Journal of the National Cancer Institute Advance Access originally published online on December 25, 2007
JNCI Journal of the National Cancer Institute 2008 100(1):14-20; doi:10.1093/jnci/djm252
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2007. Published by Oxford University Press.
ARTICLES |
HER2 Status and Efficacy of Adjuvant Anthracyclines in Early Breast Cancer: A Pooled Analysis of Randomized Trials
Affiliations of authors: National Cancer Research Institute, Genoa, Italy (AG, PP, UP, PB); Department of Health Sciences, University of Genoa, Genoa, Italy (AG, MPS, MP); Galliera Hospital, Genoa, Italy (MP); Perugia Hospital, Perugia, Italy (MC)
Correspondence to: Alessandra Gennari, MD, PhD, National Cancer Research Institute, Largo Rosanna Benzi, 10 16132 Genoa, Italy (e-mail: alessandra.gennari{at}istge.it).
 |
ABSTRACT |
|---|
 Top Abstract Context and CaveatsMethodsResultsDiscussionFundingReferencesNotes |
|---|
Background: Adjuvant chemotherapy with anthracyclines improves disease-free and overall survival compared with non–anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer. The role of HER2 status as a marker of anthracycline responsiveness has been explored by subset analyses within randomized clinical trials, with inconsistent results. We performed a pooled analysis of the interaction between HER2 status and the efficacy of adjuvant anthracyclines based on the published subset data.
Methods: We searched literature databases to identify randomized trials that compared anthracycline-based with non–anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer and reported efficacy data according to HER2 status. Log hazard ratios (HRs) for disease-free and overall survival were pooled across the studies according to HER2 status by inverse variance weighting. A pooled test for treatment by HER2 status interaction was performed by weighted linear meta-regression. All statistical tests were two-sided.
Results: Eight studies (with 6564 randomly assigned patients, of whom 5354 had HER2 status information available) were eligible for this analysis. In HER2-positive disease (n = 1536 patients), anthracyclines were superior to non–anthracycline-based regimens in terms of disease-free (pooled HR of relapse = 0.71; 95% confidence interval [CI] = 0.61 to 0.83; P < .001) and overall (pooled HR of death from any cause = 0.73; 95% CI = 0.62 to 0.85; P < .001) survival. In HER2-negative disease (n = 3818 patients), anthracyclines did not improve disease-free (HR = 1.00; 95% CI = 0.90 to 1.11; P = .75) or overall (HR = 1.03; 95% CI = 0.92 to 1.16; P = .60) survival. The test for treatment by HER2 status interaction yielded statistically significant results: for disease-free survival, the chi-square statistic for interaction was 13.7 (P < .001), and for overall survival, it was 12.6 (P < .001).
Conclusions: The added benefits of adjuvant chemotherapy with anthracyclines appear to be confined to women who have HER2 overexpressed or amplified breast tumors.
Prior knowledge In the treatment of early breast cancer, anthracycline-based adjuvant chemotherapy improves disease-free and overall survival compared with non–anthracycline-based adjuvant chemotherapy. However, it is unclear whether the HER2 status of breast tumors is a marker of anthracycline responsiveness. Study design A pooled analysis of data from eight randomized controlled trials that compared anthracycline-based with non–anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer. Contribution The added benefits of adjuvant chemotherapy with anthracyclines appear to be limited to women whose breast tumors have overexpressed or amplified HER2. Implications Patients with HER2-negative breast tumors derive no added benefits from adjuvant chemotherapy with anthracyclines. Limitations Only eight randomized clinical trials published data on the effects of adjuvant anthracyclines according to HER2 status. Summary results rather than individual patient data were analyzed, and there was no centralized reassessment of HER2 status. The methods used to determine HER2 status differed among the trials.
