c-erbB-2 Expression and Response to Adjuvant Therapy in Women with Node-Positive Early Breast Cancer
Hyman B. Muss, Ann D. Thor, Donald A. Berry, Timothy Kute, Edison T. Liu, Frederick Koerner, Constance T. Cirrincione, Daniel R. Budman, William C. Wood, Maurice Barcos, and I. Craig Henderson
Background The role of molecular markers in predicting the responseto treatment of breast cancer is poorly defined. The Cancerand Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapytrial (CALGB 8541) comparing three doses (high, moderate, andlow) of cyclophosphamide, doxorubicin, and fluorouracil in 1572women with node-positive breast cancer. This study (CALGB 8869)was designed to determine whether the DNA index, the S-phasefraction, c-erbB-2 expression, or p53 accumulation could beused as a marker to identify a subgroup of patients more likelythan others to benefit from high doses of chemotherapy.
Methods Tissue blocks were obtained from 442 patients randomlyselected from the larger CALGB trial. Paraffin sections fromthe primary lesions were analyzed for DNA content, S-phase fraction,c-erbB-2 expression, and p53 accumulation.
Results Patients randomly assigned to the high-dose regimenof adjuvant chemotherapy had significantly longer disease-freeand overall survival if their tumors had c-erbB-2 overexpression.No further information was gained by adding the data on S-phasefraction or p53 accumulation to the analysis. There was no clearevidence of a dose-response effect in patients with minimalor no c-erbB-2 expression.
Conclusions There is a significant dose-response effect of adjuvantchemotherapy with cyclophosphamide, doxorubicin, and fluorouracilin patients with overexpression of c-erbB-2 but not in patientswith no c-erbB-2 expression or minimal c-erbB-2 expression.Overexpression of c-erbB-2 may be a useful marker to identifythe patients who are most likely to benefit from high dosesof adjuvant chemotherapy.
Several molecular markers have been associated with a poor prognosisin patients with breast cancer, and it is widely assumed thatthe presence of these markers is an indication for adjuvanttherapy. Many physicians and patients believe that it is betterto try chemotherapy in such cases, even if it may be ineffective,than to do nothing and let the patient die. However, it is likelythat some prognostic factors can be used to identify a tumorthat is intrinsically resistant to moderate doses of chemotherapy,in which case such therapy is likely to compromise substantiallythe patient's quality of life without prolonging it. This issueis particularly important with such treatments as high-dosechemotherapy and autologous bone marrow transplantation, sincethe associated toxic effects and financial costs are substantial.
Prognostic factors that may help predict a recurrence of breastcancer include the size of the tumor,1 number of lymph nodesinvolved,1,2 histologic grade,3 and estrogen and progesteronestatus4. New molecular prognostic factors may also aid in theselection of a treatment5. Measurements of tumor DNA content(ploidy), cell proliferation (S-phase fraction), and oncogeneexpression have been reported to help predict relapse and survival,especially in patients with node-negative breast cancer. Flowcytometry is a rapid means of assessing cellular DNA contentand cell proliferation6 and can be performed with paraffin-embeddedtumor sections, thus facilitating a retrospective analysis7,8.The c-erbB-2 (HER-2/neu) oncogene is a potentially useful prognosticmarker that encodes a transmembrane glycoprotein whose extracellularregion is structurally similar to that of the epidermal-growth-factorreceptor9,10,11. Like the epidermal growth factor, c-erbB-2expression reflects an increase in the proliferative activityof a tumor12,13. Overexpression of c-erbB-2 has been demonstratedin 15 to 30 percent of patients with breast cancer and has beenfound by most but not all investigators to be associated withshorter survival, particularly in patients with positive nodes14,15,16,17,18.Another molecular marker is the tumor suppressor gene p5319,20,21,22.Mutations of this gene, which have been found in 13 to 49 percentof patients with breast carcinomas,23 may have prognostic importance,particularly in patients with node-negative disease24,25,26.
Patients with tumors that are positive for estrogen receptorsderive the greatest benefit from adjuvant endocrine therapy10,27.However, the relation between prognostic factors and the responseto adjuvant chemotherapy is less clear28,29,30,31. In patientswith tumors of unfavorable grade28,29 or a high thymidine-labelingindex,30,31 adjuvant chemotherapy has improved disease-freeand overall survival, but the value of flow cytometry and c-erbB-2and p53 studies to predict therapeutic responses in patientswith node-positive breast cancer is uncertain. Since the DNAcontent, S-phase fraction, and c-erbB-2 and p53 expression areindirect measures of proliferative activity, we hypothesizedthat they might help predict the outcome of treatment. We testedour hypothesis with biopsy material from a randomized trial,reported elsewhere in this issue,32 comparing three doses ofadjuvant chemotherapy to determine whether dose and dose intensitywere related to survival in women with node-positive, stageII breast cancer.
