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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 2996-3000 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.08.046 Mitotic Index and Benefit of Adjuvant Anthracycline-Based Chemotherapy in Patients With Early Breast CancerFrom the Departments of Medicine and Pathology, Institut Gustave Roussy, Villejuif, France Address reprint requests to Fabrice Andre, MD, Comite 050, Institut Gustave Roussy, 39 Rue C. Desmoulins, Villejuif, France; e-mail: fandre{at}igr.fr
PURPOSE: We have evaluated whether the mitotic index could predict the benefit of adjuvant anthracycline-based chemotherapy in patients with early breast cancer who are eligible for adjuvant chemotherapy according to Saint Gallen guidelines. PATIENTS AND METHODS: A total of 937 patients from a single institution were included in two randomized trials that compared adjuvant anthracycline-based chemotherapy with no chemotherapy. These patients account for 83% of the overall population included in these trials. The first trial included premenopausal patients with node-negative disease, and the second one included postmenopausal patients, regardless of lymph node status. The treatment benefit was assessed according to the number of mitoses per field (x400).
RESULTS: The mitotic index was assessable in 888 patients (94%). All the patients presented as either node-positive or an average-risk breast cancer according to 2003 Saint Gallen consensus conference guidelines. The 5-year overall survival rates were 91% and 87% for patients treated or not with adjuvant chemotherapy (P = .09). In patients with low/medium mitotic index (< three mitoses/field; n = 450), the 5-year overall survival rate was 95% for patients treated or not with adjuvant chemotherapy (P = .56). In patients with high mitotic index ( CONCLUSION: A high mitotic index is associated with the efficacy of adjuvant anthracycline-based chemotherapy in patients eligible for adjuvant chemotherapy in daily practice.
Adjuvant anthracycline-based chemotherapy provides a survival benefit compared with no chemotherapy in patients with early breast cancer.1 Although chemotherapy provides an uncontroversial benefit, its absolute effect on overall survival (OS) remains poor. Indeed, adjuvant polychemotherapy produces an absolute improvement of approximately 7% to 11% in 10-year survival for women who are younger than 50 years at presentation with early breast cancer and of approximately 2% to 3% for those age 50 to 69 years. According to the Saint Gallen Consensus Conference in 2003,2 only patients with at least one prognostic factor for metastatic relapse are eligible for adjuvant chemotherapy in daily practice. Although these recommendations limit the absolute number of patients treated with adjuvant chemotherapy, the rate of patients who receive this treatment without any benefit remains high. From this situation has emerged the need to identify factors that could predict the benefit of adjuvant chemotherapy to decrease the number of overtreated patients.3 The mitotic activity (assessed by Ki67 expression, S phase, number of mitoses per field, etc) has been associated with both prognosis4 and chemosensitivity5 in patients with breast cancer. Given these data, we have hypothesized that the mitotic index could predict the benefit of adjuvant chemotherapy. To answer this question, we have looked at the effect of chemotherapy according to mitotic index in patients with early breast cancer included in two randomized trials.
Patients Patients analyzed in the present study were selected to have been included in two randomized trials that compared adjuvant anthracycline-based chemotherapy with no chemotherapy and to have been treated at the Institut Gustave Roussy (IGR). The two trials have been reported elsewhere.6,7 Briefly, the first trial included postmenopausal patients who presented a breast cancer with either axillary lymph node involvement and/or Scarff-Bloom-Richardson (SBR) histologic grade 2 or 3. Of the 835 patients included in this trial, 692 patients (83%) were treated at the IGR and are included in the present study. The second trial included premenopausal patients who presented with a breast cancer without axillary lymph node involvement but with an SBR histologic grade 2 or 3. Of the 312 patients included in this trial, 245 patients (79%) have been treated at the IGR and were included in the present study. These two trials included 1,147 patients overall. Of these, 937 patients (83%) were treated at the IGR and were included in the present study. The presence of metastases and previous cancer were exclusion criteria in these trials.