|
The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of randomized trials of polychemotherapy in early-stage breast cancer demonstrated that anthracycline-based regimens are superior to non–anthracycline-based regimens with respect to disease-free and overall survival (1). However, the magnitude of the absolute benefit from adjuvant anthracyclines, although statistically significant, was modest and not consistent across individual trials (2–7). An additional concern about the widespread use of anthracyclines as adjuvant treatment for early-stage breast cancer is related to the small but clinically significant risks of cardiotoxicity and secondary leukemia that are associated with these agents. Exploratory studies (8–15) have suggested that the benefit of adjuvant treatment with anthracyclines is confined mainly to women whose breast tumors have overexpressed and/or amplified HER2. The association between HER2 status and responsiveness to adjuvant anthracyclines may be related to the tumor level of topoisomerase II alpha, the molecular target of anthracyclines. In fact, the gene encoding topoisomerase II alpha is located adjacent to the HER2 oncogene on chromosome 17, and both genes are frequently coamplified in breast tumors (16). In this regard, some retrospective studies (8,9) that have investigated the predictive value of aberrations in the topoisomerase II alpha gene in patients treated with anthracyclines have suggested that the additional benefit of adjuvant anthracyclines might be limited to women whose breast tumors have amplification of both the HER2 and topoisomerase II alpha genes.
Data from several randomized clinical trials that compared anthracycline-based adjuvant chemotherapy with non–anthracycline-based regimens have been subjected to subgroup analysis to examine whether the HER2 status of a breast tumor is a predictive marker for response to adjuvant treatment with anthracyclines (8–15). Only two of these studies (10,15) reported a positive association between HER2 positivity and a better response to anthracycline-based regimens than to non–anthracycline-based regimens. Possible reasons for this inconsistency include differences among the studies in the methods used to assess HER2 status, incomplete specimen collection, and the administration, in some trials, of outdated or suboptimal adjuvant regimens. Furthermore, subset analyses within individual studies that are intended to investigate the effects of an intervention for specific subgroups of patients are inevitably plagued by chance effects and lack of power and should be regarded as exploratory (17).
To better assess the differential efficacy of adjuvant anthracyclines according to HER2 status, we performed a meta-analysis of data from published subset analyses that were conducted in the context of randomized clinical trials that compared anthracycline-based adjuvant regimens with non–anthracycline-based adjuvant regimens in women with early-stage breast cancer. The aim of this meta-analysis was to assess the presence and degree of interaction between HER2 status and use of adjuvant anthracyclines in the treatment of early breast cancer.
|
Methods |
|---|
|
TopAbstractContext and CaveatsMethodsResultsDiscussionFundingReferencesNotes |
|---|
Identification and Selection of Trials
For this meta-analysis, we sought data from all English-language published (as full papers or as conference abstracts) and unpublished randomized trials that compared anthracycline-based adjuvant chemotherapy with non–anthracycline-based adjuvant chemotherapy in the treatment of early breast cancer and reported efficacy data according to HER2 status. All trials had to fulfill the following criteria to be included in this meta-analysis: 1) the patients had to have been randomly assigned; 2) the trial had to be designed to compare anthracycline-based with non–anthracycline-based chemotherapeutic regimens in the adjuvant treatment of early breast cancer; and 3) hazard ratios for disease-free and overall survival according to HER2 status either had to be reported or could be computed from the data presented. Studies in which hazard ratios for disease-free and/or overall survival according to HER2 status were not reported or could not be computed from the data presented were excluded.
We searched for relevant trials 1) by performing computer-aided literature searches of the MEDLINE and CANCERLIT databases; 2) by examining the reference lists of published trials, review articles, and editorials on HER2 status and efficacy of adjuvant anthracyclines; 3) by searching meetings abstracts; and 4) by consulting the US National Cancer Institute Physicians Data Query Clinical Protocol. For database searches, the following strategy was used: "Breast Neoplasms" [MeSH] AND "Chemotherapy, Adjuvant" [MeSH] AND ("Anthracyclines" [MeSH] OR "Anthracyclines/therapeutic use" [MeSH]) AND ("Receptor, erbB-2" [MeSH] OR "Genes, erbB-2" [MeSH]). The databases were searched for papers published through November 30, 2006.
Data Abstraction
The following data were abstracted from each study: the number of randomly assigned patients, the number of patients whose tumors were assessed for HER2, the description of treatment regimens, the year of publication or disclosure (for data presented as conference abstracts only), the outcome measures, and the treatment effect estimates. Hazard ratios (HRs) for breast cancer recurrence and all-cause mortality were extracted (along with 95% confidence intervals [CIs]) by using the non–anthracycline-based adjuvant chemotherapy arm as the reference group. All data were checked for internal consistency; principal investigators of the studies were contacted to retrieve missing information or to clarify inconsistencies.
