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Originally published as JCO Early Release 10.1200/JCO.2006.09.8152 on April 9 2007 © 2007 American Society of Clinical Oncology. The Role of the Number of Uninvolved Lymph Nodes in Predicting Locoregional Recurrence in Breast Cancer
From the Department of Oncology, University of Göteborg, Sahlgrenska University Hospital, Göteborg, Sweden; International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute, Harvard School of Public Health; Frontier Science and Technology Research Foundation, Boston, MA; Dartmouth Medical School, Lebanon, NH; Inselspital; IBCSG, Bern; Senology Center of Eastern Switzerland, Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Bellinzona; Swiss Group for Clinical Cancer Research, Bern, Switzerland; University of Sydney, Sydney; Department of Surgery, Royal Melbourne Hospital, Victoria; Australian New Zealand Breast Cancer Trials Group, University of Newcastle, Newcastle Mater Hospital, Newcastle, New South Wales, Australia; Division of Cancer Sciences and Molecular Pathology, Western Infirmary, University of Glasgow, Glasgow, United Kingdom; Groote Shuur Hospital and University of Cape Town, Cape Town, South Africa; The Institute of Oncology, Ljubljana, Slovenia; Centro di Riferimento Oncologico, Aviano; and European Institute of Oncology, Milan, Italy Address reprint requests to Per Karlsson, MD, Department of Oncology, University of Göteborg, Sahlgrenska University Hospital, S 413 45 Göteborg, Sweden; e-mail: per.karlsson{at}oncology.gu.se
Purpose To identify groups of early breast cancer patients with substantial risk (10-year risk > 20%) for locoregional failure (LRF) who might benefit from postmastectomy radiotherapy (RT). Patients and Methods Prognostic factors for LRF were evaluated among 6,660 patients (2,588 node-negative patients, 4,072 node-positive patients) in International Breast Cancer Study Group Trials I to IX treated with chemotherapy and/or endocrine therapy, and observed for a median of 14 years. In total, 1,251 LRFs were detected. All patients were treated with mastectomy without RT. Results No group with 10-year LRF risk exceeding 20% was found among patients with node-negative disease. Among patients with node-positive breast cancer, increasing numbers of uninvolved nodes were significantly associated with decreased risk of LRF, even after adjustment for other prognostic factors. The highest quartile of uninvolved nodes was compared with the lowest quartile. Among premenopausal patients, LRF risk was decreased by 35% (P = .0010); among postmenopausal patients, LRF risk was decreased by 46% (P < .0001). The 10-year cumulative incidence of LRF was 20% among patients with one to three involved lymph nodes and fewer than 10 uninvolved nodes. Age younger than 40 years and vessel invasion were also associated significantly with increased risk. Among patients with node-positive disease, overall survival was significantly greater in those with higher numbers of uninvolved nodes examined (P < .0001). Conclusion Patients with one to three involved nodes and a low number of uninvolved nodes, vessel invasion, or young age have an increased risk of LRF and may be candidates for a similar treatment as those with at least four lymph node metastases.