Patient Characteristics
Treatment and Follow-Up After a lumpectomy, a total dose of 45 to 50 Gy of radiotherapy was delivered to the breast using conventional fractionation, followed by a boost dose of approximately 15 Gy to the tumor bed. After a total mastectomy, postoperative radiotherapy was delivered to the chest wall and supraclavicular and internal mammary chain, only if the axillary nodes were positive. All postmenopausal patients received adjuvant tamoxifen for at least 2 years, and they were allowed to participate in a French trial comparing 2 years of tamoxifen with long-term treatment. After treatment completion, patients were seen every 6 months for the first 5 years and yearly thereafter, with a yearly mammogram and a clinical examination at each visit. Complementary examinations were performed according to the policy in each center.
Statistical Analysis
Patient Characteristics As reported in Patients and Methods under Patients, 937 patients were included in the two trials and treated at the Institut Gustave Roussy. The mitotic index was available in 888 (94%) of these patients. The analysis was therefore performed on these 888 patients. Of these 888 patients, 444 patients have been assigned to the chemotherapy arm. The fluorouracil, epirubicin 50 mg/m2, and cyclophosphamide (FE50C) regimen was used in 84% of patients (n = 373). The median follow-up is 9 years (range, 0 to 14 years). Patient characteristics are listed in Table 1. The mitotic index was high in 438 patients (49%). A high mitotic index was associated with histologic grade SBR 3 (P < .001) and negative hormone receptor status (P < .001). Characteristics did not differ between chemotherapy and observation arms, whatever the mitotic index (Table 1). No patient had a node-negative disease associated with histologic grade 1 and hormone receptor–positive status. This means that, in 2004, all patients included in the present study would be candidates for adjuvant chemotherapy according to Saint Gallen consensus conference 2003.2
Survival According to Treatment As of July 1, 2004, 215 deaths (25%) have been observed, and 189 patients (22%) had presented metastases. As reported in Figure 1, the 5-year OS rates were 91% and 87% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .09, log-rank test). Eighty-three patients assigned to the chemotherapy arm (19%) and 106 patients included in the observation arm (24%) have presented with a metastatic relapse. The 5-year metastasis-free survival rates were 85% and 81% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .03, log-rank test).
Treatment Benefit According to Mitotic Index When only patients with low/medium mitotic index were considered, the 5-year OS rate was 95% for patients treated or not with adjuvant chemotherapy (P = .56, log-rank test; Fig 2A). At the opposite, when only patients with high mitotic index were considered, the 5-year OS rates were 86% and 79% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .02, log-rank test; Fig 2B).
When only patients with low/medium mitotic index were considered, 14% of cases assigned to the chemotherapy arm or to the observation arm have presented a metastatic relapse (n = 32 and 31, respectively). The 5-year metastasis-free survival rates were 95% and 94% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .84, log-rank test). When only patients with high mitotic index were considered, 23% of the patients assigned to the chemotherapy arm (n = 51) and 33% of the patients included in the observation arm (n = 75) have presented with a metastatic relapse. The 5-year metastasis-free survival rates were 82% and 75% for patients treated or not treated with adjuvant chemotherapy (P = .02, log-rank test). Because the mitotic index is included in the histologic grade, we looked at the treatment benefit according to tumor grade. When only patients with low tumor grade (SBR 1/2) were considered (n = 602), the 5-year OS rates were 94% and 91% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .28, log-rank test). When only patients with high tumor grade (SBR 3) were considered (n = 280), the 5-year OS rates were 84% and 79% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .25, log-rank test), suggesting that tumor grade did not predict the benefit of adjuvant chemotherapy.