Statistical Methods
The primary endpoints of this analysis were disease-free and overall survival. This meta-analysis was performed using a fixed-effects model. All trials reported HER2-specific hazard ratios with 95% confidence intervals. In the Belgian study (8), which compared two dose levels of epirubicin plus cyclophosphamide with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), the hazard ratios for the two epirubicin-containing arms vs CMF were pooled by inverse variance weighting. Log hazard ratios for disease-free and overall survival were pooled across the studies, both overall and according to HER2 status by inverse variance weighting. Formal tests for treatment by HER2 status interaction were performed for each study, and the results of such tests were compared with those of interaction tests reported by the individual studies. A pooled test for treatment by HER2 status interaction was performed using a weighted linear meta-regression of the log hazard ratio with HER2 status as a binary covariate (positive/negative). Publication bias was assessed by visual inspection of funnel plots for study size against treatment effect (18) and with Egger's regression asymmetry test (19). Sensitivity analyses were performed to examine whether the strength of interaction between HER2 status and the efficacy of adjuvant anthracycline treatment was associated with the method of HER2 assessment, the type of anthracycline-based regimen used, or the proportion of patients who were assessed for HER2 status. All analyses were conducted with the use of Stata statistical software (version 9, Stata Corp., College Station, TX). All P values were two-sided and the cutoff for statistical significance was .05.
|
Results |
|---|
|
TopAbstractContext and CaveatsMethodsResultsDiscussionFundingReferencesNotes |
|---|
We identified nine randomized trials (8–15,20) that compared anthracycline-based with non–anthracycline-based regimens and that analyzed outcomes according to HER2 status; seven trials (8–11,13–15) were published as full articles in peer-reviewed journals, and two (12,20) were published as conference abstracts. One of the trials published as a conference abstract (20) was excluded because it reported P values but no other data that would allow us to estimate the hazard ratio according to HER2 status. Table 1 presents the characteristics of the eight trials included in the meta-analysis.
|
HER2 Status Assessment
The proportion of randomly assigned patients who had the HER2 status of their breast tumors assessed ranged from 46% to 94% (Table 2). Overall, 5354 (82%) of the 6564 randomly assigned patients were assessed for HER2 status. Among the patients whose HER2 status was assessed, 1536 (29%) had tumors that overexpressed the HER2 protein or had amplification of the HER2 gene. HER2 status was evaluated by immunohistochemical assay alone in five studies (10–14); by fluorescence in situ hybridization alone or as a complement to immunohistochemical assay in two studies (8,9); and by immunohistochemical assay, fluorescence in situ hybridization, and the polymerase chain reaction in one study (15). Despite this heterogeneity, the prevalence of HER2-positive tumors was reasonably constant among the eight studies, ranging from 19% to 37%. Details about HER2 testing and the scoring criteria from the individual studies are listed in Table 2.
|
Interaction Between HER2 Status and Treatment Effect
Data on disease-free survival were available for six studies (8–11,13,15) No disease-free survival data were available in the Gruppo Universitario Napoletano 3 study (12). Methodologic issues concerning an inconsistency between overall survival and disease-free survival data prevented inclusion of disease-free survival data from the Gruppo Oncologico Italiano di Ricerca Clinica study (14) in the present analysis. Data on overall survival were reported in all studies except the Belgian study (8). Overall, compared with non–anthracycline-based adjuvant chemotherapy regimens, anthracycline-based adjuvant chemotherapy was associated with a statistically significant reduction in the risk of relapse (pooled HR = 0.90; 95% CI = 0.82 to 0.98; P = .01) and a borderline statistically significant reduction in the risk of death from any cause (pooled HR = 0.91; 95% CI = 0.79 to 1.04; P = .056) (Figs. 1 and 2). There was no statistically significant heterogeneity among the trials for either outcome variable.
