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Utilization of Lymph Node Dissection, Race/Ethnicity, and Breast Cancer Outcomes | Page 1

Published Online: October 23, 2013
Zhannat Z. Nurgalieva, MD, PhD; Luisa Franzini, PhD; Robert O. Morgan, PhD; Sally W. Vernon, PhD; and Xianglin L. Du, MD, PhD
Involvement of axillary lymph nodes is the most important prognostic factor in women with invasive breast carcinoma.1 Sentinel lymph node biopsy (SLNB), a rapidly adopted and less morbid alternative to axillary lymph node dissection (ALND) for nodal  staging, has been used since the late 1990s. Based on SLNB, patients are grouped into those with regional nodal metastasis who are likely to benefit from ALND and those without nodal metastases who are unlikely to benefit from ALND.2 Compared with SLNB alone, SLNB with complete ALND was not associated with greatly improved survival for breast cancer (BC) patients with micrometastasis3,4 and macrometastasis.4

Recent studies reported that patient race/ethnicity affects receipt and/or quality of sentinel lymph node dissection (SLND).5,6  Variation in compliance with a sentinel lymph node dissection quality measure was supported by a few additional studies. For example, being African American was associated with lower odds of receiving initial SLNB.7 African American or Hispanic women were less likely to undergo initial SLNB with complete ALND,1 and disparities in receipt of SLNB persisted for African American and Hispanic women with BC in a study that looked at temporal differences in use of SLNB from 1998 to 2005.8 Although large differences by race/ethnicity in BC survival are well established,9,10 it is unknown whether disparities in nodal surgery utilization explain the racial/ethnic disparities in survival among women with micrometastasis and macrometastasis in sentinel lymph nodes.

Because the majority of BC diagnoses occur after age 65 years and because increased life expectancy and advances in treatment mean that more women will be BC survivors,11-15 we report the impact of nodal surgery utilization on survival among white, black, Hispanic, and Asian women in a large population-based cohort of women with BC diagnosed from 1998 through 2005 who were enrolled in fee-for-service Medicare plans A and B.

MATERIALS AND METHODS

Population


We used the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute to identify BC patients who underwent SLNB alone or SLNB with a complete ALND between 1998 and 2005. As previously described,3,4 patients were categorized according to their primary surgical procedure (breast-conservation surgery or mastectomy) and according to their axillary lymph node assessment as follows: no nodal evaluation, ALND only, SLNB only (without complete ALND), and SLNB with complete ALND. If a patient underwent SLNB and a modified radical mastectomy, the patient was categorized as having undergone complete ALND. Patients were excluded if they underwent ALND only (without SLNB), did not undergo a lymph node evaluation or if evaluation status was not specified in SEER data, or did not undergo primary surgery. Patients were also excluded if they had stage IV disease. We used the American Joint Committee on Cancer pathologic N category subclassifications to categorize patients according to the degree of nodal metastatic disease as follows: macrometastatic disease (>2.0 mm) and micrometastatic disease (>0.2-2.0 mm). Patients reported only as N1 were classified as having macrometastatic nodal disease as described earlier by Yi and colleagues.4 The final sample included 24,961 patients.

Statistical Analysis

We used SEER categories of non-Hispanic white, non-Hispanic black, Hispanic, and non-Hispanic Asian/Pacific Islander. Patients who underwent surgical resection of the primary breast tumor were categorized as having has mastectomy or breast conservation therapy. Beginning in 1998, SEER started recording information about the type of lymph node assessment. The SEER variable “scope of regional lymph node surgery” was used to capture the patients’ lymph node assessment. Patients were categorized according to their lymph node assessment: no nodal evaluation, ALND only, SLNB without complete ALND (the SLNB-only group), and SLNB with complete ALND (the ALND-group, node-positive women).13 Patients who underwent SLNB and a modified radical mastectomy were considered as having undergone complete ALND. To categorize patients according to their degree of nodal metastatic disease, the American Joint Committee on cancer pathologic N category subclassifications were used as follows: micrometastatic disease (>0.2-2 mm) and macrometastatic disease (>2.0 mm).16 Survival was calculated as the number of months between the date of diagnosis and the date of death, the date last known to be alive, or December 31, 2005, whichever occurred first. The day of diagnosis was defined as the 15th of the month, because SEER only reports the month and year of diagnosis. The survival end points for the present study were overall survival (OS) and diseasespecific survival (DSS). Patients who were lost to follow-up or who survived beyond December 31, 2005, were coded as censored observations. Kaplan-Meier survival curves for survival by treatment were parallel per visual inspection as well as by log-rank test supporting the proportionality assumption.There were no significant interactions among the variables.

