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Size of Breast Cancer Metastases in Axillary Lymph Nodes: Clinical Relevance of Minimal Lymph Node Involvement

From 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; and University of Milan School of Medicine, Milan, Italy

Address reprint requests to Marco Colleoni, MD, Division of Medical Oncology, Department of Medicine, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy; e-mail: marco.colleoni{at}ieo.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
BACKGROUND: Overt ipsilateral axillary lymph node metastases of breast cancer are the most significant prognostic indicators for women who have undergone surgery, yet the clinical relevance of minimal involvement (isolated tumor cells and micrometastases) of these nodes is uncertain.

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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The most relevant feature for baseline prognosis determination in patients with operable breast cancer is the degree of ipsilateral lymph node involvement. Increasing numbers of involved axillary lymph nodes are associated with an increased probability of recurrence and mortality.^1-3 Early studies performed in small cohorts of patients and using heterogeneous methodologies also indicated that the size of axillary metastases might carry prognostic relevance. In fact, the detection of axillary lymph node metastases less than or equal to 2 mm in size was associated with a more favorable prognosis than detection of axillary lymph node metastases larger than 2 mm, with disease-free survival (DFS) and overall survival (OS) being similar to those in patients without lymph node involvement.^4,5 The International Breast Cancer Study Group reassessed the axillary nodal status (negative for metastases by routine histology) of 921 patients (International Breast Cancer Study Group Trial V) after re-evaluation by serial sectioning and staining with hematoxylin and eosin and showed that the presence of micrometastases in patients was associated with an increased chance of relapse when compared with patients found to have no micrometastases on reassessment.⁶ Similar results in terms of worse DFS and OS were reported when the analysis was conducted with immunohistochemistry, although the results were statistically significant only in postmenopausal patients.⁷ In general, current information on the prognostic value of nodal involvement is largely dependent on older retrospective series that have been collected during several years. Surgical and staging procedures, as well as techniques recently developed to enhance detection of minimal axillary lymph node involvement (eg, sentinel lymph node biopsy [SNB]), underwent a substantial change in recent years, leading to the need of reconsidering the relevance of new findings from axillary lymph node assessment.

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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
We collected information on all consecutive breast cancer patients operated on at the European Institute of Oncology in Milan between April 1997 and December 2000. Data on the patient's medical history, concurrent diseases, surgery, pathologic evaluation, and results of staging procedures (blood chemistry, hematologic values, bone scan, chest film, and upper abdominal ultrasound examination) were compiled. Pathologic assessment included evaluation of the primary tumor size, grade, and histologic type and of lymph node status after axillary lymph node dissection or an SNB.⁹ Tumor grade was evaluated according to Elston and Ellis,¹⁰ and peritumoral vascular invasion (PVI) was assessed according to Rosen and Oberman.¹¹ ER and PgR status, Ki-67 labeling index determined with the MIB1 monoclonal antibody, and HER2/neu overexpression were evaluated immunocytochemically as previously reported.¹² In particular, HER2/neu overexpression was evaluated using a 1:100 dilution of a polyclonal antiserum (Dako, Glostrup, Denmark) and considering only moderate to strong complete membrane staining of at least 10% neoplastic cells as evidence of overexpression. For evaluation of ER and PgR status and Ki-67 labeling index, the percentage of cells exhibiting definite nuclear staining in more than at least 2,000 neoplastic cells examined at x400 magnification was recorded. Only nuclear immunoreactivity was evaluated for ER, PgR, and MIB1. The threshold for HER/neu overexpression was 10%, for ER and PgR positivity was 1%, and for MIB1 positivity was 20%, as previously published.¹²

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 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

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A total of 4,060 consecutive patients with breast cancer were referred for interdisciplinary evaluation between April 1997 and December 2000, and their data were included in the database. All patients with node-negative disease, minimal lymph node involvement, and pN1a disease were selected. A total of 2,657 patients were available for the analysis. Lymph node characteristics were as follows: 1,885 patients had node-negative disease, and 772 patients had a single affected lymph node (308 patients with minimal lymph node involvement: pN1mi and pN0i+; and 464 patients with pN1a disease). We subsequently excluded patients who presented with recurrent tumors (n = 38), metastatic disease at presentation (n = 32), neoadjuvant treatment (n = 274), noninvasive breast cancers (n = 72), other previous tumor (n = 119), and bilateral tumors (n = 119). Forty-four (2.2%) of the remaining 2,003 patients were lost of follow-up, allowing the analysis of a total of 1,959 patients.

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).

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).

View larger version (25K): [in this window] [in a new window]   Fig 1. Cumulative incidence of any event, local relapse, and metastasis according to nodal status and dimension of lymph node involvement. Min LN, minimal lymph node.

View larger version (18K): [in this window] [in a new window]   Fig 2. Disease-free and overall survival according to nodal status. Min LN, minimal lymph node.

	DISCUSSION

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Emerging data on the clinical significance of minimal axillary lymph node involvement has prompted the revision to the American Joint Committee on Cancer TNM Manual for the staging of breast cancer pathologic nodal stage.¹³ The current TNM staging manual now divides axillary nodal involvement into isolated tumor cells only (maximum size, 0.2 mm; pN0i+), micrometastasis (from > 0.2 mm to 2 mm; pN1mi), and larger nodal metastases (numerous designations). The size of micrometastatic disease (eg, 1 mm or > 1 mm), however, was not taken into account for staging purposes. Despite the widespread acceptance of the new staging system, the clinical implication of the size of lymph node involvement (whether isolated tumor cells or larger) continues to raise substantial uncertainty and controversy.^23-29

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

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The authors indicated no potential conflicts of interest.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted July 15, 2004; accepted December 3, 2004.

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