Site of Primary Tumor Has a Prognostic Role in Operable Breast Cancer: The International Breast Cancer Study Group Experience
http://www.100md.com
《临床肿瘤学》
the European Institute of Oncology, Milan
Centro di Riferimento Oncologico, Aviano, Italy
International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation, Boston, MA
Department of Surgery, SU/Moelndal's Hospital, Moelndal
West Swedish Breast Cancer Study Group, Sahlgrenska University Hospital, Gteborg, Sweden
The Institute of Oncology, Ljubljana, Slovenia
Department of Oncology, St Vincent's Hospital
Department of Surgery, The Royal Melbourne Hospital, Melbourne
The Cancer Council Australia and University of Sydney, Sydney, Australia
Institute of Medical Oncology, Inselspital
International Breast Cancer Study Group Coordinating Center, Bern
Kantonsspital, St Gallen
Oncology Institute of Southern Switzerland, Lugano, Switzerland
Groote Schuur Hospital and University of Cape Town, South Africa
Madrid Breast Cancer Group, Madrid, Spain.
ABSTRACT
PATIENTS AND METHODS: Eight-thousand four-hundred twenty-two patients randomly assigned to International Breast Cancer Study Group clinical trials between 1978 and 1999 were classified as medial site (1,622; 19%) or lateral, central, and other sites (6,800; 81%). Median follow-up was 11 years.
RESULTS: A statistically significant difference was observed for patients with medial tumors versus those with nonmedial tumors in disease-free survival (DFS; 10-year DFS, 46% v 48%; HR, 1.10; 95% CI, 1.02 to 1.18; P = .01) and overall survival (10-year OS 59% v 61%; HR, 1.09; 1.01 to 1.19; P = .04). This difference increased after adjustment for other prognostic factors (HR, 1.22; 95% CI, 1.13 to 1.32 for DFS; and HR, 1.24; 95% CI, 1.14 to 1.35 for OS; both P = .0001). The risk of relapse for patients with medial presentation was largest for the node-negative cohort and for patients with tumors larger than 2 cm. In the subgroup of 2,931 patients with negative axillary lymph nodes, 10-year DFS was 61% v 67%, and OS was 73% v 80% for medial versus nonmedial sites, respectively (HR 1.33; 95% CI, 1.15 to 1.54; P = .0001 for DFS; and HR 1.40; 95% CI, 1.17 to 1.67; P = .0003 for OS).
CONCLUSION: Tumor site has a significant prognostic utility, especially for axillary lymph node–negative disease, that should be considered in therapeutic algorithms. New staging procedures such as biopsy of the sentinel internal mammary nodes or novel imaging methods should be further studied in patients with medial tumors.
INTRODUCTION
Previous retrospective studies suggest that patients with tumors localized in the internal quadrants of the breast may have worse prognoses compared with patients whose tumors are confined to external quadrants.2,3 We therefore analyzed data from a large group of patients enrolled onto International Breast Cancer Study Group (IBCSG) Trials I through VII and IX to provide definitive information concerning the prognostic significance of medial presentation of primary breast cancer.
PATIENTS AND METHODS
Adjuvant systemic therapy was assigned according to the randomized clinical trials listed in Table 1.4-9 The trials investigated the role of endocrine therapy and chemoendocrine therapy (primarily "classical" cyclophosphamide, methotrexate, and fluorouracil [CMF], and tamoxifen or oophorectomy),4,9 timing and duration of chemotherapy ("classical" CMF),5,7 a single cycle of perioperative CMF (PeCMF),5,6 the duration and late reintroduction of CMF,7 and the early and/or delayed use of CMF given with tamoxifen.8
All patients were carefully observed for time to relapse and overall survival. Clinical, hematologic, and biochemical assessments of each patient were required every 3 months for 2 years, every 6 months until the end of the fifth year, and yearly thereafter until death. All sites of disease relapse, whether first or subsequent, were recorded in the study databases. In Trials I through V, chest x-rays and bone scans were required every 6 months for 2 years and once yearly up to 5 years. These tests were recommended beyond the fifth year only if clinically indicated. In Trials VI and VII, chest x-rays and bone scans were required, but further tests were performed only following clinical indications. In Trial IX, further tests were recommended only if clinically indicated. All patient data, including all disease- and survival-related events, were reviewed and classified by the medical study coordinators.
Categories of Predominant Site of Primary Tumor
The IBCSG collected information on predominant site of primary tumor on all patients in Trials I through VII and IX. The predominant site was classified as central, medial, lateral, or other, as shown in Figure 1. For these analyses, the primary objective was to compare outcomes for medial site (n = 1,622) versus nonmedial tumors (n = 6,800 central, lateral, or other). We also compared cases with medial site with those with lateral site (n = 5,048). The results for these latter analyses were similar but slightly more pronounced in each case than those comparing medial versus nonmedial (central tumors had an intermediate prognosis); for simplicity, these results are not shown here.
Statistical Methods
The primary end points were disease-free survival (DFS) and overall survival (OS). DFS was defined as the length of time from the date of random assignment to any relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer), or death, whichever occurred first. Any event was considered to be a component of a first event if diagnosed within a 2-month time frame. OS was defined as the length of time from the date of random assignment to death from any cause.
