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10.1245/ASO.2005.02.013
Annals of Surgical Oncology 12:1061-1065 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Older Age Independently Predicts a Lower Risk of Sentinel Lymph Node Metastasis in Breast Cancer

Jason Caywood, BS1, Richard J. Gray, MD1, Joseph Hentz, MS2 and Barbara A. Pockaj, MD1

1 Department of Surgery, Section of Surgical Oncology, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259
2 Department of Biostatistics, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259

Correspondence: Adress corespondence and reprint requests to: Richard J. Gray, MD; E-mail: gray.richard{at}mayo.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The influence of patient age on the risk of sentinel lymph node (SLN) metastasis in breast cancer has not been defined.

Methods: A breast cancer SLN database was analyzed. Factors associated with SLN metastasis were assessed by multiple logistic regression modeling. Age, T stage, estrogen receptor status, HER-2/neu status, grade, angiolymphatic invasion, lobular histology, tubular/ mucinous histology, and the number of SLNs resected were assessed.

Results: Data were available for 810 patients with invasive breast cancer. SLN metastasis was observed in 22% of the patients. The factors most strongly associated with SLN metastasis were angiolymphatic invasion, T stage, and age. Age ranged from 29 to 95 years. The median age was 66 years. Overall, SLN metastasis was more common in younger patients (≤66 years) than in older patients (>66 years; P < .001). Among patients without angiolymphatic invasion, SLN metastasis was nearly twice as common in the younger patients as in the older patients. The effect of angiolymphatic invasion as a risk for SLN metastasis was much greater in the older age group.

Conclusions: In addition to known risk factors, age independently predicts the risk of SLN metastasis in breast cancer. Angiolymphatic invasion seems to be a more powerful predictor of SLN metastasis in older patients.

Key Words: Breast cancer • Elderly • Sentinel node • Neoplasm metastasis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Forty-nine percent of breast cancer patients are aged ≥65 years.1 This proportion is likely to grow because increasing age is the most important risk factor for breast cancer and because life expectancy continues to increase. Although available clinical trials suggest that breast cancer treatment efficacy is not significantly altered by age,2–4 significant controversy remains regarding what constitutes appropriate care for elderly patients.5 Within the United States, elderly breast cancer patients with localized disease have been shown to be less likely to receive cancer-directed surgery.6 The necessity for and appropriateness of regional lymph node staging in the elderly is one area of controversy.

Increasing age—independent of patient health, preferences, and primary tumor characteristics—has been shown to be strongly associated with decreasing odds of undergoing breast cancer regional staging by means of axillary lymph node dissection (ALND).7 The era of sentinel lymph node (SLN) mapping and biopsy has allowed regional staging of breast cancer patients to be performed with reduced morbidity as compared with ALND,8 but it is unclear whether this has altered the use of regional lymph node staging in elderly patients. In addition to perceptions that regional staging has a lesser influence on the future therapy of elderly patients, it is widely believed that older patients are at a lower risk of regional lymph node metastasis. Although increasing age has been shown to correlate with a reduced risk of SLN metastases in melanoma patients,9 this has not been demonstrated in breast cancer patients. The utility of SLN mapping and biopsy in any patient population is dependent on the prior probability of detecting SLN metastases. We therefore undertook this study to investigate whether, when controlling for the known risk factors for lymph node metastases, older breast cancer patients have a reduced risk of SLN metastasis.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The protocol was approved by the Mayo Clinic Institutional Review Board. We reviewed a prospective breast cancer SLN mapping database at the Mayo Clinic in Scottsdale, AZ. All patients undergoing breast SLN mapping from 1995 to June 2004 are included in the database. Data points analyzed for predicting the risk of SLN metastasis were age, T stage, grade, angiolymphatic invasion, estrogen receptor status, HER-2/neu expression status, lobular histology, tubular/mucinous histology, and the number of SLNs resected.

The methods of SLN mapping and pathologic analysis were reported previously.10 Patients were considered to have SLN metastasis if metastatic disease was detected by hematoxylin and eosin staining regardless of size. Those with "metastases" detected by immunohistochemistry staining only were considered N0.

