Abstract
Background:
In women with clinically node-negative breast cancer, sentinel lymph node biopsy is the first step in axillary staging. A randomized trial published in 2013 concluded that patients with sentinel lymph node micrometastases (N1mi) do not benefit from axillary lymph node dissection (ALND). We hypothesized that disparities exist in management of the axilla in node-negative patients.
Methods:
We included women aged>40 years with non-metastatic, clinically node-negative breast cancer from 2014 to 2016 in the National Cancer Database. Women treated neoadjuvantly, with large tumors (cT4), or no tumor (cT0) were excluded. Multivariable logistic regression identified patient and facility characteristics associated with undergoing ALND as first axillary surgery and completion ALND in the setting of N1mi disease.
Results:
Of 273,951 patients, 22,898 (8%) underwent ALND first. These patients were more likely to be Hispanic (OR: 1.21, 95% CI: 1.10, 1.32), have Medicare (OR: 1.13, 95% CI: 1.03, 1.24),be uninsured (OR: 1.28, 95% CI: 1.08, 1.53), have lower educational attainment (OR: 1.24, 95%CI: 1.17, 1.32), be treated at a community hospital (OR: 1.62, 95% CI: 1.52, 1.74), or reside in the South (OR: 1.19, 95% CI: 1.12, 1.26). In the sentinel lymph node biopsy first group, 8,882(4%) were classified as N1mi and 1,872 (21%) underwent subsequent ALND. These patients were more likely to be Hispanic (OR: 1.70, 95% CI: 1.19, 2.42) and have the lowest income(OR: 1.62, 95% CI: 1.15, 2.27).
Conclusion:
Disparities persist in implementation of evidence-based management of the axilla in women with clinically node-negative breast cancer.
Introduction
The management of the axilla in women with breast cancer has undergone extensive transformation over the past few decades. Sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection (ALND) for the clinically node negative patient based upon studies demonstrating its accuracy, low false-negative rate, and randomized trials demonstrating no difference in survival or local recurrence in women with negative sentinel lymph nodes treated by no further surgery compared to ALND (1-5). Perhaps most importantly, patients treated by SLNB alone have a 5% risk of lymphedema, compared to almost 30% in those treated by ALND (3(3-5). A randomized trial (International Breast Cancer Study Group (IBCSG) 23-01) in which women treated by lumpectomy or mastectomy with sentinel lymph node micrometastases (<2.0mm, staged as N1mi) were assigned to axillary dissection or no further axillary intervention, showed no difference in disease-free survival and decreased morbidity in the SLNB only group at 5 and 10 years follow-up (6, 7). The findings from this trial were incorporated into National Comprehensive Cancer Network (NCCN) guidelines in 2017(8) and were confirmed in a review of a large national database(9). These guidelines state that in clinically node negative women (cN0) found to have minimal disease at SLNB (pN0 or pN1mi), no further axillary surgery is needed.
Socioeconomic and racial disparities influence outcomes in the care of cancer patients and have been demonstrated across various cancers. Among patients with breast cancer, disparities in a multitude of facets of cancer care exist (10-20). Specifically, there is evidence of both age and racial disparities in the appropriate use of SLNB in clinically node negative women treated soon after studies demonstrating its safety were published (14, 17). Notably, in some patients, (women >70 years old with HR+ breast cancer), no axillary staging may be appropriate. (21-23).
The purpose of this study was to investigate whether disparities in SLNB usage in clinically node negative women persist as well as assess disparities in the adoption of omission of ALND in women with micrometastases. It is well known that disparities contribute to undertreatment, but given the potential for slower adoption and dissemination of evidence-based guidelines, we aimed to explore overtreatment in the management of the axilla in early breast cancer. We hypothesized there would be persistent disparities in the adherence to evidence-based management of the axilla through use of SLNB as well as in adoption of newer evidence to omit ALND in the setting of minimal axillary disease (N1mi).
Methods
Study Design and Patient Population
Women were identified using the National Cancer Database (NCDB), a database of incident cancer cases developed by the American Cancer Society and the Commission on Cancer of the American College of Surgeons. The NCDB was established in 1989, and is a nationwide, facility-based, comprehensive clinical surveillance oncology dataset that captures roughly 70% of all newly diagnosed cancer cases each year in the United States (24). Adult women diagnosed with non-metastatic (cM0), clinically node negative (cN0), ductal (International Classification of Disease for Oncology, Third Edition [ICD-O-3] 8500), lobular (ICD-O-3 8520), or special histologic subtype (tubular, mucinous, cribriform, and papillary adenocarcinoma with invasion; ICD-O-3 8211, 8480, 8503, 8201) between 2014 and 2016 were eligible for inclusion. Women were excluded if they did not undergo lumpectomy or mastectomy, underwent neoadjuvant radiation or chemotherapy, had a large tumor (cT4) or no tumor (cT0, cTis) on clinical evaluation, or were missing data on tumor size or treatment were excluded from analyses, Figure 1. Younger women (<40 years old) were also excluded because NCDB suppresses facility type and location in these patients and we felt these variables could be important predictors of guideline adherence.