Survival curves for medial and nonmedial cohorts were estimated using the Kaplan-Meier method. Relative risks, 95% CIs, and P values were estimated using Cox proportional hazards regression models.10 P values ≤ .05 were deemed statistically significant. We report model estimates of relative risk, always comparing patients with medial tumors with patients having tumors confined to the external quadrants of the breast, with their corresponding 95% CIs. All P values are two-sided.
Factors included in multiple regression analyses were axillary nodal status (node-negative; node-positive), menopausal status (premenopausal; postmenopausal), estrogen-receptor (ER) status (ER-negative; ER-positive; ER-unknown), vessel invasion (no; yes; unknown), tumor grade (1; 2; 3; unknown), tumor size (≤ 2 cm; > 2 cm; unknown), age at randomization, and adjuvant systemic therapy regimen. For the adjuvant systemic therapy regimen we created three groups: patients randomly assigned to an observation arm (no adjuvant therapy) of IBCSG Trials III, IV, or V (all were postmenopausal); patients randomly assigned to receive hormonal therapy (tamoxifen for 6 months to 5 years or surgical oophorectomy) with or without chemotherapy (96% were postmenopausal, and 62% were in chemotherapy groups); and patients randomly assigned to receive chemotherapy without hormonal therapy (85% were premenopausal). As an additional analysis, we classified patients into four groups according to Treament Guidelines defined in the recent St Gallen Consensus Conference1 and the effectiveness of treatment defined in a previous IBCSG publication11: node-negative with less effective adjuvant treatment (Trial V all node-negative); node-negative with more effective treatment (Trial IX); node-positive with less effective adjuvant treatment (Trials III and IV observation arms, Trial V node-positive receiving PeCMF alone); and node-positive with more effective adjuvant treatment (Trials I, II, III, and IV treatment arms, V node-positive receiving more than PeCMF alone, VI, and VII). All categories were defined before data analysis.
We explored all the Cox regression models that included the predominant site of primary tumor, one of the eight factors, and the two-way interaction between that factor and the predominant site of primary tumor. Our goal was to ascertain if there were factors for which the magnitude of the effect of the predominant site of the primary tumor differed according to the level of the factor. For any significant interaction effects, we estimated the predominant site of primary tumor effect separately for each level of the factor. We report and examine hazard ratios and the respective CIs for each level of the factor unadjusted and adjusted for all other factors.
We used graphical methods and Akaike's Information Criteria to assess the fit of all the regression models.12 In addition, we tested all hypotheses using the Wald test13 and associated P value.
RESULTS
Table 2 shows the distribution of patient characteristics according to the predominant site of primary tumor: medial versus nonmedial. Patients with medial presentation were more likely to have axillary lymph node–negative disease (P < .0001) and were more likely to have tumors ≤ 2 cm (P = .0004) compared with patients having nonmedial tumors. The distributions of other patient characteristics were not significantly different according to site of presentation. The median age of the patients at random assignment was 54 years; for the observation, hormonal therapy with or without chemotherapy, and chemotherapy without hormonal therapy groups, the median ages were 58, 60, and 46 years, respectively.
The median follow-up for the study cohort was 11 years. The overall distribution of medial and nonmedial tumors according to the site of first failure is presented in Table 3. Of the 1,622 patients with medial tumors, 54.4% had an event, compared with 52.4% among 6,800 patients with lateral, central, or other tumors. There were increases in incidence of distant soft tissue, bone, and visceral relapse for patients with medial tumors compared with the others, that were not statistically significant. Six hundred eighty-one patients (42.0%) died in the medial cohort, and 2,750 (40.4%) died in the lateral/central/other cohort.
Table 4 presents 10-year Kaplan-Meier DFS and OS percentages, hazards ratios, 95% CIs, and P values according to site of primary tumor. The Kaplan-Meier curves for DFS and OS for the entire study cohort are displayed in Figures 2A and 2B. Considering all patients, there was a statistically significant worse DFS and OS for those with medial tumors versus those with nonmedial tumors (P = .01 and P = .04, respectively). The relative risk of relapse was 10% higher (10-year DFS, 46% v 48%), and the relative risk of death, 9% higher (10-year OS, 59% v 61%) for patients with medial tumors compared with other patients (Table 4). The prognosis for central tumors (10-year DFS, 47%; 10-year OS, 60%) was intermediate between medial tumors (10-year DFS, 46%; 10-year OS, 59%) and lateral tumors (10-year DFS, 48%; 10-year OS, 62%). The statistical significance of the poorer prognosis associated with medial presentation increased in Cox models adjusted for all eight factors. In the multiple regression analyses, the relative risk of relapse was 22% higher (P = .0001), and the relative risk of death, 24% higher (P = .0001) for patients with medial tumors compared with other patients (Table 4). The difference between the unadjusted and adjusted analyses was due primarily to the higher incidence of axillary lymph node–negative presentation among patients with medial tumors.
