Citations

Abstract Background: Benign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis, and how these relate to risk of incident BC. Methods: A subset of a long-term BBD cohort was selected to examine DNA variation across three BBD groups (42 future estrogen receptor-positive (ER+) BC, 36 future estrogen receptor-negative (ER-) BC and 42 controls cancer-free for at least 16 years post-BBD). DNA extracted from archival formalin fixed, paraffin-embedded (FFPE) tissue blocks was tested and analyzed for presence of DNA alterations using a targeted panel of 93 BC-associated genes. To address artifacts frequently observed in FFPE tissues (e.g., C>T changes), we applied three filtering strategies based on alternative allele frequencies and nucleotide substitution context. Gene-level associations were performed using two burden tests, SKAT-O and logistic regression, and adjusted for clinical and technical covariates including epithelial percentage, histologic impression, patient age and year of BBD biopsy. Results: After filtering, the variant frequency of SNPs in our samples was highly consistent with population allele frequencies reported in 1KG/ExAC (0.986, p <1e-16). Ten genes were found to be associated with later cancer status by four of 12 association methods, with nominal p-values <0.05: MED12, MSH2, BRIP1, PMS1, GATA3, MUC16, FAM175A, EXT2, MLH1 and TGFB1. Additionally, analysis revealed 11 and 19 gene-level associations with p-values <0.05 and OR<1 for all cancer cases and ER- cases, respectively. Comparing between the three case groups, BBD ER+ cases were closer to controls in mutation profile, while BBD ER- cases were distinct. Notably, the variant burden was significantly higher in controls than in either ER+ or ER- cases. CD45 expression was associated with mutational burden (p=0.003).Conclusions: Somatic mutations were more frequent in benign breast tissue from women who did not develop cancer, opening questions of clonal diversity or immune-mediated restraint on future cancer development. CD45 expression was positively associated with mutational burden, most strongly in controls. Further studies in both normal and premalignant tissues are needed to better understand the role of somatic gene mutations and their contribution to future cancer development.

Abstract Background: Women with benign breast disease (BBD) are at increased risk of breast cancer (BC). Classic studies based on film-based mammographic screening and pathology diagnosis of surgical biopsies conducted in the 1980s established a hierarchy of increasing BC risk: non-proliferative (NP) BBD, proliferative BBD without atypia (PDWA) and atypical hyperplasia (AH). Given changes in epidemiological BC risk factors and introduction of percutaneous core needle biopsy (CNB) in mid-1990s, and later, digital mammography, we hypothesized that the patient characteristics and relative frequency of BBD diagnoses have changed over time. Accordingly, we performed a longitudinal analysis of the frequency of patient characteristics and BBD diagnoses in the Mayo BBD cohort. Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had a BBD biopsy between 1/1/67 and 12/31/13 were identified. Breast pathologists reviewed biopsies masked to diagnoses of incident BC diagnosed in follow-up. Demographic characteristics and BC events were obtained by query of institutional data sources and participant surveys. Trends were evaluated for the following eras: 1: pre-mammogram (1967-1981), 2: pre-CNB (1982-1992), 3: CNB Transition (1993-2001), and 4: CNB (2002-2013). Demographics were formally compared across eras using chi-square tests for categorical variables and analyses of variance (ANOVAs) for continuous variables. Results: From 1967-2013, the cohort includes 19,582 unique women with BBD. The frequency of CNB increased from eras 1-4: 0.04%, 0.6%, 51.3 %, and 88.9%, respectively. Mean age at BBD diagnosis was younger in era 1 (48.0 years) vs eras 2-4 (53.2, 52.0, and 51.8, respectively, p&lt;0.001). The percentage of biopsies diagnosed as PDWA increased from era 1-4 (25.7%, 34.3%, 35.2%, 46.2%, p&lt;0.001), as did the percentage with AH (2.4%, 5.1%, 8.6%, 12.3%, p&lt;0.001). Over eras 1-4, the percentages of women with a strong family history of BC increased (9.9%, 12.7%, 17.1%, and 29.0%, p&lt;0.001) as did mean BMI (24.8, 26.4, 27.4, and 28.6, p&lt;0.001). With a median follow-up of 10.9 years, 1,719 breast cancers have developed, with increasing proportion of noninvasive (DCIS-only) disease across eras 1-4: 15.0%, 21.1%, 21.2%, and 33.2%, p&lt; 0.001. Conclusions: Analysis of this large, single institution BBD cohort for the 46 year period 1967-2013 demonstrates that BC risk factors among BBD patients has changed over time, with subjects demonstrating increasing age, BMI, and family history, and that the percentages of BBD classified as PDWA and AH have increased. Impact on BC risk will be further investigated. Citation Format: Amy Degnim, Karthik Ghosh, Jodi M Carter, Robert A Vierkant, Matthew R Jensen, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Teresa M Allers, Denise L Gehling, Mindy J Kern, Laura M Pacheco-Spann, Celine M Vachon, Derek C Radisky, Daniel W Visscher, Mark E Sherman. Benign breast disease: Temporal trends from 1967 to 2013 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-11.

