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© 2000 American Society for Clinical Oncology Early Start of Adjuvant Chemotherapy May Improve Treatment Outcome for Premenopausal Breast Cancer Patients With Tumors not Expressing Estrogen ReceptorsFrom the European Institute of Oncology, Milan; Centro di Riferimento Oncologico, Aviano; and Oncologia Medica e Fondazione Beretta, Spedali Civili, Brescia, Italy; International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard School of Public Health, and Frontier Science and Technology Research Foundation, Boston, MA; Australian Cancer Society; University of Sydney, Sydney; Anti-Cancer Council of Victoria, Melbourne, Australia; International Breast Cancer Study Group Coordination Center, Bern; Ospedale Civico, Lugano; and Kantonsspital, St Gallen, Switzerland; West Swedish Breast Cancer Study Group, Sahlgrenska University Hospital, Göteberg, Sweden; and Institute of Oncology, Ljubljana, Slovenia. Address reprint requests to Marco Colleoni, MD, Division of Medical Oncology, European Institute of ncology, Via Ripamonti 435, 20141, Milan, Italy; email marco.colleoni{at}ieo.it
PURPOSE: The proper time to commence adjuvant chemotherapy after primary surgery for breast cancer is unknown. An analysis of the International (Ludwig) Breast Cancer Study Group (IBCSG) Trial V at a median follow-up of 11 years suggested that early initiation of adjuvant chemotherapy might improve outcome for premenopausal, node-positive patients whose tumors did not express any estrogen receptor (ER). PATIENTS AND METHODS: We investigated the relationship between early initiation of adjuvant chemotherapy, ER status, and prognosis in 1,788 premenopausal, node-positive patients treated on IBCSG trials I, II, and VI. The disease-free survival for 599 patients (84 with ER-absent tumors) who commenced adjuvant chemotherapy within 20 days (early initiation) was compared with the disease-free survival for 1,189 patients (142 with ER-absent tumors) who started chemotherapy 21 to 86 days after surgery (conventional initiation). The median follow-up was 7.7 years. RESULTS: Among patients with ER-absent tumors, the 10-year disease-free survival was 60% for the early initiation group compared with 34% for the conventional initiation group (226 patients; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33 to 0.72; P = .0003). This difference remained statistically significant in a Cox multiple regression analysis controlling for study group, number of positive nodes, tumor size, age, vessel invasion, and institution (HR, 0.60; 95% CI, 0.39 to 0.92; P = .019). Conversely, early initiation of chemotherapy did not significantly improve disease-free survival for patients with tumors expressing ER (1,562 patients; multiple regression HR, 0.93; 95% CI, 0.79 to 1.10; P = .40). CONCLUSION: In premenopausal patients with ER-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. Further confirmatory studies are required before any widespread modification of current clinical practice. In premenopausal patients with tumors expressing some ER, gains from early initiation are unlikely to be clinically significant.
THE INITIATION Of adjuvant chemotherapy has typically been delayed a few weeks after surgery.1-3 Surgical trauma and removal of the primary tumor may lead to an increased number of circulating tumor cells4 and to an accelerated growth of micrometastases.5,6 Tissue trauma is known to enhance biologic processes, which may stimulate both wound healing and tumor progression.7,8 In addition, a correlation between increase in neo-angiogenesis (in terms of vascular density) and circulating tumor cells has been observed after surgery.9 Moreover, the presence of increased vascular density was correlated with poor prognosis for patients who received adjuvant chemotherapy.10,11 These data provide a plausible rationale for initiation of chemotherapy as close as possible to the surgical removal of macroscopic tumor. Between 1981 and 1985, the International (Ludwig) Breast Cancer Study Group (IBCSG) conducted a randomized clinical trial (Trial V) to evaluate the timing and duration of adjuvant therapy for women with operable breast cancer.12 Four hundred seventy-five premenopausal breast cancer patients with node-positive disease were randomized to receive either perioperative cyclophospha-mide, methotrexate, fluorouracil (CMF) chemotherapy followed by conventionally timed chemotherapy (CMF plus low-dose prednisone given for 6 months) or the conventionally timed chemotherapy alone. At a median follow-up of 11 years, among the 101 women whose tumors did not express any estrogen receptors (ER-absent), the 10-year disease-free survival rate was 48% for 46 patients who received perioperative CMF compared with 38% for 55 women who received conventionally timed chemotherapy alone (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.48 to 1.34; P = .40). Despite the small number of patients, the estimated HR of 0.80 (20% reduction in the risk of recurrence) provided motivation to investigate whether early initiation of chemotherapy might be beneficial for a subgroup of premenopausal patients. We, therefore, examined all other IBCSG trials of classical CMF chemotherapy for premenopausal patients (Trials I, II, and VI). The treatment outcome according to the timing of initiation of chemotherapy after primary surgery in these trials is the subject of this report.
