapy, as compared with chemotherapy alone, was an effectivetreatment for HER2/neu-positive cancer. None of the women whowere treated with trastuzumab had cardiac failure, and unexpectedly,these women had slightly better maintenance of left ventricularejection fraction than did those who did not receive the antibody.Administration of trastuzumab before FEC and radiotherapy aswell as the small cumulative dose of epirubicin given may havecontributed to the preservation of cardiac function. Regimenscontaining more than 60 mg of epirubicin per square meter percycle may have better efficacy than smaller doses,19 but epirubicinat a dose of 90 mg per square meter, given for four to six cycleswith cyclophosphamide and trastuzumab, may frequently decreasethe left ventricular ejection fraction and occasionally causecongestive heart failure.20
This prospective study confirms the adverse effect of HER2/neuamplification on prognosis. Survival free of distant diseasewas substantially less favorable among women with HER2/neu-positivecancer who did not receive trastuzumab than among those withHER2/neu-negative cancer (Figure 3). Trastuzumab abrogates muchof the adverse effect of HER2/neu amplification on outcome.
The proportion of women with HER2/neu-positive disease was 23percent, and thus only 232 women participated in randomizationwith respect to trastuzumab. The small size of this subgroupand the short duration of the follow-up are limitations of thestudy. Nevertheless, the number was large enough to allow detectionof a statistically significant difference in recurrence-freesurvival between treatments. When designing the study, we anticipatedthat HER2/neu amplification would be associated with frequentrelapses4,5,6 and that trastuzumab would be effective, accordingto findings in studies of its use in metastatic disease.7 Thelikelihood of detecting a difference was expected to be furtherimproved by the use of in situ hybridization to determine thenumber of copies of HER2/neu during patient selection and bythe concomitant use of potentially synergistic chemotherapy.13,14
The optimal duration of adjuvant trastuzumab therapy is notknown and may be clarified only in further randomized trials.Our results indicate that a nine-week period of trastuzumabadministration is effective in women with HER2/neu-positivebreast cancer. Regimens in which only a few cycles of trastuzumabare administered concurrently with chemotherapy reduce the numberof patient visits and may be more cost-effective than regimensthat require administration over a period of 12 to 24 months.9,10,21In addition, such regimens may result in few cardiac adverseeffects.
Events in the study are described in Table S1 of the Supplementary Appendix,available with the full text of this article at www.nejm.org.
Drs. Joensuu and Kellokumpu-Lehtinen report having receivedcompensation for time served on the Sanofi-Aventis advisoryboard; Dr. Joensuu, compensation for time served on the Rocheadvisory board; Drs. Joensuu, Kellokumpu-Lehtinen, Bono, Hemminki,and Turpeenniemi-Hujanen, lecture fees from Sanofi-Aventis;and Drs. Joensuu, Kellokumpu-Lehtinen, Bono, Alanko, Isola,and Turpeenniemi-Hujanen lecture fees from Roche. No other potentialconflict of interest relevant to this article was reported.
We are indebted to Professor Kaija Holli, Dr. Riikka Huovinen,and Kirsi Rouhento of the Finnish Breast Cancer Group for administrativehelp; to the members of the study monitoring committee, physician-in-chiefTapani Hakala, physician-in-chief Terhi Hermansson, and ProfessorLyly Teppo; to member of parliament Osmo Soininvaara, editor-in-chiefJussi Huttunen, and director general Jorma Huuhtanen for theirsupport in obtaining financing of the study; to members of theFinHer Study Group, study nurse Mrs. Kaija Seppälä,and many medical, nursing, and clerical staff members for theirsupport at the participating centers; and to all the women participatingin the FinHer trial for their contribution to this research.
* Other FinHer (Finland Herceptin) Study investigators are listedin the Appendix.