Figure 1.
STROBE diagram for study.
Women were categorized according the first LN surgery they received and were classified as undergoing ALND, SLNB, or no lymph node surgery (no LN surgery). Women who underwent SLNB as their first axillary surgery and went on to ALND were classified as SLNB for these initial analyses. Among women who underwent axillary surgery, pathologic nodal positivity was also assessed. Extent of nodal disease was categorized as negative (pN0), micrometastases (pN1mi), or positive (pN1-pN4). In women with micrometastatic nodal disease who underwent SLNB, we also assessed whether they subsequently underwent ALND (i.e. SLNB and ALND or SLNB alone).
Statistical Analyses
Patient demographics and cancer characteristics, stratified by initial lymph node surgery), were compared using chi-squared, ANOVA, and Wilcoxon tests, where appropriate. The same tests were also used to compare demographics and cancer characteristics, stratified by subsequent ALND use, among women who initially underwent SLNB and were classified as having micrometastases (pN1mi). Cochran-Armitage trend tests were used to assess whether changes in initial ALND use (all women) and ALND use after initial SLNB (pN1mi women only) have changed between 2014 and 2016.
Multivariable logistic regression was used to identify patient and facility characteristics associated with undergoing ALND first, compared to undergoing either SLNB first or having no LN surgery. Patient and facility characteristics examined included race/ethnicity, primary insurance type, median residential income for the patient's ZIP code (median residential income), proportion of adults that did not graduate high school in the patient's ZIP code (residential educational attainment), current Commission on Cancer (CoC) accreditation of the treatment facility, facility region, and patient distance to care. Residential income and residential educational attainment were estimated using 2016 American Community Survey data, which spans 2012-2016. Distance to care is measured as the miles between the centroid of the patient's ZIP code (or city if ZIP code was not available) and the street address of the treatment facility. The model was also adjusted for year of diagnosis, age at diagnosis (modeled as a restricted quadratic spline), Charlson-Deyo comorbidity score, cancer histology (ductal, lobular, or special subtype), AJCC 6th edition clinical T stage, cancer type, and surgery type (lumpectomy versus mastectomy). Cancer type was defined as HER2+ (irrespective of ER and PR status), hormone-receptor positive (HER2− and ER and/or PR positive), and triple negative.
Additionally, in the subset of women who underwent SLNB and were classified as having micrometastases (pN1mi), multivariable logistic regression was used to estimate the association between patient and facility characteristics and undergoing a subsequent ALND. The same model as described above was used.
All analyses were performed using SAS 9.4 (SAS Inc., Cary, NC).
Results
376, 551 women were diagnosed with non-metastatic, clinically node negative breast cancer (ductal, lobular, special histologic subtype) in 2014-2016, and of those 273,951 (73%) met the inclusion criteria (Figure 1). Of the women analyzed, 22,898 (8%) underwent ALND first and 232,072 (85%) underwent SLNB (with or without subsequent ALND), while 18,981 (7%) had no axillary surgery. Baseline characteristics of women included in the study are shown in Tables 1 and 2. The utilization of upfront ALND for women with clinically node negative cancers remained relatively consistent, decreasing only from 9% to 8% during the study period, Figure 2A.
Table 1.
Patient demographics and clinical characteristics, stratified by initial LN treatment.