Methods
Subjects
The patients in this study (CALGB 8869) were drawn from thelarger trial of adjuvant chemotherapy (CALGB 8541). They wererandomly selected from the 12 strata defined by the year ofenrollment in the study (1985, 1986, 1987, or 1988) and thetreatment received (a low-, moderate-, or high-dose regimenof cyclophosphamide, doxorubicin, and fluorouracil) in the adjuvanttrial. Eligibility requirements for enrollment in the largertrial included a radical mastectomy, modified radical mastectomy,or breast-conservation therapy within six weeks before initiationof the chemotherapy protocol; no prior chemotherapy or irradiation;a CALGB performance score of 0 or 1 (no symptoms or minimalsymptoms); an age of at least 16 years; a white-cell count of3500 or more per cubic millimeter and a platelet count of 100,000or more per cubic millimeter; a hemoglobin level of 100 g ormore per liter; blood urea nitrogen, serum creatinine, and bilirubinlevels less than 1.5 times normal values; no concomitant cancer;and informed consent. Information on estrogen-receptor statuswas recorded at the time of enrollment in the study; standardizationof estrogen- and progesterone-receptor assays was not required,but almost all participating institutions have certified laboratoriesmeeting the requirements of the College of American Pathologists.For patients treated with lumpectomy or segmental mastectomy,a standardized irradiation protocol was administered after thecompletion of chemotherapy. All patients were followed in astandardized fashion after treatment to determine the frequencyand rate of recurrent disease and overall survival.
Treatment
Patients were randomly assigned to receive cyclophosphamide,doxorubicin, and fluorouracil at one of three levels of doseintensity: 600 mg, 60 mg, and 600 mg per square meter of body-surfacearea, respectively, every four weeks for four cycles (group1); 400 mg, 40 mg, and 400 mg per square meter every four weeksfor six cycles (group 2); or 300 mg, 30 mg, and 300 mg per squaremeter every four weeks for four cycles (group 3). Fluorouracilwas repeated on day 8 of each cycle. The cumulative doses ofcyclophosphamide, doxorubicin, and fluorouracil were identicalin groups 1 and 2 and 50 percent lower in group 3. The protocolwas amended in April 1988 to require tamoxifen therapy (10 mgorally twice a day for five years) for all disease-free perimenopausalor postmenopausal patients who were positive for estrogen orprogesterone receptors ( 7 fmol per milligram of protein). Tamoxifenwas instituted after the completion of chemotherapy.
Specimen Preparation
Formalin-fixed, paraffin-embedded blocks from the primary breastlesions were obtained from participating CALGB institutions.A slide stained with hematoxylin and eosin was prepared fromeach block and used for pathological confirmation of breastcancer. From the same block, 4-microm tissue sections were preparedfor immunohistochemical studies, and 50-microm sections forflow-cytometric analysis. All tumors were graded according toa nuclear grading system modified from that described by Blacket al.33 and were histologically categorized by a referencepathologist without knowledge of the case.
Flow-Cytometric Analyses
All flow-cytometric analyses were performed in a single referencelaboratory. The procedure of Hedley et al.,34 as modified byKute et al.,8 was used to determine DNA content and cell-cyclekinetics. The 50-microm sections were deparaffinized, and flowcytometry was performed on malignant areas dissected from thespecimen with the help of a tissue map (tumor enrichment). Adiploid DNA standard was obtained from the nonmalignant tissuein the block, and the histogram for the DNA standard was comparedwith the histogram for the tumor-enriched area of the same blockto correct for artifacts in fixation and preparation. The DNAindex was obtained by comparing the ratio of the G1 peak channelof the malignant cells to that of the nonmalignant cells. Samplesin which the G0G1 peaks of the diploid standard and the tumordid not match were not used for analysis. Three methods wereused to analyze cell kinetics: the rectangular-fit model,35a computer modeling procedure (Modfit)8 that determines G1,S, and G2 activity and corrects for variability in the coefficientof variation and the location of the peak channel, and an area-fitprocedure. Only the Modfit model corrects for debris. The resultsof the three methods were closely correlated (data not shown);the rectangular-fit model was used in this analysis becausethe S-phase differences computed with this method provided thebest correlation with prognosis. The relatively high medianvalue of S-phase activity in the analysis is most likely relatedto the use of the rectangular-fit model. Flow-cytometric studieswere performed without knowledge of information about the patients.
