This cohort study evaluate rates and risk factors associated with breast cancer–related lymphedema in patients treated with axillary lymph node dissection.
Key Points
Question
What are the lymphedema incidence and risk factors in a diverse cohort of women treated with axillary lymph node dissection and radiotherapy using defined measurement protocols?
Findings
In this cohort study of 276 patients with breast cancer, the 24-month lymphedema rate was 23.8%, which differed based on race and ethnicity. Black race and Hispanic ethnicity had the greatest association with lymphedema development; neoadjuvant chemotherapy receipt, older age, and longer follow-up were also independently associated with lymphedema development.
Meaning
Future studies should address the biologic mechanisms behind racial and ethnic disparities in lymphedema development to inform preventive strategies, and alternatives to neoadjuvant chemotherapy in patients with node-positive disease unlikely to downstage are necessary to minimize lymphedema risk.
Abstract
Importance
Risk factors for breast cancer–related lymphedema (BCRL) after axillary lymph node dissection (ALND) are poorly understood.
Objective
To evaluate rates of and risk factors associated with BCRL in a prospective cohort of women treated with ALND.
Design, Setting, and Participants
This prospective BCRL screening study performed at a tertiary cancer center enrolled women with breast cancer 18 years and older undergoing breast surgery and unilateral ALND in the primary setting or after sentinel lymph node biopsy.
Exposures
Risk of BCRL during the first 2 years after ALND and radiotherapy.
Main Outcomes and Measures
Patients were prospectively evaluated with arm volume (perometer) measurements, and BCRL was defined as a relative volume change of 10% or greater from baseline. Cumulative incidence of BCRL was assessed using competing risk analysis. Risk factors for BCRL were assessed on univariate and multivariable analyses.
Results
From November 2016 to March 2020, 304 patients were enrolled; 276 had at least 1 longitudinal measurement. Median (IQR) age was 48 (40-57) years; median (IQR) body mass index, calculated as weight in kilograms divided by height in meters squared, was 26.4 (22.5-31.2). Of the 276 patients included in the analysis, 29 (11%) self-identified as Asian, 55 (20%) as Black, 16 (6%) as Hispanic, 166 (60%) as White, and 10 (3%) as unknown race and ethnicity; 70% received neoadjuvant chemotherapy (NAC); 93% received nodal irradiation. The 24-month BCRL rate was 23.8% (95% CI, 17.9%-29.8%), with significant variation by race and ethnicity (24-month rate: 37.2% [Black], 27.7% [Hispanic], 22.5% [Asian], and 19.8% [White]; P = .004). The BCRL rates were also higher among patients receiving NAC vs up-front surgery (24-month rate: 29.3% vs 11.1%; P = .01). On multivariable analysis, Black race and Hispanic ethnicity (compared with White race) (odds ratio [OR], 3.88; 95% CI, 2.14-7.08 and OR, 3.01; 95% CI, 1.10-7.62, respectively; P < .001 for each), receipt of NAC (compared with up-front surgery) (OR, 2.10; 95% CI, 1.16-3.95; P = .01), older age (OR, 1.04; 95% CI, 1.02-1.07 per 1-year increase; P = .001), and a longer follow-up interval (OR, 1.57; 95% CI, 1.30-1.90 per 6-month increase; P < .001) were independently associated with an increased risk of BCRL, while ERBB2-positive subtype was associated with a decreased risk of BCRL (compared with hormone receptor positive/ERBB2 negative): OR, 0.50; 95% CI, 0.23-0.99; P = .04).
Conclusion and Relevance
In this cohort study, Black race, Hispanic ethnicity, NAC receipt, older age, and longer follow-up were independently associated with risk of BCRL. Studies are warranted to evaluate the biologic mechanisms behind racial and ethnic disparities in BCRL development and alternatives to NAC to avoid ALND in tumor subtypes unlikely to achieve nodal pathologic complete response.