|
2) test statistics were used to test for the presence of heterogeneity across studies both in HER2-positive and in HER2-negative patients. A pooled test for treatment by HER2 status interaction was performed using an inverse variance weighted linear meta-regression; the
|
Among patients with HER2-positive breast tumors, anthracycline-based adjuvant chemotherapy was associated with a marked reduction in the risks of relapse (pooled HR = 0.71, 95% CI = 0.61 to 0.83; P < .001) and death (pooled HR = 0.73, 95% CI = 0.62 to 0.85; P < .001). Conversely, among patients with HER2-negative breast tumors, there was no difference between those who received anthracycline-based adjuvant chemotherapy and those who received non–anthracycline-based adjuvant chemotherapy with respect to disease-free (pooled HR of relapse = 1.00, 95% CI = 0.90 to 1.11; P = .75) or overall (pooled HR of death from any cause = 1.03, 95% CI = 0.92 to 1.16; P = .60) survival (Figs. 1 and 2). The test for treatment by HER2 status interaction yielded statistically significant results: for disease-free survival, the chi-square statistic for interaction was 13.7 (P < .001), and for overall survival it was 12.6 (P < .001), allowing us to reject the null hypothesis that the effect of adjuvant anthracyclines is independent of HER2 status (Table 3).
|
Neither a visual assessment of funnel plots nor formal statistical tests (Egger's test for bias P > .3; Begg's rank correlation test P > .5) indicated the existence of publication bias, suggesting that studies in which anthracyclines showed a differential effect on disease-free and/or overall survival according to HER2 status were not more or less likely to be published than those that did not show such an effect.
Sensitivity Analyses
To examine whether the overall interaction observed between HER2 status and the use of anthracyclines was due to an effect that was present only in some groups of trials, we conducted sensitivity analyses in which patients were grouped according to the assessment method used to determine the HER2 status of their tumors (immunohistochemistry vs fluorescence in situ hybridization), the type of anthracycline-based regimen they received (doxorubicin vs epirubicin), and the proportion that was assessed for HER2 status (>60% vs 
60%). The latter cutpoint was chosen because all but two studies had large proportions (ie, >75%) of patients assessed for HER2 status. The magnitudes of the differential effects of anthracyclines in HER2-positive patients and in HER2-negative patients were remarkably similar across groups of trials (Fig. 3), suggesting that the interaction between anthracycline use and HER2 status is independent of the type of HER2 assay, the proportion of patients assessed for HER2 status, and the type of anthracycline.
|
|
Discussion |
|---|
|
TopAbstractContext and CaveatsMethodsResultsDiscussionFundingReferencesNotes |
|---|
We conducted this meta-analysis to examine whether anthracycline-based adjuvant chemotherapy would be more efficacious than non–anthracycline-based adjuvant chemotherapy in HER2-positive women but not in HER2-negative women. The pooled estimates of the benefits associated with anthracyclines in all patients included in this meta-analysis are consistent with those reported by the EBCTCG systematic overview (1) both in terms of disease-free survival (HR of relapse = 0.90 in our analysis vs 0.89 in the EBCTCG overview) and overall survival (HR of death from any cause = 0.91 vs 0.84, respectively). Our results confirm that the added benefit of adjuvant chemotherapy with anthracyclines is confined to women who have breast tumors in which HER2 is overexpressed or amplified. Most of the studies included in this analysis showed this association (8,9,11–14), and two studies (10,15) reported a statistically significant interaction between HER2 status and adjuvant anthracyclines for disease-free survival. The statistically significant interaction for both disease-free and overall survival revealed by our meta-analysis provides convincing statistical evidence of a quantitative interaction between HER2 status and responsiveness to adjuvant anthracyclines.
Our study has several limitations that should be considered when interpreting the data. First, as with all meta-analyses, our findings and interpretations are limited by the quality and quantity of available evidence (ie, trials) on the effects of adjuvant anthracyclines according to HER2 status. Second, we used published summary results rather than individual patient data, and it was not possible to check the original data and analyses, to undertake additional evaluations, or to perform a centralized reassessment of participants' HER2 status. Third, a number of unpublished studies might exist, which could lead to possible publication bias if studies that did not show an interaction between HER2 status and treatment with anthracyclines were less likely to be published. However, we found no indication of publication bias by using statistical methods that are designed to detect it. A fourth limitation of our meta-analysis is the variability in methods used to assess HER2 status. However, a sensitivity analysis for methods of HER2 assessment (immunohistochemistry vs fluorescence in situ hybridization) showed no substantial differences in the degree of interaction between HER2 status and the efficacy of adjuvant anthracyclines according to type of HER2 assay.