Abstract Background: Women with benign breast disease (BBD) experience an increased risk of breast cancer (BC). Histologic classification of BBD, as non-proliferative disease (NP), proliferative disease without atypia (PDWA) or atypical hyperplasia (AH), stratifies groups of patients into progressively higher categories of BC risk. However, this classification does not comprehensively assess the proliferative state of the epithelium throughout the biopsy. In addition, while AH is considered the most high-risk class of BBD, it is not always a highly proliferative lesion; atypical ductal lesions may reflect focal cytologic and architectural changes. We evaluated the association of an alternative classification of BBD severity and BC risk based on subjective grading of: 1) the maximal degree of epithelial proliferation and 2) multifocality of epithelial proliferation. Methods: Pathologists reviewed biopsies from participants aged 18 to 85 years in the Mayo BBD cohort (2002-2013), masked to BC outcomes, ascertained via questionnaires, tumor registry data and medical record review. Biopsies were classified as NP, PDWA or AH and semi-quantitatively scored for: 1) maximal degree of epithelial proliferation within a focus (DP) (0-3; none to severe) and 2) multifocality of proliferation (MP) (0-3; none to multiple foci). DP and MP scores were also summed to give a DP+MP score (0-6). Associations of DP and MP with BC risk were examined using Cox proportional hazards regression analyses, adjusting for age at BBD biopsy. Women were followed from date of initial biopsy to date of BC, death or last follow-up. Results: Of the 1529 assessable biopsies, 544 (35.6%) were classified as NP, 708 (46.3%) as PDWA and 277 (18.1%) as AH. Both DP and MP scores had significant positive correlation with increasing BBD severity (DP: r=0.51, p&lt; 0.001; MP: r=0.52, p&lt; 0.001). Mean (SD) DP scores were 0.6 (0.6) for NP, 1.6 (0.9) for PDWA, and 1.8 (0.7) for AH (ANOVA p&lt;0.001). Mean (SD) for MP scores were 0.6 (0.6) for NP, 1.4 (0.8) for PDWA, and 1.8 (0.8) for AH (ANOVA p&lt;0.001). Mean (SD) for DP+MP scores were 1.2 (1.2) for NP, 2.9 (1.5) for PDWA, and 3.6 (1.2) for AH (ANOVA p&lt;0.001). With median follow-up of 8.8 years for controls and 5.3 years for cases, 10.6% of the women in the cohort developed BC. Compared to those with DP scores of 0, women with DP scores of 3 had significantly increased BC risk (HR 1.42, 95% CI: 1.16, 1.74, p=0.003). MP was associated with a non-significant increase in BC risk for scores of 3 versus 0 (HR: 1.20, 95% CI: 0.97,1.49, p=0.11). DP+MP scores of 6 conferred the highest BC risk (HR (score 6 vs. 0): 1.62, 95% CI 1.18,2.21, p=0.02). Results did not substantively differ after adjusting for BBD severity as NP, PDWA or AH. Conclusions: In this preliminary analysis within the Mayo BBD cohort, both proliferative degree (DP) and multifocality (MP) scores were correlated with histologic severity of BBD. DP and DP+MP scores were each associated with increased BC risk. We conclude that improved characterization of epithelial proliferation in BBD biopsies may enable refined prediction of individual BC risk. Citation Format: Jodi M Carter, Matthew R Jensen, Robert A Vierkant, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Karthik Ghosh, Derek C Radisky, Amy C Degnim, Mark E Sherman. Epithelial proliferation score as an independent breast cancer risk predictor in benign breast disease [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-10.

