Table 1.

Overview of the epidemiologic studies examining CLS-B and female breast cancer.

First Author (Year)	Study Design	Institutions/ Affiliations	Country, Race/ Ethnicity Distribution	Study Population	Study Years	CLS-B Analyses Conducted
Breast cancer incidence studies (n = 2)
Shaik (2020) [84]	Nested case–control + cross-sectional analysis	Detroit BBD cohort and KTB	USA 100% AA	n = 84 BBD cases n = 47 BBD controls n = 50 KTB volunteers without BBD or breast cancer	BBD diagnosis: 1997–2010 Follow up for breast cancer through 2016	Association between CLS-B and breast cancer among AA women with BBD CLS-B occurrence in normal breast tissue BMI and CLS-B associations Adipocyte diameter and CLS-B Associations between IL (another inflammatory marker) with breast cancer and BBD among AA women
Carter (2017) [85]	Nested case–control + cross-sectional analysis	Mayo BBD cohort and KTB	USA Unknown	n = 86 BBD cases n = 86 BBD controls n = 86 KTB volunteers without clinical breast abnormalities	BBD diagnosis: 1967–2001 Follow up for breast cancer: Unknown	Association between CLS-B and breast cancer among BBD patients CLS-B occurrence in normal breast tissue Participant and clinical characteristics associated with CLS-B Stromal CD68+ macrophage infiltration by BBD and breast cancer status
Breast cancer prognosis studies (n = 4)
Maliniak (2020) [69]	Cohort + cross-sectional analysis	Emory University-affiliated tumor registries	USA 51% AA 49% White	n = 342 breast cancer patients Age ≥ 18 years old Stage I–III, invasive Underwent mastectomy No neoadjuvant treatment	Breast cancer diagnosis: 2007–2012 Follow up for breast cancer outcomes: 2018	Association between CLS-B and breast cancer prognosis Occurrence of CLS-B by race (AA vs. White) Participant and tumor characteristics associated with CLS-B Adipocyte number and CLS-B
Cha (2018) [86]	Cohort + cross-sectional analysis	Yonsei University	South Korea	Group 1: n = 56 non-breast cancer patients Tissue from reduction mammoplasty Group 2: n = 84 breast cancer patients Non-tumor breast tissue Group 3: n = 140 breast cancer patients Tumor-containing breast tissue	Unknown	Association between CLS-B and breast cancer prognosis (Group 3 only) Occurrence of CLS-B by breast cancer status and type of tissue among breast cancer patients (non-neoplastic vs. neoplastic) Participant and tumor characteristics associated with CLS-B (Group 3 only) Associations between number of infiltrating CD68+ and CD163+ in adipose tissue and tumor tissue with CLS-B detected by CD68 and CD163 (Group 3 only)
Koru-Sengul (2016) [87]	Cohort + cross-sectional analysis	University of Miami/Jackson Memorial Hospital tumor registry	USA 33% Black 33% non-Black Latina 33% Caucasian	n = 150 breast cancer patients Stage I–IV No previous exposure to chemotherapy, radiotherapy, or hormonal therapy	Cases obtained: 1978–1997 Followed for at least 5 years	Association between CLS-B and breast cancer prognosis Density of CLS-B across racial groups (Black, non-Black Latina, and Caucasian) Differences in densities of CLS-B macrophage phenotypes (M1, M2, pan) across racial groups Densities of TAMs by macrophage marker type and across racial groups Proliferative capacity of TAMs by proximity to tumor cells and across racial ethnic groups
Iyengar (2016) [82]	Cohort + cross-sectional analysis	MSKCC	USA 83% White 13% Black 3% Asian	Cohort 1: n = 100 patients (mostly breast cancer) Underwent mastectomy Cohort 2: n = 127 breast cancer patients All developed distant metastases but initially diagnosed with stage I–III breast cancer	Mastectomy: 2011–2013 (Cohort 1); 2001–2006 (Cohort 2) Cohort 2: Follow up for breast cancer outcomes: 2014	Cohort 1: Participant and tumor characteristics associated with CLS-B Circulating metabolic and inflammatory markers associated with CLS-B Cohort 2: Association between CLS-B and breast cancer prognosis Participant and tumor characteristics associated with CLS-B
Cross-sectional studies of CLS-B (n = 8)