Introduction
Despite great efforts to de-escalate axillary surgery, breast cancer–related lymphedema (BCRL) remains a frequent complication of locoregional treatment.1 Axillary lymph node dissection (ALND) remains the main risk factor for BCRL development; other associated factors, including older age, increasing body mass index (BMI), and radiotherapy (RT), are inconsistent across studies.2 Although epidemiological studies have suggested a higher susceptibility to BCRL in Black women,3,4 the association of race with BCRL risk is poorly understood. Additionally, the effect of therapeutic approaches such as neoadjuvant chemotherapy (NAC) on BCRL risk requires further study.
We enrolled women treated with ALND into a prospective lymphedema screening trial, using strict measurement protocols, to assess incidence and risk factors associated with BCRL development.
Methods
Patients with breast cancer 18 years and older undergoing breast surgery and unilateral ALND either in the primary setting or after sentinel lymph node biopsy were enrolled. Arm volume measurements using a perometer (Perometer 350 NT, Pero-System) and BMI, calculated as weight in kilograms divided by height in meters squared, were obtained at baseline, postoperatively, and longitudinally every 6 months, with a median (IQR) time from baseline measurement to surgery of 8 (2-20) days. Breast cancer–related lymphedema was defined as a relative volume change (RVC) of 10% or greater from baseline calculated using the formula, RVC = [(A2U1)/(U2A1)] − 1, where A1 and A2 are arm volumes on the side of the treated breast at baseline and follow-up, and U1 and U2 are volumes on the opposite arm at the same time points.5 This study was approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board, and all patients gave written informed consent to participate.
Cumulative incidence of BCRL was assessed using a competing risk analysis, with death, locoregional recurrence, and contralateral breast surgery considered competing events. The Gray test was used to compare difference in BCRL rates between groups. Wilcoxon rank or t tests and χ2 or Fisher exact tests were used to compare clinicopathological characteristics. Univariate and multivariable logistic regressions using generalized estimating equations were conducted to assess the association between BCRL development and clinicopathological factors, with time after surgery considered a covariate due to the repeated longitudinal measures. All covariates that were significant at the α = .05 level in the univariate analysis were tested in the multivariable model. Statistical analysis was performed using R, version 3.6.3 (R Core Development Team).
Results
From November 2016 to March 2020, 304 patients undergoing ALND were enrolled; 276 had at least 1 longitudinal measurement after baseline and were included in this analysis, with 88% of the cohort having at least 12 months of follow-up. Median (IQR) age was 48 (40-57) years; median (IQR) BMI was 26.4 (22.5-31.2). Of the 276 patients, 29 (11%) self-identified as Asian, 55 (20%) as Black, 16 (6%) as Hispanic, 166 (60%) as White, and 10 (3%) as unknown race and ethnicity. Clinicopathological features, stratified by race and ethnicity and treatment group (NAC vs up-front surgery), are summarized in Table 1 and the eTable in the Supplement.
Table 1. Clinicopathological Features of the Study Cohort, Stratified by Race and Ethnicity.
| Characteristic | Frequency, column No. (%) | P value | ||||
|---|---|---|---|---|---|---|
