Size of Breast Cancer Metastases in Axillary Lymph Nodes: Clinical Relevance of Minimal Lymph Node Involvement
http://www.100md.com
《临床肿瘤学》
the Division of Medical Oncology, Department of Medicine, Unit of Quality Control, Division of Epidemiology and Biostatistics, Division of Pathology, and Division of Senology, European Institute of Oncology
University of Milan School of Medicine, Milan, Italy
ABSTRACT
PATIENTS AND METHODS: We evaluated biologic features, adjuvant treatment recommendations, and prognosis for 1,959 consecutive patients with pT1-3, pN0, minimal lymph node involvement (pN1mi or pN0i+), or pN1a (single positive node) and M0, who were operated on and counseled for medical therapy from April 1997 to December 2000.
RESULTS: Patients with pN1a and pN1mi/pN0i+, when compared with patients with pN0 disease, were more often prescribed anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively; P < .0001) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001). At the multivariate analysis, a statistically significant difference in disease-free survival (DFS) and in the risk of distant metastases was observed for patients with pN1a versus pN0 disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases) and for patients with pN1mi/pN0i+ versus pN0 disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases).
CONCLUSION: Even minimal involvement of a single axillary node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Further studies are required before widespread modification of clinical practice.
INTRODUCTION
A series of guidelines and recommendations for selection of adjuvant systemic treatments was recently proposed at the 8th International Conference on Adjuvant Therapy of Primary Breast Cancer.8 Treatment guidelines for patients with node-negative disease differ substantially from treatment guidelines indicated for patients with node-positive disease. For patients with minimal axillary node involvement, treatment choice follows an algorithm similar to that for node-positive disease. The uncertainty on estimation of risk for patients with micrometastatic disease in axillary nodes is often reflected on intensity of cytotoxic treatments, when the choice of endocrine therapies as the only adjuvant option is questionable (eg, low estrogen receptor [ER] and progesterone receptor [PgR] expression, overexpression of HER2/neu, and so on).
The aim of this retrospective study was to evaluate, in a large series of patients who had a homogeneous diagnostic and therapeutic environment for surgery, histopathology, and treatment assignment, the distribution of biologic features and adjuvant treatment recommendations, taking into account even the smallest metastatic involvement of axillary nodes. We also investigated the prognostic role of the size of axillary lymph node metastases.
PATIENTS AND METHODS
The nodal status was determined according to the revised tumor-node-metastasis (TNM) staging system for breast cancer, as presented in the sixth edition of the American Joint Committee on Cancer Cancer Staging Manual.13 In particular, if no regional lymph node metastasis were detected, the tumor was classified as pN0. In cases of only isolated tumor cells, defined as a single tumor cell or small clusters of cells not more than 0.2 mm in greatest dimension detected by immunohistochemistry or hematoxylin and eosin stains, the tumor was classified as pN0i+. In case of micrometastasis (larger than 0.2 mm, but none larger than 2 mm in greatest dimension), the tumor was classified as pN1mi. If nodal metastases larger than 2 mm were diagnosed, the tumor was classified as pN1a.
Data were entered by surgeons into a user-friendly database (designed with Microsoft Access; Microsoft, Redmond, WA) once weekly on a mean number of 25 patients per week and checked by a data manager. The database was then used for an interdisciplinary discussion (among surgeons, medical and radiation oncologists, and pathologists), resulting in a proposal of an adjuvant treatment program. Typically, a medical oncologist (and a radiation oncologist, if applicable) discussed the proposed treatment with the patient and verified the accuracy of the items entered into the database (internal quality control).
Statistical Analysis
The Mantel-Haenszel {chi}2 test for trend was used to assess the association between ordinal variables. The primary end points were DFS and OS. DFS was defined as the length of time from the date of surgery to any relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer), or death, whichever occurred first. OS was defined as the time from surgery until the date of death (from any cause) or the date of last follow-up. Secondary end points were distant metastasis, locoregional relapse, and contralateral breast cancer. We estimated the cumulative incidence of locoregional relapse (defined as confined to the ipsilateral breast, chest wall including mastectomy scars, ipsilateral axillary, supraclavicular, and internal mammary lymph nodes) and contralateral breast cancer because this could be associated with the degree of nodal involvement and with risk factors related with nodal involvement (eg, PVI and high grade), as previously published by others.14,15 Plots of the survival according to nodal status and dimension of the micrometastasis were drawn using the Kaplan-Meier method. The log-rank test was used to assess the survival difference between strata. Multivariate Cox proportional hazards regression was used to assess the independent prognostic significance of various clinical and histopathologic characteristics of the tumor on survival. Factors included in multiple regression analyses included degree of nodal involvement, tumor size, and tumor grade, ER and PgR expression, Ki 67 expression, HER2/neu overexpression, PVI, concomitant intraductal carcinoma extension, histotype, type of surgery, and method used in the staging of the axilla. In multivariate analysis, only variables that retained statistical significance were included in the final model. All analyses were performed with the SAS software (SAS Institute, Cary, NC). All tests were two sided.