Despite recent advances, questions remain about the optimal locoregional treatment of breast cancer. The overview of randomized trials on the effect of radiotherapy (RT) and differences in the extent of surgery for early breast cancer shows that variations in local treatment, which affect the risk of locoregional failure (LRF), also affect long-term breast cancer mortality.1 Generally, patients with at least four metastatic lymph nodes are considered at sufficiently high risk for LRF to benefit from postoperative RT, but the balance between benefit and adverse effects of RT is less certain with only one to three involved nodes.2,3 However, in Danish Breast Cancer Study Group trials 82b and 82c,4,5 postmastectomy RT significantly reduced LRF and improved overall survival in pre- and postmenopausal women with one to three involved nodes or high-risk, node-negative disease. When postoperative RT was not administered in these trials, LRF was considerably more frequent than that observed in previous studies of patients treated without RT.6-8 In these studies, the average number of lymph nodes examined was 15 to 17, compared with only seven in the Danish trials. These findings raise the question whether some of the benefit of postoperative RT in the Danish trials might be the result of suboptimal surgical lymph node dissection.9 Vinh-Hung et al10 investigated the influence of number of lymph nodes examined on mortality using the Surveillance, Epidemiology, and End Results database. They concluded that the relationship between number of lymph nodes and number of involved nodes is complex, and suggest that the number of involved nodes and number of uninvolved nodes or the ratio of involved to all examined nodes will give better prognostic information. Our previous study, based on data from International Breast Cancer Study Group (IBCSG) Trials I to VII, showed that predictors of LRF after mastectomy without RT included number of involved lymph nodes as well as tumor-related features: larger size, grade, and vascular invasion.7 The purpose of this study is to expand the analysis to include patients from Trials VIII and IX, all with node-negative disease, and to investigate the role of uninvolved nodes. All nine trials required that a minimum number of nodes should be examined as described below. Our hypothesis was that patients with a low number of uninvolved nodes after mastectomy may be at higher risk for LRF, and that in some patients, such as in whom the number of involved nodes is fewer than four, this increase in risk might be sufficient to justify the use of RT.
Designs of the Studies IBCSG Trials I to IX accrued 9,570 patients from 1978 to 1999. Results of the treatment comparisons, and detailed definitions for menopausal status, patient characteristics, and eligibility, have been described elsewhere.7,11-17 With the exception of Trial V, onto which patients were entered before the pathologic work-up was completed, patients were included only if the tumors were pT1, pT2, or pT3, and the margins of resection were free of tumor cells. Study guidelines required axillary dissection and that at least five (Trials I to IV) or eight (Trials V to IX) lymph nodes should be removed in the axillary specimen. All patients on Trials I to V were to receive mastectomy with no RT. Patients enrolled onto Trials VI to IX received either mastectomy with no RT, or breast-conserving surgery, mostly with RT. Patients treated with breast-conserving surgery were excluded from the present analysis. The nine randomized trials evaluated the timing and/or duration of chemotherapy (classical cyclophosphamide, methotrexate, fluorouracil [CMF]), endocrine therapy (tamoxifen or goserelin), chemotherapy plus endocrine therapy, or no adjuvant therapy. Institutional review boards reviewed and approved the protocols, and informed consent was required according to the criteria established within the individual countries. For Trials I to V and VIII to IX, a central pathology review process included the histologic evaluation of primary tumor specimens for invasion of vessel space (lymphatic or blood vessel) around the primary tumor.18 No central pathology review was conducted for Trials VI to VII, and the information about vessel invasion was provided by the local pathology work-up from the participating centers. Vessel invasion was defined as the presence of tumor cell emboli within a vessel space, which were identified by associated fibrin clot and/or an endothelial cell lining. The study protocol required that at least two sections of primary tumor be taken at right angles to one another to include the interface of the growing tumor border and the adjacent breast tissue. Generally, about 6 cm2 of breast tissue immediately adjacent to the primary tumor, but within 1 cm of the tumor border, was available for the assessment of peritumoral vessel invasion.