| ALND 22,898 (8%) |
SLNB 232,072 (85%) |
No LN Surgery 18,981 (7%) |
|
|---|---|---|---|
| Age, median (IQR) | |||
| Race/ethnicity, n (%) | |||
| Non-Hispanic White | 17,482 (79) | 185,517 (82) | 15,601 (84) |
| Non-Hispanic Black | 2,496 (11) | 20,605 (9) | 1,661 (9) |
| Hispanic | 1,360 (6) | 10,689 (5) | 693 (4) |
| Non-Hispanic Other | 884 (4) | 9,775 (4) | 590 (3) |
| Comorbidities, n (%) | |||
| 0 | 18,769 (82) | 189,851 (82) | 14,481 (76) |
| 1 | 3,114 (14) | 32,391 (14) | 3,045 (16) |
| 2 | 700 (3) | 7,037 (3) | 947 (5) |
| ≥3 | 315 (1) | 2,793 (1) | 508 (3) |
| Primary insurance, n (%) | |||
| Private insurance/Managed care | 10,013 (45) | 114,183 (50) | 4,639 (25) |
| Medicare | 10,279 (46) | 99,876 (43) | 13,285 (71) |
| Medicaid | 1,376 (6) | 11,145 (5) | 541 (3) |
| Other government insurance | 251 (1) | 2,373 (1) | 122 (.7) |
| Uninsured | 327 (1) | 2,326 (1) | 109 (0.6) |
| Median residential income a , n (%) | |||
| <$40,227 | 4,288 (19) | 32,303 (14) | 2,659 (14) |
| $40,227 - $50,353 | 5,422 (24) | 45,241 (20) | 3,673 (20) |
| $50,354 - $63,332 | 5,301 (23) | 54,299 (24) | 4,236 (23) |
| ≥$63,333 | 7,571 (34) | 97,594 (43) | 8,234 (44) |
| Residential educational attainment b , n (%) | |||
| ≥17.6% | 4,749 (21) | 35,851 (16) | 2,846 (15) |
| 10.9-17.5% | 6,134 (27) | 54,140 (24) | 4,375 (23) |
| 6.3-10.8% | 6,472 (29) | 68,267 (30) | 5,558 (30) |
| <6.3% | 5,265 (23) | 71,498 (31) | 6,049 (32) |
| Cancer histology, n (%) | |||
| Ductal | 19,088 (83) | 194,397 (84) | 15,514 (82) |
| Lobular | 3,110 (14) | 29,177 (13) | 2,278 (12) |
| Special histology | 700 (3) | 8,498 (4) | 1,189 (6) |
| AJCC clinical T stage, n (%) | |||
| cT1 | 16,564 (72) | 187,964 (81) | 15,339 (81) |
| cT2 | 5705 (25) | 41,265 (18) | 3,375 (18) |
| cT3 | 629 (3) | 2,843 (1) | 267 (1) |
| Primary breast surgery, n (%) | |||
| Lumpectomy | 11,443 (50) | 162,249 (70) | 13,918 (73%)) |
| Mastectomy | 11,455 (50) | 69,823 (30) | 5,063 (27) |
| Cancer subtype, n (%) | |||
| ER positive and/or PR positive | 17,535 (81) | 192,541 (86) | 15,033 (85) |
| HER2 positive | 1,758 (8) | 13,432 (6) | 1,256 (7) |
| Triple negative | 2,271 (11) | 19,131 (9) | 1,501 (8) |
| Current CoC accreditation, n (%) | |||
| Community | 3,342 (15) | 21,859 (9) | 1,810 (10) |
| Comprehensive community | 10,438 (46) | 105,844 (46) | 8,343 (44) |
| Academic/research | 6,418 (28) | 69,949 (30) | 6,055 (32) |
| Integrated network | 2700 (12) | 34,420 (15) | 2,773 (15) |
| Facility region, n (%) | |||
| Northeast | 4,014 (18) | 49,199 (21) | 5,233 (28) |
| Midwest | 5,691 (25) | 60,681 (26) | 4,541 (24) |
| South | 9,793 (43) | 81,200 (35) | 5,960 (31) |
| West | 3,400 (15) | 40,992 (18) | 3,247 (17) |
| Distance to care, miles, median (IQR) | 9.4 (4.3, 20.1) | 9.2 (4.4, 19.0) | 7.8 (3.8, 16.6) |
Abbreviations: ALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy; LN, lymph node; IQR, interquartile range; AJCC, American Joint Committee on Cancer; ER, Estrogen Receptor; PR, Progesterone Receptor; CoC, Commission on Cancer
Median household income in patient’s ZIP code; estimated and categorized into quartiles using the 2016 American Community Survey data, spanning 2012-2016
Proportion of adults ≥25 years old in patient’s ZIP code that did not graduate from high school; estimated and categorized into quartiles using the 2016 American Community Survey data, spanning 2012-2016
Table 2.