Treatment Received
All patients received adequate local treatment (breast conserving surgery or total mastectomy) plus SNB or complete axillary dissection. Patients with primary breast cancer were assigned to SNB in case of cytologic or histologically verified breast carcinoma of 3 cm or less in size (measured clinically and/or by imaging techniques) and clinically uninvolved axillary lymph nodes. SNB was followed by axillary dissection if the sentinel lymph node contained metastasis or minimal node involvement. The sentinel lymph node was identified and isolated using a gamma probe as a guide, as previously published.16
Postoperative breast irradiation was proposed to all the patients who received breast-conserving surgery, excluding only those elderly patients for whom radiation was considered inappropriate.17 Systemic adjuvant therapy was recommended according to the St Gallen's treatment guidelines.18,19 In particular, the selection of adjuvant systemic treatment was based on indicators of responsiveness to treatment (endocrine responsiveness of the tumor) and indicators of risk. For patients with node-negative and endocrine-responsive disease, adjuvant endocrine therapy alone, according to menopausal status, was indicated (tamoxifen for a duration of 5 years in postmenopausal patients and the combination of tamoxifen for 5 years plus gonadotropin-releasing hormone analogs for at least 2 years in premenopausal patients).18 In patients with higher risk disease (eg, PVI and pN1a disease) and/or indicators of limited endocrine responsiveness, chemotherapy was added to the endocrine treatment program. Anthracycline-containing chemotherapy was considered as the first option in patients with higher risk disease (eg, doxorubicin and cyclophosphamide for four courses)20; in case of comorbidities, patients' preferences, and limited risk (eg, pN0-1mi disease), oral cyclophosphamide, methotrexate, and fluorouracil (CMF) for a duration of three to six courses was considered.21 In case of endocrine nonresponsive disease, 6 months of chemotherapy was indicated. The regimens used were classical CMF for six courses in node-negative disease and doxorubicin and cyclophosphamide for four courses followed by classical CMF for three courses20 or intensive cyclophosphamide, epirubicin, and fluorouracil for six courses22 in node-positive disease, according to the degree of the patient risk.
RESULTS
Patient characteristics are listed in Tables 1 and 2. A total of 1,400 patients were classified as pN0 (or pN sentinel negative), 232 were classified as pN0i+ or pN1mi, and 327 were classified as pN1a, according to the sixth edition of the American Joint Committee on Cancer Cancer Staging Manual.13 In the pN1a and pN0i+/pN1mi groups, when compared with the pN0 patients, there were higher percentages of tumors classified as PgR absent (28.2% v 22.3% v 32.0%, respectively; P = .042), with a Ki-67 labeling index of more than 20% of the cells (59.4% v 44.1% v 48.4%, respectively; P = .003), and with PVI (36.1% v 36.0% v 15.0%, respectively; P < .0001). Tumors in the pN0i+/pN1mi and pN1a groups were also of higher grade (P = .015) and were larger (P < .0001) than tumors in the pN0 group (Table 1). Of all the clinicopathologic variables considered, only age was associated with the size of the minimal lymph node involvement (P = .028; Table 2).
Treatment
Three hundred twenty patients (16.3%) had a total mastectomy as the primary treatment, and only six of them had SNB (all negative for metastasis). Of the 1,639 remaining patients, 792 had quadrantectomy with axillary clearance, whereas SNB was performed in 847 patients. In 343 of these patients, a sentinel node was positive, and completion with axillary dissection was then performed.
Patients with pN1a disease, compared with patients with minimal lymph node involvement and node-negative disease, had a larger chance of receiving anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001).
In endocrine unresponsive disease, anthracycline-containing chemotherapy was indicated in 22 patients (8.7%) with pN0 disease compared with three patients (15.8%) and 22 patients (38.6%) with pN0i+/pN1mi and pN1a disease, respectively (P < .001; Table 3). Moreover, chemoendocrine therapy was indicated in 44.5% of patients with pN0 disease compared with 78.6% and 98.1% of patients with pN0i+/pN1mi and pN1a disease, respectively (P < .001).