Immunohistochemical Analysis of c-erbB-2 Expression
All immunohistochemical analyses were performed in a singlereference laboratory with the use of previously described methods31.Briefly, a polyclonal antibody (OA-11-854; Cambridge ResearchBiochemicals, Wilmington, Del.) reactive with the cytoplasmicdomain of c-erbB-2 was used with avidin-biotin-peroxidase immunohistochemicalmethods. All slides were evaluated for c-erbB-2 overexpressionby two investigators without knowledge of patient information.The percentage of stained invasive malignant cells was estimated,and tissue was considered to be positive for c-erbB-2 expressionif any membranous activity was found in these cells at a magnificationof 100. All malignant cells on each slide were evaluated. Thetwo investigators had generally similar estimates of the frequencyof stained cells on the slides (less than a 5 percent discrepancybetween estimates). In a previous study, an immunohistochemicalanalysis of c-erbB-2 expression was shown to be closely correlatedwith HER-2/neu gene amplification36.
Immunohistochemical Analysis of p53 Expression
Expression of p53 was evaluated according to previously publishedmethods24. Briefly, a monoclonal anti-p53 antibody (anti-p53PAb1801; Cambridge Research Biochemicals) diluted 1:4000 wasapplied after the sections had been incubated overnight withdiluted normal horse serum at 4 °C. The slides were rinsedand sequentially incubated with biotin-horse-antimouse and streptavidin-horseradishperoxidase (Zymed Laboratories, San Francisco). Diaminobenzidine(Sigma Chemical, St. Louis) was used to visualize antibody binding.Slides were counterstained with 1 percent aqueous methyl green,dehydrated, cleared, and mounted. For each assay, slides fromfixed, embedded cell pellets from MDA-MB-231 (positive control)and HTB5 (negative control) (both from the American Type CultureCollection, Rockville, Md.) were included to ensure interassayconsistency24. Two investigators evaluated each slide by lightmicroscopy. If invasive tumor cells displayed nuclear brownstaining, the slide was considered to be positive for p53 overexpression.An estimate was made of the percentage of positive invasivetumor cells visible at a magnification of 100.
Study Design and Statistical Analysis
At the time this trial was initiated, DNA content appeared tobe the strongest flow-cytometric predictor of recurrent diseasein patients with early-stage breast cancer37. A sample sizeof 134 patients per treatment group was estimated to have thecapacity to detect a 25 percent difference in disease-free survivalwithin each treatment group for patients whose tumors had aneuploidas compared with diploid DNA content (a power of 0.8 and a two-sidedP value of 0.05). Blocks from a total of 442 patients were obtainedfor analysis. The demographic, clinicopathological, and laboratoryvariables we analyzed included treatment group, age at the timeof enrollment in the study, menopausal status, tumor size, numberof positive nodes, histologic type and grade, estrogen- andprogesterone-receptor status, tamoxifen therapy, DNA content,S-phase fraction, c-erbB-2 expression, and p53 accumulation.We analyzed tumor size as a dichotomous variable ( 2 cm or>2 cm), as a continuous (linear) variable, and with square-rootand logarithmic transformations. In both univariate and multivariateanalyses, the dichotomous variables predicted overall and disease-freesurvival better than the other variables. Some variables weretransformed to increase their predictive value. For example,we used the square root of the number of positive nodes, whichperformed better than the number of positive nodes in both linearand logarithmic scales. With the square-root transformation,an increase in the number of positive nodes from 1 to 4 carriedabout the same incremental risk as an increase in the numberof positive nodes from 4 to 9 or from 9 to 16.
Overall survival was defined as the time from enrollment inthe study to death; data on survivors were censored at the lastfollow-up visit. Disease-free survival was defined as the timefrom enrollment to a documented relapse or death without a relapse.Data on patients who did not have a relapse were censored atthe last follow-up visit. To date, 98 of the 442 patients inthis study have died, 95 of recurrent breast cancer. Survivalcurves were drawn according to the Kaplan-Meier product-limitmethod38,39,40. Two or more survival distributions were comparedwith the log-rank test. We used the Cox proportional-hazardsmodel to relate the various covariables to disease-free andoverall survival41. We used this method in univariate analysesto screen for prognostic variables and in multivariate analysesto identify sets of prognostic variables while controlling forthe effects of other variables. This model assumes a constantratio of hazard rates for different levels of therapy with prognosticvariables. Categorical variables were compared with the chi-squaretest or Fisher's exact test. We used the Kruskal-Wallis testto compare variables across dose levels. Correlation coefficientswere calculated to measure the association between pairs ofvariables that were potential predictors of survival.