Menopausal status was defined consistently across the nine trials. Premenopausal and perimenopausal were grouped together and referred to as premenopausal in this report. Pre/perimenopausal patients were defined as age older than 52 years, with the last normal menstrual period within 1 year; age
Patient Selection
Statistical Analysis The primary end point was LRF with or without distant failure (LRF ± DF). LRF was defined as a first recurrence on the chest wall, the ipsilateral axilla, ipsilateral supraclavicular or infraclavicular fossa, or the ipsilateral internal mammary region. Time to LRF ± DF was defined as the interval from study entry (date of random assignment) until documented LRF with or without simultaneous distant failure. Overall survival time was defined as the interval from study entry to death as a result of any cause. We analyzed LRF ± DF using methods for cumulative incidence, treating all other events as competing risks. We determined the 10-year cumulative incidence rate based on the estimated cumulative incidence function (CIF).19 The CIF describes the probability of an event occurring within a specified period of time in the presence of competing risks (eg, death from noncancer causes).19,20 We analyzed overall survival using the product-limit method.21 When considering number of uninvolved nodes, we grouped patients based on quartiles determined separately for node-negative and node-positive patients. These groups were then compared in terms of LRF ± DF risk using tests for cumulative incidence19 and in terms of overall survival using log-rank tests. A regression model for the CIF was then used to evaluate the joint effect of predictor factors22 and to determine the effect of number of uninvolved nodes after adjustment for other prognostic factors. Within each patient group, we used a model-selection process to determine which prognostic factors were important independent predictors. Initially, each factor was evaluated alone using a Wald-type test. Factors found to be significant (ie, two-sided P < .05) in this analysis were then included together in a multivariable model. Likelihood ratio tests were then used to evaluate the joint significance of each factor. Those with P > .10 were removed from the model sequentially. Next, likelihood ratio tests were used to individually evaluate factors not included in the first step, and those with P < .05 were added. The procedure was repeated until no additional variables met the model inclusion/exclusion criteria. Number of uninvolved nodes (quartiles) was then added to each model. After this, the interaction between number of positive nodes and number of uninvolved nodes was considered by adding product terms to the model and using a likelihood ratio test. For improved interpretation, parameter estimates were converted to risk ratios, and 95% CIs were based on corresponding SEs using the normal distribution. Overall P values for multilevel factors were determined using likelihood ratio tests. The influence of number of uninvolved nodes on LRF was evaluated descriptively using a subpopulation treatment effect pattern plot analysis,23 in which patients were divided into overlapping subgroups based on the number of uninvolved nodes. Each subgroup was designed to contain at least 150 patients and to overlap with the previous subgroup by at most 130 patients. The 10-year cumulative incidence of LRF ± DF was determined within each subgroup, and the results were plotted on a graph (v the midpoint of the interval) to illustrate how LRF ± DF risk changes as the number of uninvolved nodes increases.
Table 1 summarizes the patient and tumor characteristics of the 6,660 patients eligible for this analysis according to the four subgroups defined according to menopausal status and nodal status. Table 2 lists the median follow-up and the number of LRFs (with or without distant failure; n = 1,251) for the trials and in total. The median follow-up in the total patient sample is 14 years, and the trial-specific median follow-up ranges from 7 to 22 years.
The median number of uninvolved nodes was 15 for patients with node-negative disease and 10 for those with node-positive disease. Patients were grouped according to quartile of number of uninvolved nodes in nodal status subgroups. In the node-negative subgroup, these quartiles were one to 10 nodes (22% of patients), 11 to 14 nodes (27%), 15 to 18 nodes (23%), and  19 nodes (28%). In the node-positive subgroup, these quartiles were zero to five nodes (24%), six to nine nodes (26%), 10 to 14 nodes (25%), and 15 nodes (25%). Table 3 lists the crude (unadjusted) 10-year cumulative incidence rates of LRF ± DF and the crude 10-year overall survival rates for each quartile of uninvolved nodes. Overall, the risk of LRF and the risk of death tend to decrease as the number of uninvolved nodes increases, and for the node-positive group the effect is statistically significant (Table 3). These trends are also illustrated in a subpopulation treatment effect pattern plot analysis shown in Figure 1.
In the evaluation of the role of uninvolved nodes after adjustment for other prognostic factors (Table 4), we found the following factors to be statistically significant predictors of increased likelihood of LRF: for premenopausal node-negative patients, younger age (< 40 or 40 years; P = .017) and vessel invasion (P = .0031); for postmenopausal node-negative patients, vessel invasion (P < .0001); for premenopausal node-positive patients, number of nodes involved (one to three or four; P < .0001), younger age (< 40 or 40 years; P = .0076), tumor grade (P = .0001), and vessel invasion (P < .0001); for postmenopausal node-positive patients, nodes involved (one to three or four; P < .0001), younger age (< 60 or 60 years, P = .042), and tumor grade (P = .015). Number of uninvolved nodes was included in these models to obtain adjusted estimates of its effect. Number of uninvolved nodes was not significantly associated with LRF risk in the node-negative subgroups (P = .72, premenopausal; P = .13, postmenopausal). Among patients with node-positive disease, a statistically significant effect of number of uninvolved nodes was observed in both pre- and postmenopausal patients (P = .0074 and P = .0007, respectively), although no significant interaction was found between number of nodes involved and number of uninvolved nodes (P = .14 and P = .69, respectively). These results show that, among patients with node-positive disease, the risk of LRF is significantly decreased with increased number of uninvolved nodes even after adjustment for other important prognostic factors. In particular, in the premenopausal node-positive subgroup, the risk of LRF is decreased by 35% when the highest quartile of uninvolved nodes is compared versus the lowest quartile (P = .0010). The corresponding effect in the postmenopausal node-positive subgroup is a 46% decrease in risk (P < .0001). In addition, we fit models using the proportion of nodes positive (number of positive nodes divided by the number of nodes examined), and interpretation of the results was similar (data not shown).