Further support for our results comes from studies that have compared different dose intensities of adjuvant anthracyclines (8,21,22). These studies have shown that the benefit of more intensive anthracycline-based regimens is limited to HER2-positive patients.
Interpretation of our results must also take into account that HER2 is not the true anthracycline molecular target and that changes in expression of the topoisomerase II alpha gene or protein may be a more accurate and biologically related predictive factor of response to anthracyclines. Indeed, several studies have suggested that the added benefit of adjuvant anthracyclines may be restricted to the small proportion of patients whose tumors have amplification of or deletions in the topoisomerase II alpha gene itself or in topoisomerase II alpha protein expression (8,9,23). Furthermore, topoisomerase II alpha protein levels are regulated by gene amplification and by the tumor proliferation rate (24), which suggests that anthracycline superiority may also be seen in the subset of HER2-negative tumors that overexpress topoisomerase II alpha protein. Clarification of whether topoisomerase II alpha status rather than HER2 status is actually predictive of increased sensitivity to anthracyclines will require a meta-analysis of individual patient data from randomized clinical trials that have compared adjuvant anthracyclines with non–anthracycline-based regimens and that include patients for whom both the HER2 status and the topoisomerase II alpha status are known.
In conclusion, our results suggest that HER2 status is a predictor of responsiveness to adjuvant anthracycline therapy for early breast cancer. The absence, in our study, of any effect of anthracyclines observed in patients with HER2-negative disease suggests that this group of patients could be spared unnecessary toxic effects related to the use of this class of agents and raises questions as to the appropriateness of control arms in randomized clinical trials in which anthracycline-based regimens are used in unselected patient populations.
|
Funding |
|---|
|
TopAbstractContext and CaveatsMethodsResultsDiscussionFundingReferencesNotes |
|---|
Italian Association for Cancer Research; University of Genoa, Italy.
|
NOTES |
|---|
|
TopAbstractContext and CaveatsMethodsResultsDiscussionFundingReferencesNotes |
|---|
The sponsors had no role in the study design, data collection and analysis, interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication.
|
REFERENCES |
|---|
|
TopAbstractContext and CaveatsMethodsResultsDiscussionFundingReferencesNotes |
|---|
1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. (2005) 365:1687–1717.[CrossRef][Web of Science][Medline]
2. Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate and fluorouracil in positive-node breast cancer patients with tamoxifen non responsive tumours: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. (1990) 8:1483–1496.[Abstract]
3. Fisher B, Anderson S, Tan-Chiu E, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. (2001) 19:931–942.
4. Piccart MJ, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol (2001) 19:3103–3110.
5. Bang SM, Heo DS, Lee KH, et al. Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma. Cancer. (2000) 89:2521–2526.[CrossRef][Medline]
6. Colozza M, Bisagni G, Mosconi AM, et al. Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study. Eur J Cancer. (2002) 38:2279–2288.[CrossRef][Web of Science][Medline]
7. Moliterni A, Bonadonna G, Valagussa P, Ferrari L, Zambetti M. Cyclophosphamide, methotrexate and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Clin Oncol. (1991) 9:1124–1130.[Abstract]
8. Di Leo A, Gancberg D, Larsimont D, et al. HER-2 amplification and topoisomerase II alpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res. (2002) 8:1107–1116.
9. Knoop AS, Knudsen H, Balslev E, et al. Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil. J Clin Oncol (2005) 23:7483–7490.
10. Paik S, Bryant J, Park C, et al. ErbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst (1998) 90:1361–1370.
11. Paik S, Bryant J, Tan-Chiu E, et al. HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst. (2000) 92:1991–1998.
12. De Laurentiis M, Caputo F, Massarelli E, Forestieri V, Vernaglia A, Carlomagno C. HER2 expression and anthracycline effect: results from the Naple GUN 3 randomized trial. Proc Am Soc Clin Oncol. (2001) 20:A133.
13. Moliterni A, Menard S, Valagussa P, et al. HER2 overexpression and doxorubicin in adjuvant chemotherapy for resectable breast cancer. J Clin Oncol (2003) 21:458–462.