Results
Patient Sample and Clinical Variables
Tissue blocks were obtained from 442 patients randomly selectedfrom the 1572 patients enrolled in the adjuvant-chemotherapytrial. Of these 442 blocks, 397 (90 percent) were technicallysatisfactory for analysis of DNA content (ploidy) and c-erbB-2expression, 394 (89 percent) for analysis of p53 expression,and 302 (68 percent) for analysis of the S-phase fraction. Aneuploidtumors were found in 59 percent of the patients, and the medianS-phase fraction was 11 percent. At least some c-erbB-2 expressionwas found in 59 percent of the samples, and in 29 percent ofthe samples at least 50 percent of the cells stained for c-erbB-2.Some p53 expression was found in 42 percent of the samples,and in 17 percent of the samples 10 percent or more of the cellsdisplayed p53 expression. This report includes follow-up dataas of January 1, 1992. The median follow-up for all patientswas 38.5 months, with a range of 1 week to 80 months.
Table 1 provides clinical data for the 442 patients in the threetreatment groups, as well as for the total patient population.These data indicate that our sample was representative of theoverall patient population. Patients in the three treatmentgroups had similar clinicopathological features except for histologictype; there were fewer infiltrating ductal carcinomas in group3 than in groups 1 and 2 (87 percent vs. 95 and 97 percent,respectively). Although significant (P<0.01), this differencedid not affect the outcome in either univariate or multivariateanalyses. DNA content, c-erbB-2 expression, and p53 expressionwere similar among the three treatment groups (Table 2). Therewas a correlation between the S-phase fraction and c-erbB-2expression (r = 0.13, P = 0.03) and between the S-phase fractionand p53 accumulation (r = 0.25, P<0.01).
Table 2. DNA Content, S-Phase Fraction, and c-erbB-2 and p53 Expression.
Disease-free and Overall Survival
The data from the larger CALGB trial at 3.2 years of follow-upshowed that disease-free survival and overall survival in groups1 and 2 (patients treated with high- or moderate-dose chemotherapy)were significantly longer than in group 3 (patients treatedwith low-dose chemotherapy)32. The data from the 442 patientsin this analysis show a similar trend: a moderate- or high-doseregimen was associated with significantly longer disease-freesurvival (P<0.01) and overall survival (P = 0.13) (data notshown).
A univariate analysis demonstrated that the well-establishedclinical prognostic factors -- larger tumor size, higher numberof positive nodes, higher tumor grade, and lack of estrogenand progesterone receptors -- were associated with shorter survival(Table 3). In contrast, older age and postmenopausal statuswere significantly associated with longer survival, and patientswho received tamoxifen did better than those who did not receivethis drug; tamoxifen, however, was administered to a selectgroup of patients.
Table 3. Results of Univariate Analyses of Overall and Disease-free Survival.
Factors that were found to be significant in the univariateanalysis (P<0.05), as well as c-erbB-2 expression, p53 accumulation,and S-phase fraction, were examined in the multivariate Coxmodel for their relation to disease-free and overall survival.Initially, we analyzed the results for the 269 patients whosetumor blocks were technically satisfactory for analyses of c-erbB-2expression, p53 accumulation, S-phase fraction, and ploidy;the pretreatment characteristics of these patients and the 442in the entire sample were similar (data not shown). This multivariateanalysis revealed that a larger number of positive lymph nodes,a larger tumor size, premenopausal status, and greater c-erbB-2expression were significant predictors of shorter disease-freeand overall survival. In contrast, p53 accumulation was of marginalsignificance as a predictor of survival. Chemotherapy dose,age, histologic type and grade, estrogen- and progesterone-receptorstatus, and S-phase fraction were not predictors of either disease-freeor overall survival.
By omitting the S-phase fraction from the model, we increasedthe sample size from 269 to 388 patients. Analysis of this groupwith the Cox model showed that all variables were significantpredictors of survival except p53 accumulation and that menopausalstatus was no longer a significant factor for overall survival.A third multivariate analysis omitted both p53 accumulationand S-phase fraction (Table 4). Again, the number of positivelymph nodes, tumor size, and c-erbB-2 expression were significantlyrelated to both disease-free and overall survival. Moreover,there was a highly significant interaction between chemotherapydose and c-erbB-2 expression for both disease-free and overallsurvival. Once the interaction between chemotherapy dose andc-erbB-2 expression had been accounted for, the interactionsbetween the dose and the other variables did not provide additionalpredictive information. Replacing the S-phase fraction withhistologic grade in the model did not give additional information.The dose of chemotherapy was not independently related to disease-freeor overall survival in any of the models used in the multivariateanalysis.
Table 4. Multivariate Analysis of Overall and Disease-free Survival (Cox Regression Model).