| Overall (n = 266)a | Asian patients (n = 29) | Black patients (n = 55) | Hispanic patients (n = 16) | White patients (n = 166) | ||
| Age, median (IQR), y | 48 (40-57) | 44 (35-52) | 49 (42-54) | 44 (33-49) | 49 (40-59) | .007b |
| Baseline BMI, median (IQR) | 26.4 (22.5-31.2) | 22.2 (20.6-29.1) | 30.3 (26.0-34.0) | 28.1 (23.5-32.9) | 25.2 (22.3-30.3) | <.001b |
| Dominant arm affected | ||||||
| Yes | 123 (46) | 11 (38) | 26 (47) | 9 (56) | 77 (46) | .70 |
| No | 143 (54) | 18 (62) | 29 (53) | 7 (44) | 89 (54) | |
| Clinical T stage | ||||||
| 1 | 55 (21) | 7 (24) | 9 (16) | 4 (25) | 35 (21) | .50 |
| 2 | 121 (45) | 18 (62) | 26 (47) | 8 (50) | 69 (42) | |
| 3 | 44 (17) | 1 (3) | 8 (15) | 2 (12) | 33 (20) | |
| 4 | 42 (16) | 3 (10) | 10 (18) | 2 (12) | 27 (16) | |
| X | 4 (2) | 0 | 2 (4) | 0 | 2 (1) | |
| Clinical N stage | ||||||
| 0 | 72 (27) | 12 (41) | 9 (16) | 3 (19) | 48 (29) | .02b |
| 1 | 173 (65) | 14 (48) | 45 (82) | 9 (56) | 105 (63) | |
| 2 | 6 (2) | 1 (3.4) | 0 | 1 (6) | 4 (2) | |
| 3 | 15 (6) | 2 (6.9) | 1 (1.8) | 3 (19) | 9 (5) | |
| Receptor subtype | ||||||
| HR+/ERBB2− | 180 (68) | 23 (79) | 32 (58) | 10 (62) | 115 (69) | .10 |
| ERBB2 + | 52 (20) | 4 (14) | 9 (16) | 4 (25) | 35 (21) | |
| HR−/ERBB2− | 34 (13) | 2 (6.9) | 14 (25) | 2 (12) | 16 (10) | |
| Histology | ||||||
| Ductal | 221 (83) | 27 (93) | 50 (91) | 12 (75) | 132 (80) | .20 |
| Lobular or mixed | 37 (14) | 1 (3) | 4 (7) | 4 (25) | 28 (17) | |
| Other | 8 (3) | 1 (3) | 1 (2) | 0 (0) | 6 (4) | |
| Tumor differentiation | ||||||
| Well | 8 (3) | 2 (7) | 0 | 0 | 6 (4) | .60 |
| Moderately | 121 (48) | 14 (50) | 24 (45) | 7 (47) | 76 (48) | |
| Poorly | 124 (49) | 12 (43) | 29 (55) | 8 (53) | 75 (48) | |
| Unknown | 13 | 1 | 2 | 1 | 9 | |
| LVI | ||||||
| Present | 126 (48) | 19 (66) | 20 (38) | 6 (38) | 81 (50) | .08 |
| Absent | 135 (52) | 10 (34) | 33 (62) | 10 (62) | 82 (50) | |
| Unknown | 5 | 0 | 2 | 0 | 3 | |
| ECE | ||||||
| Present | 104 (41) | 9 (32) | 17 (33) | 5 (33) | 73 (46) | .20 |
| Absent | 148 (59) | 19 (68) | 35 (67) | 10 (67) | 84 (54) | |
| Unknown | 14 | 1 | 3 | 1 | 9 | |
| Neoadjuvant chemotherapyc | ||||||
| Yesd | 186 (70) | 17 (59) | 43 (78) | 13 (81) | 113 (68) | .20 |
| No | 80 (30) | 12 (41) | 12 (22) | 3 (19) | 53 (32) | |
| Type of axillary surgery | ||||||
| SLNB + ALND | 204 (77) | 24 (83) | 40 (73) | 14 (88) | 126 (76) | .60 |
| ALND only | 62 (33) | 5 (17) | 15 (27) | 2 (12) | 40 (24) | |
| Total No. of lymph nodes removed, median (IQR) | 18 (14-23) | 15 (12-23) | 17 (13-22) | 22 (18-24) | 19 (14-23) | .04b |
| Total No. of positive nodes, median (IQR) | 2 (1-5) | 2 (1-4) | 2 (1-3) | 2 (1-3) | 3 (1-7) | .05 |
| Type of breast surgery | ||||||
| BCS | 64 (24) | 3 (10) | 19 (35) | 6 (38) | 36 (22) | .04b |
| Mastectomy | 202 (76) | 26 (90) | 36 (65) | 10 (62) | 130 (78) | |
| Type of reconstructione | ||||||
| None | 54 (27) | 8 (31) | 9 (25) | 1 (10) | 36 (28) | .13 |
| Autologous/flap | 22 (15) | 2 (11) | 8 (30) | 1 (11) | 11 (12) | |
| TE/implant | 126 (85) | 16 (89) | 19 (70) | 8 (89) | 83 (88) | |
| Any RT | ||||||
| Yes | 252 (95) | 26 (90) | 55 (100) | 16 (100) | 155 (93) | .08 |
| No | 14 (5) | 3 (10) | 0 | 0 | 11 (7) | |
| Nodal RTf | ||||||
| Yes | 248 (93) | 25 (86) | 55 (100) | 16 (100) | 152 (92) | .02b |
| No | 18 (7) | 4 (14) | 0 | 0 | 14 (8) | |
Abbreviations: ALND, axillary lymph node dissection; BCS, breast-conserving surgery; BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; ECE, extracapsular extension; HR, hormone receptor; LVI, lymphovascular invasion; RT, radiotherapy; SLNB, sentinel lymph node biopsy; TE, tissue expander.