Events
The median follow-up was 49.9 months (range, 0.2 to 81.4 months). The types of relapse according to size of nodal involvement, with particular reference to the size of minimal lymph node involvement, and the event rates (defined as the incidence rate per 1,000 women per year) are listed in Table 4. Figure 1 shows plots of the cumulative incidence of contralateral breast cancer, locoregional recurrence, and metastasis drawn using the Kaplan-Meier methods and stratified according to nodal status and to the size of the minimal lymph node involvement. Four-year DFS rates for patients with node-negative disease, minimal lymph node involvement, and macrometastasis were 93.0%, 89.2%, and 84.5%, respectively (log-rank, P < .0001). Four-year OS rates for patients with node-negative disease, minimal lymph node involvement, and macrometastasis were 98.0%, 99.6%, and 94.1%, respectively (log-rank, P = .0007). The Kaplan-Meier curves for DFS and OS are displayed in Figure 2.
Multivariate Analysis
After univariate analysis (Table 5), we investigated the independent association between nodal status, biologic features, and probability of relapse using the Cox proportional hazards regression analysis (Table 6). A statistically significant difference in DFS, risk of distant metastases, and OS was observed at the multivariate analysis for patients with macrometastatic disease versus patients with node-negative disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases; HR = 2.41; 95% CI, 1.38 to 4.21; P = .002 for OS). A statistically significant difference in DFS and risk of distant metastases was observed also for patients with minimal lymph node involvement versus patients with node-negative disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases). Minimal lymph node involvement was associated with poorer DFS independently of whether it was detected in sentinel node or after complete axillary dissection (P = .32 for interaction).
In the multivariate analysis, size of tumor greater than 2 cm was significantly associated with increased risk of distant metastasis (HR = 2.88, P = .01) and poorer DFS (HR = 2.67, P = .0002) and OS (HR = 5.70, P = .01). Similarly, the absence of ER and PgR expression significantly correlated with increased risk of distant metastasis (HR = 1.99, P = .01) and poorer DFS (HR = 1.64, P = .009) and OS (HR = 4.15, P < .001). High Ki-67 expression (> 20%) was found to be associated with increased risk of locoregional relapse (HR = 1.86, P = .047), contralateral breast cancer (HR = 5.32, P = .008), and poorer DFS (HR = 1.61, P = .005). PVI was associated with increased risk of locoregional relapse (HR = 1.92, P = .040), and grade 3 tumor was associated with increased risk of distant metastases (HR = 3.34, P = .01; Table 6).
DISCUSSION
This study provides useful insights into the treatment and prognosis of breast cancer because it is based on a large number of patients who were collected in a relatively short time, thus allowing adoption of modern procedures. The pathologists, surgeons, and medical oncologists used consistent approaches during the years of reference. The adjuvant treatment proposed was largely based on the degree of nodal involvement as well as on known prognostic features according to the recent St Gallen Consensus Conferences Guidelines.18,19 As displayed in Table 2, patients without nodal involvement or with minimal involvement received significantly less chemotherapy in general and less anthracycline-containing chemotherapy in particular, when compared with patients with macrometastases in axillary nodes. For patients with endocrine-responsive disease and especially for patients with node-negative disease, significantly less chemotherapy was prescribed within the adjuvant program.
As reported in Table 1, the size of nodal involvement was significantly correlated with other prognostic features, such as presence of vascular invasion, high grade, and large tumor size. Others have already reported the correlation of degree of nodal involvement with other unfavorable prognostic factors. In particular, a significant correlation between micrometastases and large tumor size or presence of vascular invasion was reported.6
The finding that the size of nodal involvement is an important prognostic factor that is significantly associated with increased risk of metastases, DFS, and OS when compared with node-negative disease was observed in a population subjected to an adjuvant therapy program that might have interfered with the outcome. An HR of 1.94 for distant metastases was detected for the presence of minimal lymph node involvement, and an HR of 2.32 was detected for the presence of macrometastases in one lymph node. DFS was significantly worse for both patients with macrometastatic disease (HR = 2.04) and minimal lymph node involvement (HR = 1.58) versus patients with node-negative disease, whereas a statistically significant difference in OS was observed at the multivariate analysis for patients with macrometastatic disease versus patients with node-negative disease (HR = 2.41). In the multivariate analysis, other known prognostic factors were found to be significantly associated with the outcome of the patients. As shown in Table 6, tumor size and lack of steroid hormone receptors significantly correlated with DFS, risk of distant metastasis, and OS. Moreover, high tumor grade was found to significantly correlate with increased risk of distant metastases. All these factors should be properly taken into account in the treatment decision-making procedure. Further investigations are still needed on the role of Ki-67 index as a prognostic factor because it is not commonly accepted as a relevant feature for such a purpose.8
Other authors30 have found, based on a study of 696 patients followed for a short period of time, a comparable DFS for patients with node-negative disease and patients with micrometastases detected with SNB either using hematoxylin and eosin staining or aided by immunohistochemistry. However, one might explain the difference between the two observations with the limited sample size and the short follow-up. In the present study, minimal lymph node involvement was associated with poorer DFS, independently of whether it was detected in sentinel node or after complete axillary dissection (P = .32 for interaction).