Factors associated with SLN metastasis were assessed by using multiple logistic regression modeling. We used a forward selection strategy, beginning with the hierarchically well formed interaction of each factor with age. Patients with bilateral disease were included once. The side with SLN metastasis was selected if only one side had SLN metastasis. Otherwise, the side was chosen arbitrarily. For presentation, continuous and ordinal variables were categorized by whether or not the value was above the median value. Likewise, for the analysis of the effect of age, the median age of our group (66 years) was used as the upper limit for the younger age group. The statistical significance of the subgroup comparisons was calculated by using Fisher’s exact test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Data were available for 810 patients with invasive breast carcinoma. The patient ages ranged from 29 to 95 years, and the median age was 66 years. The number of SLNs resected ranged from 1 to 6, with a median of 2. The primary tumor characteristics of the patients are listed in Table 1Go. SLN metastasis was observed in 22% of these patients.


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  		TABLE 1. Characteristics of primary tumors
 
Older patients were less likely than younger patients to have SLN metastases (Fig. 1Go), even though there was a similar distribution of T stages between these age groups (Table 2Go). Grade 1 tumors were less likely to be associated with SLN metastases (13%) than either grade 2 (27% P < .01) or grade 3 (26%; P < .01) tumors. Tumors with mucinous or tubular histology were less likely to be associated with SLN metastasis (6%) than tumors of other histologies (23%; P < .01). Tumors with primary or mixed lobular histology were more likely to be associated with SLN metastases (27%) than tumors without lobular histology (20%; P = .04). The number of SLNs resected, the presence of estrogen receptors, and HER-2/neu overexpression did not predict the risk of SLN metastasis (Table 3Go).


Figure 1
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  		FIG. 1. Sentinel lymph node (SLN) metastasis rate by age range.

 

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  		TABLE 2. Percentage of patients in each T stage by age groupa
 

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  		TABLE 3. Predictors of sentinel lymph node (SLN) metastasis
 
The factors most strongly associated with SLN metastasis were angiolymphatic invasion, T stage, and age. The relationship between SLN metastasis and these three factors is summarized in Table 4Go. SLN metastasis was more common in patients with angiolymphatic invasion than in patients without angiolymphatic invasion (P < .001). Angiolymphatic invasion was more common among younger women (13.7%) than among older women (7.3%; P = .004). SLN metastasis was also more common in patients with a higher T stage (P < .001). Overall, SLN metastasis was more common in younger patients (≤66 years) than in older patients (>66 years; P < .001). The effect of age was strongest in patients without angiolymphatic invasion.


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  		TABLE 4. Rates of sentinel lymph node metastases by age when controlled for other major risk factors
 
Among patients without angiolymphatic invasion, SLN metastasis was nearly twice as common in younger patients compared with older patients. However, in the subgroup of patients with angiolymphatic invasion, SLN metastasis was 15% less common in the younger patients than in the older patients. The sample of patients in the subgroup with angiolymphatic invasion was smaller than in the subgroup without angiolymphatic invasion, and the results are therefore more uncertain.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The lack of inclusion of substantial numbers of older women in clinical breast cancer trials is a major reason for the controversy about what constitutes optimal care for older women with breast cancer. The care of breast cancer patients clearly varies with age: older patients are less likely to receive definitive care for newly diagnosed breast cancer.11–14 One aspect of breast cancer care considered routine for younger patients that is often omitted in the care of older patients is regional lymph node staging.7 Two widely held beliefs that likely influence the reduced use of regional staging in elderly patients are that the results will not influence future therapy decisions and that older patients have more indolent disease and, therefore, a lower risk of metastasis. We (unpublished data) and others15 have shown that SLN staging does influence the systemic therapy recommendations for elderly patients. It has also been demonstrated that when compared stage for stage, there is no evidence that women aged >70 years have more indolent breast cancer.16 Whether age independently influences the risk of breast cancer SLN metastasis, however, has not been well defined.

An understanding of the risk factors for lymph node metastasis in breast cancer patients is essential. During the era of ALND, it has been important to weigh the risk of lymph node metastasis against the morbidity of the procedure necessary to provide regional staging information. The lower morbidity of SLN mapping and biopsy8 has altered the ratio of morbidity risk to metastasis risk, but this ratio is still an important consideration. In addition, the SLN biopsy has introduced the possibility of a false-negative result. To properly judge the posterior probability of lymph node metastasis and, therefore, the risk of a false-negative result, one must understand the risk of metastasis before the results of the procedure are known. This study adds to this understanding.