All trials have been previously described.13-15 The study designs are listed in Table 1. All trials used classical CMF.1,8 Briefly, between 1978 and 1981, Trial I13 accrued 491 eligible premenopausal women with one to three positive axillary lymph nodes who were randomized to receive 12 28-day cycles of adjuvant CMF chemotherapy or CMF plus continuous low-dose prednisone (CMFp). At a median follow-up of 16 years, there were no statistically significant differences in disease-free survival or overall survival between the treatment groups. Trial II also enrolled patients from 1978 to 1981 and included premenopausal women with four or more positive axillary lymph nodes who were randomized to receive either surgical oophorectomy followed by 12 28-day cycles of CMFp or CMFp alone.14 For the current analysis, only those women randomized to chemotherapy alone (without oophorectomy) were considered. Between 1986 and 1993, Trial VI enrolled 1,476 eligible premenopausal women with node-positive disease who were randomized to receive either three or six initial cycles of CMF therapy either alone or followed by three single cycles of reintroduction CMF delivered 3 months apart.15 At a median follow-up of 7 years, there was no statistically significant difference in disease-free survival or overall survival among the four treatment groups.
The data analyses presented in this report included 1,788 patients (84% of the 2,127 eligible patients enrolled onto Trials I, II, and VI) who received chemotherapy and had quantitative ER levels available. ER levels were determined by the dextran-coated charcoal assay16 performed in laboratories participating in regular quality control programs.17 Fourteen patients who never started chemotherapy (three in Trial I, two in Trial II, and nine in Trial VI) and 325 patients who did not have quantitative ER values (225 in Trial I, 70 in Trial II, and 30 in Trial VI) were not included in these analyses. The evaluated group, compared with the nonevaluated group, had more patients with four or more positive nodes (33% v 26%, respectively), fewer patients with vessel invasion (71% v 82%, respectively, among cases with known vessel invasion status), and more patients from one of the larger participating centers (institution A: 15% v 8%, respectively). Because more than 97% of the patients in Trial VI could be evaluated, almost all of the differences arise from the smaller earlier trials. Patients were classified as receiving early initiation of adjuvant chemotherapy if treatment was started before 21 days from definitive primary surgery. The date of the most extensive surgery, which ordinarily included the axillary dissection, was taken as the definitive surgical procedure. Biopsies might have preceded this date. The cut point of 21 days was selected before starting data analysis primarily for two reasons: (1) the eligibility for enrollment was within 6 weeks of definitive surgery, so 21 days represented the middle of this period; and (2) only 6% of the patients in the conventionally timed chemotherapy arm of Trial V commenced their treatment before day 21 compared with 47% between days 21 and 27 and 47% after day 27.
Data available as of May 1998 were used for the analysis. Median follow-up was 7.7 years. Disease-free survival was defined as the interval from randomization to relapse, the appearance of a second primary cancer (including a contralateral breast cancer), or death, whichever occurred first. Disease-free survival curves were estimated using the Kaplan-Meier method.18 Cox proportional hazards regression model was used to test for differences between the disease-free survival curves, to provide analyses adjusted for a variety of covariates, and to test for interactions between the effect of timing of chemotherapy initiation and covariates.19 Covariates considered for the multiple regression models included ER-content group (ER-absent; ER-low: 1 to 9 fmol/mg cytosol protein; or ER-positive:
A total of 599 patients (33.5%) commenced chemotherapy within 20 days from surgery, whereas 1,189 patients started chemotherapy 21 to 86 days after surgery. Chemotherapy was initiated within 2 weeks of surgery (  13 days) for 10.1% of the patients, during week 3 after surgery for 23.4%, during week 4 for 29.4%, during weeks 5 or 6 for 32.6%, during weeks 7 or 8 for 4.4%, and beyond week 8 (56 to 86 days) for 0.4% (seven patients). Table 2 lists the patient characteristics according to timing of the initiation of adjuvant chemotherapy. Characteristics were well-balanced between the early initiation and conventional initiation groups, especially with respect to nodal status and tumor size, features known to have prognostic relevance. In addition, the incidence of comorbid conditions and treatment assignment were well-balanced across the different patient groups. The only exception was with respect to patients enrolled from institution A, more of whom started adjuvant chemotherapy early compared with the incidence of early initiation in other centers. The percentage of patients with ER-absent tumors was 12.6%.