The decision to administer adjuvant chemotherapy is currently based on lymph node involvement, hormone receptor status, tumor size, and histologic grade according to consensus conferences.2,9 Using these criteria, only a few subsets of patients do not receive adjuvant chemotherapy, and most of the patients treated do not benefit from adjuvant chemotherapy. There is therefore a need to find markers that predict the efficacy of adjuvant chemotherapy. In the present study, we have shown that mitotic index, but not tumor grade, was correlated with the benefit of adjuvant chemotherapy in 888 patients included in two randomized trials who were eligible for adjuvant chemotherapy according to Saint Gallen guidelines.2 The mitotic index has been reported for a long time to be a prognostic factor in patients with early breast cancer.4,8 More recently, several series have suggested that cell proliferation is associated with chemosensitivity in patients with locally advanced breast cancer treated with preoperative chemotherapy.10,11 From these data has emerged the hypothesis that mitotic activity could be a useful parameter to predict the benefit of adjuvant chemotherapy. The correlation between the mitotic activity and the benefit of adjuvant chemotherapy has been suggested in previous reports. In a randomized study that included 290 node-negative tumors, Amadori et al12 have reported that adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) improved the outcome of patients with highly proliferating tumors. In a Swedish trial comparing polychemotherapy (CMF) with local radiotherapy, the benefit of CMF was confined to patients with highly proliferative tumors.13 Pronzato et al14 have reported that thymidine index labeling was a predictive factor for the benefit of perioperative anthracycline-based chemotherapy in a series of 197 patients included in a randomized study. Our study is concordant with these previous ones, and suggests that the mitotic activity could be a useful marker to better select patients for adjuvant chemotherapy. From these data rise several questions: First, is the mitotic index independent of tumor grade? Second, are the patients included in the present study representative of patients currently treated with adjuvant chemotherapy? Third, because most of the patients received the FE50C regimen, are these data available in patients who receive higher doses of chemotherapy? Fourth, how should we integrate these findings in the current research of predictive biomarkers? Fifth, would it be possible in the future to avoid adjuvant chemotherapy in patients who present with low/medium mitotic index? Because the mitotic activity is a parameter included in the tumor grade, it could be argued that mitotic index will not present any added value compared with tumor grade. In the present study, where all patients are eligible to adjuvant chemotherapy in daily practice, the mitotic index, but not the tumor grade, was a predictive factor for the benefit of adjuvant chemotherapy. Our study is concordant with previous series that suggested that mitotic activity is a better parameter than tumor grade to predict prognosis.15 All the patients included in the present study were eligible to receive adjuvant chemotherapy according to Saint Gallen conference consensus.2 This population is therefore a good population to test how a parameter could allow a better selection of patients for adjuvant chemotherapy in daily practice. In addition, the number of patients with low/medium mitotic grade (n = 450) is large enough to suggest that chemotherapy does not provide any benefit in this subset of patients. Indeed, both the 5-year OS rates and the metastases rates (14%) were strictly similar between the two groups, and there was therefore no trend to suggest that a treatment efficacy could be observed in a larger population. If these results are confirmed, mitotic index could avoid adjuvant chemotherapy in about half of the patients who fulfilled the inclusion criteria of these trials. Most of the patients (84%) assigned to the chemotherapy arm received an FE50C regimen. Because it has been shown recently that the FE100C regimen (with 100 mg/m2 of epirubicin) is superior to FE50C,16 the chemotherapy regimen performed in most of the patients included in this study is not the most commonly used currently in daily practice. Whether the mitotic index is a predictive parameter when an FE100C or AC regimen are applied cannot be answered in our study. Although mitotic index is a promising tool to predict the benefit of adjuvant chemotherapy, it is not the only parameter to be investigated in this setting. Indeed, several biomarkers have been shown to be correlated with chemosensitivity or prognosis and could therefore be used to select patients for adjuvant chemotherapy. DNA topoisomerase II alpha subunit expression,17 urokinase-type plasminogen activator/plasminogen activator inhibitor 1 (uPA/PAI1) expression,18 and DNA microarrays19 are the most promising markers in this setting. It is of note that topoisomerase II expression has been correlated with mitotic activity20 and that the poor prognosis signature provided by Van't Veer et al21 includes some genes involved in cell cycle (cyclin E2). Several prospective studies are evaluating the clinical usefulness of these biomarkers. The most interesting finding from our study was the observation that the patients with low/medium mitotic index had identical 5-year OS and virtually identical 5-year metastases-free survival regardless of whether they were treated with anthracycline-based adjuvant chemotherapy. The finding that anthracycline-based adjuvant chemotherapy does not increase OS and metastases-free survival among patients with low/medium mitotic index raises several issues regarding the postoperative management of early breast cancer. Indeed, if confirmed by other analyses of previous, well-designed randomized clinical trials, our findings would indicate that the mitotic index could be used to avoid unnecessary adjuvant chemotherapy in a substantial proportion of patients with early breast cancer. In conclusion, our study suggests that the mitotic index is a parameter that could predict the benefit of adjuvant anthracycline-based chemotherapy in patients with early breast cancer. This parameter could be used to decrease the number of overtreated patients. Although promising, the clinical usefulness of this parameter needs to be confirmed in other randomized trials and evaluated in studies that include new biomarkers.