Race and ethnicity were unknown in 10 cases, which are excluded from the table.
Statistically significant values.
Of the 148 patients with ERBB2− disease treated with NAC, 66 (45%) received capecitabine.
A total of 264 patients received chemotherapy (n = 193 [NAC], n = 71 [adjuvant chemotherapy]); 93% received a regimen containing an anthracycline and taxane in a dose-dense fashion (over 16-20 weeks).
Applies to patients who underwent mastectomy only (n = 202).
Includes the ipsilateral supraclavicular and infraclavicular fossa, level 1 and 2 axillary nodes, and the internal mammary nodal chain, encompassing the first 3 intercostal spaces.
BCRL Rates Among Patients Who Underwent ALND
At median follow-up of 22.6 months, 56 patients developed BCRL. The 24-month BCRL rate was 23.8% (95% CI, 17.9%-29.8%) (Figure, A). The BCRL rates varied significantly by race and ethnicity, with the highest rate observed in Black women (24-month rate, Asian patients: 22.5%; 95% CI, 2.2%-42.8%; Black patients: 37.2%; 95% CI, 22.6%-51.9%; Hispanic patients: 27.7%; 95% CI, 3.3%-52.1%; White patients: 19.8%; 95% CI, 12.5%-27.0%; P = .004) (Figure, B). The BCRL rates were also higher among patients treated with NAC vs up-front surgery (24-month rate: 29.3%; 95% CI, 21.7%-36.9%; vs 11.1%; 95% CI, 3.0%-19.2%; P = .01) (Figure, C), with the highest BCRL rates observed among patients who received NAC who were treated with adjuvant capecitabine (24-month rate, capecitabine: 44.3%; 95% CI, 30.2%-58.3%; vs no capecitabine: 23.9%; 95% CI, 12.0%-35.7%; P = .02) (eFigure in the Supplement).
Figure. Competing Risk Analysis of Breast Cancer–Related Lymphedema by Overall Cohort, Race and Ethnicity, and Treatment Group.
The blue vertical dashed lines indicate the 24-month lymphedema rate. In panel A, the shaded area indicates the 95% CI. NAC indicates neoadjuvant chemotherapy.
Factors Associated With BCRL After ALND
Factors associated with BCRL development on univariate analysis are shown in Table 2. On multivariable analysis, Black race and Hispanic ethnicity (compared with White race) (odds ratio [OR], 3.88; 95% CI, 2.14-7.08 and OR, 3.01; 95% CI, 1.10-7.62, respectively; P < .001 for each), receipt of NAC (compared with up-front surgery) (OR, 2.10; 95% CI, 1.16-3.95; P = .01), older age (OR, 1.04; 95% CI, 1.02-1.07 per 1-year increase; P = .001), and longer follow-up interval (OR, 1.57; 95% CI, 1.30-1.90 per 6-month increase; P < .001) were independently associated with BCRL development, while ERBB2-positive subtype was associated with decreased risk of BCRL (compared with hormone receptor positive, ERBB2 negative) (OR, 0.50; 95% CI, 0.23-0.99; P = .04) (Table 2).