We used χ2 testing to compare the differences in categorical variables and proportions between patients who underwent SLNB alone and patients who underwent SLNB with complete ALND. In preliminary analyses, we compared the outcomes of patients  undergoing SLNB alone with those of patients undergoing SLNB with complete ALND. We also performed univariate analyses to determine the influence of patient, tumor, and treatment factors with known or potential prognostic value on OS and DSS as determined by the Kaplan-Meier method. Variables subjected to univariate analysis included age (continuous); socioeconomic  status; comorbidity index17-21; tumor grade (low/intermediate vs high); tumor size (T1-T3); estrogen receptor and progesterone receptor status (positive, negative, unknown); use of chemotherapy; use of radiotherapy after surgery (yes vs no); year of diagnosis(split, before 2000 and after 2000); and use of ALND. Significant factors from the univariate analysis were included in a multivariate Cox proportional hazard model to identify significant predictors of OS and DSS. In the unadjusted model (model 1) race is the only predictor.The covariates age and tumor size were analyzed as continuous variables in the multivariate models. Covariates added in our regression models included patient and tumor characteristics (age, year of diagnosis, treatment [chemotherapy, surgery, radiation], tumor stage, tumor size, tumor grade and number of positive lymph nodes, diameter of positive lymph nodes, comorbidities, socioeconomic status) (model 2); and receipt of nodal surgery (model 3). Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained for all regressions. Analyses were performed using SAS release 9.2 (SAS Institute Inc, Cary, North Carolina). All tests were 2-tailed with statistical significance set at P <.05.

RESULTS

Of the 24,961 women in the SEER database who underwent SLNB as part of their surgical treatment for BC from 1998 to 2005, 5364 (21%) had nodal metastases and comprised the cohort we analyzed. Of the patients in the cohort, 1028 (19%) underwent SLNB alone and 4336 (81%) underwent SLNB with a complete ALND. Most patients (n = 4098) had macrometastasis, and 1831 patients had micrometastasis.

Proportions of patients receiving SLNB alone or receiving SLNB with a complete ALND were not statistically different among women of different racial/ethnic backgrounds (P = .8) in a cohort of BC patients restricted to those with nodal metastases. A higher proportion of patients underwent SLNB alone if they were diagnosed after 2000 (81.7% vs 18.3%). Patients who underwent SLNB alone rather than SLNB with complete ALND were more likely to have smaller (median tumor size, 15 mm vs 20 mm) or low-grade tumors (69.2% low/intermediate vs 23.6% high grade) (Table 1). Most patients (84.2%) who underwent SLNB alone had breast-conservation surgery. The median number of lymph nodes removed during surgery was 2 in the patients who underwent SLNB alone and 12 in those who underwent SLNB with complete ALND (P <.0001). The mean number of lymph nodes removed was 3.9 (range, 1-32 nodes) in the SLNB-alone group and 13 (range, 1-52 nodes) in the SLNB plus ALND group.

Of the patients undergoing SLNB alone, 52.4% had micrometastases, compared with only 22.1% of the patients undergoing SLNB with complete ALND. Table 2 shows a multivariate analysis for factors associated with undergoing SLNB alone. Patients were more likely to undergo SLNB alone compared with SLNB with complete ALND if they had smaller or low-grade tumors, had  micrometastases, had positive estrogen receptor status, and were undergoing segmental mastectomy. Of the study population, 551 patients (10.5%) had died of any cause, and 297 patients (5.5%) had died of BC. Overall survival was not greatly different for patients undergoing SLNB alone compared with those undergoing SLNB with complete ALND in the entire cohort and in patients with micrometastases or macrometastases. Table 3 shows the clinical and pathologic factors affecting OS and DSS.

Patients of African American descent or of Hispanic origin had reduced OS after adjusting for selected covariates. Older women or those with macrometastases, highgrade tumors, larger tumors, negative estrogen receptor status, or more positive lymph nodes found during surgery had reduced OS. Adjusting for nodal surgery did not reduce racial/ethnic disparities in OS. Patients of Hispanic origin who were older or who had high-grade tumors, larger tumors, or negative estrogen receptor or progesterone receptor status; who underwent complete ALND after SLNB; or who had more positive lymph nodes found during surgery had reduced DSS. Disease-specific survival was decreased in patients with macrometastasis (not statistically significant). Adjusting for nodal surgery did not reduce racial/ethnic disparities in DSS.

DISCUSSION

Yi and colleagues4 recently examined differences in survival for patients with nodal disease undergoing SLNB alone versus SLNB with complete ALND. Similar to their results, we found no significant differences in utilization of SLNB alone or SLNB with a complete ALND between Caucasian and African American older BC patients in a cohort restricted to those with micrometastasis and macrometastasis in sentinel lymph nodes. In our study, this observation also held true for Hispanics and Asians/Pacific Islanders. Our study is unique in that it is one of the first reports of health outcomes in older BC patients with nodal disease for Hispanics, Asians, and Pacific Islanders. Previously mentioned studies did observe racial/ethnic disparities in utilization or quality of nodal surgery.1,5-8 This difference probably reflects the fact that their purpose was not to address BC survival with receipt of nodal surgery; therefore, they did not restrict their study population to only those with nodal disease. Similar to the findings reported by Bilimoria and colleagues3 and Yi and colleagues,4 our study suggests that patients are more likely to receive SLNB alone if they undergo breast-conservation therapy, are older, and have smaller primary tumors.

We observed that adjusting for receipt of nodal surgery did not reduce racial/ethnic disparities. Being of African American descent was associated with reduced OS, while being of Hispanic origin was associated with reduced DSS and OS compared with being Caucasian. This finding is consistent with the findings of Ooi and colleagues,9 who used SEER data to study women diagnosed with invasive breast carcinoma between 2000 and 2006. Ooi and colleagues showed elevated risk of BC-specific mortality among Hispanic whites and blacks that persisted after adjustments for important outcome predictors.

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Issue: October 2013
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