Given the large sample size, the magnitude of the difference in outcome for medial versus nonmedial presentation was significantly different according to several factors. For DFS, interaction effects in Cox models were significant for tumor size (P = .01), adjuvant systemic therapy group (P = .02), menopausal status (P = .04), and ER status (P = .05), with marginal significance observed for axillary node group (P = .06). For OS, interactions were significant for tumor size (P = .04), axillary node group (P = .05), and ER status (P = .05). The results comparing medial versus nonmedial cohorts within subsets defined by these factors are presented in Table 4. The poorer outcome for patients with medial tumors was greater for axillary lymph node–negative disease, larger tumor size, pre-/perimenopausal age, ER-negative tumors, and assignment to adjuvant chemotherapy without hormonal treatment.
Among patients with axillary lymph node–negative disease, we observed an effect on prognosis of the site of primary tumor in the breast irrespective of tumor size, though a tendency toward a higher risk was observed for patients who were both axillary lymph node–negative and had larger tumors (Table 5). Results according to nodal status and adjuvant treatment are also presented in Table 5 to ascertain whether the magnitude of the poor prognosis associated with medial presentation might be influenced by more effective adjuvant therapy. The largest impact of medial presentation was for patients with axillary lymph node–negative disease who were in the less effective treatment groups, though the interactions were not statistically significant (P = .07 for DFS and P = .21 for OS).
DISCUSSION
Although several studies on the prognostic role of medial tumors are available in the literature, the site of the tumor is commonly not considered in the decision of the treatment algorithm. In fact, available data have some limitations. Several of the published studies were presented with short follow-up,3,19,20 no description of adjuvant systemic treatment received,2,19,20 and limited sample size.2 Moreover, subgroup analysis in order to identify patients at significantly higher risk of relapse was uncommonly reported. The present study, based on prospectively defined and quality-controlled databases of IBCSG randomized clinical trials, provides the largest population (8,422 patients) of patients included in clinical trials, with long follow-up (median, 11 years) available to examine this subject. We demonstrated a statistically significant worse outcome in terms of both DFS and OS for patients who presented with medial tumors compared with those who had nonmedial breast disease. Statistical significance was increased after adjustment for other prognostic factors. More importantly, the magnitude of the prognostic impact differed significantly in various subgroups. The difference in outcome according to site of presentation was greater among those with no axillary lymph node metastases than among those with axillary node–positive disease. In the IBCSG trials, a large proportion of patients with lymph node–negative disease were assigned to receive either no adjuvant systemic therapy or an adjuvant systemic treatment program currently considered suboptimal, while the majority of women with lymph node–positive disease had a more effective adjuvant treatment program. This disparity might partially explain the larger effect of medial site on prognosis in patients with axillary lymph node–negative disease. Similarly, the magnitude of increased risk associated with medial tumors was smaller for patients who were in the more effective adjuvant therapy group compared with patients in the less effective treatment group in both lymph node–negative and lymph node–positive cohorts. We also observed a larger impact of medial presentation on prognosis for patients with larger tumors, which also suggests a greater opportunity for metastatic spread into the internal mammary lymph node chain for larger tumors, as demonstrated by others.14
The main issue to be discussed is whether the medial site of primary tumor presentation should be a factor influencing a targeted treatment choice, possibly affecting decisions about whether local and regional treatment should include the internal mammary chain, and whether intensified systemic treatment should be given. There are no convincing results from randomized trials on the role of local-regional radiation therapy according to the site of the primary, though some data from old studies indicated some benefit for parasternal radiation to patients with medial site of the primary tumor.21 Recent randomized trials that demonstrated a reduction in the risk of death for local-regional radiation therapy in combination with modified radical mastectomy did not present data according to location of the primary.22-24 In addition, these trials did not use very effective adjuvant systemic therapy, and patients were enrolled without proper axillary surgery.25 Therefore, the role of radiation therapy to internal mammary lymph nodes should not be regarded as established until the results of current randomized trials are available (eg, European Organisation for Research and Treatment of Cancer [EORTC] Trial 22,922-10925; http://www.eortc.be).
Given the limited evidence supporting a benefit for local treatment of the internal mammary nodes, medial presentation is likely to be most important for stimulating efforts to properly stage the disease. Since sentinel internal mammary lymph node biopsy and work-up has been demonstrated to be feasible,26 this procedure deserves further study to determine how to use the information obtained to properly stage the disease and tailor adjuvant therapies. Novel imaging procedures, such as 18-fluorodeoxyglucose positron emission tomography, might improve our ability to detect occult disease specifically in internal mammary lymph nodes and/or in other regional lymph nodes.27
Regarding the relevance of tumor site in the breast at disease presentation and its relationship to adjuvant systemic treatment, the results of this study suggest that the higher risk conferred by medial site might influence treatment choice in the future. In fact, although the selection of adjuvant systemic treatment should be based on indicators of responsiveness to treatment rather than indicators of risk,1 some patients with endocrine-responsive disease and indicators of dire prognosis associated with medial presentation (eg, large tumors, vascular invasion, one or few axillary nodes involved) might increase their chance for improved prognosis if chemotherapy is added to an endocrine treatment program.