Patient characteristics among women who underwent SLNB first and were classified as pathologic N1mi, stratified by subsequent ALND.
| ALND 1,872 (21%) |
No Additional LN Surgery 7,010 (79%) |
|
|---|---|---|
| Age, median (IQR) | 60.0 (51,69) | 60.2 (53,70) |
| Race/ethnicity, n (%) | ||
| Non-Hispanic White | 1,454 (80) | 5,606 (82) |
| Non-Hispanic Black | 175 (10) | 615 (9) |
| Hispanic | 114 (6) | 310 (5) |
| Non-Hispanic Other | 93 (5) | 314 (5) |
| Comorbidities, n (%) | ||
| 0 | 1,542 (82) | 5,741 (82) |
| 1 | 269 (14) | 980 (14) |
| 2 | 43 (2) | 218 (3) |
| ≥3 | 18 (1) | 71 (1) |
| Primary insurance, n (%) | ||
| Private insurance/Managed care | 1,041 (56) | 3,752 (54) |
| Medicare | 669 (36) | 2,714 (39) |
| Medicaid | 99 (5) | 337 (5) |
| Other government insurance | 20 (1) | 75 (1) |
| Uninsured | 25 (1) | 67 (1) |
| Median residential income a , n (%) | ||
| <$40,227 | 275 (15) | 949 (14) |
| $40,227 - $50,353 | 348 (19) | 1,316 (19) |
| $50,354 - $63,332 | 453 (24) | 1,648 (24) |
| ≥$63,333 | 783 (42) | 3,008 (43) |
| Residential educational attainment b , n (%) | ||
| ≥17.6% | 316 (17) | 1,050 (15) |
| 10.9-17.5% | 428 (23) | 1,611 (23) |
| 6.3-10.8% | 557 (30) | 2,053 (30) |
| <6.3% | 562 (30) | 2,218 (32) |
| Cancer histology, n (%) | ||
| Ductal | 1,584 (85) | 5,975 (85) |
| Lobular | 253 (14) | 931 (13) |
| Special histology | 35 (2) | 104 (2) |
| AJCC clinical T stage, n (%) | ||
| cT1 | 1,260 (67) | 5,023 (72) |
| cT2 | 563 (30) | 1,848 (26) |
| cT3 | 49 (3) | 139 (2) |
| Primary breast surgery, n (%) | ||
| Lumpectomy | 697 (37) | 4693 (67) |
| Mastectomy | 1175 (63) | 2317 (33) |
| Breast cancer subtype, n (%) | ||
| ER and/or PR positive | 1,596 (88) | 6,158 (90) |
| HER-2 positive | 98 (5) | 303 (4) |
| Triple negative | 118 (7) | 409 (6) |
| Current CoC accreditation, n (%) | ||
| Community | 149 (8) | 586 (8) |
| Comprehensive community | 796 (43) | 3,164 (45) |
| Academic/research | 622 (33) | 2,188 (31) |
| Integrated network | 305 (16) | 1,072 (15) |
| Facility region, n (%) | ||
| Northeast | 393 (21) | 1,395 (20) |
| Midwest | 481 (26) | 1,937 (28) |
| South | 694 (37) | 2,357 (34) |
| West | 304 (16) | 1,321 (19) |
| Distance to care, miles, median (IQR) | 9.2 (4.4, 18.9) | 9.5 (4.5, 19.6) |
Abbreviations: ALND, axillary lymph node dissection; LN, lymph node; IQR, interquartile range; AJCC, American Joint Committee on Cancer; ER, Estrogen Receptor; PR, Progesterone Receptor; CoC, Commission on Cancer
Median household income in patient’s ZIP code; estimated and categorized into quartiles using the 2016 American Community Survey data, spanning 2012-2016
Proportion of adults ≥25 years old in patient’s ZIP code that did not graduate from high school; estimated and categorized into quartiles using the 2016 American Community Survey data, spanning 2012-2016
Figure 2.
Proportion of women undergoing ALND as A) initial lymph node surgery treatment (all women) and B) after undergoing SLNB and being classified as pathologic N1mi, over time.
Among women who underwent SLNB first (n=232,072), 84% were pathologically node negative (pN0, n=193,565), 4% were pN1mi (n=8,882), and 12% were pN1-N3 (pN1: 23,969, 10%; pN2: 3,001, 1%; pN3: 970, <1%; pN4: 0), Figure 1. The utilization of subsequent ALND among women with micrometastases (pN1mi) also decreased over time (23% to 19%, p=0.0002), Figure 2B.