14. Colozza M, Sidoni A, Mosconi AM, et al. HER2 overexpression as a predictive marker in a randomized trial comparing adjuvant cyclophosphamide/methotrexate/5-fluorouracil with epirubicin in patients with stage I/II breast cancer: long-term results. Clin Breast Cancer (2005) 6:253–259.[Medline]
15. Pritchard KI, Shepherd LE, O'Malley FP, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. (2006) 354:2103–2111.
16. Jarvinen TAH, Tanner M, Rantanen V, et al. Amplification and deletion of topoisomerase IIa associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol. (2000) 156:839–847.
17. Oxman AD, Guyatt GH. A consumers' guide to subgroup analyses. Ann Intern Med. (1992) 116:78–84.
18. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics (1994) 50:1088–1101.[CrossRef][Web of Science][Medline]
19. Egger M, Smith GD, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ (1997) 315:629–634.
20. Vera R, Albanell J, Lirola JL, Bermejo B, Sole LA, Baselga J. HER2 overexpression as a predictor of survival in a trial comparing adjuvant FAC and CMF in breast cancer. Proc Am Soc Clin Oncol (1999) 18:A265.
21. Del Mastro L, Bruzzi P, Nicolo G, et al. HER2 expression and efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients. Br J Cancer. (2005) 93:7–14.[CrossRef][Web of Science][Medline]
22. Muss HB, Thor AD, Berry DA, et al. C-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. (1994) 330:1260–1266.
23. Di Leo A, Claudino WM, Pestrin M, Licitra S, Biganzoli L. Using specific cytotoxics with a targeted mind. Breast. (2007) 16:S120–S126.[Medline]
24. Jarvinen TA, Kononen J, Pelto-Huikko M, Isola J. Expression of topoisomerase IIa is associated with rapid cell proliferation, aneuploidy, and c-erb B-2 overexpression in breast cancer. Am J Pathol. (1996) 148:2073–2082.[Abstract]
Manuscript received April 4, 2007; revised October 23, 2007; accepted November 9, 2007.
Correspondence about this Article
Editorial about this Article
Related Articles in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 680.
J Natl Cancer Inst 2008 100: 2-4.
J Natl Cancer Inst 2008 100: 1.
J Natl Cancer Inst 2008 100: 1.
This article has been cited by other articles:
|
|
 |
|
  K. I. Pritchard, F. O'malley, L. Shepherd, M. N. Levine, D. Tu, V. Bramwell, I. Andrulis, and S. Chia Response J Natl Cancer Inst, November 5, 2009; (2009) djp403v1. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gianni, L. Norton, N. Wolmark, T. M. Suter, G. Bonadonna, and G. N. Hortobagyi Role of Anthracyclines in the Treatment of Early Breast Cancer J. Clin. Oncol., October 1, 2009; 27(28): 4798 - 4808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Robson and S. Verma Anthracyclines in Early-Stage Breast Cancer: Is It the End of an Era? Oncologist, October 1, 2009; 14(10): 950 - 958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. I. Pritchard Are HER2 and TOP2A Useful As Prognostic or Predictive Biomarkers for Anthracycline-Based Adjuvant Chemotherapy for Breast Cancer? J. Clin. Oncol., August 20, 2009; 27(24): 3875 - 3876. [Full Text] [PDF]
|
|
|
|
|
|
F. J. Esteva and G. N. Hortobagyi Topoisomerase II{alpha} Amplification and Anthracycline-Based Chemotherapy: The Jury Is Still Out J. Clin. Oncol., July 20, 2009; 27(21): 3416 - 3417. [Full Text] [PDF]
|
|
|
|
|
|
F. P. O'Malley, S. Chia, D. Tu, L. E. Shepherd, M. N. Levine, V. H. Bramwell, I. L. Andrulis, and K. I. Pritchard Topoisomerase II Alpha and Responsiveness of Breast Cancer to Adjuvant Chemotherapy J Natl Cancer Inst, May 6, 2009; 101(9): 644 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Slamon and M. F. Press Alterations in the TOP2A and HER2 Genes: Association With Adjuvant Anthracycline Sensitivity in Human Breast Cancers J Natl Cancer Inst, May 6, 2009; 101(9): 615 - 618. [Full Text] [PDF]
|
|
|
|
|
|
