Program Official
Principal Investigator
Babak J
Mehrara
Awardee Organization
Sloan-Kettering Inst Can Research
United States
Fiscal Year
2025
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date
NIH RePORTER
For more information, see NIH RePORTER Project 5R01CA278599-03
Mechanisms of racial disparity in breast cancer-related lymphedema
This proposal is significant because we aim to study the cellular mechanisms that regulate the increased risk of breast cancer-related lymphedema (BCRL) development in Black women. This is important because BCRL is a highly morbid disease that causes chronic and progressive arm swelling. Patients who develop BRCL have diminished quality of life, require life-long care with compression garments, and can develop recurrent infections that require hospitalization. Due to the high prevalence of breast cancer, BCRL is the most common form of lymphedema in developed countries, afflicting 20–35% of women who undergo axillary lymph node dissection (ALND). To identify risk factors for BCRL, our group has prospectively followed 276 women with arm measurements before and after ALND for 2 years. We have found that Black women have the highest risk of BCRL even after adjusting for confounding variables. In our study, Black race increased the risk of BCRL development by >3.6 fold compared with White race. These findings are supported by two other published studies reporting increased risk of BCRL development in Black women who undergo ALND for breast cancer. Thus, while there is strong evidence that Black women have a significantly increased risk of developing BCRL, the cellular mechanisms that regulate this risk remain unknown. This gap in our knowledge is important and a major barrier to developing novel therapies that prevent or treat lymphedema in this patient population. In addition, understanding how Black race increases the risk of BCRL may shed light on the mechanisms that regulate the pathophysiology of this disease in general. Based on prior research and our preliminary studies, our central hypothesis is that Black women have an increased risk of developing BCRL due to a baseline increased propensity for inflammation and fibrosis. We propose to test this hypothesis using two Specific Aims. In Aim 1, we will analyze how racial disparities modulate inflammatory responses following lymphatic injury. This hypothesis is based on the finding that the pathophysiology of lymphedema is linked to chronic inflammation and development of T-helper 2 (Th2)-biased immune responses. Black patients have a propensity for inflammation in other pathological settings, suggesting that these differences may also contribute to an increased risk for developing BCRL. In Aim 2, we will test the hypothesis that Black women have an increased fibrotic response to lymphedema. This hypothesis is based on the observation that fibrosis is a key pathological feature of lymphedema and plays a major role in regulating lymphatic function. Black individuals have an increased potential for fibrosis in a variety of pathological settings including inflammatory skin disorders.
- Kuonqui KG, Campbell AC, Pollack BL, Shin J, Sarker A, Brown S, Park HJ, Mehrara BJ, Kataru RP. Regulation of VEGFR3 signaling in lymphatic endothelial cells. Frontiers in cell and developmental biology. 2025 Feb 13;13:1527971. doi: 10.3389/fcell.2025.1527971. eCollection 2025. PMID: 40046235
- Rochlin DH, Barrio AV, McLaughlin S, Van Zee KJ, Woods JF, Dayan JH, Coriddi MR, McGrath LA, Bloomfield EA, Boe L, Mehrara BJ. Feasibility and Clinical Utility of Prediction Models for Breast Cancer-Related Lymphedema Incorporating Racial Differences in Disease Incidence. JAMA surgery. 2023 Sep 1;158(9):954-964. PMID: 37436762
- Brown S, Nores GDG, Sarker A, Ly C, Li C, Park HJ, Hespe GE, Gardenier J, Kuonqui K, Campbell A, Shin J, Kataru RP, Aras O, Mehrara BJ. Topical captopril: a promising treatment for secondary lymphedema. Translational research : the journal of laboratory and clinical medicine. 2023 Jul;257:43-53. Epub 2023 Feb 1. PMID: 36736951
- Campbell AC, Fei T, Baik JE, Park HJ, Shin J, Kuonqui K, Brown S, Sarker A, Kataru RP, Mehrara BJ. Skin microbiome alterations in upper extremity secondary lymphedema. PloS one. 2023 May 17;18(5):e0283609. doi: 10.1371/journal.pone.0283609. eCollection 2023. PMID: 37196005
- Coriddi M, Dayan J, Bloomfield E, McGrath L, Diwan R, Monge J, Gutierrez J, Brown S, Boe L, Mehrara B. Efficacy of Immediate Lymphatic Reconstruction to Decrease Incidence of Breast Cancer-related Lymphedema: Preliminary Results of Randomized Controlled Trial. Annals of surgery. 2023 Oct 1;278(4):630-637. Epub 2023 Jun 14. PMID: 37314177
- Brown S, Campbell AC, Kuonqui K, Sarker A, Park HJ, Shin J, Kataru RP, Coriddi M, Dayan JH, Mehrara BJ. The Future of Lymphedema: Potential Therapeutic Targets for Treatment. Current breast cancer reports. 2023 Jun 1: 1-9. Epub 2023 Jun 1. PMID: 37359311
- Brown S, Dayan JH, Kataru RP, Mehrara BJ. The Vicious Circle of Stasis, Inflammation, and Fibrosis in Lymphedema. Plastic and reconstructive surgery. 2023 Feb 1;151(2):330e-341e. Epub 2022 Nov 15. PMID: 36696336
- Kuonqui K, Campbell AC, Sarker A, Roberts A, Pollack BL, Park HJ, Shin J, Brown S, Mehrara BJ, Kataru RP. Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease. Cells. 2023 Dec 28;13. (1). PMID: 38201272
- Heller DR, Axelrod B, Sevilimedu V, Morrow M, Mehrara BJ, Barrio AV. Quality of Life After Axillary Lymph Node Dissection Among Racial and Ethnic Minority Women. JAMA surgery. 2024 Jun 1;159(6):668-676. PMID: 38536186
- Brown S, Kokosis G, Graziano FD, Haran O, Smith-Montes E, Zivanovic O, Ariyan CE, Coit DG, Coriddi M, Mehrara BJ, Dayan JH. Immediate Lymphatic Reconstruction with Vascularized Omentum Lymph Node Transplant: Reducing the Risk of Both Painful Contracture and Lymphedema. Plastic and reconstructive surgery. Global open. 2024 Apr 19;12(4):e5747. doi: 10.1097/GOX.0000000000005747. eCollection 2024 Apr. PMID: 38645629
- Friedman R, Johnson AR, Brunelle CL, Chang DW, Coriddi M, Dayan JH, Mehrara BJ, Skoracki R, Taghian AG, Singhal D. Lymphatic Microsurgical Preventative Healing Approach for the Primary Prevention of Lymphedema: A 4-Year Follow-Up. Plastic and reconstructive surgery. 2024 Feb 1;153(2):491e-492e. Epub 2023 May 26. PMID: 38266142