Abstract Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

Abstract The role of active antitumor immunity in hormone receptor–positive (HR+) breast cancer has been historically underlooked. The aim of this study was to determine the contribution of the immune system to antiprogestin-induced tumor growth inhibition using a hormone-dependent breast cancer model. BALB/c-GFP+ bone marrow (BM) cells were transplanted into immunodeficient NSG mice to generate an immunocompetent NSG/BM-GFP+ (NSG-R) mouse model. Treatment with the antiprogestin mifepristone (MFP) inhibited growth of 59–2-HI tumors with similar kinetics in both animal models. Interestingly, MFP treatment reshaped the tumor microenvironment, enhancing the production of proinflammatory cytokines and chemokines. Tumors in MFP-treated immunocompetent mice showed increased infiltration of F4/80+ macrophages, natural killer, and CD8 T cells, displaying a central memory phenotype. Mechanistically, MFP induced immunogenic cell death (ICD) in vivo and in vitro, as depicted by the expression and subcellular localization of the alarmins calreticulin and HMGB-1 and the induction of an ICD gene program. Moreover, MFP-treated tumor cells efficiently activated immature dendritic cells, evidenced by enhanced expression of MHC-II and CD86, and induced a memory T-cell response, attenuating tumor onset and growth after re-challenge. Finally, MFP treatment increased the sensitivity of HR+ 59–2-HI tumor to PD-L1 blockade, suggesting that antiprogestins may improve immunotherapy response rates. These results contribute to a better understanding of the mechanisms underlying the antitumor effect of hormonal treatment and the rational design of therapeutic combinations based on endocrine and immunomodulatory agents in HR+ breast cancer. Significance: Antiprogestin therapy induces immunogenic tumor cell death in PRA-overexpressing tumors, eliciting an adaptive immune memory response that protects mice from future tumor recurrence and increases sensitivity to PD-L1 blockade.

Abstract Tumor-associated fibroblasts (TAFs) exhibit an activated/fibrotic phenotype in all subtypes of non-small cell lung cancer. In contrast, we previously reported that lung TAFs exhibit premature senescence selectively in large cell neuroendocrine carcinoma of the lung (LCNEC), which is among the most aggressive subtypes of lung cancer. Moreover, we also reported that senescent fibroblasts enhance the growth and invasion of LCNEC cells in vitro and in vivo, and that the co-culture of LCNEC cells with normal fibroblasts was sufficient to induce fibroblast senescence. Intriguingly, whole-genome transcriptional profiling identified MMP1 as highly overexpressed in a panel of LCNEC cells versus non-LCNEC cell lines. Here we examined the role of MMP1 in LCNEC paracrine induction of fibroblast senescence. MMP-1 expression was silenced in LCNEC cancer cell lines by shRNA, and common senescent markers were analyzed after co-culture with normal fibroblasts, including β-galactosidase staining, cyclin-dependent kinase Inhibitor 2A expression (CDKN2A) and growth arrest. In addition, the tumor-promoting effects of fibroblast conditioned medium in LCNEC growth and invasion were measured. We confirmed that the LCNEC cell lines used in this study exhibited an increased expression of 3 neuroendocrine markers (CHGA, NCAM1 and SYP) compared to non-LCNEC cells. Induction of fibroblast senescence was confirmed after coculture with shScramble LCNEC cells. Moreover, knocking-down MMP1 in LCNEC cells was sufficient to abrogate fibroblast induced senescence upon co-culture, as well as the tumor-promoting traits of fibroblast's conditioned medium. The addition of active recombinant MMP1 (rMMP1) partially rescued the fibroblast senescent phenotype in co-culture with knocked-down MMP1 LCNEC cells, yet it was not sufficient to induce senescence when added to fibroblasts cultured alone. In contrast, treating fibroblasts with rMMP1 and the potent pro-fibrotic cytokine TGFβ1 was sufficient to induce both senescence and protumorigenic properties. Our results unveil a process of “niche construction” by LCNEC cells that is driven by their overexpression of MMP1, which induces senescence in adjacent fibroblasts that secrete factors that enhance the growth and invasion of LCNEC cells, thereby contributing to the aggressive nature of these tumors. In addition, our results reveal a new pathologic synergy between MMP1 and TGFβ1 in eliciting fibroblast senescence and enhancing its tumor-promoting traits. Moreover, our findings support that the aberrant carcinoma cell-fibroblast crosstalk mediated by MMP1 may be a suitable therapeutic target in LCNEC, which currently lacks targeted therapies. Citation Format: Marta Gabasa, Rafael Ikemori, Marselina Arshakyan, Evette Radisky, Noemí Reguard, Derek Radisky, Jordi Alcaraz. Large-cell neuroendocrine carcinoma cells of the lung induce a tumor-promoting senescent phenotype in fibroblasts through MMP1 overexpression and TGFβ1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5099.