This study demonstrates that medial site of breast cancer is an important prognostic feature, especially for patients with axillary lymph node–negative disease and larger tumor size. Relying on axillary staging alone to guide the selection of adjuvant systemic therapy may be insufficient for medial tumors, especially if tumor size is large. Patients with medial presentation represent a cohort in whom studies of more focused staging procedures are required to assess internal mammary node metastases. Furthermore, treatment programs should be studied to determine whether this disease presentation should receive a specifically tailored therapy.
Authors' Disclosures of Potential Conflicts of Interest
Appendix. International Breast Cancer Study Group (IBCSG) Participants and Authors Trials I-VII and IX
Acknowledgment
We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials. We also acknowledge Professor Umberto Veronesi for his critical and thoughtful contribution. We gratefully acknowledge the initial support provided by the Ludwig Institute for Cancer Research and the Cancer League of Ticino, and the continuing support for central coordination, data management, and statistics provided by the Swedish Cancer League, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, the Swiss Cancer League, and the US National Cancer Institute (CA-75362). We also acknowledge support for the Cape Town participants from the Cancer Association of South Africa and for the St Gallen participants from the Foundation for Clinical Cancer Research of Eastern Switzerland. In addition, we acknowledge IBCSG participating institutions and investigators for Trials I through VII and IX: IBCSG Data Management: R. Hinkle; West Swedish Breast Cancer Study Group, Gteborg, Sweden: C.M. Rudenstam; The Institute of Oncology, Ljubljana, Slovenia: J. Lindtner; The Cancer Council Victoria, Melbourne, Australia: J. Collins; Kantonsspital, St Gallen, Switzerland: H.J. Senn; Inselspital, Bern, Switzerland: M.F. Fey; Groote Schuur Hospital and University of Cape Town, South Africa: E. Murray; Sandton Oncology Center, Johannesburg, South Africa: D. Vorobiof; University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia: M.H.N. Tattersall; Madrid Breast Cancer Group, Madrid, Spain: H. Cortes-Funes; Institute of Oncology of Southern Switzerland, Bellinzona, Switzerland: F. Cavalli; Spedali Civili and Fondazione Beretta, Brescia, Italy: G. Marini; General Hospital, Gorizia, Italy: S. Foladore; European Institute of Oncology, Milano, Italy: A. Goldhirsch; Ospedale Infermi, Rimini, Italy: A. Ravaioli; Ospedale S. Eugenio, Roma, Italy: M. Antimi; Ospedale S. Bortolo, Vicenza, Italy: M. Magazu; University of Düsseldorf, Germany: HG Schnürch; Sir Charles Gairdner Hospital, Nedlands, W Australia: M. Byrne; University Hospital of Zürich, Zürich, Switzerland: C. Sauter; Kantonsspital, Basel, Switzerland: R. Herrmann; Auckland Breast Cancer Study Group, Auckland, New Zealand: R.G. Kay; Centro di Riferimento Oncologico, Aviano, Italy: A. Veronesi; Hpital Cantonal, Geneva, Switzerland: P. Alberto; Centre Hpitalier Universitaire, Lausanne, Switzerland: S. Leyvraz; Hpital des Cadolles, Neuchtel, Switzerland: P. Siegenthaler; University of Newcastle, Newcastle, Australia: J. Forbes.
NOTES
Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Goldhirsch A, Wood WC, Gelber RD, et al: Meeting highlights: Updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 21:3357-3365, 2003
2. Zucali R, Mariani L, Marubini E, et al: Early breast cancer: Evaluation of the prognostic role of the site of the primary tumor. J Clin Oncol 16:1363-1366, 1998
3. Lohrisch C, Jackson J, Jones A, et al: Relationship between tumor location and relapse in 6,781 women with early invasive breast cancer. J Clin Oncol 18:2828-2835, 2000
4. Castiglione-Gertsch M, Johnsen C, Goldhirsch A, et al: The International Breast Cancer Study Group Trials I-IV: 15 years of follow-up. Ann Oncol 5:717-724, 1994
5. Ludwig Breast Cancer Study Group: Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med 320:491-496, 1989
6. Ludwig Breast Cancer Study Group: Combination adjuvant chemotherapy for node-positive breast cancer: Inadequacy of a single perioperative cycle. N Engl J Med 319:677-683, 1988
7. 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
8. International Breast Cancer Study Group: Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. J Clin Oncol 15:1385-1394, 1997
9. International Breast Cancer Study Group (IBCSG): Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 94:1054-1065, 2002
10. Cox R: Regression models and life tables (with discussion). J R Stat Soc B (Methodology) 34:187-220, 1972
11. Goldhirsch A, Gelber RD, Price KN, et al: Effect of systemic adjuvant treatment on first sites of breast cancer relapse. Lancet 343:377-381, 1994
12. Akaike H: A new look at the statistical model identification. IEEE Trans Automatic Control 19:716-723, 1974