Previous studies suggested that the cutoff close to 1 mm might have a clinical relevance in breast cancer. It was recently demonstrated that tumors in patients with sentinel lymph node micrometastases measuring more than 1 mm in greatest dimension were more likely to colonize in nonsentinel axillary lymph nodes.31 Moreover, Fisher et al 32 reported a poorer prognosis for patients with axillary lymph node micrometastases measuring more than 1.3 mm compared with patients with smaller micrometastatic size. As shown in Figure 1, although we observed a trend to a higher rate of distant metastases for axillary micrometastases when compared with isolated tumor cells, the difference was not statistically significant, and further studies are needed to clarify the role of size in micrometastases.
Literature data indicated that patients with synchronous or metachronous bilateral breast carcinoma are more likely to have node-positive disease at initial diagnosis compared with patients with unilateral breast carcinoma.14 A number of factors have been suggested as major contributors to the incidence of contralateral breast carcinoma, including a possible secondary metastatic spread of cancer cells to the opposite breast.15 In the present study, however, the presence of macrometastatic nodal involvement was associated only with a nonstatistically significant increased risk of contralateral breast cancer. Moreover, although it was demonstrated that the number of lymph node metastases and risk factors for nodal involvement (eg, PVI and high grade) might be associated with subsequent locoregional relapse,33 no clear correlation between the degree of nodal involvement in one lymph node and locoregional relapse was detected in the present study.
The efficacy of adjuvant systemic therapy for early breast cancer depends on various variables, which include features of the tumor, the patient, and the treatment itself. We demonstrated that even minimal involvement of a single axillary lymph node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Despite the statistically significant detrimental prognostic effect associated with minimal lymph node involvement, the potential for bias still exists because of the retrospective nature of the evaluation. Further studies using database analyses or prospective trials are required to confirm the prognostic value of minimal involvement of a single axillary lymph node in breast cancer. If confirmed, the presence of micrometastases in axillary nodes should be added to the list of features that must be taken into account while making a proper treatment choice.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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2. Saez RA, McGuire WL, Clark CM: Prognostic factors in breast cancer. Semin Surg Oncol 5:102-110, 1989
3. The 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 320:461-496, 1989
4. Saphir O, Amromin GD: Obscure axillary lymph-node metastases in carcinoma of the breast. Cancer 1:238-241, 1948
5. Hainsworth PJ, Tjandra JJ, Stillwell RG, et al: Detection and significance of occult metastases in node-negative breast cancer. Br J Surg 80:459-463, 1993
6. International (Ludwig) Breast Cancer Study Group: Prognostic importance of occult axillary lymph node micrometastases from breast cancer. Lancet 335:1565-1568, 1990
7. Cote RJ, Peterson HF, Chaiwun B, et al: Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. Lancet 354:896-900, 1999
8. 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
9. Veronesi U, Paganelli G, Galimberti V, et al: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 349:1864-1867, 1997
10. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer: I. The value of histological grade in breast cancer—Experience from a large study with long-term follow-up. Histopathology 41:151, 2002
11. Rosen PP, Oberman H: Tumors of the Mammary Gland. Washington, DC, Armed Forces Institute of Pathology, 1993
12. Colleoni M, Orvieto E, Nolè F, et al: Prediction of response to primary chemotherapy for operable breast cancer. Eur J Cancer 35:574-579, 1999
13. Singletary SE, Allred C, Ashley P, et al: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20:3628-3636, 2002
14. Heron DE, Komarnicky LT, Hyslop T, et al: Bilateral breast carcinoma risk factors and outcomes for patients with synchronous and metachronous disease. Cancer 88:2739-2750, 2000
15. Tulusan AH, Ronay G, Egger H, et al: A contribution to the natural history of breast cancer: V. Bilateral primary breast cancer—Incidence, risks and diagnosis of simultaneous primary cancer in the opposite breast. Arch Gynecol 237:85-91, 1985
16. Veronesi U, Paganelli G, Viale G, et al: A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 349:546-553, 2003
17. Gennari R, Curigliano G, Rotmensz, et al: Breast carcinoma in elderly women: Features of disease presentation, choice of local and systemic treatments compared with younger postmenopausal patients. Cancer 101:1302-1310, 2004