Source Information
From the Department of Oncology, Helsinki University Central Hospital, Helsinki (H.J., P.B., T.A., T.U., A.H., M.T., A.-S.J., I.E.); the Department of Oncology, Tampere University Hospital (P.-L.K.-L., T.S.), and the Laboratory of Cancer Biology, Institute of Medical Technology, University of Tampere and Tampere University Hospital (J.I.), Tampere; the Department of Oncology, Kuopio University Hospital, Kuopio (V.K.); Satakunta Central Hospital, Pori (R.A.); Hämeenlinna Central Hospital, Hämeenlinna (R.K.); the Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu (T.T.-H.); the Department of Oncology, Turku University Central Hospital, Turku (S.J.); South Karelia Central Hospital, Lappeenranta (M.F.); Kotka Central Hospital, Kotka (L.H.); Vaasa Central Hospital, Vaasa (S.I.); Kokkola Central Hospital, Kokkola (K.J.); Jyväskylä Central Hospital, Jyväskylä (M.P.); Kajaani Central Hospital, Kajaani (M.R.); Kemi Central Hospital, Kemi (J.K.-K.); and 4Pharma, Turku (M.L.) — all in Finland.
Address reprint requests to Dr. Joensuu at the Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, P.O.B. 180, FIN-00029 Helsinki, Finland.
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Appendix
In addition to the authors, the following investigators participatedin the FinHer Study: Helsinki University Hospital, Helsinki:A.-L. Kautio, L. Teerenhovi, M. Hernberg, and L. Vehmanen; TampereUniversity Hospital, Tampere: T. Korhonen; Satakunta CentralHospital, Pori: E. Korkeila; Oulu University Hospital, Oulu:G. Blanco and M. Heikkinen; Seinäjoki Central Hospital,Seinäjoki: T. Ala-Luhtala; Kuopio University Hospital,Kuopio: H. Virsunen; Joensuu Central Hospital, Joensuu: R. Keskikuru;Rovaniemi Central Hospital, Rovaniemi: A. Maiche; Vaasa CentralHospital, Vaasa: E. Thölix; and South Karelia Central Hospital,Lappeenranta: K. Möykkynen — all in Finland.
Taube, S. E., Clark, G. M., Dancey, J. E., McShane, L. M., Sigman, C. C., Gutman, S. I.
(2009). A Perspective on Challenges and Issues in Biomarker Development and Drug and Biomarker Codevelopment. JNCI J Natl Cancer Inst
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Reim, F., Dombrowski, Y., Ritter, C., Buttmann, M., Hausler, S., Ossadnik, M., Krockenberger, M., Beier, D., Beier, C. P., Dietl, J., Becker, J. C., Honig, A., Wischhusen, J.
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(2009). Role of Anthracyclines in the Treatment of Early Breast Cancer. JCO
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Sikov, W. M., Dizon, D. S., Strenger, R., Legare, R. D., Theall, K. P., Graves, T. A., Gass, J. S., Kennedy, T. A., Fenton, M. A.
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VAN ROOIJ, F. G., DORRESTEIJN, L. D.A., VAN BOKHOVEN, M. M.J.A., VERSTAPPEN, C. C.P.
(2009). A Throbbing Pain in the Head: Trastuzumab-induced Migraine. Anticancer Res
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Normanno, N., Morabito, A., De Luca, A., Piccirillo, M. C., Gallo, M., Maiello, M. R, Perrone, F.
(2009). Target-based therapies in breast cancer: current status and future perspectives. Endocr Relat Cancer
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Hurria, A., Wong, F. L., Pal, S., Chung, C. T., Bhatia, S., Mortimer, J., Somlo, G., Hurvitz, S., Villaluna, D., Naeim, A.
(2009). Perspectives and Attitudes on the Use of Adjuvant Chemotherapy and Trastuzumab in Older Adults with HER-2+ Breast Cancer: A Survey of Oncologists. The Oncologist
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Gong, Y., Sweet, W., Duh, Y.-J., Greenfield, L., Tarco, E., Trivedi, S., Symmans, W. F., Isola, J., Sneige, N.
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Goldhirsch, A., Ingle, J. N., Gelber, R. D., Coates, A. S., Thurlimann, B., Senn, H.-J., Panel members,
(2009). Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009. Ann Oncol
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(2009). Metastatic Breast Cancer: Therapeutic Options According to Molecular Subtypes and Prior Adjuvant Therapy. The Oncologist
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Dowsett, M., Procter, M., McCaskill-Stevens, W., de Azambuja, E., Dafni, U., Rueschoff, J., Jordan, B., Dolci, S., Abramovitz, M., Stoss, O., Viale, G., Gelber, R. D., Piccart-Gebhart, M., Leyland-Jones, B.