13. Cox DR, Hinkley DV: Theoretical Statistics. New York, NY, Chapman and Hall, 1974
14. Veronesi U, Cascinelli N, Bufalino R, et al: Risk of internal mammary lymph node metastases and its relevance on prognosis of breast cancer patients. Ann Surg 198:681-684, 1983
15. Handley R: Natural history of breast cancer, in Harris J, Lippman ME, Morrow M, et al (eds): Diseases of the Breast. Philadelphia, PA, WB Saunders, 1996, pp 384
16. Urban J: Is there a rationale for an extended radical procedure Int J Radiat Oncol Biol Phys 2:985-988, 1977
17. Lacour J, Mle M, Caceres E, et al: Radical mastectomy versus radical mastectomy plus internal mammary dissection. Cancer 51:1941-1943, 1983
18. Veronesi U, Marubini E, Mariani L, et al: The dissection of internal mammary nodes does not improve the survival of breast cancer patients: 30-year results of a randomised trial. Eur J Cancer 35:1320-1325, 1999
19. Gaffney DK, Tsodikov A, Wiggins CL: Diminished survival in patients with inner versus outer quadrant breast cancers. J Clin Oncol 21:467-472, 2003
20. Kroman N, Wohlfahrt J, Mouridesn HT: Influence of tumor location on breast cancer prognosis. Int J Cancer 105:542-545, 2003
21. Host H, Brennhovd IO, Loeb M: Postoperative radiotherapy in breast cancer: Long-term results from the Oslo study. Int J Radiat Oncol Biol Phys 12:727-732, 1986
22. 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
23. 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
24. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997
25. Goldhirsch A, Coates AS, Colleoni M: Radiotherapy and chemotherapy in high-risk breast cancer. N Engl J Med 338:330-331, 1998
26. Sacchini V, Borgen PI, Galimberti V, et al: Surgical approach to internal mammary lymph node biopsy. J Am Coll Surg 193:709-713, 2001
27. Eubank WB, Mankoff DA, Takasugi J, et al: 18-fluorodeoxyglucose positron emission tomography to detect mediastinal or internal mammary metastases in breast cancer. J Clin Oncol 19:3516-3523, 2001(Marco Colleoni, David Zah)
Centro di Riferimento Oncologico, Aviano, Italy
International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation, Boston, MA
Department of Surgery, SU/Moelndal's Hospital, Moelndal
West Swedish Breast Cancer Study Group, Sahlgrenska University Hospital, Gteborg, Sweden
The Institute of Oncology, Ljubljana, Slovenia
Department of Oncology, St Vincent's Hospital
Department of Surgery, The Royal Melbourne Hospital, Melbourne
The Cancer Council Australia and University of Sydney, Sydney, Australia
Institute of Medical Oncology, Inselspital
International Breast Cancer Study Group Coordinating Center, Bern
Kantonsspital, St Gallen
Oncology Institute of Southern Switzerland, Lugano, Switzerland
Groote Schuur Hospital and University of Cape Town, South Africa
Madrid Breast Cancer Group, Madrid, Spain.
ABSTRACT
PATIENTS AND METHODS: Eight-thousand four-hundred twenty-two patients randomly assigned to International Breast Cancer Study Group clinical trials between 1978 and 1999 were classified as medial site (1,622; 19%) or lateral, central, and other sites (6,800; 81%). Median follow-up was 11 years.
RESULTS: A statistically significant difference was observed for patients with medial tumors versus those with nonmedial tumors in disease-free survival (DFS; 10-year DFS, 46% v 48%; HR, 1.10; 95% CI, 1.02 to 1.18; P = .01) and overall survival (10-year OS 59% v 61%; HR, 1.09; 1.01 to 1.19; P = .04). This difference increased after adjustment for other prognostic factors (HR, 1.22; 95% CI, 1.13 to 1.32 for DFS; and HR, 1.24; 95% CI, 1.14 to 1.35 for OS; both P = .0001). The risk of relapse for patients with medial presentation was largest for the node-negative cohort and for patients with tumors larger than 2 cm. In the subgroup of 2,931 patients with negative axillary lymph nodes, 10-year DFS was 61% v 67%, and OS was 73% v 80% for medial versus nonmedial sites, respectively (HR 1.33; 95% CI, 1.15 to 1.54; P = .0001 for DFS; and HR 1.40; 95% CI, 1.17 to 1.67; P = .0003 for OS).
CONCLUSION: Tumor site has a significant prognostic utility, especially for axillary lymph node–negative disease, that should be considered in therapeutic algorithms. New staging procedures such as biopsy of the sentinel internal mammary nodes or novel imaging methods should be further studied in patients with medial tumors.
INTRODUCTION
Previous retrospective studies suggest that patients with tumors localized in the internal quadrants of the breast may have worse prognoses compared with patients whose tumors are confined to external quadrants.2,3 We therefore analyzed data from a large group of patients enrolled onto International Breast Cancer Study Group (IBCSG) Trials I through VII and IX to provide definitive information concerning the prognostic significance of medial presentation of primary breast cancer.