Overexpression of c-erbB-2 as a Predictive Factor for Survival
Although a cutoff point is occasionally used to define a high-or low-risk group,37 this approach tends to oversimplify andeven distort the relations between variables and outcomes. Inthe statistical modeling, we analyzed c-erbB-2 overexpressionas a continuous variable. To portray these data graphically,however, we used a 50 percent cutoff point (Figure 1). Patientswhose tumors had 50 percent or more c-erbB-2 overexpressionconstituted 29 percent of the study population. Separation ofthe curves for both disease-free and overall survival in thisgroup was both substantial and significant, indicating a dose-responseeffect (Figure 1C and Figure 1D). Notably, of the patients whowere enrolled in group 1 of the adjuvant trial, those whosetumors overexpressed c-erbB-2 had longer disease-free and overallsurvival than those whose tumors did not overexpress c-erbB-2.In contrast, no dose-response effect was seen when the 71 percentof patients with no or low c-erbB-2 overexpression were groupedtogether. This relation between the dose-response effect andthe c-erbB-2 level was relatively independent of other riskfactors, such as the number of nodes involved. There was littledifference in disease-free survival among the three treatmentgroups for patients whose tumors had no or low c-erbB-2 expression,regardless of the nodal status (Figure 1A and Figure 1B). Amongthose with a high level of overexpression, there was a significantdose-response effect for all nodal groups (data not shown).
Figure 1. Disease-free and Overall Survival According to Treatment Group (High-Dose, Moderate-Dose, or Low-Dose Chemotherapy) and Level of c-erbB-2 Expression.
Discussion
This analysis of molecular markers in breast cancer suggeststhat increasing the dose intensity of adjuvant chemotherapymay not result in a similar benefit for all patients with positivenodes. It appears that patients whose tumors overexpress c-erbB-2may derive the greatest benefit from higher doses of chemotherapy.In contrast, no benefit from dose intensification was observedin patients with no or low c-erbB-2 expression. These resultsshould not be misconstrued to mean that lower doses of adjuvanttherapy are not beneficial in patients with node-positive breastcancer. On the contrary, the results of an overview analysissuggest that combination chemotherapy significantly improvessurvival in such patients as compared with similar patientsnot receiving chemotherapy27.
Adjuvant chemotherapy appears to be more effective in patientswhose tumors have a high thymidine-labeling index than in thosewhose tumors have a lower thymidine-labeling index30. Adjuvantchemotherapy has also been associated with improved disease-freeand overall survival in patients with a higher tumor grade thanin those with a lower tumor grade28,29. In a study of preoperativechemotherapy in patients with primary breast cancer, a highS-phase fraction was associated with a better response ratethan a low S-phase fraction42. Similar correlations betweenthe response to chemotherapy and the rate of tumor proliferationhave been found in small cohorts of patients with locally advancedbreast cancer43 or distant metastases44.
Two previous studies suggest that overexpression of c-erbB-2may be associated with resistance to chemotherapy45,46. Boththese studies used conventional doses of cyclophosphamide, methotrexate,and fluorouracil. In one of the studies, patients with node-negativebreast cancer were randomly assigned to receive either six monthsof adjuvant chemotherapy or no chemotherapy at all45. Chemotherapyresulted in significantly longer disease-free survival amongpatients whose tumors did not express c-erbB-2 than among thosewith c-erbB-2 overexpression. In the other study, patients withpositive nodes were randomly assigned to six months or one monthof adjuvant chemotherapy. The longer period of therapy was associatedwith longer disease-free and overall survival46. However, amongthe patients who received six months of chemotherapy, disease-freesurvival was significantly longer among those whose tumors didnot express c-erbB-2 than among those whose tumors overexpressedthe oncogene.
What accounts for the differences between the results of thesestudies and our results? An important distinction is that ouradjuvant-chemotherapy regimen included doxorubicin, whereasthe regimens in the previous trials did not. Furthermore, c-erbB-2expression may indeed be a marker of relative resistance tochemotherapy, but an escalation of the dose may overcome thatresistance. Patients whose tumors overexpress c-erbB-2 may thusbenefit from higher doses of chemotherapy given in regimenscontaining anthracyclines. On the other hand, patients whosetumors do not overexpress c-erbB-2 may not need higher dosesof chemotherapy regimens that include anthracyclines to obtainthe maximal benefit from adjuvant chemotherapy.