Greenlee (2018) [70]	Cross-sectional	Columbia University Medical Center	USA 100% Hispanic a	n = 91 breast cancer patients Stage 0–III Underwent mastectomy 16% had neoadjuvant chemotherapy	Mastectomy: 2007–2012	Occurrence of CLS-B among Hispanic/Latina breast cancer patients Participant and tumor characteristics associated with CLS-B Adipocyte diameter and CLS-B Liver function biomarkers and CLS-B
Iyengar (2018) [81]	Cross-sectional	National Taiwan University Hospital and MSKCC	Taiwan USA 100% Caucasian	n = 72 Taiwanese breast cancer patients Non-metastatic Underwent mastectomy n = 267 US Caucasian patients Underwent mastectomy	Mastectomy: 2011–2016 (Taiwanese); 2011–2013 (US Caucasian)	Comparisons of CLS-B and breast adipocyte size in Taiwanese vs.US Caucasian women Participant and tumor characteristics associated with CLS-B (Taiwanese only) Body composition (body fat, VAT, SAT) factors associated with CLS-B (Taiwanese only) Circulating metabolic and inflammatory markers associated with CLS-B (Taiwanese only) Adipocyte diameter and CLS-B
Iyengar (2017) [71]	Cross-sectional	MSKCC	USA 76% Caucasian 9% Black, Asian, or Other 14% Unknown	n = 72 patients (mostly breast cancer) Normal weight (BMI < 25 kg/m2) Underwent mastectomy	Mastectomy: 2011–2013	Occurrence of CLS-B in normal weight women Participant and tumor characteristics associated with CLS-B Circulating metabolic and inflammatory markers associated with CLS-B Circulating leptin and CLS-B, aromatase expression, and adipocyte diameter associations Adipocyte diameter and CLS-B Aromatase activity and CLS-B, BMI, and adipocyte diameter associations
Mullooly (2017) [80]	Cross-sectional	PBCS	Poland	n = 83 breast cancer patients Invasive breast cancer Postmenopausal and not taking hormone replacement Underwent surgery No neoadjuvant treatment	Study recruitment: 2000–2003	Participant and tumor characteristics associated with CLS-B and number of CD68-positive cells CLS-B associations with concentrations and ratios of sex-steroid hormones in breast adipose tissue vs. systemic circulation
Vaysse (2017) [83]	Cross-sectional	Energy Balance and Breast Cancer Aspects-II	Norway	n = 107 breast cancer patients Aged 25–75 years Stage I–II, invasive 71% underwent breast conserving surgery	Unknown	BMI, WHR, % truncal fat and CLS-B associations overall and by menopausal status Circulating metabolic and inflammatory markers associated with CLS-B overall and by menopausal status Adipocyte diameter and CLS-B
Brown (2017) [72]	Cross-sectional	MSKCC	USA	n = 161 patients (mostly breast cancer) Aged 27–74 years Underwent mastectomy	Unknown	Menopause and CLS-B association The effect of menopause on CLS-B and aromatase expression associations
Iyengar (2015) [73]	Cross-sectional	MSKCC	USA 86% White 7% Black 6% Asian	n = 237 patients (mostly breast cancer) Aged 22–90 years Underwent mastectomy 14% received preoperative chemotherapy 39% of those tested had BRCA1/2 mutation	Mastectomy: 2011–2013	Participant and tumor characteristics associated with CLS-B Adipocyte diameter and CLS-B Comparison of CLS-B status between bilateral breasts Comparison of CLS-B status with abdominal CLS status
Morris (2011) [67]	Cross-sectional (pilot study)	MSKCC	USA	n = 30 patients (mostly breast cancer) Aged 26–70 years Underwent mastectomy	Enrolled: 2010	BMI and CLS-B association Adipocyte diameter and CLS-B Aromatase expression and activity and CLS-B NF-kB binding activity and CLS-B

Abbreviations: BBD = benign breast disease; BMI = body mass index; CLS-B = crown-like structures in breast adipose tissue; IL = infiltrating lymphocytes; KTB = Komen Normal Tissue Bank; MSKCC = Memorial Sloan Kettering Cancer Center; PBCS = Polish Breast Cancer Study; TAMs = tumor-associated macrophages; WHR = waist-to-hip ratio; USA = United States of America. ^a Greenlee et al. (2018) also included information on country of origin: 63% Dominican Republic, 16% Puerto Rican, 2% South American, 2% Mexican, and 16% Other Hispanic.