Abstract Tumor associated fibroblasts (TAFs) are important regulators of tumor growth and resistance to therapies. We have recently shown that lung TAFs in vitro respond to the antifibrotic drug nintedanib in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). We also showed that the tumor-promoting effects of TAFs are driven by different mechanisms in ADC and SCC, which remain to be elucidated. Tissue inhibitor of metalloproteinases 1 (TIMP-1) has been associated with poor prognosis in lung cancer, its expression is downregulated by nintedanib, and our preliminary results reveal that its putative receptor, CD63, is overexpressed in ADC patients compared to SCC, supporting a selective crosstalk between TAFs and cancer cells in ADC through TIMP-1 and CD63. The aim of this study was to test this hypothesis using in vitro preclinical models. Primary fibroblasts were obtained with the patient informed consent, and using protocols approved by the Ethics Committee of the Hospital Clinic. ADC-TAFs and SCC-TAFs were stimulated with TGF-β1 in the presence or absence of nintedanib, and the TIMP-1 content in their conditioned medium was determined by ELISA. TIMP-1 was knocked-down in ADC-TAFs by siRNA, and the corresponding conditioned medium was used to stimulate growth and invasion of the high-CD63 ADC cell line, H1437. Likewise, CD63 expression in H1437 cells was reduced by siRNA. Our in vitro results showed that TIMP-1 secretion induced by TGF-β1 is significantly larger in ADC-TAFs compared to SCC-TAFs. Likewise, nintedanib elicited a higher downregulation of secreted TIMP-1 in ADC-TAFs compared to SCC-TAFs. Of note, TIMP-1 from ADC-TAFs was necessary to induce growth and invasion of H1437 cells. Likewise, knocking-down CD63 in H1437 ADC cells was sufficient to reduce the growth and invasion elicited by the conditioned medium of TGF-β1 activated ADC-TAFs. Collectively, our results unveil a novel stroma-carcinoma crosstalk driven by TIMP-1 and CD63 selectively in lung ADC, and support that such heterotypic crosstalk may underlie the aberrant tumor-promoting effects of ADC-TAFs that are selectively downregulated by nintedanib. Citation Format: Paula Duch, Marta Gabasa, Rafael Ikemori, Marselina Arshakyan, Frank Hillberg, Noemí Reguart, Derek Radisky, Jordi Alcaraz. TIMP-1 in tumor-associated fibroblasts drives tumor progression in lung adenocarcinoma through CD63 interaction [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5091.

Abstract Background: Parity reduces risk of late onset breast cancer (BC), but childbirth is associated with a transient rise in BC risk. In a prior analysis of normal breast tissues donated for research to the Komen Tissue Bank (KTB), we reported that numbers of lobules (the primary structures from which BCs arise) are increased among parous versus nulliparous women. To further define the histological features that may be related to the transient rise in post-partum BC risk, we performed an expanded histologic review of 757 breast tissues donated to the KTB by women ≤45 years of age and compared lobule number, acinar count per lobule, and abundance of immune cells, and specifically plasma cells, between nulliparous and parous women. Methods: We assessed digital scans of H&E stained tissue sections of KTB tissues for total number of lobules, and evaluated acini / lobule (ordinal categories) and lobule span (um) for ≤10 lobules per section. Masked to epidemiologic data, we subjectively assessed images including ≥5 lobules for the presence of benign breast disease (BBD), ≥3 plasma cells per section and increased immune cells in lobules. We compared parous women according to time since last birth (≤5 years or &gt;5 years) to nulliparas (referent) using age-adjusted regression models appropriate for data type (count, continuous, ordinal, or categorical). Results: Compared to nulliparous women, parous women ≤5 years of a birth had a 1.83-fold increase in lobule counts (95% confidence interval [CI]: 1.47-2.28, P&lt;0.001), increased plasma cells in lobules (OR=1.86; 95% CI: 1.08-3.18, P&lt;0.025), and subjectively, increased immune cells in lobules (OR=2.46, 95% CI: 1.39-4.36, P&lt;0.002). Comparisons of parous women ≥5 years post-partum to nulliparas revealed a 1.83-fold increase in numbers of lobules (95% CI: 1.42-2.36, P&lt;0.001); however, lobule span in parous women was 0.89 times that of nulliparous women (95% CI: 0.80-0.99, P=0.037) and other features assessed did not show statistically significant differences. Conclusion: Histologically, normal breast tissues reveal persistently increased lobule counts and increased plasma cells and inflammation for ≤5 years post-partum compared with nulliparous women, although other lobular features decrease between ≤5 and &gt;5 years after a birth. Future molecular studies will define how these changes in the epithelium and microenvironment during the post-partum period may inform mechanisms that mediate the transient increase in BC risk after childbirth and the reduction in BC risk that occurs later in life. Citation Format: Joshua Ogony, DereK C. Radisky, Amy C. Degnim, Marlene Frost, Tanya L. Hoskin, Michael G. Heckman, Launia J. White, Mark E. Sherman. Analysis of post-partum breast tissue to understand early onset breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4635.