Table 3 lists the results of disease-free survival analysis according to time of initiation of adjuvant chemotherapy. The 10-year disease-free survival among patients with ER-absent tumors was 60% for patients who started adjuvant chemotherapy within 20 days of surgery compared with 34% for those who started treatment 21 days or more after surgery (226 patients; HR, 0.49; 95% CI, 0.33 to 0.72; P = .0003). In contrast, the estimated magnitude of effect of early initiation was much smaller for patients with tumors expressing ER. This is displayed as disease-free survival curves in Fig 1A, 1B, and 1C according to timing of the initiation of chemotherapy for each of the three levels of ER in the primary tumor.
Table 4 lists the results of the multiple regression model. The difference in outcome according to timing of start of adjuvant chemotherapy remained statistically significant for the patients with ER-absent tumors (HR, 0.60; 95% CI, 0.39 to 0.92; P = .019). Early initiation of chemotherapy was associated with a 40% reduction in the risk of relapse compared with later initiation. Reductions in the risk of relapse were observed in all three trials (Trial I: HR, 0.18; 95% CI, 0.06 to 0.54; P = .003; Trial II: HR, 0.62; 95% CI, 0.18 to 2.08; P = .44; and Trial VI: HR, 0.62; 95% CI, 0.34 to 1.14; P = .12). Figure 2 shows the multiple regression HRs and 95% CIs comparing early versus later initiation of chemotherapy, both overall and separately according to ER content of the primary tumor. The solid vertical line in the figure indicates no difference between early and later commencement of chemotherapy (HR, 1.0), and the area of each black square is proportional to the amount of information (larger squares are associated with shorter CI). In contrast to the ER-absent group, early initiation of chemotherapy did not significantly improve disease-free survival for patients with tumors expressing ER (1,562 patients; multiple regression HR, 0.93; 95% CI, 0.79 to 1.10; P = .40). The improvement in disease-free survival associated with early initiation of chemotherapy for the ER-absent subgroup was significantly greater than the disease-free survival difference observed for patients with tumors expressing ER (P = .0054, multiple regression interaction term).
Even though disease risk factors and comorbid conditions were well-balanced between the early chemotherapy and later chemotherapy groups, it is possible that other postoperative factors may have influenced the ability of patients to start chemotherapy early. We noted, however, that among patients with ER-absent tumors, the percents with non–breast-cancer–related events were 3.6% for the early chemotherapy group and 3.5% for the later chemotherapy group.
The optimal time to start adjuvant chemotherapy after primary surgery for early breast cancer is unknown. Previous retrospective studies suggested that early initiation might be beneficial. Improved disease-free survival was observed among breast cancer patients with one to three positive nodes who received adjuvant doxorubicin plus cyclophosphamide during the first 4 postoperative weeks versus patients who had received delayed chemotherapy.20 Another small retrospective study demonstrated improved disease-free survival associated with chemotherapy initiation within 35 days of surgery compared with a later commencement.21 The Scandinavian Adjuvant Chemotherapy Study Group reported a significant increase in disease-free survival with perioperative cyclophosphamide (given immediately after surgery) compared with no adjuvant treatment but failed to show any benefit in a subgroup of patients treated in a single center where chemotherapy was delayed by 2 to 4 weeks because of radiation therapy.22 The results from trials that compared a short duration of perioperative therapy with no adjuvant treatment might be useful for identifying subgroups of patients that could benefit the most from early initiation of adjuvant chemotherapy. In particular, a recent meta-analysis indicated that perioperative chemotherapy reduced the risk of relapse by 17% for women younger than 50 years of age.23 Data on treatment effect according to ER status were not provided. In addition to the trials included in the above meta-analysis, the National Surgical Adjuvant Breast and Bowel Project demonstrated an advantage for perioperative thiotepa in terms of disease-free survival in premenopausal patients.24 Sertoli et al25 studied the impact of perioperative cyclophosphamide, epirubicin, and fluorouracil and concluded that ER-negative status was the most important predictor of the effect of perioperative treatment compared with no perioperative therapy. A statistically significant improvement in disease-free survival was observed among patients with ER-negative disease, whereas no treatment effect was observed among those with ER-positive tumors.