After adjusting for age, year of diagnosis, Charlson-Deyo comorbidity score, cancer histology, and clinical T-stage, patients who underwent first ALND, instead of SLNB or no axillary surgery, were more likely to be Hispanic (OR 1.20, 95% CI 1.13, 1.29), have Medicaid (OR 1.21, 95% CI 1.13, 1.29), or be uninsured (OR 1.28, 95% CI 1.12,1.45), Table 3. They were also more likely to be treated at a community hospital (OR 1.69, 95% CI 1.60,1.77), reside in the South (OR 1.19, 95% CI 1.13,1.24) or live in areas with lowest residential education attainment (OR 1.28, 95% CI 1.21, 1.36). Women who underwent mastectomy (OR 2.21, 95% CI 2.14, 2.28), compared to lumpectomy, as well as women with HER2+ (OR 1.22, 95% CI 1.16, 1.29) or triple negative cancer (OR 1.14, 95% CI 1.09, 1.20), compared to hormone positive, were also significantly more likely to initially undergo ALND first. Median residential income and distance to care appeared to have minimal impact. Among women who underwent breast conserving surgery, there was no difference in the use of upfront ALND (6.1% versus 5.9%) among women who did or did not undergo adjuvant radiation.
Table 3.
Patient characteristics and their association with undergoing ALND first, compared to SLNB or no lymph node surgery, among women ≥40 years old and diagnosed with non-metastatic, clinically node-negative breast cancer between 2014 and 2016 and underwent either lumpectomy or mastectomy.
| ALND vs SLNB first | ALND after SLNB, pN1mi |
|
|---|---|---|
| OR (95 CI)a | OR (95 CI)a | |
| Race/ethnicity | ||
| Non-Hispanic White | ref | ref |
| Non-Hispanic Black | 1.09 (1.04, 1.15) | 1.11 (0.91, 1.35) |
| Hispanic | 1.20 (1.13, 1.29) | 1.38 (1.08, 1.78) |
| Non-Hispanic Other | 0.99 (0.92, 1.07) | 1.05 (0.81, 1.37) |
| Primary insurance | ||
| Private insurance/Managed care | ref | ref |
| Medicare | 1.09 (1.04, 1.14) | 1.09 (0.90, 1.30) |
| Medicaid | 1.21 (1.13, 1.29) | 0.97 (0.75, 1.25) |
| Other government insurance | 1.14 (0.99, 1.31) | 1.05 (0.88, 1.27) |
| Uninsured | 1.28 (1.12, 1.45) | 1.27 (0.75, 2.13) |
| Median residential income b | ||
| <$40,227 | 1.27 (1.20, 1.34) | 1.04 (0.83, 1.31) |
| $40,227 - $50,353 | 1.25 (1.19, 1.31) | 1.05 (0.88, 1.27) |
| $50,354 - $63,332 | 1.12 (1.07, 1.17) | 1.04 (0.89, 1.22) |
| ≥$63,333 | ref | ref |
| Residential educational attainment c | ||
| ≥17.6% | 1.28 (1.21, 1.36) | 1.10 (0.87, 1.27) |
| 10.9-17.5% | 1.22 (1.16, 1.29) | 1.06 (0.88, 1.27) |
| 6.3-10.8% | 1.16 (.111, 1.21) | 1.13 (0.97, 1.31) |
| <6.3% | ref | ref |
| Cancer subtype | ||
| HER2 + | 1.22 (1.16, 1.29) | 1.08 (0.84, 1.39) |
| ER positive and/or PR positive | ref | ref |
| Triple negative | 1.14 (1.09, 1.20) | 1.02 (0.82, 1.28) |
| Mastectomy | 2.21 (2.14, 2.28) | 3.65 (3.24, 4.10) |
| Current CoC accreditation | ||
| Community | 1.69 (1.60, 1.77) | 0.95 (0.76, 1.19) |
| Comprehensive community | 1.10 (1.06, 1.77) | 0.88 (0.77, 1.01) |
| Academic/research | ref | ref |
| Integrated network | 0.89 (0.85, 0.94) | 0.97 (0.81, 1.15) |
| Facility region | ||
| Northeast | ref | ref |
| Midwest | 1.05 (1.01, 1.10) | 0.88 (0.77, 1.04) |
| South | 1.19 (1.13, 1.24) | 0.95 (0.81, 1.11) |
| West | 0.94 (0.86, 0.99) | 0.79 (0.66, 0.95) |
| Distance to care | ||
| <5 miles | ref | ref |
| 5-9.9 miles | 1.00 (0.96, 1.04) | 1.00 (0.86, 1.17) |
| 10-19.9 miles | 1.03 (0.99, 1.08) | 0.90 (0.77, 1.06) |
| ≥20 miles | 0.95 (0.91, 0.99) | 0.83 (0.71, 0.97) |
Abbreviations: OR, odds ratio; CI, confidence interval
Adjusted for all variables in the model and year of diagnosis, age, Charlson-Deyo comorbidity score, cancer histology, and clinical T-stage
Median household income in patient’s ZIP code; estimated and categorized into quartiles using the 2016 American Community Survey data, spanning 2012-2016
Proportion of adults ≥25 years old in patient’s ZIP code that did not graduate from high school; estimated and categorized into quartiles using the 2016 American Community Survey data, spanning 2012-2016