Doxorubicin is generally recognized as the most effective agentagainst breast cancer. It is possible that its efficacy is duein part to its ability to overcome the relative resistance tochemotherapy associated with c-erbB-2 overexpression. In a recentin vitro study, breast-cancer cells overexpressing c-erbB-2frequently overexpressed topoisomerase IIalpha, a target enzymefor doxorubicin47. We are planning to measure the expressionof topoisomerase II in available tissue specimens from patientsin this study to determine whether c-erbB-2 expression is amarker for topoisomerase II expression through linkage. Tsaiand colleagues have recently reported that increased resistanceto the cytotoxicity of doxorubicin was directly related to increasedc-erbB-2 expression in non-small-cell lung-cancer cell lines48.These data suggest that a high dose of doxorubicin may be necessaryto kill tumor cells in patients with a high level of c-erbB-2expression.
Expression of c-erbB-2 was significantly associated with treatmentoutcome in this trial, but it is not necessarily the ideal markerfor predicting sensitivity to chemotherapy. Estimation of c-erbB-2overexpression is imprecise, and no standardized assay is available.Estimates of c-erbB-2 expression are currently provided by manylaboratories as part of a prognostic profile, but further dataare needed before this marker can be used in making clinicaldecisions. Moreover, differences in assay and reporting methodsmake comparisons of our data and those of others tenuous.
Adjuvant chemotherapy prolongs disease-free and overall survivalin patients with node-positive early breast cancer. However,the majority of patients with clinically occult metastases atthe time of diagnosis ultimately have a relapse and die in spiteof receiving a moderate-dose regimen of cyclophosphamide, doxorubicin,and fluorouracil or cyclophosphamide, methotrexate, and fluorouracil27.Trials are under way to determine whether high-dose chemotherapywith autologous bone marrow support improves the outcome forwomen with node-positive breast cancer. Such treatment involvessubstantial toxicity as well as a high cost49. Therefore, measurementsthat help identify those patients most likely to benefit fromintensive treatment will be important. Data from other prospectivetrials are needed to corroborate our observations and determinewhether either c-erbB-2 expression or other biologic markerscan identify tumors that are particularly responsive or resistantto specific chemotherapeutic agents or to escalated doses ofsuch agents.
Supported by grants (CA-03927, CA-44768, CA-31946, CA-33601,CA-47559, CA-07968, CA-12449, CA-37207, and CA-32291) from theNational Cancer Institute.
Source Information
From the Bowman Gray School of Medicine, Winston-Salem, N.C. (H.B.M., T.K.); Massachusetts General Hospital, Boston (A.D.T., F.K.); the Statistical Office of the Cancer and Leukemia Group B, Durham, N.C. (D.A.B., C.T.C.); the Department of Medicine, University of North Carolina School of Medicine, Chapel Hill (E.T.L.); North Shore University Hospital (New York Hospital), New York (D.R.B.); Emory University, Atlanta (W.C.W.); the Department of Medicine, Roswell Park Memorial Institute, Buffalo, N.Y. (M.B.); and the University of California, San Francisco (I.C.H.).
Address reprint requests to Dr. Thor at the Department of Pathology, University of Vermont School of Medicine, Medical Alumni Bldg., Burlington, VT 05405.
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Adjuvant Therapy for Breast Cancer
Muller H.-J., Gleiter C. H., Gundert-Remy U., Melnychuk D., Panasci L. C., Coppin C. M.L., Goldie J. H., Sauter C., Garey J., Lehrer S., Farkas D. H., Umek R. M., Morrison B. W., Atkins C. D., Wood W. C., Budman D., Henderson I. C., Muss H. B., Thor A. D., Berry D. A., Goldhirsch A., Gelber R. D.
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331:741-746, Sep 15, 1994.
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(2003). Weekly Docetaxel as Neoadjuvant Chemotherapy for Stage II and III Breast Cancer: Efficacy and Correlation with Biological Markers in a Phase II, Multicenter Study. Clin. Cancer Res.
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Varella-Garcia, M.
(2003). Molecular Cytogenetics in Solid Tumors: Laboratorial Tool for Diagnosis, Prognosis, and Therapy. The Oncologist
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Climent, J., Martinez-Climent, J. A., Blesa, D., Garcia-Barchino, M. J., Saez, R., Sanchez-Izquierdo, D., Azagra, P., Lluch, A., Garcia-Conde, J.
(2002). Genomic Loss of 18p Predicts an Adverse Clinical Outcome in Patients with High-Risk Breast Cancer. Clin. Cancer Res.
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Bachleitner-Hofmann, T., Pichler-Gebhard, B., Rudas, M., Gnant, M., Taucher, S., Kandioler, D., Janschek, E., Dubsky, P., Roka, S., Sporn, E., Jakesz, R.
(2002). Pattern of Hormone Receptor Status of Secondary Contralateral Breast Cancers in Patients Receiving Adjuvant Tamoxifen. Clin. Cancer Res.
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Chen, H. H. W., Su, W.-C., Guo, H.-R., Chang, T.-W., Lee, W.-Y.