Historically, patients were classified as having ER-negative (< 10 fmol/mg cytosol protein) and ER-positive ( The results of the present study show that premenopausal patients with ER-absent tumors and patients with tumors expressing some ER represent distinct populations with respect to responsiveness to early commencement of adjuvant chemotherapy. The magnitude of the effect of early initiation of chemotherapy was significantly greater for the ER-absent subpopulation compared with other patients (P = .0054). Although the classification of patients into an early initiation group based on commencement of chemotherapy before 21 days after definitive surgery was made before data analysis, this cut point was arbitrary and should not be considered as having special significance. In fact, many patients started chemotherapy during the weeks just preceding (23.4% of patients) and just after (29.2% of patients) the 21-day cutpoint. Several models of tumor progression may provide biologic rationale for these results. A delay in the initiation of systemic therapy has been hypothesized to increase the probability of drug resistance of micrometastatic disease present at surgery.29 Experimental kinetic data reported by Fisher et al30,31 support the hypothesis that administration of chemotherapy as close as possible to operation may improve patient outcome. In mice bearing both a large primary and a secondary tumor focus, the removal of the large primary tumor increased the labeling index of the distant focus compared with preoperative levels. In this animal model, cyclophosphamide was most effective against metastatic growth when the drug was administered either preoperatively or immediately after tumor removal compared with delayed administration.30 Neo-angiogenesis is essential for growth of metastases, and only cells that induce the formation of new blood vessels can give rise to larger tumors. Removing the primary tumors in nude mice increased angiogenesis in the vascular bed surrounding metastases leading to their growth.32 The growth promoting effect on metastases of the removal of primary tumor seems related to the reduction of angiogenesis inhibitors such as angiostatin, which is a 38-kd fragment of plasminogen.6,32 Moreover, a significant correlation between detectable cancer cells in effluent venous blood during surgery for breast cancer and high vessel counts in the tumor9 suggest that increased angiogenesis is strongly involved in the metastatic process and that early start of systemic treatment may efficiently influence this process. Several common anticancer agents have been shown to have anti-angiogenic activity. Low doses of methotrexate inhibited endothelial cell proliferation in vitro and inhibited neovascularisation by endothelial cell growth factor in the rabbit cornea assay.33 Cyclophosphamide also has anti-angiogenic activity.34 Therefore, it is possible that conventional cytotoxic agents may exert a tumor suppressive effect partially through an anti-angiogenic mechanism and that early initiation of treatment may result in increased efficacy. Tissue trauma caused by surgery is known to enhance tumor proliferation through the production of growth factors such as transforming growth factor alfa.8,35 Estrogens may amplify the effects of growth factors on tumor cells that are rapidly proliferating, such as those that do not contain ER.36 Early initiation of chemotherapy may, therefore, be particularly relevant to inhibit the growth of tumors that are not susceptible to the effects of endocrine therapies because of lack of ER. It is well known that chemotherapy exerts some of its effect via an endocrine mechanism in premenopausal women with ER-positive tumors.37 The benefits of early initiation of chemotherapy may not be important for these patients because endocrine mechanisms are available to interfere with tumor cell growth. In contrast, patients with ER-absent tumors benefit exclusively from the cytotoxic mechanisms of chemotherapy. Early initiation of chemotherapy, therefore, may be relevant especially for this subpopulation of patients. The results of this analysis are in apparent contradiction with those of the National Surgical Adjuvant Breast and Bowel Project Trial B-18, which demonstrated comparable disease-free survival for patients who received preoperative chemotherapy or postoperative chemotherapy.38 Unfortunately, no analyses are available concerning treatment effects within the subpopulation of premenopausal