18. Goldhirsch A, Wood WC, Senn HJ, et al: Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 87:1441-1445, 1995
19. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 90:1601-1608, 1998
20. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990
21. Colleoni M, Litman HJ, Castiglione-Gertsch M, et al: Duration of adjuvant chemotherapy for breast cancer: A joint analysis of two randomised trials investigating three versus six courses of CMF. Br J Cancer 86:1705-1714, 2002
22. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16:2651-2658, 1998
23. Carlson RW: Clinical implications of lymph node and bone marrow micrometastasis in breast cancer, in Perry MC (ed): 2003 ASCO Educational Book. Alexandria, VA, American Society of Clinical Oncology, 2003, pp 5561-5565
24. Allred DC, Elledge RM: Caution concerning micrometastatic breast carcinoma in sentinel lymph nodes. Cancer 86:905-907, 1999
25. Page DL, Anderson TJ, Carter BA: Minimal solid tumor involvement of regional and distant sites: When is a metastasis not a metastasis Cancer 86:2589-2592, 1999
26. Sedmak DD, Meineke TA, Knechtges DS, et al: Prognostic significance of cytokeratin-positive breast cancer metastases. Mod Pathol 2:516-520, 1989
27. Trojani M, de Mascarel I, Bonichon F, et al: Micrometastases to axillary lymph nodes for carcinoma of breast: Detection by immunohistochemistry and prognostic significance. Br J Cancer 55:303-306, 1987
28. Redding WH, Coombes RC, Monaghan P, et al: Detection of micrometastases in patients with primary breast cancer. Lancet 2:1271-1274, 1983
29. Dearnaley DP, Ormerod MG, Sloane JP: Micrometastases in breast cancer: Long-term follow-up of the first patient cohort. Eur J Cancer 27:236-239, 1991
30. Hansen MN, Grube BJ, Te W: Clinical significance of axillary micrometastases in breast cancer: How small is too small Proc Am Soc Clin Oncol 20:24, 2001 (abstr 91)
31. Viale G, Maiorano E, Mazzarol G, et al: Histologic detection and clinical implications of micrometastases in axillary sentinel lymph nodes for patients with breast carcinoma. Cancer 92:1378-1384, 2001
32. Fisher ER, Palekar A, Rockette H, et al: Pathologic findings from the National Surgical Adjuvant Breast Project (protocol no. 4). Cancer 42:2032-2038, 1978
33. Wallgren A, Bonetti M, Gelber RD, et al: International Breast Cancer Study Group Trials I through VII: 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(Marco Colleoni, Nicole Ro)
University of Milan School of Medicine, Milan, Italy
ABSTRACT
PATIENTS AND METHODS: We evaluated biologic features, adjuvant treatment recommendations, and prognosis for 1,959 consecutive patients with pT1-3, pN0, minimal lymph node involvement (pN1mi or pN0i+), or pN1a (single positive node) and M0, who were operated on and counseled for medical therapy from April 1997 to December 2000.
RESULTS: Patients with pN1a and pN1mi/pN0i+, when compared with patients with pN0 disease, were more often prescribed anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively; P < .0001) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001). At the multivariate analysis, a statistically significant difference in disease-free survival (DFS) and in the risk of distant metastases was observed for patients with pN1a versus pN0 disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases) and for patients with pN1mi/pN0i+ versus pN0 disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases).
CONCLUSION: Even minimal involvement of a single axillary node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Further studies are required before widespread modification of clinical practice.
INTRODUCTION
A series of guidelines and recommendations for selection of adjuvant systemic treatments was recently proposed at the 8th International Conference on Adjuvant Therapy of Primary Breast Cancer.8 Treatment guidelines for patients with node-negative disease differ substantially from treatment guidelines indicated for patients with node-positive disease. For patients with minimal axillary node involvement, treatment choice follows an algorithm similar to that for node-positive disease. The uncertainty on estimation of risk for patients with micrometastatic disease in axillary nodes is often reflected on intensity of cytotoxic treatments, when the choice of endocrine therapies as the only adjuvant option is questionable (eg, low estrogen receptor [ER] and progesterone receptor [PgR] expression, overexpression of HER2/neu, and so on).
The aim of this retrospective study was to evaluate, in a large series of patients who had a homogeneous diagnostic and therapeutic environment for surgery, histopathology, and treatment assignment, the distribution of biologic features and adjuvant treatment recommendations, taking into account even the smallest metastatic involvement of axillary nodes. We also investigated the prognostic role of the size of axillary lymph node metastases.