Table 2. Univariate and Multivariable Associations Between Clinicopathological Factors and the Odds of Developing Breast Cancer–Related Lymphedema for the Entire Study Cohort.
| Factor | Univariate analysis | Multivariable analysis | ||
|---|---|---|---|---|
| Odds ratio (95% CI) | P value | Odds ratio (95% CI) | P value | |
| Age, per 1-y increase | 1.03 (1.02-1.05) | <.001a | 1.04 (1.02-1.07) | .001a |
| Baseline BMI [referent: <25] | ||||
| 25-30 | 1.31 (0.74-2.30) | .04a | 0.84 (0.44-1.60) | .40 |
| >30 | 1.94 (1.16-3.26) | 1.29 (0.73-2.29) | ||
| Change in BMI over time | 1.01 (0.91-1.12) | .80 | ||
| Dominant arm affected [referent: no] | 0.76 (0.49-1.18) | .20 | ||
| Race and ethnicity [referent: White] | ||||
| Asian | 1.32 (0.58-2.72) | <.001a | 1.78 (0.72-4.01) | <.001a |
| Black | 3.19 (1.92-5.28) | 3.88 (2.14-7.08) | ||
| Hispanic | 2.28 (0.93-5.01) | 3.01 (1.10-7.62) | ||
| Other/unknown | 0.89 (0.14-3.16) | 0.96 (0.14-3.80) | ||
| Clinical T stage [referent: T1] | ||||
| 2 | 1.02 (0.59-1.82) | .50 | ||
| 3 | 0.88 (0.41-1.81) | |||
| 4 | 0.86 (0.40-1.77) | |||
| X | 2.80 (0.72-9.24) | |||
| Clinical N stage [referent: N0] | ||||
| 1 | 1.75 (1.03-3.12) | .09 | ||
| 2 | 1.71 (0.25-6.85) | |||
| 3 | 2.65 (1.11-6.05) | |||
| Subtype [referent: HR+/ERBB2−] | ||||
| ERBB2+ | 0.50 (0.24-0.94) | .006a | 0.50 (0.23-0.99) | .04a |
| HR−/ERBB2− | 1.81 (0.99-3.18) | 1.45 (0.73-2.81) | ||
| Histology [referent: ductal] | ||||
| Lobular or mixed | 1.04 (0.55-1.86) | .12 | ||
| Other | NA | |||
| Tumor differentiation [referent: poorly differentiated] | ||||
| Well | NA | .06 | ||
| Moderately | 0.97 (0.62-1.51) | |||
| LVI [referent: no LVI] | 0.86 (0.55-1.34) | .50 | ||
| ECE [referent: no ECE] | 1.14 (0.72-1.80) | .60 | ||
| Total No. of lymph nodes removed, per 1-lymph-node increase | 1.04 (1.01-1.06) | .007a | 1.04 (1.00-1.08) | .03 |
| Total No. of positive lymph nodes, per 1-lymph-node increase | 1.04 (1.01-1.06) | .02a | 1.02 (0.98-1.06) | .30 |
| Type of breast surgery [referent: BCS] | ||||
| Mastectomy | 0.46 (0.29-0.72) | <.001a | 0.76 (0.44-1.30) | .30 |
| Reconstruction [referent: no reconstruction] | ||||
| Autologous/flap | 1.16 (0.49-2.63) | .20 | ||
| TE/implant | 0.65 (0.35-1.24) | |||
| Up-front surgery vs NAC [referent: up-front surgery] | ||||
| NAC | 1.88 (1.13-3.27) | .02a | 2.10 (1.16-3.95) | .01a |
| Breast pCR [referent: no pCR] | 0.46 (0.16-1.09) | .08 | ||
| Nodal RT [referent: no nodal RT] | 1.49 (0.58-5.03) | .40 | ||
| Time from surgery to last follow-up, per 6-mo increase | 1.57 (1.28-1.94) | <.001a | 1.57 (1.30-1.90) | <.001a |
Abbreviations: BCS, breast-conserving surgery; BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; ECE, extracapsular extension; HR, hormone receptor; LVI, lymphovascular invasion; NA, not applicable; NAC, neoadjuvant chemotherapy; pCR, pathological complete response; RT, radiotherapy; TE, tissue expander.
Statistically significant values.