Of the 8,882 (4%) of women with micrometastasis on SLNB, 1,872 (21%) underwent a subsequent ALND. After adjustment, women who underwent subsequent ALND, compared to no additional surgery, were also more likely to be Hispanic (OR 1.38, 95% CI 1.08, 1.78) and may be more likely to be uninsured, although estimates were imprecise (OR 1.27, 95% CI 0.75, 2.13), Table 3. Women in the West, compared to the Northeast, were less likely to have ALND (OR 0.79, 95% CI 0.66, 0.95). Similar to patients who underwent ALND as their first axillary surgery, mastectomy was also the biggest predictor of subsequent ALND after SLNB demonstrated pN1mi disease (OR 3.65, 95% CI 3.24, 4.10), however cancer subtype (hormone positive, triple negative, or Her-2 positive) was not associated with ALND for N1mi disease. Residential income, residential education, cancer subtype, and cancer treatment center appeared to impact whether a patient underwent ALND for N1mi disease.
Discussion
The management of the axilla in women with clinically node negative breast cancer has undergone major changes in the past two decades, marked first by the advent of the sentinel lymph node biopsy (SLNB) as an alternative for axillary lymph node dissection (ALND) (1, 5) and followed by progressive scaling back of the extent of axillary surgery in a variety of settings (6, 7, 25-27). Despite showing modest improvements in adherence to evidence-based care over time, the results of our study show persistent use of ALND as a first operation in clinically node negative women as well as ALND for women found to have axillary micrometastases on SLNB. Improvement in adherence to guidelines for upfront ALND remained relatively stable over the time period, given the absolute reduction in its use was only 1%. The seemingly inappropriate use of ALND as a first axillary surgery for clinically node negative women disproportionately effects Hispanic women, women residing in the South, those without insurance, and those living in areas with lowest rates of education and income. Treatment by ALND for pathologic N1mi disease was also more likely in Hispanic women and may be more likely in the uninsured (OR 1.27, 95% CI 0.75, 2.13). The association between being uninsured and overtreatment was essentially identical in both overtreatment analyses; however, because of the wide confidence interval (likely due to the smaller sample size) this association is uncertain and requires additional research.
In their 2011 study of patients captured from 2000-2002 in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, Reeder-Hayes et al. noted significant underutilization of SLNB in black, elderly, and economically disadvantaged patients (17). Similarly, in a 2014 study of women captured in SEER from 2002-2007, Black et al. found that black patients were significantly less likely to undergo SLNB compared to white patients (14). Both authors found improved uptake of SLNB use over the time period studied. Several other studies examining patient populations around the time of implementation of SLNB showed similar finding (28, 29) and surgeon specialization has also been linked with inappropriate overuse of ALND compared to SLNB (30). Interestingly, despite studying a population treated over a decade later, we also found disparities across several domains in the utilization of SLNB for axillary staging in clinically node negative women with breast cancer.
Our data suggests there are persistent deficiencies in the way evidence-based care is implemented in breast cancer patients, despite almost two decades since the widespread adoption of SLNB. And while we found a lower rate of inappropriate use of ALND first in our patient population compared to the earlier populations in existing studies, the disparities in application of SLNB suggest that evidence-based care is not being implemented equally in all patients. To our knowledge, no other studies have evaluated the use of ALND for patients with pathologic N1mi disease, however our results are not surprising given the known disparities in the use of ALND as first axillary staging procedure in clinically node negative patients.
Mastectomy (compared to lumpectomy) was strongly associated with inappropriate use of ALND over SLNB and ALND for N1mi disease. While others have also found mastectomy was associated with ALND(29), it is unclear why- and somewhat surprising- we saw this in our modern cohort. It is possible that surgeons were uncomfortable pursuing SLNB in a cohort of patients potentially selected for advanced disease (despite the proven accuracy of SLNB in T1-T3 lesions). This association was less surprising for patients treated by ALND for pN1mi disease as those treated by mastectomy were under-represented in the randomized trial comparing ALND to no further surgery, representing only around 10% of the total cohort (6, 7).