PATIENTS AND METHODS
The nodal status was determined according to the revised tumor-node-metastasis (TNM) staging system for breast cancer, as presented in the sixth edition of the American Joint Committee on Cancer Cancer Staging Manual.13 In particular, if no regional lymph node metastasis were detected, the tumor was classified as pN0. In cases of only isolated tumor cells, defined as a single tumor cell or small clusters of cells not more than 0.2 mm in greatest dimension detected by immunohistochemistry or hematoxylin and eosin stains, the tumor was classified as pN0i+. In case of micrometastasis (larger than 0.2 mm, but none larger than 2 mm in greatest dimension), the tumor was classified as pN1mi. If nodal metastases larger than 2 mm were diagnosed, the tumor was classified as pN1a.
Data were entered by surgeons into a user-friendly database (designed with Microsoft Access; Microsoft, Redmond, WA) once weekly on a mean number of 25 patients per week and checked by a data manager. The database was then used for an interdisciplinary discussion (among surgeons, medical and radiation oncologists, and pathologists), resulting in a proposal of an adjuvant treatment program. Typically, a medical oncologist (and a radiation oncologist, if applicable) discussed the proposed treatment with the patient and verified the accuracy of the items entered into the database (internal quality control).
Statistical Analysis
The Mantel-Haenszel {chi}2 test for trend was used to assess the association between ordinal variables. The primary end points were DFS and OS. DFS was defined as the length of time from the date of surgery to any relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer), or death, whichever occurred first. OS was defined as the time from surgery until the date of death (from any cause) or the date of last follow-up. Secondary end points were distant metastasis, locoregional relapse, and contralateral breast cancer. We estimated the cumulative incidence of locoregional relapse (defined as confined to the ipsilateral breast, chest wall including mastectomy scars, ipsilateral axillary, supraclavicular, and internal mammary lymph nodes) and contralateral breast cancer because this could be associated with the degree of nodal involvement and with risk factors related with nodal involvement (eg, PVI and high grade), as previously published by others.14,15 Plots of the survival according to nodal status and dimension of the micrometastasis were drawn using the Kaplan-Meier method. The log-rank test was used to assess the survival difference between strata. Multivariate Cox proportional hazards regression was used to assess the independent prognostic significance of various clinical and histopathologic characteristics of the tumor on survival. Factors included in multiple regression analyses included degree of nodal involvement, tumor size, and tumor grade, ER and PgR expression, Ki 67 expression, HER2/neu overexpression, PVI, concomitant intraductal carcinoma extension, histotype, type of surgery, and method used in the staging of the axilla. In multivariate analysis, only variables that retained statistical significance were included in the final model. All analyses were performed with the SAS software (SAS Institute, Cary, NC). All tests were two sided.
Treatment Received
All patients received adequate local treatment (breast conserving surgery or total mastectomy) plus SNB or complete axillary dissection. Patients with primary breast cancer were assigned to SNB in case of cytologic or histologically verified breast carcinoma of 3 cm or less in size (measured clinically and/or by imaging techniques) and clinically uninvolved axillary lymph nodes. SNB was followed by axillary dissection if the sentinel lymph node contained metastasis or minimal node involvement. The sentinel lymph node was identified and isolated using a gamma probe as a guide, as previously published.16
Postoperative breast irradiation was proposed to all the patients who received breast-conserving surgery, excluding only those elderly patients for whom radiation was considered inappropriate.17 Systemic adjuvant therapy was recommended according to the St Gallen's treatment guidelines.18,19 In particular, the selection of adjuvant systemic treatment was based on indicators of responsiveness to treatment (endocrine responsiveness of the tumor) and indicators of risk. For patients with node-negative and endocrine-responsive disease, adjuvant endocrine therapy alone, according to menopausal status, was indicated (tamoxifen for a duration of 5 years in postmenopausal patients and the combination of tamoxifen for 5 years plus gonadotropin-releasing hormone analogs for at least 2 years in premenopausal patients).18 In patients with higher risk disease (eg, PVI and pN1a disease) and/or indicators of limited endocrine responsiveness, chemotherapy was added to the endocrine treatment program. Anthracycline-containing chemotherapy was considered as the first option in patients with higher risk disease (eg, doxorubicin and cyclophosphamide for four courses)20; in case of comorbidities, patients' preferences, and limited risk (eg, pN0-1mi disease), oral cyclophosphamide, methotrexate, and fluorouracil (CMF) for a duration of three to six courses was considered.21 In case of endocrine nonresponsive disease, 6 months of chemotherapy was indicated. The regimens used were classical CMF for six courses in node-negative disease and doxorubicin and cyclophosphamide for four courses followed by classical CMF for three courses20 or intensive cyclophosphamide, epirubicin, and fluorouracil for six courses22 in node-positive disease, according to the degree of the patient risk.