Discussion
In this prospective cohort of women treated with ALND and nodal RT, 24-month BCRL incidence was 23.8%. Black race, Hispanic ethnicity, NAC receipt, older age, and longer follow-up were independently associated with BCRL development, while presumed risk factors, such as high baseline BMI and increasing BMI after surgery, were not. Association between Black race and BCRL development has been reported in prior population-based studies,3,4 but with limited accuracy because lymphedema diagnosis was based on self-reporting and International Classification of Diseases, Ninth Revision codes, and there are limited data on BCRL risk in Hispanic women.
The cause of the higher observed incidence of BCRL in Black women is unknown. Increased fibrosis and chronic inflammation are possible underlying mechanisms. Dysregulated scarring and connective tissue overgrowth is common in African-origin populations and present with various clinical manifestations, such as hypertrophic scar formation, nephrosclerosis, and scleroderma.6 Additionally, altered inflammatory pathways with increased interleukin (IL)-4/IL-13 signaling, commonly identified in lymphedematous tissues, have also been reported in Black populations.7 Studies evaluating the mechanism for this increased risk are necessary to identify targeted treatment strategies to mitigate BCRL risk. While Hispanic women also had increased risk of BCRL development, the number of Hispanic women in the study was small; confirmation in a larger data set is needed.
We also observed a 2-fold increased risk of BCRL development in patients who underwent ALND who were treated with NAC vs up-front surgery, similar to the elevated risk observed in patients treated with NAC enrolled in the American College of Surgeons Oncology Group Z1071 lymphedema substudy.8 Possible underlying mechanisms for the higher observed BCRL rate in patients treated with NAC include fibrosis of tumor-filled lymphatics and lymphatic endothelial damage prior to surgery,9 resulting in higher BCRL rates vs the up-front surgery setting, where the lymphatic endothelial cells have not yet been exposed to systemic chemotherapy. Alternatively, the increased risk in patients treated with NAC may be attributed to those receiving additional chemotherapy with capecitabine, which has also been shown to damage endothelial cells,10 with further study needed to explore this novel finding.
While NAC is typically given to downstage the axilla, patients with hormone receptor–positive/ERBB2-negative breast cancer have the lowest nodal pathologic complete response (pCR) rates11 and comprised the majority (58%) of our NAC cohort. Additionally, data from the RxPONDER trial12 demonstrated that postmenopausal patients with limited nodal burden and low 21-gene recurrence score did not benefit from chemotherapy. Therefore, there is an unmet need to identify alternative strategies to avoid ALND in this patient group. Conversely, for patients who need NAC but who do not achieve nodal pCR, nodal RT as an alternative approach to ALND is currently being investigated in 2 large randomized clinical trials, Alliance A01120213 and TAXIS,14 which may reduce the future need for ALND.
Strengths and Limitations
Strengths of our study include its prospective design, study population diversity, and strict BCRL measurement protocol. Limitations include its short median follow-up; however, BCRL is most likely to occur within the first 2 years after surgery,1 with peak incidence after ALND and nodal RT occurring 18 to 24 months after surgery.15 Additionally, data on socioeconomic status, which may contribute to BCRL risk, were not available, although patients in our study received similar treatments across racial and ethnic groups. Finally, we were unable to assess the independent effect of nodal RT on BCRL risk because most patients received this treatment.
Conclusions
In a prospectively screened cohort of patients treated with ALND and nodal RT, Black race, Hispanic ethnicity, receipt of NAC, older age, and longer follow-up were independently associated with BCRL development. Future studies should address biologic mechanisms behind racial and ethnic disparities in BCRL development, further explore the mechanism for BCRL development in patients treated with NAC, and evaluate alternatives to NAC, to avoid ALND in tumor subtypes unlikely to achieve nodal pCR.
eTable. Clinicopathological features of the study cohort, stratified by treatment group
eFigure. Competing risk analysis of breast cancer-related lymphedema among HER2 negative patients treated with NAC, stratified by receipt of capecitabine
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable. Clinicopathological features of the study cohort, stratified by treatment group
eFigure. Competing risk analysis of breast cancer-related lymphedema among HER2 negative patients treated with NAC, stratified by receipt of capecitabine