S. Jones, F. A. Holmes, J. O'Shaughnessy, J. L. Blum, S. J. Vukelja, K. J. McIntyre, J. E. Pippen, J. H. Bordelon, R. L. Kirby, J. Sandbach, et al. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735 J. Clin. Oncol., March 10, 2009; 27(8): 1177 - 1183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gianni and P. Valagussa Anthracyclines and Early Breast Cancer: The End of an Era? J. Clin. Oncol., March 10, 2009; 27(8): 1155 - 1157. [Full Text] [PDF]
|
|
|
|
|
|
E. de Azambuja, M. Paesmans, M. Beauduin, A. Vindevoghel, N. Cornez, C. Finet, F. Ries, M. T. Closon-Dejardin, J. Kerger, P. Gobert, et al. Long-Term Benefit of High-Dose Epirubicin in Adjuvant Chemotherapy for Node-Positive Breast Cancer: 15-Year Efficacy Results of the Belgian Multicentre Study J. Clin. Oncol., February 10, 2009; 27(5): 720 - 725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. G. Morris, H. L. McArthur, C. T. Dang, and C. A. Hudis Selection of Appropriate Patients for Anthracycline Therapy ASCO Educational Book, January 1, 2009; 2009(1): 11 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dowsett and A. K. Dunbier Emerging Biomarkers and New Understanding of Traditional Markers in Personalized Therapy for Breast Cancer Clin. Cancer Res., December 15, 2008; 14(24): 8019 - 8026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Sturgeon, M. J. Duffy, U.-H. Stenman, H. Lilja, N. Brunner, D. W. Chan, R. Babaian, R. C. Bast Jr., B. Dowell, F. J. Esteva, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers Clin. Chem., December 1, 2008; 54(12): e11 - e79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Duffy and J. Crown A Personalized Approach to Cancer Treatment: How Biomarkers Can Help Clin. Chem., November 1, 2008; 54(11): 1770 - 1779. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Cazzaniga, P. Pronzato, G. Mustacchi, A. De Matteis, F. Di Costanzo, E. Rulli, and I. Floriani The anthracyclines and the clinical practice: do all breast cancer patients benefit? Results from the NORA study Ann. Onc., October 1, 2008; 19(10): 1811 - 1812. [Full Text] [PDF]
|
|
|
|
|
|
R. Simon The Use of Genomics in Clinical Trial Design Clin. Cancer Res., October 1, 2008; 14(19): 5984 - 5993. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Rayson, D. Richel, S. Chia, C. Jackisch, S. van der Vegt, and T. Suter Anthracycline-trastuzumab regimens for HER2/neu-overexpressing breast cancer: current experience and future strategies Ann. Onc., September 1, 2008; 19(9): 1530 - 1539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C B Nunes, R M Rocha, J S Reis-Filho, M B Lambros, G F S Rocha, F S F Sanches, F N Oliveira, and H Gobbi Comparative analysis of six different antibodies against Her2 including the novel rabbit monoclonal antibody (SP3) and chromogenic in situ hybridisation in breast carcinomas J. Clin. Pathol., August 1, 2008; 61(8): 934 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Harputluoglu and K. Altundag How can we use anthracylines in the management of newly diagnosed metastatic breast cancer patients overexpressing HER-2? Ann. Onc., June 1, 2008; 19(6): 1203 - 1203. [Full Text] [PDF]
|
|
|
|
|
|
R. S. Mehta and T. Schubbert Re: HER2 Status and Efficacy of Adjuvant Anthracyclines in Early Breast Cancer: A Pooled Analysis of Randomized Trials J Natl Cancer Inst, May 7, 2008; 100(9): 680 - 680. [Full Text] [PDF]
|
|
|
|
|
|
E. Sari, N. Bulut, and K. Altundag Re: Adjuvant Chemotherapy With Sequential or Concurrent Anthracycline and Docetaxel: Breast International Group 02-98 Randomized Trial J Natl Cancer Inst, May 7, 2008; 100(9): 683 - 683. [Full Text] [PDF]
|
|
|
|
|
|
K. I. Pritchard, H. Messersmith, L. Elavathil, M. Trudeau, F. O'Malley, and B. Dhesy-Thind HER-2 and Topoisomerase II As Predictors of Response to Chemotherapy J. Clin. Oncol., February 10, 2008; 26(5): 736 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F. Hayes Markers for Predicting and Evaluating Response to Therapy for Breast Cancer ASCO Educational Book, January 1, 2008; 2008(1): 30 - 34. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||