Historically, research has frequently focused on the lack of intervention in underserved populations; however, in the management of the axilla with clinically node-negative breast cancer, we have also found that certain populations (Hispanic, low residential income, low educational attainment, Medicaid, and uninsured) are more likely to be overtreated, presumably through lack of adoption of new techniques and evidence. These disparities are equally important, and highlight that access to care and quality of care can both cause undertreatment and overtreatment, due to a lack of dissemination of the most up to date guidelines. In that regard, future studies should focus on examining disparities in the delivery of appropriate intervention.
This study is not without limitations. First, this was a retrospective cohort study using the National Cancer Database, which captures only 70% of all incident cancers in the United States. However, hospitals that participate are probably more likely to be large, academic centers, suggesting that we are underestimating the prevalence of over-treatment in women with clinically node negative breast cancer. We also excluded women <40 years old due to data restrictions, and are unable to comment if these disparities are seen in younger women. We also had no information on patient preferences or frailty, that may explain some of the surgical decision making. Additionally, a small percentage may have failed to map adequately and therefore ALND was the appropriate surgery. Similarly, it is possible that patients who inappropriately underwent ALND were treated in safety net hospitals without access to nuclear medicine capabilities, although SLNB can be safely performed with single-agent mapping using widely available blue dye. Lastly, with such a large database, the improvement seen in upfront ALND is likely not clinically significant and it is necessary to interpret the clinical impact of findings. We also had no information on patient preferences or frailty, that may explain some of the surgical decision making. Future studies could benefit from including surgeon characteristics not readily available in the NCDB (training, specialty and years in practice) and their impact on surgical decision-making and adherence to treatment guidelines.
Substantial disparities in the utilization of appropriate treatment in women with clinically node negative (cN0) breast cancer and those with micrometastases (pN1mi) exist in the United States. And while there has been modest improvement in the adherence of the guidelines for management of axilla in breast cancer patients, thousands of women are overtreated each year. Future research should be focused on identifying why surgeons are not following evidence-based guidelines and if disparities can be reduced through improved dissemination of evidence-based practices and training. This is essential to improving the management of the axilla in clinically node negative breast cancer and ensuring that treatments are appropriately tailored to the individual and to minimize morbidity.
References
- 1.Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220(3):391–8; discussion 8-401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: a metaanalysis. Cancer. 2006;106(1):4–16. [DOI] [PubMed] [Google Scholar]
- 3.Mansel RE, Fallowfield L, Kissin M, Goyal A, Newcombe RG, Dixon JM, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst. 2006;98(9):599–609. [DOI] [PubMed] [Google Scholar]
- 4.Veronesi U, Viale G, Paganelli G, Zurrida S, Luini A, Galimberti V, et al. Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study. Ann Surg. 2010;251(4):595–600. [DOI] [PubMed] [Google Scholar]
- 5.Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010;11(10):927–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Galimberti V, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P, et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol. 2013;14(4):297–305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Galimberti V, Cole BF, Viale G, Veronesi P, Vicini E, Intra M, et al. Axillary dissection versus no axillary dissection in patients with breast cancer and sentinel-node micrometastases (IBCSG 23-01): 10-year follow-up of a randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(10):1385–93. [DOI] [PubMed] [Google Scholar]
- 8.Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, et al. NCCN Guidelines Insights: Breast Cancer, Version 1.2017. J Natl Compr Canc Netw. 2017;15(4):433–51. [DOI] [PubMed] [Google Scholar]
- 9.Bilimoria KY, Bentrem DJ, Hansen NM, Bethke KP, Rademaker AW, Ko CY, et al. Comparison of sentinel lymph node biopsy alone and completion axillary lymph node dissection for node-positive breast cancer. J Clin Oncol. 2009;27(18):2946–53. [DOI] [PubMed] [Google Scholar]