We also evaluated the unadjusted cumulative incidence of LRF according to number of involved nodes and number of uninvolved nodes (Table 5). Particularly noteworthy is the elevated risk among patients with one to three involved lymph nodes and fewer than 10 uninvolved nodes. The 10-year cumulative incidence of LRF among these patients is approximately 20% (Fig 1).
In this retrospective study, patients with one to three involved lymph nodes and fewer than 10 uninvolved nodes had a cumulative incidence of LRF of 20% or more. Such patients could thus be candidates for postmastectomy RT. We also found that age younger than 40 years (premenopausal women) or younger than 60 (postmenopausal women), tumor grade 3, and vascular invasion (in premenopausal women) were all predictors of increased LRF risk. We analyzed risk factors for LRF among patients who had been treated with mastectomy and axillary dissection without RT but with adjuvant systemic treatment. The IBCSG trials were restricted to patients who had unifocal, radically removed tumors and a specified minimum number of axillary nodes examined. Despite this restricted inclusion, LRF (with or without concurrent distant failure) was observed in 19%. The recent Early Breast Cancer Trialists' Collaborative Group updated overview of outcome according to locoregional treatment1 reported that locoregional control improved overall survival, although achieving this control with RT increased the risk of death from other causes (mainly cardiac events and other cancers). The overview concluded that for every four local recurrences avoided, about one breast cancer death might be avoided during the next 15 years (in the hypothetical absence of other causes of death). Thus, better locoregional control with RT is generally considered worthwhile in some settings. Our finding that vascular invasion is associated with LRF is supported by other investigators.24,25 Our finding that young age (younger than 40 years) is associated with increased risk of LRF is consistent with another large study.8 It is possible that this finding is related to the generally poorer survival in women younger than age 35 years.26 Our multivariable analysis showed that, in the node-positive groups, a higher number of uninvolved nodes was associated with decreased risk of LRF, even after adjustment for other prognostic factors. This finding is consistent with several other studies.8,10,27-29 There is, however, at least one study showing a reverse association.30 The number of nodes examined is a function of the amount of axillary tissue removed, individual anatomic variability, and the thoroughness of pathologic examination. An association between fewer uninvolved lymph nodes and outcome therefore might reflect either inadequate surgical dissection (leaving involved nodes in the patient) or understaging, which might result in a local or systemic undertreatment. Similarly, in colorectal cancer, inadequate surgery (ie, removing fewer than 14 regional lymph nodes) represents a higher risk of recurrence and therefore is an indication for adjuvant chemotherapy in Dukes B2 stage, for which adjuvant chemotherapy would otherwise not be necessary.31 If 20% LRF were considered as the cutoff point for offering women postoperative RT after mastectomy, the majority of our patients with at least four involved nodes would be candidates in accordance with the present consensus.2,3 However, the most controversial prognostic group for postmastectomy RT is women with fewer than four involved nodes. In the Danish studies, this group had a survival benefit from postoperative RT.4,5 In a retrospective analysis of the impact of locoregional treatment of patients in three EORTC trials, the conclusion was that the effect of adjuvant RT on LRF and overall survival was most profound in patients with one to three positive nodes,32 but this is not supported by the findings of Early Breast Cancer Trialists' Collaborative Group.1 Our study thus shows that the better prognosis regarding LRF of a few versus many involved