RESULTS
Patient characteristics are listed in Tables 1 and 2. A total of 1,400 patients were classified as pN0 (or pN sentinel negative), 232 were classified as pN0i+ or pN1mi, and 327 were classified as pN1a, according to the sixth edition of the American Joint Committee on Cancer Cancer Staging Manual.13 In the pN1a and pN0i+/pN1mi groups, when compared with the pN0 patients, there were higher percentages of tumors classified as PgR absent (28.2% v 22.3% v 32.0%, respectively; P = .042), with a Ki-67 labeling index of more than 20% of the cells (59.4% v 44.1% v 48.4%, respectively; P = .003), and with PVI (36.1% v 36.0% v 15.0%, respectively; P < .0001). Tumors in the pN0i+/pN1mi and pN1a groups were also of higher grade (P = .015) and were larger (P < .0001) than tumors in the pN0 group (Table 1). Of all the clinicopathologic variables considered, only age was associated with the size of the minimal lymph node involvement (P = .028; Table 2).
Treatment
Three hundred twenty patients (16.3%) had a total mastectomy as the primary treatment, and only six of them had SNB (all negative for metastasis). Of the 1,639 remaining patients, 792 had quadrantectomy with axillary clearance, whereas SNB was performed in 847 patients. In 343 of these patients, a sentinel node was positive, and completion with axillary dissection was then performed.
Patients with pN1a disease, compared with patients with minimal lymph node involvement and node-negative disease, had a larger chance of receiving anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001).
In endocrine unresponsive disease, anthracycline-containing chemotherapy was indicated in 22 patients (8.7%) with pN0 disease compared with three patients (15.8%) and 22 patients (38.6%) with pN0i+/pN1mi and pN1a disease, respectively (P < .001; Table 3). Moreover, chemoendocrine therapy was indicated in 44.5% of patients with pN0 disease compared with 78.6% and 98.1% of patients with pN0i+/pN1mi and pN1a disease, respectively (P < .001).
Events
The median follow-up was 49.9 months (range, 0.2 to 81.4 months). The types of relapse according to size of nodal involvement, with particular reference to the size of minimal lymph node involvement, and the event rates (defined as the incidence rate per 1,000 women per year) are listed in Table 4. Figure 1 shows plots of the cumulative incidence of contralateral breast cancer, locoregional recurrence, and metastasis drawn using the Kaplan-Meier methods and stratified according to nodal status and to the size of the minimal lymph node involvement. Four-year DFS rates for patients with node-negative disease, minimal lymph node involvement, and macrometastasis were 93.0%, 89.2%, and 84.5%, respectively (log-rank, P < .0001). Four-year OS rates for patients with node-negative disease, minimal lymph node involvement, and macrometastasis were 98.0%, 99.6%, and 94.1%, respectively (log-rank, P = .0007). The Kaplan-Meier curves for DFS and OS are displayed in Figure 2.
Multivariate Analysis
After univariate analysis (Table 5), we investigated the independent association between nodal status, biologic features, and probability of relapse using the Cox proportional hazards regression analysis (Table 6). A statistically significant difference in DFS, risk of distant metastases, and OS was observed at the multivariate analysis for patients with macrometastatic disease versus patients with node-negative disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases; HR = 2.41; 95% CI, 1.38 to 4.21; P = .002 for OS). A statistically significant difference in DFS and risk of distant metastases was observed also for patients with minimal lymph node involvement versus patients with node-negative disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases). Minimal lymph node involvement was associated with poorer DFS independently of whether it was detected in sentinel node or after complete axillary dissection (P = .32 for interaction).
In the multivariate analysis, size of tumor greater than 2 cm was significantly associated with increased risk of distant metastasis (HR = 2.88, P = .01) and poorer DFS (HR = 2.67, P = .0002) and OS (HR = 5.70, P = .01). Similarly, the absence of ER and PgR expression significantly correlated with increased risk of distant metastasis (HR = 1.99, P = .01) and poorer DFS (HR = 1.64, P = .009) and OS (HR = 4.15, P < .001). High Ki-67 expression (> 20%) was found to be associated with increased risk of locoregional relapse (HR = 1.86, P = .047), contralateral breast cancer (HR = 5.32, P = .008), and poorer DFS (HR = 1.61, P = .005). PVI was associated with increased risk of locoregional relapse (HR = 1.92, P = .040), and grade 3 tumor was associated with increased risk of distant metastases (HR = 3.34, P = .01; Table 6).