patients with ER-absent tumors. In addition, the timing of initiation of postoperative chemotherapy relative to definitive surgery has not been presented. The method used for ER assessment (dextran-coated charcoal assay)17 in the IBCSG studies may have influenced the results. More recently, the immunohistochemical (IHC) staining method has gained increasing popularity because it is suitable for use on fixed paraffin-embedded tissue and is less expensive.39,40 Despite some controversies over the accuracy of IHC staining compared with that of dextran-coated charcoal assays in ER determination, IHC staining provides reasonable information on ER content and on the degree of heterogeneity of its distribution in the tumor tissue.41 In fact, there is significant correlation between the two methods in the majority of studies,39-42 suggesting that the conclusions that are presented here may be extended also when an IHC analysis is performed. Additional research related to response to cytotoxics and heterogeneity of receptor distribution in the tumor might be useful. The efficacy of adjuvant systemic therapy for early breast cancer depends on features of the tumor, the patient, and the treatment. Among treatment-related factors we have previously drawn attention to duration43 and schedule.44 The present results indicate that timing of initiation of chemotherapy might be important for premenopausal patients with tumors not expressing ER. Despite the impressive magnitude of the observed effect associated with early initiation of chemotherapy in this subgroup of patients, the compelling biologic explanations for this effect and the balance between groups with respect to prognostic factors, comorbid conditions, and non–breast-cancer–related mortality, the potential for bias still exists because of the retrospective nature of the evaluation. Further studies designed to confirm the importance of early initiation of chemotherapy for premenopausal patients with ER-absent tumors are required before widespread modification of current clinical practice.
Supported by the Ludwig Institute for Cancer Research, the SwissCancer League, the Cancer League of Ticino, the Swedish Cancer League, the Australia-New Zealand Breast Cancer Trials Group (National Health and Medical Research Council grants no. 880513 and 910420), the Australian Cancer Society, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, the American-Italian Cancer Foundation (grant no. 101-98), and the National Cancer Institute (grant no. CA-75362). We thank the patients, physicians, nurses, and data managers who participate in the IBCSG trials. We also acknowledge Mary Isley for her special contributions as Coordinating Data Manager for the IBCSG and Dr. Laura Orlando for participating in the data analysis.
1. Goldhirsch A, Gelber RD, Davis BW: Adjuvant chemotherapy trials in breast cancer: An appraisal and lessons for patient care outside the trials, in Forbes JF (ed): Breast Disease. Edinburgh, United Kingdom,Churchill Livingstone, 1986, pp 123-138 2. Kinne DW: Primary treatment of breast cancer surgery, in Harris JR, Hellman S, Henderson IC, et al (eds): Breast Diseases (ed 2). Philadelphia, PA,Lippincott, 1991, pp 347-373 3. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. Med 294:405-410, 1976[Abstract] 4. McCulloch P, Choy A: Effect of menstrual phase on surgical treatment of breast cancer. Lancet 344:402-403, 1994
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The International Breast Cancer Study Group: Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol 14:1885-1894, 1996 16. Paulsen SM, Pedersen KO: Comparison of histo- and biochemical methods for estrogen and progesterone receptor analysis in primary human breast carcinoma. Eur J Cancer Clin Oncol 21:1331-1336, 1985[Medline] 17. Zava DT, Wyler-von Ballmoos A, Goldhirsch A, et al: A quality control study to assess the interlaboratory variability of routine estrogen and progesterone receptor assays. Eur J Cancer Clin Oncol 18:713-721, 1982[Medline] 18. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 19. Cox DR: Regression models and life tables (with discussion). B 34:187-220, 1972 20. Brooks RJ, Jones SE, Salmon SE, et al: Improved outcome with early treatment in an adjuvant breast cancer program. Clin Oncol 2:110, 1983 (abstr C-431) 21. Pronzato P, Campora E, Amoroso D, et al: Impact of administration-related factors on outcome of adjuvant chemotherapy for primary breast cancer. Am J Clin Oncol 12:481-485, 1989[Medline] 22. Nissen-Meyer R, Kjellgren K, Malmio K, et al: Surgical adjuvant chemotherapy: Results with one short course with cyclophosphamide after mastectomy from breast cancer. Cancer 41:2088-2098, 1978[Medline] 23. Clahsen PC, van de Velde CJH, Goldhirsch A, et al: Overview of randomized perioperative polychemotherapy trials in women with early stage breast cancer. J Clin Oncol 15:2525-2535, 1997 24. Fisher B, Slack N, Katrych D, et al: Ten-year follow-up results of patients with carcinoma of the breast in a co-operative clinical trial evaluating surgical adjuvant chemotherapy. Obstet 140:528-534, 1975 25. Sertoli MR, Bruzzi P, Pronzato P, et al: Randomized cooperative study of perioperative chemotherapy in breast cancer. Clin Oncol 13:2712-2721, 1995 26. Early Breast Cancer Trialists Collaborative Groups: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998[Medline] 27. Kiang DT, Frenning DH, Goldman AI, et al: Estrogen receptors and responses to chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med 299:1330-1334, 1978[Abstract] 28. Lippman ME, Allegra JC: Lack of estrogen receptor associated with an increased response rate to cytotoxic chemotherapy in metastatic breast cancer? Res 71:155-161, 1980 29. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979[Medline]
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Fisher B, Gunduz N, Saffer EA: Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastasis. Cancer Res 43:1488-1492, 1983
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Fisher B, Gunduz N, Coile J, et al: Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 49:1996-2001, 1989
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Folkman J: What is the evidence that tumors are angiogenesis dependent? Cancer Inst 82:4-6, 1990 33. Hirata S, Matsubara T, Saura R, et al: Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularisation by low dose methotrexate. Arthritis Rheum 32:1065-1073, 1989[Medline] 34. Steiner R: Angiostatic activity of anticancer agents in the chick allantoic membrane (CHE-CAM) assay, in Steiner R, Weisz PB, Langer R (eds): Angiogenesis: Key Principles-Science-Technology-Medicine. Basel, Switzerland,Birkhaeuser Verlag, 1992, pp 449-454 35. Eggermont AMM, Steller EP, Sugarbaker PH: Laparotomy enhances intraperitoneal tumor growth and abrogates the antitumor effects of interleukin 2 and limphokine-activated killer cells. Surgery 102:71-78, 1987 36. Dickson RB, Lippman ME: Control of human breast cancer by estrogens, growth factors, and oncogenes, in Lippman ME, Dickson RB (eds): Breast Cancer: Cellular and Molecular Biology. Boston, MA,Kluwer Academic Publishers, 1988, pp 119-165 37. Pagani O, O’Neill A, Castiglione M, et al: Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: Results of The International Breast Cancer Study Group (IBCSG) Trial VI. Eur J Cancer 34:632-640, 1998 38. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. Clin Oncol 16:2672-2685, 1998 39. Saccani Jotti G, Johnston SR, Salter J, et al: Comparison of new immunohistochemical assay for oestrogen receptor in paraffin wax embedded breast carcinoma tissue with quantitative enzyme immunoassay. Pathol 47:900-905, 1994 40. Alberts SR, Ingle JN, Roche PR, et al: Comparison of estrogen receptor determinations by a biochemical ligand-binding assay and immunohistochemical staining with monoclonal antibody ER1D5 in females with lymph node positive breast carcinoma entered on two prospective clinical trials. Cancer 78:764-772, 1996[Medline] 41. Barnes DM, Harris WH, Smith P, et al: Immunohistochemical determination of oestrogen receptor: Comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 74:1445-1451, 1996[Medline] 42. Esteban JM, Ahn C, Battifora H, et al: Predictive value of estrogen receptors evaluated by quantitative immunohistochemical analysis in breast cancer. Am J Clin Pathol 102:9-12, 1994 43. International Breast Cancer Study Group: Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. Oncol 15:1385-1394, 1997
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Goldhirsch A, Coates AS, Colleoni M, et al: Adjuvant chemoendocrine therapy in postmenopausal breast cancer: Cyclophosphamide, methotrexate and fluorouracil dose and schedule may make a difference. J Clin Oncol 16:1358-1362, 1998 Submitted January 21, 1999; accepted September 7, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
10 fmol/mg cytosol protein), number of positive axillary lymph nodes (one to three or four or more), tumor size (