- 10.Warner ET, Tamimi RM, Hughes ME, Ottesen RA, Wong YN, Edge SB, et al. Time to diagnosis and breast cancer stage by race/ethnicity. Breast Cancer Res Treat. 2012;136(3):813–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ooi SL, Martinez ME, Li CI. Disparities in breast cancer characteristics and outcomes by race/ethnicity. Breast Cancer Res Treat. 2011;127(3):729–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Lantz PM, Mujahid M, Schwartz K, Janz NK, Fagerlin A, Salem B, et al. The influence of race, ethnicity, and individual socioeconomic factors on breast cancer stage at diagnosis. Am J Public Health. 2006;96(12):2173–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Keating NL, Kouri E, He Y, Weeks JC, Winer EP. Racial differences in definitive breast cancer therapy in older women: are they explained by the hospitals where patients undergo surgery? Med Care. 2009;47(7):765–73. [DOI] [PubMed] [Google Scholar]
- 14.Black DM, Jiang J, Kuerer HM, Buchholz TA, Smith BD. Racial disparities in adoption of axillary sentinel lymph node biopsy and lymphedema risk in women with breast cancer. JAMA Surg. 2014;149(8):788–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Roberts MC, Wheeler SB, Reeder-Hayes K. Racial/Ethnic and socioeconomic disparities in endocrine therapy adherence in breast cancer: a systematic review. Am J Public Health. 2015;105Suppl 3:e4–e15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Roberts MC, Weinberger M, Dusetzina SB, Dinan MA, Reeder-Hayes KE, Carey LA, et al. Racial Variation in the Uptake of Oncotype DX Testing for Early-Stage Breast Cancer. J Clin Oncol. 2016;34(2):130–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Reeder-Hayes KE, Bainbridge J, Meyer AM, Amos KD, Weiner BJ, Godley PA, et al. Race and age disparities in receipt of sentinel lymph node biopsy for early-stage breast cancer. Breast Cancer Res Treat. 2011;128(3):863–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Hershman DL, Wang X, McBride R, Jacobson JS, Grann VR, Neugut AI. Delay in initiating adjuvant radiotherapy following breast conservation surgery and its impact on survival. Int J Radiat Oncol Biol Phys. 2006;65(5):1353–60. [DOI] [PubMed] [Google Scholar]
- 19.Hershman D, McBride R, Jacobson JS, Lamerato L, Roberts K, Grann VR, et al. Racial disparities in treatment and survival among women with early-stage breast cancer. J Clin Oncol. 2005;23(27):6639–46. [DOI] [PubMed] [Google Scholar]
- 20.Fedewa SA, Ward EM, Stewart AK, Edge SB. Delays in adjuvant chemotherapy treatment among patients with breast cancer are more likely in African American and Hispanic populations: a national cohort study 2004-2006. J Clin Oncol. 2010;28(27):4135–41. [DOI] [PubMed] [Google Scholar]
- 21.Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31(19):2382–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.International Breast Cancer Study G, Rudenstam CM, Zahrieh D, Forbes JF, Crivellari D, Holmberg SB, et al. Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Group Trial 10-93. J Clin Oncol. 2006;24(3):337–44. [DOI] [PubMed] [Google Scholar]
- 23.Martelli G, Boracchi P, Orenti A, Lozza L, Maugeri I, Vetrella G, et al. Axillary dissection versus no axillary dissection in older T1N0 breast cancer patients: 15-year results of trial and out-trial patients. Eur J Surg Oncol. 2014;40(7):805–12. [DOI] [PubMed] [Google Scholar]
- 24.Merkow RP, Rademaker AW, Bilimoria KY. Practical Guide to Surgical Data Sets: National Cancer Database (NCDB). JAMA Surg. 2018;153(9):850–1. [DOI] [PubMed] [Google Scholar]
- 25.Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305(6):569–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Donker M, van Tienhoven G, Straver ME, Meijnen P, van de Velde CJ, Mansel RE, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15(12):1303–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Mamtani A, Barrio AV, King TA, Van Zee KJ, Plitas G, Pilewskie M, et al. How Often Does Neoadjuvant Chemotherapy Avoid Axillary Dissection in Patients With Histologically Confirmed Nodal Metastases? Results of a Prospective Study. Ann Surg Oncol. 2016;23(11):3467–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Chen AY, Halpern MT, Schrag NM, Stewart A, Leitch M, Ward E. Disparities and trends in sentinel lymph node biopsy among early-stage breast cancer patients (1998-2005). J Natl Cancer Inst. 2008;100(7):462–74. [DOI] [PubMed] [Google Scholar]
- 29.Rescigno J, Zampell JC, Axelrod D. Patterns of axillary surgical care for breast cancer in the era of sentinel lymph node biopsy. Ann Surg Oncol. 2009;16(3):687–96. [DOI] [PubMed] [Google Scholar]
- 30.Yen TW, Laud PW, Sparapani RA, Nattinger AB. Surgeon specialization and use of sentinel lymph node biopsy for breast cancer. JAMA Surg. 2014;149(2):185–92. [DOI] [PMC free article] [PubMed] [Google Scholar]