DISCUSSION
This study provides useful insights into the treatment and prognosis of breast cancer because it is based on a large number of patients who were collected in a relatively short time, thus allowing adoption of modern procedures. The pathologists, surgeons, and medical oncologists used consistent approaches during the years of reference. The adjuvant treatment proposed was largely based on the degree of nodal involvement as well as on known prognostic features according to the recent St Gallen Consensus Conferences Guidelines.18,19 As displayed in Table 2, patients without nodal involvement or with minimal involvement received significantly less chemotherapy in general and less anthracycline-containing chemotherapy in particular, when compared with patients with macrometastases in axillary nodes. For patients with endocrine-responsive disease and especially for patients with node-negative disease, significantly less chemotherapy was prescribed within the adjuvant program.
As reported in Table 1, the size of nodal involvement was significantly correlated with other prognostic features, such as presence of vascular invasion, high grade, and large tumor size. Others have already reported the correlation of degree of nodal involvement with other unfavorable prognostic factors. In particular, a significant correlation between micrometastases and large tumor size or presence of vascular invasion was reported.6
The finding that the size of nodal involvement is an important prognostic factor that is significantly associated with increased risk of metastases, DFS, and OS when compared with node-negative disease was observed in a population subjected to an adjuvant therapy program that might have interfered with the outcome. An HR of 1.94 for distant metastases was detected for the presence of minimal lymph node involvement, and an HR of 2.32 was detected for the presence of macrometastases in one lymph node. DFS was significantly worse for both patients with macrometastatic disease (HR = 2.04) and minimal lymph node involvement (HR = 1.58) versus patients with node-negative disease, whereas a statistically significant difference in OS was observed at the multivariate analysis for patients with macrometastatic disease versus patients with node-negative disease (HR = 2.41). In the multivariate analysis, other known prognostic factors were found to be significantly associated with the outcome of the patients. As shown in Table 6, tumor size and lack of steroid hormone receptors significantly correlated with DFS, risk of distant metastasis, and OS. Moreover, high tumor grade was found to significantly correlate with increased risk of distant metastases. All these factors should be properly taken into account in the treatment decision-making procedure. Further investigations are still needed on the role of Ki-67 index as a prognostic factor because it is not commonly accepted as a relevant feature for such a purpose.8
Other authors30 have found, based on a study of 696 patients followed for a short period of time, a comparable DFS for patients with node-negative disease and patients with micrometastases detected with SNB either using hematoxylin and eosin staining or aided by immunohistochemistry. However, one might explain the difference between the two observations with the limited sample size and the short follow-up. In the present study, minimal lymph node involvement was associated with poorer DFS, independently of whether it was detected in sentinel node or after complete axillary dissection (P = .32 for interaction).
Previous studies suggested that the cutoff close to 1 mm might have a clinical relevance in breast cancer. It was recently demonstrated that tumors in patients with sentinel lymph node micrometastases measuring more than 1 mm in greatest dimension were more likely to colonize in nonsentinel axillary lymph nodes.31 Moreover, Fisher et al 32 reported a poorer prognosis for patients with axillary lymph node micrometastases measuring more than 1.3 mm compared with patients with smaller micrometastatic size. As shown in Figure 1, although we observed a trend to a higher rate of distant metastases for axillary micrometastases when compared with isolated tumor cells, the difference was not statistically significant, and further studies are needed to clarify the role of size in micrometastases.
Literature data indicated that patients with synchronous or metachronous bilateral breast carcinoma are more likely to have node-positive disease at initial diagnosis compared with patients with unilateral breast carcinoma.14 A number of factors have been suggested as major contributors to the incidence of contralateral breast carcinoma, including a possible secondary metastatic spread of cancer cells to the opposite breast.15 In the present study, however, the presence of macrometastatic nodal involvement was associated only with a nonstatistically significant increased risk of contralateral breast cancer. Moreover, although it was demonstrated that the number of lymph node metastases and risk factors for nodal involvement (eg, PVI and high grade) might be associated with subsequent locoregional relapse,33 no clear correlation between the degree of nodal involvement in one lymph node and locoregional relapse was detected in the present study.
The efficacy of adjuvant systemic therapy for early breast cancer depends on various variables, which include features of the tumor, the patient, and the treatment itself. We demonstrated that even minimal involvement of a single axillary lymph node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Despite the statistically significant detrimental prognostic effect associated with minimal lymph node involvement, the potential for bias still exists because of the retrospective nature of the evaluation. Further studies using database analyses or prospective trials are required to confirm the prognostic value of minimal involvement of a single axillary lymph node in breast cancer. If confirmed, the presence of micrometastases in axillary nodes should be added to the list of features that must be taken into account while making a proper treatment choice.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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