This study reinforces findings that several well-known factors increase the risk of SLN metastasis: angiolymphatic invasion, increasing tumor size, and higher histological grade all predicted an increased risk of SLN metastasis. It is also well known that patients with mucinous or tubular primary tumors are at lower risk for lymph node metastasis, as was again demonstrated in our patient cohort. We found that lobular histology, either pure lobular carcinomas or tumors with mixed lobular and ductal features, predicted an increased risk of SLN metastasis. Although this risk factor is less well known, lobular histology has been previously demonstrated to confer an increased risk of lymphatic metastasis.17

This study demonstrates that age independently predicts the risk of SLN metastasis in breast cancer. Older patients were 45% less likely to have SLN metastasis than younger patients, and there was a steady decline in the rates of SLN metastasis with increasing age (Fig. 1Go). The rates of SLN metastasis ranged from 42% in patients aged 29 to 39 years to 0% in patients aged ≥90 years. The influence of age on the SLN metastasis risk was independent of the other risk factors, but the difference in risk was most pronounced in patients without angiolymphatic invasion.

The interaction of angiolymphatic invasion and age in our data was striking. For patients with no angiolymphatic invasion of the primary tumor, age had a profound influence on the risk of SLN metastasis, with older patients having nearly half the risk of younger patients (Table 4Go). In contrast, among those with angiolymphatic invasion, older patients actually had a slightly higher risk of SLN metastasis than the younger patients. Accordingly, angiolymphatic invasion becomes increasingly important as a risk factor when patients are otherwise at low risk for SLN metastasis. For example, among our older patients with T1 tumors without angiolymphatic invasion, the rate of SLN metastasis was 10%, whereas among the same age and T-stage group with angiolymphatic invasion, the rate was 56% (Table 4Go). Thus, because older age independently decreases the risk of SLN metastasis, angiolymphatic invasion is a more powerful influence on the SLN metastasis risk in older patients.

Others have previously reported lower lymph node metastasis rates in older patients. Singh et al.16 reported that among patients with breast cancer who underwent ALND for staging, women older than 70 were less likely than younger women to have lymph node metastases. In their series, though, 43 (17%) of 251 patients over age 70 did not have regional lymph node staging, and there was no analysis of the influence of other known risk factors on this finding. McMasters et al.9 demonstrated that older age independently reduced the risk of SLN metastasis in melanoma patients. In their series, melanoma patients older than 60 years were 26% less likely than younger patients to have SLN metastases, and age remained independently predictive in multivariate regression analysis. This was a surprising finding given that melanoma patients over the age of 60 are known to have lower survival rates than younger patients.18 The similar finding in our series of breast cancer patients is less surprising because older breast cancer patients have a disease-specific survival similar to that of younger patients when they are comparably treated.16

Some caveats regarding this study are noteworthy. The database analyzed included only breast cancer patients who underwent SLN mapping and biopsy; thus, it is unknown how many patients did not undergo lymph node staging. It is, however, our institutional practice to offer SLN mapping and biopsy to all clinically node-negative patients, regardless of age, so it is unlikely that the number of patients not captured in the database would alter our findings. It is also important to appreciate that this study assessed only the risk of detecting SLN metastasis and not the effect of SLN metastasis on these patients’ regional control or overall and disease-free survival.

Among this series of patients, we were unable to identify a subgroup in which the risk of SLN metastasis was negligible. Even among the older group of patients with T1 primary tumors without angiolymphatic invasion, 10% were found to have SLN metastases. This does not, however, mean that the performance of SLN mapping in these patients necessarily leads to improved outcomes. Hughes et al.19 recently reported a randomized trial that observed an axillary recurrence in only 2 of 204 patients ≥70 years old with clinical T1N0M0 breast cancer who were treated by lumpectomy alone followed by tamoxifen. These authors questioned the value of lymph node evaluation in this group of patients. Although this question remains to be answered, we suggest on the basis of the current trial that lymph node evaluation should at least be included for older patients, even those with T1 tumors, who have angiolymphatic invasion.

In summary, patient age, tumor size, histology, histological grade, and angiolymphatic invasion predict the risk of SLN metastasis in breast cancer. Older age independently predicts a lower risk of SLN metastasis, and angiolymphatic invasion is a powerful risk factor in older patients. These factors should be considered when the risks and benefits of SLN biopsy are gauged in breast cancer patients.

Received for publication February 10, 2005. Accepted for publication July 20, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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