PATIENTS AND METHODS
Adjuvant systemic therapy was assigned according to the randomized clinical trials listed in Table 1.4-9 The trials investigated the role of endocrine therapy and chemoendocrine therapy (primarily "classical" cyclophosphamide, methotrexate, and fluorouracil [CMF], and tamoxifen or oophorectomy),4,9 timing and duration of chemotherapy ("classical" CMF),5,7 a single cycle of perioperative CMF (PeCMF),5,6 the duration and late reintroduction of CMF,7 and the early and/or delayed use of CMF given with tamoxifen.8
All patients were carefully observed for time to relapse and overall survival. Clinical, hematologic, and biochemical assessments of each patient were required every 3 months for 2 years, every 6 months until the end of the fifth year, and yearly thereafter until death. All sites of disease relapse, whether first or subsequent, were recorded in the study databases. In Trials I through V, chest x-rays and bone scans were required every 6 months for 2 years and once yearly up to 5 years. These tests were recommended beyond the fifth year only if clinically indicated. In Trials VI and VII, chest x-rays and bone scans were required, but further tests were performed only following clinical indications. In Trial IX, further tests were recommended only if clinically indicated. All patient data, including all disease- and survival-related events, were reviewed and classified by the medical study coordinators.
Categories of Predominant Site of Primary Tumor
The IBCSG collected information on predominant site of primary tumor on all patients in Trials I through VII and IX. The predominant site was classified as central, medial, lateral, or other, as shown in Figure 1. For these analyses, the primary objective was to compare outcomes for medial site (n = 1,622) versus nonmedial tumors (n = 6,800 central, lateral, or other). We also compared cases with medial site with those with lateral site (n = 5,048). The results for these latter analyses were similar but slightly more pronounced in each case than those comparing medial versus nonmedial (central tumors had an intermediate prognosis); for simplicity, these results are not shown here.
Statistical Methods
The primary end points were disease-free survival (DFS) and overall survival (OS). DFS was defined as the length of time from the date of random assignment to any relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer), or death, whichever occurred first. Any event was considered to be a component of a first event if diagnosed within a 2-month time frame. OS was defined as the length of time from the date of random assignment to death from any cause.
Survival curves for medial and nonmedial cohorts were estimated using the Kaplan-Meier method. Relative risks, 95% CIs, and P values were estimated using Cox proportional hazards regression models.10 P values ≤ .05 were deemed statistically significant. We report model estimates of relative risk, always comparing patients with medial tumors with patients having tumors confined to the external quadrants of the breast, with their corresponding 95% CIs. All P values are two-sided.
Factors included in multiple regression analyses were axillary nodal status (node-negative; node-positive), menopausal status (premenopausal; postmenopausal), estrogen-receptor (ER) status (ER-negative; ER-positive; ER-unknown), vessel invasion (no; yes; unknown), tumor grade (1; 2; 3; unknown), tumor size (≤ 2 cm; > 2 cm; unknown), age at randomization, and adjuvant systemic therapy regimen. For the adjuvant systemic therapy regimen we created three groups: patients randomly assigned to an observation arm (no adjuvant therapy) of IBCSG Trials III, IV, or V (all were postmenopausal); patients randomly assigned to receive hormonal therapy (tamoxifen for 6 months to 5 years or surgical oophorectomy) with or without chemotherapy (96% were postmenopausal, and 62% were in chemotherapy groups); and patients randomly assigned to receive chemotherapy without hormonal therapy (85% were premenopausal). As an additional analysis, we classified patients into four groups according to Treament Guidelines defined in the recent St Gallen Consensus Conference1 and the effectiveness of treatment defined in a previous IBCSG publication11: node-negative with less effective adjuvant treatment (Trial V all node-negative); node-negative with more effective treatment (Trial IX); node-positive with less effective adjuvant treatment (Trials III and IV observation arms, Trial V node-positive receiving PeCMF alone); and node-positive with more effective adjuvant treatment (Trials I, II, III, and IV treatment arms, V node-positive receiving more than PeCMF alone, VI, and VII). All categories were defined before data analysis.
We explored all the Cox regression models that included the predominant site of primary tumor, one of the eight factors, and the two-way interaction between that factor and the predominant site of primary tumor. Our goal was to ascertain if there were factors for which the magnitude of the effect of the predominant site of the primary tumor differed according to the level of the factor. For any significant interaction effects, we estimated the predominant site of primary tumor effect separately for each level of the factor. We report and examine hazard ratios and the respective CIs for each level of the factor unadjusted and adjusted for all other factors.
We used graphical methods and Akaike's Information Criteria to assess the fit of all the regression models.12 In addition, we tested all hypotheses using the Wald test13 and associated P value.
RESULTS
Table 2 shows the distribution of patient characteristics according to the predominant site of primary tumor: medial versus nonmedial. Patients with medial presentation were more likely to have axillary lymph node–negative disease (P < .0001) and were more likely to have tumors ≤ 2 cm (P = .0004) compared with patients having nonmedial tumors. The distributions of other patient characteristics were not significantly different according to site of presentation. The median age of the patients at random assignment was 54 years; for the observation, hormonal therapy with or without chemotherapy, and chemotherapy without hormonal therapy groups, the median ages were 58, 60, and 46 years, respectively.