nodes is worsened if the number of uninvolved nodes in the axillary specimen also is low. Among node-negative patients, however, we neither found a significant association between the number of uninvolved nodes and LRF, nor groups with high risk of LRF. Thus, the present study gives no indication of worse prognosis based on few uninvolved nodes in node-negative disease identified through sentinel node biopsy, or through selective node sampling based on a few palpable nodes.33,34 Furthermore, a more extensive axillary dissection may lead to unnecessary morbidity and thus the balance between risks and benefits of more extensive axillary surgery must be considered on a patient-by-patient basis. Our study supports the use of postmastectomy RT for certain groups of patients with fewer than four involved nodes because they may have a similar rate of LRF as patients with four or more involved nodes. Such groups could be defined by few uninvolved nodes, vascular invasion, or young age. However, although the patients in our study received systemic treatments, it is possible that the use of modern therapies such as aromatase inhibitors, anthracyclines, and taxanes, as well as trastuzumab, may have changed the risk for LRF and thus the indication for postmastectomy RT. Ideally, the benefit of such treatment combinations should be tested in prospective trials with sufficient power to detect survival benefits in relevant prognostic subgroups.
The authors indicated no potential conflicts of interest.
Conception and design: Per Karlsson, Bernard F. Cole, Arne Wallgren Administrative support: Karen N. Price, Monica Castiglione-Gertsch Provision of study materials or patients: Per Karlsson, Alan S. Coates, Monica Castiglione-Gertsch, Barry A. Gusterson, Elizabeth Murray, Jurij Lindtner, John P. Collins, Stig B. Holmberg, Martin F. Fey, Beat Thürlimann, Diana Crivellari, John F. Forbes, Aron Goldhirsch, Arne Wallgren Collection and assembly of data: Karen N. Price, Monica Castiglione-Gertsch, Barry A. Gusterson, Richard D. Gelber, Aron Goldhirsch Data analysis and interpretation: Per Karlsson, Bernard F. Cole, Alan S. Coates, Arne Wallgren Manuscript writing: Per Karlsson, Bernard F. Cole, Karen N. Price, Alan S. Coates, Arne Wallgren Final approval of manuscript: Per Karlsson, Bernard F. Cole, Karen N. Price, Alan S. Coates, Monica Castiglione-Gertsch, Barry A. Gusterson, Elizabeth Murray, Jurij Lindtner, John P. Collins, Stig B. Holmberg, Martin F. Fey, Beat Thürlimann, Diana Crivellari, John F. Forbes, Richard D. Gelber, Aron Goldhirsch, Arne Wallgren
We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials.
published online ahead of print at www.jco.org on April 9, 2007. Supported in part by Swiss Group for Clinical Cancer Research, Frontier Science and Technology Research Foundation, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group (National Health Medical Research Council), National Cancer Institute (CA-75362), Swedish Cancer Society, Cancer Association of South Africa, and Foundation for Clinical Cancer Research of Eastern Switzerland. Presented in part as a poster at the European Breast Cancer Conference, March 21-25, 2006, Nice, France. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366: 2087-2106, 2005[Medline] 2. Recht A, Edge SB, Solin LJ, et al: Postmastectomy radiotherapy: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19: 1539-1569, 2001 3. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16: 1569-1583, 2005 4. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337: 949-955, 1997 5. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353: 1641-1648, 1999[CrossRef][Medline] 6. Recht A, Gray R, Davidson N, et al: Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17: 1689-1700, 1999 7. Wallgren A, Bonetti M, Gelber RD, et al: Risk factors for locoregional recurrence among breast cancer patients: Results from International Breast Cancer Study Group Trials I through VII. J Clin Oncol 21: 1205-1213, 2003 8. Taghian A, Jeong JH, Mamounas E, et al: Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: Results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 22: 4247-4254, 2004 9. Goldhirsch A, Coates AS, Colleoni M, et al: Radiotherapy and chemotherapy in high-risk breast cancer. N Engl J Med 338: 330-331, 1998[Medline] 10. Vinh-Hung V, Cserni G, Burzykowski T, et al: Effect of the number of uninvolved nodes on survival in early breast cancer. Oncol Rep 10: 363-368, 2003[Medline] 11. Castiglione-Gertsch M, Johnsen C, Goldhirsch A, et al: The International (Ludwig) Breast Cancer Study Group Trials I-IV: 15 years follow-up. Ann Oncol 5: 717-724, 1994 12. Ludwig Breast Cancer Study Group: Combination adjuvant chemotherapy for node-positive breast cancer: Inadequacy of a single perioperative cycle. 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International Breast Cancer Study Group: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 95: 1833-1846, 2003 18. Davis BW, Gelber R, Goldhirsch A, et al: Prognostic significance of peritumoral vessel invasion in clinical trials of adjuvant therapy for breast cancer with axillary lymph node metastasis. Hum Pathol 16: 1212-1218, 1985[Medline] 19. Kalbfleish JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980 20. Satagopan JM, Ben-Porat L, Berwick M, et al: A note on competing risks in survival data analysis. Br J Cancer 91: 1229-1235, 2004[CrossRef][Medline] 21. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 22. Fine JP, Gray RJ: A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94: 496-509, 1999[CrossRef] 23. Bonetti M, Gelber RD: Patterns of treatment effects in subsets of patients in clinical trials. Biostatistics 5: 465-481, 2004[Abstract] 24. Sundquist M, Thorstenson S, Klintenberg C, et al: Indicators of loco-regional recurrence in breast cancer: The South East Swedish Breast Cancer Group. Eur J Surg Oncol 26: 357-362, 2000[CrossRef][Medline] 25. Voogd AC, Nielsen M, Peterse JL, et al: Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: Pooled results of two large European randomized trials. J Clin Oncol 19: 1688-1697, 2001 26. Aebi S, Gelber S, Castiglione-Gertsch M, et al: Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 355: 1869-1874, 2000[CrossRef][Medline] 27. Mersin H, Yildirim E, Bulut H, et al: The prognostic significance of total lymph node number in patients with axillary lymph node-negative breast cancer. Eur J Surg Oncol 29: 132-138, 2003[CrossRef][Medline] 28. Salama JK, Heimann R, Lin F, et al: Does the number of lymph nodes examined in patients with lymph node-negative breast carcinoma have prognostic significance? Cancer 103: 664-671, 2005[CrossRef][Medline] 29. Nielsen HM, Overgaard M, Grau C, et al: Loco-regional recurrence after mastectomy in high-risk breast cancer–risk and prognosis: An analysis of patients from the DBCG 82 b&c randomization trials. Radiother Oncol 79: 147-155, 2006[CrossRef][Medline] 30. Camp RL, Rimm EB, Rimm DL, et al: A high number of tumor free axillary lymph nodes from patients with lymph node negative breast carcinoma is associated with poor outcome. Cancer 88: 108-113, 2000[CrossRef][Medline] 31. Le Voyer TE, Sigurdson ER, Hanlon AL, et al: Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of intergroup trial INT-0089. J Clin Oncol 21: 2912-2919, 2003 32. van der Hage JA, Putter H, Bonnema J, et al: Impact of locoregional treatment on the early-stage breast cancer patients: A retrospective analysis. Eur J Cancer 39: 2192-2199, 2003[CrossRef][Medline] 33. Chetty U, Jack W, Prescott RJ, et al: Management of the axilla in operable breast cancer treated by breast conservation: A randomized clinical trial. Br J Surg 87: 163-169, 2000[CrossRef][Medline] 34. Ahlgren J, Holmberg L, Bergh J, et al: Five-node biopsy of the axilla: An alternative to axillary dissection of levels I-II in operable breast cancer. Eur J Surg Oncol 28: 97-102, 2002[CrossRef][Medline] Submitted November 3, 2006; accepted February 21, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
52 years, with the last normal menstrual period within 3 years, or currently menstruating; age 