The authors indicated no potential conflicts of interest.
F.A. and A.K. contributed equally to this work. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. Hamilton A, Piccart M: The contribution of molecular markers to the prediction of response in the treatment of breast cancer: A review of the literature on HER-2, p53 and BCL-2. Ann Oncol 11:647–663, 2000
4. Stal O, Dufmats M, Hatschek T, et al: S-phase fraction is a prognostic factor in stage I breast carcinoma. J Clin Oncol 11:1717–1722, 1993 5. Daidone MG, Silvestrini R: Prognostic and predictive role of proliferation indices in adjuvant therapy of breast cancer. J Natl Cancer Inst Monogr 30:27–35, 2001
6. Arriagada R, Spielmann M, Koscielny S, et al: Patterns of failure in a randomized trial of adjuvant chemotherapy in postmenopausal patients with early breast cancer treated with tamoxifen. Ann Oncol 13:1378–1386, 2002 7. Tursz T, Arriagada R, Koscielny S, et al: Patterns of failure in two randomized trials of adjuvant anthracycline-based chemotherapy in 1,146 patients with early breast cancer. Proc Am Soc Clin Oncol 22:10, 2003 (abstr A36)
8. Contesso G, Mouriesse H, Friedman S, et al: The importance of histologic grade in long-term prognosis of breast cancer: A study of 1,010 patients, uniformly treated at the Institut Gustave-Roussy. J Clin Oncol 5:1378–1386, 1987 9. National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference statement: Adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst Monogr 30:5–15, 2001 10. Aas T, Geisler S, Eide GE, et al: Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy. Eur J Cancer 39:438–446, 2003 11. MacGrogan G, Mauriac L, Durand M, et al: Primary chemotherapy in breast invasive carcinoma: Predictive value of the immunohistochemical detection of hormonal receptors, p53, c-erbB-2, MiB1, pS2 and GST pi. Br J Cancer 74:1458–1465, 1996[Medline]
12. Amadori D, Nanni O, Marangolo M, et al: Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: A randomized multicenter study. J Clin Oncol 18:3125–3134, 2000 13. Stal O, Skoog L, Rutqvist LE, et al: S-phase fraction and survival benefit from adjuvant chemotherapy or radiotherapy of breast cancer. Br J Cancer 70:1258–1262, 1994[Medline] 14. Pronzato P, Queirolo P, Vecchio S, et al: Thymidine labeling index analysis in early breast cancer patients randomized to receive perioperative chemotherapy. Oncology 60:88–93, 2001[CrossRef][Medline]
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16. French Adjuvant Study Group: Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 19:602–611, 2001
17. Di Leo A, Larsimont D, Gancberg D, et al: HER-2 and topoisomerase II alpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide. Ann Oncol 12:1081–1089, 2001
18. Zemzoum I, Kates RE, Ross JS, et al: Invasion factors uPA/PAI-1 and HER2 status provide independent and complementary information on patient outcome in node-negative breast cancer. J Clin Oncol 21:1022–1028, 2003
19. van de Vijver MJ, He YD, van't Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009, 2002 20. Depowski PL, Rosenthal SI, Brien TP, et al: Topoisomerase II alpha expression in breast cancer: Correlation with outcome variables. Mod Pathol 13:542–547, 2000[CrossRef][Medline] 21. Van't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536, 2002[CrossRef][Medline] Submitted August 5, 2004; accepted December 29, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
three mitoses/field; n = 438), the 5-year overall survival rates were 86% and 79% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .02). 
2 test. OS was the primary end point of the trials. Survival curves were determined by the Kaplan and Meier method. Survival curves were compared using the log-rank test. All tests were two-sided, and a P value of .05 was considered significant. In 1996, the group decided to close the trials because the fourth round of the Early Breast Cancer Trialists' Collaborative Group overview demonstrated a benefit with adjuvant chemotherapy in high-risk node-negative younger patients and in older patients receiving adjuvant tamoxifen.