The median follow-up for the study cohort was 11 years. The overall distribution of medial and nonmedial tumors according to the site of first failure is presented in Table 3. Of the 1,622 patients with medial tumors, 54.4% had an event, compared with 52.4% among 6,800 patients with lateral, central, or other tumors. There were increases in incidence of distant soft tissue, bone, and visceral relapse for patients with medial tumors compared with the others, that were not statistically significant. Six hundred eighty-one patients (42.0%) died in the medial cohort, and 2,750 (40.4%) died in the lateral/central/other cohort.
Table 4 presents 10-year Kaplan-Meier DFS and OS percentages, hazards ratios, 95% CIs, and P values according to site of primary tumor. The Kaplan-Meier curves for DFS and OS for the entire study cohort are displayed in Figures 2A and 2B. Considering all patients, there was a statistically significant worse DFS and OS for those with medial tumors versus those with nonmedial tumors (P = .01 and P = .04, respectively). The relative risk of relapse was 10% higher (10-year DFS, 46% v 48%), and the relative risk of death, 9% higher (10-year OS, 59% v 61%) for patients with medial tumors compared with other patients (Table 4). The prognosis for central tumors (10-year DFS, 47%; 10-year OS, 60%) was intermediate between medial tumors (10-year DFS, 46%; 10-year OS, 59%) and lateral tumors (10-year DFS, 48%; 10-year OS, 62%). The statistical significance of the poorer prognosis associated with medial presentation increased in Cox models adjusted for all eight factors. In the multiple regression analyses, the relative risk of relapse was 22% higher (P = .0001), and the relative risk of death, 24% higher (P = .0001) for patients with medial tumors compared with other patients (Table 4). The difference between the unadjusted and adjusted analyses was due primarily to the higher incidence of axillary lymph node–negative presentation among patients with medial tumors.
Given the large sample size, the magnitude of the difference in outcome for medial versus nonmedial presentation was significantly different according to several factors. For DFS, interaction effects in Cox models were significant for tumor size (P = .01), adjuvant systemic therapy group (P = .02), menopausal status (P = .04), and ER status (P = .05), with marginal significance observed for axillary node group (P = .06). For OS, interactions were significant for tumor size (P = .04), axillary node group (P = .05), and ER status (P = .05). The results comparing medial versus nonmedial cohorts within subsets defined by these factors are presented in Table 4. The poorer outcome for patients with medial tumors was greater for axillary lymph node–negative disease, larger tumor size, pre-/perimenopausal age, ER-negative tumors, and assignment to adjuvant chemotherapy without hormonal treatment.
Among patients with axillary lymph node–negative disease, we observed an effect on prognosis of the site of primary tumor in the breast irrespective of tumor size, though a tendency toward a higher risk was observed for patients who were both axillary lymph node–negative and had larger tumors (Table 5). Results according to nodal status and adjuvant treatment are also presented in Table 5 to ascertain whether the magnitude of the poor prognosis associated with medial presentation might be influenced by more effective adjuvant therapy. The largest impact of medial presentation was for patients with axillary lymph node–negative disease who were in the less effective treatment groups, though the interactions were not statistically significant (P = .07 for DFS and P = .21 for OS).
DISCUSSION
Although several studies on the prognostic role of medial tumors are available in the literature, the site of the tumor is commonly not considered in the decision of the treatment algorithm. In fact, available data have some limitations. Several of the published studies were presented with short follow-up,3,19,20 no description of adjuvant systemic treatment received,2,19,20 and limited sample size.2 Moreover, subgroup analysis in order to identify patients at significantly higher risk of relapse was uncommonly reported. The present study, based on prospectively defined and quality-controlled databases of IBCSG randomized clinical trials, provides the largest population (8,422 patients) of patients included in clinical trials, with long follow-up (median, 11 years) available to examine this subject. We demonstrated a statistically significant worse outcome in terms of both DFS and OS for patients who presented with medial tumors compared with those who had nonmedial breast disease. Statistical significance was increased after adjustment for other prognostic factors. More importantly, the magnitude of the prognostic impact differed significantly in various subgroups. The difference in outcome according to site of presentation was greater among those with no axillary lymph node metastases than among those with axillary node–positive disease. In the IBCSG trials, a large proportion of patients with lymph node–negative disease were assigned to receive either no adjuvant systemic therapy or an adjuvant systemic treatment program currently considered suboptimal, while the majority of women with lymph node–positive disease had a more effective adjuvant treatment program. This disparity might partially explain the larger effect of medial site on prognosis in patients with axillary lymph node–negative disease. Similarly, the magnitude of increased risk associated with medial tumors was smaller for patients who were in the more effective adjuvant therapy group compared with patients in the less effective treatment group in both lymph node–negative and lymph node–positive cohorts. We also observed a larger impact of medial presentation on prognosis for patients with larger tumors, which also suggests a greater opportunity for metastatic spread into the internal mammary lymph node chain for larger tumors, as demonstrated by others.14
The main issue to be discussed is whether the medial site of primary tumor presentation should be a factor influencing a targeted treatment choice, possibly affecting decisions about whether local and regional treatment should include the internal mammary chain, and whether intensified systemic treatment should be given. There are no convincing results from randomized trials on the role of local-regional radiation therapy according to the site of the primary, though some data from old studies indicated some benefit for parasternal radiation to patients with medial site of the primary tumor.21 Recent randomized trials that demonstrated a reduction in the risk of death for local-regional radiation therapy in combination with modified radical mastectomy did not present data according to location of the primary.22-24 In addition, these trials did not use very effective adjuvant systemic therapy, and patients were enrolled without proper axillary surgery.25 Therefore, the role of radiation therapy to internal mammary lymph nodes should not be regarded as established until the results of current randomized trials are available (eg, European Organisation for Research and Treatment of Cancer [EORTC] Trial 22,922-10925; http://www.eortc.be).