(2002). p53 and c-erbB-2 but Not bcl-2 are Predictive of Metastasis-free Survival in Breast Cancer Patients Receiving Post-mastectomy Adjuvant Radiotherapy in Taiwan. Jpn J Clin Oncol
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Press, M. F., Slamon, D. J., Flom, K. J., Park, J., Zhou, J.-Y., Bernstein, L.
(2002). Evaluation of HER-2/neu Gene Amplification and Overexpression: Comparison of Frequently Used Assay Methods in a Molecularly Characterized Cohort of Breast Cancer Specimens. JCO
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Parton, M., Krajewski, S., Smith, I., Krajewska, M., Archer, C., Naito, M., Ahern, R., Reed, J., Dowsett, M.
(2002). Coordinate Expression of Apoptosis-associated Proteins in Human Breast Cancer before and during Chemotherapy. Clin. Cancer Res.
8: 2100-2108
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Schilsky, R. L., Dressler, L. M., Bucci, D., Monovich, L., Jewell, S., Suster, S., Caligiuri, M. A., Kantoff, P. W., Compton, C.
(2002). Cooperative Group Tissue Banks As Research Resources: The Cancer and Leukemia Group B Tissue Repositories. Clin. Cancer Res.
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Park, J. W., Hong, K., Kirpotin, D. B., Colbern, G., Shalaby, R., Baselga, J., Shao, Y., Nielsen, U. B., Marks, J. D., Moore, D., Papahadjopoulos, D., Benz, C. C.
(2002). Anti-HER2 Immunoliposomes: Enhanced Efficacy Attributable to Targeted Delivery. Clin. Cancer Res.
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Seidman, A., Hudis, C., Pierri, M. K., Shak, S., Paton, V., Ashby, M., Murphy, M., Stewart, S. J., Keefe, D.
(2002). Cardiac Dysfunction in the Trastuzumab Clinical Trials Experience. JCO
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Barnes, C. J., Li, F., Mandal, M., Yang, Z., Sahin, A. A., Kumar, R.
(2002). Heregulin Induces Expression, ATPase Activity, and Nuclear Localization of G3BP, a Ras Signaling Component, in Human Breast Tumors. Cancer Res.
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Guidi, A. J., Berry, D. A., Broadwater, G., Helmchen, B., Bleiweiss, I. J., Budman, D. R., Henderson, I. C., Norton, L., Hayes, D. F.
(2002). Association of Angiogenesis and Disease Outcome in Node-Positive Breast Cancer Patients Treated With Adjuvant Cyclophosphamide, Doxorubicin, and Fluorouracil: A Cancer and Leukemia Group B Correlative Science Study From Protocols 8541/8869. JCO
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Ravdin, P. M.
(2001). Is Her2 of Value in Identifying Patients Who Particularly Benefit From Anthracyclines During Adjuvant Therapy? A Qualified Yes.. J Natl Cancer Inst Monogr
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Kim, Y. S., Konoplev, S. N., Montemurro, F., Hoy, E., Smith, T. L., Rondon, G., Champlin, R. E., Sahin, A. A., Ueno, N. T.
(2001). HER-2/neu Overexpression As a Poor Prognostic Factor for Patients with Metastatic Breast Cancer undergoing High-dose Chemotherapy with Autologous Stem Cell Transplantation. Clin. Cancer Res.
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Colleoni, M., Gelber, S., Coates, A. S., Castiglione-Gertsch, M., Gelber, R. D., Price, K., Rudenstam, C.-M., Lindtner, J., Collins, J., Thurlimann, B., Holmberg, S. B., Cortes-Funes, H., Simoncini, E., Murray, E., Fey, M., Goldhirsch, A.
(2001). Influence of Endocrine-Related Factors on Response to Perioperative Chemotherapy for Patients With Node-Negative Breast Cancer. JCO
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Baron, A. T., Lafky, J. M., Suman, V. J., Hillman, D. W., Buenafe, M. C., Boardman, C. H., Podratz, K. C., Perez, E. A., Maihle, N. J.
(2001). A Preliminary Study of Serum Concentrations of Soluble Epidermal Growth Factor Receptor (sErbB1), Gonadotropins, and Steroid Hormones in Healthy Men and Women. Cancer Epidemiol. Biomarkers Prev.
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Paradiso, A., Schittulli, F., Cellamare, G., Mangia, A., Marzullo, F., Lorusso, V., De Lena, M.
(2001). Randomized Clinical Trial of Adjuvant Fluorouracil, Epirubicin, and Cyclophosphamide Chemotherapy for Patients With Fast-Proliferating, Node-Negative Breast Cancer. JCO
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Hait, W. N.
