Abstract
This case series evaluates whether differences in immune filtration are associated with breast cancer risk in Black vs White women.
Population-based breast cancer mortality rates are 40% higher in Black women than White women.1 This disparity is partly explained by Black women having a 2-fold higher incidence of tumors negative for expression of estrogen receptor, progesterone receptor, and ERBB2, ie, triple-negative breast cancer (TNBC).1 Advances in cancer genomics have generated insights regarding immunotherapeutics in breast cancer. TNBC is more likely to respond to immunomodulation with cell cycle checkpoint inhibitors; it is hypothesized that this response is related to frequency of tumor-infiltrating lymphocytes or tumor-associated leukocytes (TALs).2 Several millennia of evolutionary selection pressure on the human genome shaped by exposure to infectious pathogens in Africa have resulted in germline genetic variants associated with African ancestry that were acquired because of their association with resistance to deadly diseases. Some of these variants may have consequences on the mammary tissue microenvironment, immune landscape, and risk of TNBC.3,4,5
In this case series, we evaluated whether differences in immune infiltration, which may be related to these variants, might also be associated with breast cancer risk in women with African ancestry.
Methods
We used publicly available, anonymized data from The Cancer Genome Atlas (TCGA; cases diagnosed 1978-2013) to evaluate TALs in breast cancers of Black vs White patients. Owing to the use of deidentified data, this study was exempt from review by the Weill Cornell Medicine institutional review board and informed consent was not required. Race was determined from TCGA enrollment forms and originated from self-reported data. Entry options for race included American Indian or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific Islander; White; not evaluated; and unknown. Entry options for ethnicity included not Hispanic or Latino; Hispanic or Latino; not evaluated; and unknown.
TAL estimation was calculated by deconvolution of RNA sequencing.4 High and low categories were determined using a stratified median cutoff. Overall survival was calculated using Kaplan-Meier survival estimates, visualized as survival curves. Log-rank tests were used to calculate differences in survival for each stratified category. R version 3.6.3 (R Foundation) was used for analysis. Two-sided P < .05 was considered significant.
Results
The Table summarizes characteristics of the 923 patients analyzed (743 White women, 180 Black women; mean [SD] age, 58.1 [13.1] years); 598 (64.8%) had high TALs and 325 (35.2%) had low TALs. Patients with high TALs were significantly younger than those with low TALs (median [range], 56.9 [27-90] vs 60.1 [26-90] years; P < .001). Patients with TNBC were more likely to have high TALs than patients without TNBC (79.8% vs 63.0%; P = .001). The frequency of high TALs was similar for Black and White patients (124 of 180 [68.9%] vs 474 of 743 [63.8%]; P = .23). Approximately two-thirds of patients had high TALs regardless of disease stage.
Table. Clinicopathologic Features of the Study Population, Stratified by High vs Low Tumor-Associated Lymphocytes (TALs)a.
| Characteristic | No./total No. (%) | P value | |
|---|---|---|---|
| High TALs (n = 598) | Low TALs (n = 325) | ||
| Age, median (range), y | 56.9 (27-90) | 60.1 (26-90) | <.001 |
| TNBC status | |||
| Non-TNBC | 519/824 (63.0) | 305/824 (37.0) | .001 |
| TNBC | 79/99 (79.8) | 20/99 (20.2) | |
| AJCC stage | |||
| I | 113/172 (65.7) | 59/172 (34.3) | .046 |
| II | 331/511 (64.8) | 180/511 (35.2) | |
| III | 138/207 (66.7) | 69/207 (33.3) | |
| IV | 7/15 (46.7) | 8/15 (53.3) | |
| Stage group | |||
| Advanced stageb | 145/222 (65.3) | 77/222 (34.7) | >.99 |
| Early stage | 444/683 (65.1) | 239/683 (35.0) | |
| Racec | |||
| Black | 124/180 (68.9) | 56/180 (31.1) | .23 |
| White | 474/743 (63.8) | 269/743 (36.2) | |
Abbreviations: AJCC, American Joint Committee on Cancer; TNBC, triple-negative breast cancer.
Numbers do not add up to a total sample size of 923 because of missing information regarding selected features.
Advanced stage indicates AJCC stages I and II.
Race was determined from The Cancer Genome Atlas enrollment forms and originated from self-reported data. Entry options for race included American Indian or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific Islander; not evaluated; unknown; and White. Entry options for ethnicity included not Hispanic or Latino; Hispanic or Latino; not evaluated; and unknown.
Having high TALs was associated with improved overall survival (Figure). Overall survival rates stratified by race demonstrated divergent results; having high TALs was correlated with higher survival for White patients but not Black patients.
Figure. Overall Survival (OS) by Tumor-Associated Lymphocytes (TALs).
OS by TALs in all patients (A) and stratified by Black (B) and White (C) women.
Discussion
Our analysis of TCGA data suggests a disparate impact of TALs on breast cancer outcomes in Black vs White women. We previously demonstrated that African ancestry–associated variants such as Duffy null have a phenotype-agnostic impact on breast cancer outcomes based on TCGA data.6 Others have shown that breast tumors of Black patients feature a unique signature of “exhausted T cells” that can potentially mitigate the expected favorable effect of TALs on breast cancer survival.5
Limitations include the fact that small sample sizes of TNBC cases precluded meaningful subset analyses based on phenotype. Patients with TCGA data also tend to be cases selected by tumor availability rather than adjacent stromal tissue, and TAL expression in the microenvironment with tumor and stroma cross talk may have heightened relevance in assessing prognosis and predicting treatment response.
Despite these limitations, our findings indicate that race and ethnicity and/or genetic ancestry are relevant in understanding the potential value of immunotherapeutics in contemporary breast cancer management.
Data Sharing Statement
References
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Supplementary Materials
Data Sharing Statement