Given the limited evidence supporting a benefit for local treatment of the internal mammary nodes, medial presentation is likely to be most important for stimulating efforts to properly stage the disease. Since sentinel internal mammary lymph node biopsy and work-up has been demonstrated to be feasible,26 this procedure deserves further study to determine how to use the information obtained to properly stage the disease and tailor adjuvant therapies. Novel imaging procedures, such as 18-fluorodeoxyglucose positron emission tomography, might improve our ability to detect occult disease specifically in internal mammary lymph nodes and/or in other regional lymph nodes.27
Regarding the relevance of tumor site in the breast at disease presentation and its relationship to adjuvant systemic treatment, the results of this study suggest that the higher risk conferred by medial site might influence treatment choice in the future. In fact, although the selection of adjuvant systemic treatment should be based on indicators of responsiveness to treatment rather than indicators of risk,1 some patients with endocrine-responsive disease and indicators of dire prognosis associated with medial presentation (eg, large tumors, vascular invasion, one or few axillary nodes involved) might increase their chance for improved prognosis if chemotherapy is added to an endocrine treatment program.
This study demonstrates that medial site of breast cancer is an important prognostic feature, especially for patients with axillary lymph node–negative disease and larger tumor size. Relying on axillary staging alone to guide the selection of adjuvant systemic therapy may be insufficient for medial tumors, especially if tumor size is large. Patients with medial presentation represent a cohort in whom studies of more focused staging procedures are required to assess internal mammary node metastases. Furthermore, treatment programs should be studied to determine whether this disease presentation should receive a specifically tailored therapy.
Authors' Disclosures of Potential Conflicts of Interest
Appendix. International Breast Cancer Study Group (IBCSG) Participants and Authors Trials I-VII and IX
Acknowledgment
We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials. We also acknowledge Professor Umberto Veronesi for his critical and thoughtful contribution. We gratefully acknowledge the initial support provided by the Ludwig Institute for Cancer Research and the Cancer League of Ticino, and the continuing support for central coordination, data management, and statistics provided by the Swedish Cancer League, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, the Swiss Cancer League, and the US National Cancer Institute (CA-75362). We also acknowledge support for the Cape Town participants from the Cancer Association of South Africa and for the St Gallen participants from the Foundation for Clinical Cancer Research of Eastern Switzerland. In addition, we acknowledge IBCSG participating institutions and investigators for Trials I through VII and IX: IBCSG Data Management: R. Hinkle; West Swedish Breast Cancer Study Group, Gteborg, Sweden: C.M. Rudenstam; The Institute of Oncology, Ljubljana, Slovenia: J. Lindtner; The Cancer Council Victoria, Melbourne, Australia: J. Collins; Kantonsspital, St Gallen, Switzerland: H.J. Senn; Inselspital, Bern, Switzerland: M.F. Fey; Groote Schuur Hospital and University of Cape Town, South Africa: E. Murray; Sandton Oncology Center, Johannesburg, South Africa: D. Vorobiof; University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia: M.H.N. Tattersall; Madrid Breast Cancer Group, Madrid, Spain: H. Cortes-Funes; Institute of Oncology of Southern Switzerland, Bellinzona, Switzerland: F. Cavalli; Spedali Civili and Fondazione Beretta, Brescia, Italy: G. Marini; General Hospital, Gorizia, Italy: S. Foladore; European Institute of Oncology, Milano, Italy: A. Goldhirsch; Ospedale Infermi, Rimini, Italy: A. Ravaioli; Ospedale S. Eugenio, Roma, Italy: M. Antimi; Ospedale S. Bortolo, Vicenza, Italy: M. Magazu; University of Düsseldorf, Germany: HG Schnürch; Sir Charles Gairdner Hospital, Nedlands, W Australia: M. Byrne; University Hospital of Zürich, Zürich, Switzerland: C. Sauter; Kantonsspital, Basel, Switzerland: R. Herrmann; Auckland Breast Cancer Study Group, Auckland, New Zealand: R.G. Kay; Centro di Riferimento Oncologico, Aviano, Italy: A. Veronesi; Hpital Cantonal, Geneva, Switzerland: P. Alberto; Centre Hpitalier Universitaire, Lausanne, Switzerland: S. Leyvraz; Hpital des Cadolles, Neuchtel, Switzerland: P. Siegenthaler; University of Newcastle, Newcastle, Australia: J. Forbes.
NOTES
Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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