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Hayes, D. F., Yamauchi, H., Broadwater, G., Cirrincione, C. T., Rodrigue, S. P., Berry, D. A., Younger, J., Panasci, L. L., Millard, F., Duggan, D. B., Norton, L., Henderson, I. C.
(2001). Circulating HER-2/erbB-2/c-neu (HER-2) Extracellular Domain as a Prognostic Factor in Patients with Metastatic Breast Cancer: Cancer and Leukemia Group B Study 8662. Clin. Cancer Res.
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Simon, R., Nocito, A., Hubscher, T., Bucher, C., Torhorst, J., Schraml, P., Bubendorf, L., Mihatsch, M. M., Moch, H., Wilber, K., Schotzau, A., Kononen, J., Sauter, G.
(2001). Patterns of HER-2/neu Amplification and Overexpression in Primary and Metastatic Breast Cancer. JNCI J Natl Cancer Inst
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Petit, T., Borel, C., Ghnassia, J.-P., Rodier, J.-F., Escande, A., Mors, R., Haegele, P.
(2001). Chemotherapy Response of Breast Cancer Depends on HER-2 Status and Anthracycline Dose Intensity in the Neoadjuvant Setting. Clin. Cancer Res.
7: 1577-1581
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Birner, P., Oberhuber, G., Stani, J., Reithofer, C., Samonigg, H., Hausmaninger, H., Kubista, E., Kwasny, W., Kandioler-Eckersberger, D., Gnant, M., Jakesz, R.
(2001). Evaluation of the United States Food and Drug Administration-approved Scoring and Test System of HER-2 Protein Expression in Breast Cancer. Clin. Cancer Res.
7: 1669-1675
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Liu, S., Edgerton, S. M., Moore, D. H. II, Thor, A. D.
(2001). Measures of Cell Turnover (Proliferation and Apoptosis) and Their Association with Survival in Breast Cancer. Clin. Cancer Res.
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Akewanlop, C., Watanabe, M., Singh, B., Walker, M., Kufe, D. W., Hayes, D. F.
(2001). Phagocytosis of Breast Cancer Cells Mediated by Anti-MUC-1 Monoclonal Antibody, DF3, and Its Bispecific Antibody. Cancer Res.
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Yamauchi, H., Stearns, V., Hayes, D. F.
(2001). When Is a Tumor Marker Ready for Prime Time? A Case Study of c-erbB-2 as a Predictive Factor in Breast Cancer. JCO
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Zhou, Z., Jia, S.-F., Hung, M.-C., Kleinerman, E. S.
(2001). E1A Sensitizes HER2/neu-overexpressing Ewing's Sarcoma Cells to Topoisomerase II-targeting Anticancer Drugs. Cancer Res.
61: 3394-3398
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Bast, R. C. Jr, Ravdin, P., Hayes, D. F., Bates, S., Fritsche, H. Jr, Jessup, J. M., Kemeny, N., Locker, G. Y., Mennel, R. G., Somerfield, M. R.
(2001). 2000 Update of Recommendations for the Use of Tumor Markers in Breast and Colorectal Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology. JCO
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Braun, S., Schlimok, G., Heumos, I., Schaller, G., Riethdorf, L., Riethmüller, G., Pantel, K.
(2001). erbB2 Overexpression on Occult Metastatic Cells in Bone Marrow Predicts Poor Clinical Outcome of Stage I-III Breast Cancer Patients. Cancer Res.
61: 1890-1895
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Menard, S., Valagussa, P., Pilotti, S., Gianni, L., Biganzoli, E., Boracchi, P., Tomasic, G., Casalini, P., Marubini, E., Colnaghi, M. I., Cascinelli, N., Bonadonna, G.
(2001). Response to Cyclophosphamide, Methotrexate, and Fluorouracil in Lymph Node-Positive Breast Cancer According to HER2 Overexpression and Other Tumor Biologic Variables. JCO
19: 329-335
[Abstract][Full Text]
A correction has been published: N Engl J Med 1994;331(3):211.
7 fmol per milligram of protein). Tamoxifen was instituted after the completion of chemotherapy. 
2 cm or >2 cm), as a continuous (linear) variable, and with square-root and logarithmic transformations. In both univariate and multivariate analyses, the dichotomous variables predicted overall and disease-free survival better than the other variables. Some variables were transformed to increase their predictive value. For example, we used the square root of the number of positive nodes, which performed better than the number of positive nodes in both linear and logarithmic scales. With the square-root transformation, an increase in the number of positive nodes from 1 to 4 carried about the same incremental risk as an increase in the number of positive nodes from 4 to 9 or from 9 to 16. 
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