(2009). Disease-Free Survival According to Degree of HER2 Amplification for Patients Treated With Adjuvant Chemotherapy With or Without 1 Year of Trastuzumab: The HERA Trial. JCO
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Halyard, M. Y., Pisansky, T. M., Dueck, A. C., Suman, V., Pierce, L., Solin, L., Marks, L., Davidson, N., Martino, S., Kaufman, P., Kutteh, L., Dakhil, S. R., Perez, E. A.
(2009). Radiotherapy and Adjuvant Trastuzumab in Operable Breast Cancer: Tolerability and Adverse Event Data From the NCCTG Phase III Trial N9831. JCO
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Kataja, V., Castiglione, M., On behalf of the ESMO Guidelines Working Group,
(2009). Primary breast cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol
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Sparano, J. A., Moulder, S., Kazi, A., Coppola, D., Negassa, A., Vahdat, L., Li, T., Pellegrino, C., Fineberg, S., Munster, P., Malafa, M., Lee, D., Hoschander, S., Hopkins, U., Hershman, D., Wright, J. J., Kleer, C., Merajver, S., Sebti, S. M.
(2009). Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer. Clin. Cancer Res.
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Gong, Y., Sweet, W., Duh, Y.-J., Greenfield, L., Fang, Y., Zhao, J., Tarco, E., Symmans, W. F., Isola, J., Sneige, N.
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Bono, P., Kellokumpu-Lehtinen, P.-L., Alanko, T., Kokko, R., Asola, R., Turpeenniemi-Hujanen, T., Jyrkkio, S., Kataja, V., Leinonen, M., Joensuu, H.
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Sinclair, S., Zimmer, A. S., Swain, S. M.
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Cortes, J., Di Cosimo, S., Climent, M. A., Cortes-Funes, H., Lluch, A., Gascon, P., Mayordomo, J. I., Gil, M., Benavides, M., Cirera, L., Ojeda, B., Rodriguez, C. A., Trigo, J. M., Vazquez, J., Regueiro, P., Dorado, J. F., Baselga, J., on behalf of the Spanish Breast Cancer Cooperative,
(2009). Nonpegylated Liposomal Doxorubicin (TLC-D99), Paclitaxel, and Trastuzumab in HER-2-Overexpressing Breast Cancer: A Multicenter Phase I/II Study. Clin. Cancer Res.
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Martin, M., Esteva, F. J., Alba, E., Khandheria, B., Perez-Isla, L., Garcia-Saenz, J. A., Marquez, A., Sengupta, P., Zamorano, J.
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Chia, S., Norris, B., Speers, C., Cheang, M., Gilks, B., Gown, A. M., Huntsman, D., Olivotto, I. A., Nielsen, T. O., Gelmon, K.
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Vanden Bempt, I., Van Loo, P., Drijkoningen, M., Neven, P., Smeets, A., Christiaens, M.-R., Paridaens, R., De Wolf-Peeters, C.
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(2008). Trastuzumab-Induced Hepatotoxicity. The Annals of Pharmacotherapy
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Schmidt, M., Hasenclever, D., Schaeffer, M., Boehm, D., Cotarelo, C., Steiner, E., Lebrecht, A., Siggelkow, W., Weikel, W., Schiffer-Petry, I., Gebhard, S., Pilch, H., Gehrmann, M., Lehr, H.-A., Koelbl, H., Hengstler, J. G., Schuler, M.
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Goldstein, L. J., Gray, R., Badve, S., Childs, B. H., Yoshizawa, C., Rowley, S., Shak, S., Baehner, F. L., Ravdin, P. M., Davidson, N. E., Sledge, G. W. Jr, Perez, E. A., Shulman, L. N., Martino, S., Sparano, J. A.
(2008). Prognostic Utility of the 21-Gene Assay in Hormone Receptor-Positive Operable Breast Cancer Compared With Classical Clinicopathologic Features. JCO
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Rayson, D., Richel, D., Chia, S., Jackisch, C., van der Vegt, S., Suter, T.
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Anderson, J. R., Cain, K. C., Gelber, R. D.