Abstract Background: Biopsy diagnosis of benign breast disease (BBD) based on the most severe lesion in a sample predicts future breast cancer risk and has implications for screening and management. Lobules are the functional unit of the breast and the structures from which BBD arises. We developed and preliminarily validated an automated computational pathology algorithm to discriminate normal from BBD breast lobules as a step toward automated comprehensive characterization of benign biopsies. Methods: 152 BBD biopsies (27 training, 125 validation) from the Mayo Clinic were examined using scanned digital images of H&E stained sections. For each image, a pathologist annotated up to 10 representative lobules as normal or BBD using standard pathology criteria. A deep learning algorithm to quantify lobular features was developed using 129 lobules from 27 subjects. Nine features were identified that discriminate normal vs BBD lobules, expressing lobule size, acini size and number, acinar lumen size, proportion of lobular stroma, and capillaries. Here, we validate their performance to discriminate normal vs BBD lobules in a set of 1250 lobules from 125 subjects using area under the ROC curve (AUC) analysis. Random forest analysis was used for multivariable modeling; model performance was assessed with a tenfold cross-validation approach. Results: Median subject age was 52 years. Among the 125 validation subjects, BBD findings were nonproliferative in 39%, proliferative in 45%, and atypical hyperplasia in 16%. Sections included 552 (44%) normal lobules and 698 BBD (56%) lobules, with representation of both lobule types on each section. In univariate analyses, four individual features showed good discrimination between normal vs. BBD lobules, yielding the following AUCs: lobule size= 0.74, mean acini size= 0.75, epithelial area= 0.75, and number of acini with large lumens= 0.76. Lobule size and epithelial area were highly correlated (Spearman rank correlation r = 0.95), but both of these features showed lower correlation with mean acini size and number of acini with large lumens (each r &lt; 0.5). With random forest modeling, number of acini with large lumens was the strongest discriminating feature, followed by mean acini size, lobule size, and epithelial area. With ten-fold cross validation of the multivariable random forest model, the overall AUC was 0.82 (95% CI: 0.79-0.85). Conclusion: Our validation showed that automated quantitative computational pathology assessment of breast lobules can discriminate normal versus BBD on a per lobule basis. This finding supports the feasibility of developing automated algorithms to classify every lesion in breast biopsies, expanding beyond visual assessment. Further studies using deep learning may reveal novel pathology features for classifying BBD biopsies with the potential to strengthen estimation of breast cancer risk. Citation Format: Amy C. Degnim, Thomas de Bel, Mark E. Sherman, Derek C. Radisky, Stacey J. Winham, Tanya L. Hoskin, Melody L. Stallings Mann, Marlene Frost, Robert A. Vierkant, Brendan T. Broderick, Ethan P. Heinzen, Rushin Brahmbhatt, Muhammad Arshad, Celine M. Vachon, Jodi M. Carter, Lori A. Denison, Daniel W. Visscher, Jeroen van der Laak. Discrimination of benign breast disease from normal lobules using an automated computational pathology algorithm [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2113.

AbstractThe etiology of triple-negative breast cancers (TNBC) is poorly understood. As many TNBCs develop prior to the initiation of breast cancer screening or at younger ages when the sensitivity of mammography is comparatively low, understanding the etiology of TNBCs is critical for discovering novel prevention approaches for these tumors. Furthermore, the higher incidence rate of estrogen receptor–negative breast cancers, and specifically, of TNBCs, among young African American women (AAW) versus white women is a source of racial disparities in breast cancer mortality. Whereas immune responses to TNBCs have received considerable attention in relation to prognosis and treatment, the concept that dysregulated immune responses may predispose to the development of TNBCs has received limited attention. We present evidence that dysregulated immune responses are critical in the pathogenesis of TNBCs, based on the molecular biology of the cancers and the mechanisms proposed to mediate TNBC risk factors. Furthermore, proposed risk factors for TNBC, especially childbearing without breastfeeding, high parity, and obesity, are more prevalent among AAW than white women. Limited data suggest genetic differences in immune responses by race, which favor a stronger Thr type 2 (Th2) immune response among AAW than white women. Th2 responses contribute to wound-healing processes, which are implicated in the pathogenesis of TNBCs. Accordingly, we review data on the link between immune responses and TNBC risk and consider whether the prevalence of risk factors that result in dysregulated immunity is higher among AAW than white women.