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Nunes, C B, Rocha, R M, Reis-Filho, J S, Lambros, M B, Rocha, G F S, Sanches, F S F, Oliveira, F N, Gobbi, H
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Holmes, J. P., Benavides, L. C., Gates, J. D., Carmichael, M. G., Hueman, M. T., Mittendorf, E. A., Murray, J. L., Amin, A., Craig, D., von Hofe, E., Ponniah, S., Peoples, G. E.
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Untch, M., Gelber, R. D., Jackisch, C., Procter, M., Baselga, J., Bell, R., Cameron, D., Bari, M., Smith, I., Leyland-Jones, B., de Azambuja, E., Wermuth, P., Khasanov, R., Feng-yi, F., Constantin, C., Mayordomo, J. I., Su, C.-H., Yu, S.-Y., Lluch, A., Senkus-Konefka, E., Price, C., Haslbauer, F., Sahui, T. S., Srimuninnimit, V., Colleoni, M., Coates, A. S., Piccart-Gebhart, M. J., Goldhirsch, A., for the HERA Study Team,
(2008). Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol
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Belkacemi, Y., Gligorov, J., Ozsahin, M., Marsiglia, H., De Lafontan, B., Laharie-Mineur, H., Aimard, L., Antoine, E.-C., Cutuli, B., Namer, M., Azria, D.
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Ignatiadis, M., Kallergi, G., Ntoulia, M., Perraki, M., Apostolaki, S., Kafousi, M., Chlouverakis, G., Stathopoulos, E., Lianidou, E., Georgoulias, V., Mavroudis, D.
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Dang, C., Fornier, M., Sugarman, S., Troso-Sandoval, T., Lake, D., D'Andrea, G., Seidman, A., Sklarin, N., Dickler, M., Currie, V., Gilewski, T., Moynahan, M. E., Drullinsky, P., Robson, M., Wasserheit-Leiblich, C., Mills, N., Steingart, R., Panageas, K., Norton, L., Hudis, C.
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Peoples, G. E., Holmes, J. P., Hueman, M. T., Mittendorf, E. A., Amin, A., Khoo, S., Dehqanzada, Z. A., Gurney, J. M., Woll, M. M., Ryan, G. B., Storrer, C. E., Craig, D., Ioannides, C. G., Ponniah, S.
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Sengupta, P. P., Northfelt, D. W., Gentile, F., Zamorano, J. L., Khandheria, B. K.
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Wang, Y., Ikeda, D. M., Narasimhan, B., Longacre, T. A., Bleicher, R. J., Pal, S., Jackman, R. J., Jeffrey, S. S.
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Revillion, F., Lhotellier, V., Hornez, L., Bonneterre, J., Peyrat, J.-P.
(2008). ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol
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Bird, B. R.J. H., Swain, S. M.
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Wolff, A. C., Paik, S., Press, M. F.
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Sapino, A., Montemurro, F., Marchio, C., Viale, G., Kulka, J., Donadio, M., Bottini, A., Botti, G., dei Tos, A. P., Bersiga, A., Di Palma, S., Truini, M., Sanna, G., Aglietta, M., Bussolati, G.
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Harris, L., Fritsche, H., Mennel, R., Norton, L., Ravdin, P., Taube, S., Somerfield, M. R., Hayes, D. F., Bast, R. C. Jr
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Arnould, L., Arveux, P., Couturier, J., Gelly-Marty, M., Loustalot, C., Ettore, F., Sagan, C., Antoine, M., Penault-Llorca, F., Vasseur, B., Fumoleau, P., Coudert, B. P.
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Hayes, D. F., Thor, A. D., Dressler, L. G., Weaver, D., Edgerton, S., Cowan, D., Broadwater, G., Goldstein, L. J., Martino, S., Ingle, J. N., Henderson, I. C., Norton, L., Winer, E. P., Hudis, C. A., Ellis, M. J., Berry, D. A., the Cancer and Leukemia Group B (CALGB) Investiga,
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Carver, J. R., Shapiro, C. L., Ng, A., Jacobs, L., Schwartz, C., Virgo, K. S., Hagerty, K. L., Somerfield, M. R., Vaughn, D. J., for the ASCO Cancer Survivorship Expert Panel,
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