Medullary thymic epithelial cells (mTECs) are essential for establishing central tolerance by expressing a diverse array of self-peptides that delete autoreactive thymocytes and/or divert thymocytes into the regulatory T cell lineage. Activation of the NFκB signaling pathway in mTEC precursors is indispensable for mTEC maturation and proliferation resulting in proper medullary region formation. Here we show that the Stat3-mediated signaling pathway also plays a key role in mTEC development and homeostasis. Expression of a constitutively active Stat3 transgene targeted to the mTEC compartment increases mTEC cellularity and bypasses the requirement for signals from positively selected thymocytes to drive medullary region formation. Conversely, conditional deletion of Stat3 disrupts medullary region architecture and reduces the number of mTECs. Stat3 signaling does not affect mTEC proliferation, but rather promotes survival of immature MHCIIloCD80lo mTEC precursors. In contrast to striking alterations in the mTEC compartment, neither enforced expression nor deletion of Stat3 affects cTEC cellularity or organization. These results demonstrate that in addition to the NFkB pathway, Stat3-mediated signals play an essential role in regulating mTEC cellularity and medullary region homeostasis.

Veterinary allergen extracts labelled as the same species and PNU/mL are not standardized; they show heterogeneity in composition and potency within and between manufacturers. Variability in extract content may require adjustment of intradermal testing concentrations.

Luminal breast cancers are the most common genomic subtype of breast cancers where Luminal A cancers have a better prognosis than Luminal B. Exposure to sex steroids and inflammatory status due to obesity are key contributors of Luminal tumor development. In this study, 1928 patients with Luminal A breast cancer and 1610 patients with Luminal B breast cancer were compared based on body mass index (BMI), age, race, menopausal status, and expressed receptors (i.e., estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2)). Patients with Luminal B tumors had a significantly higher mean BMI (Δ = 0.69 kgm−2 [0.17, 1.21], p = 0.010) versus Luminal A. Interestingly, the risks of Luminal B tumors were higher among Black/African American patients versus White and Hispanic patients (p < 0.001 and p = 0.001, respectively). When controlled for each other, Black/African American race (p < 0.001) and increased BMI (p = 0.008) were associated with increased risks of Luminal B carcinoma, while postmenopausal status was associated with a decreased risk (p = 0.028). Increased BMI partially mediated the strong association between Black/African American race and the risk of Luminal B carcinoma. Thus, Black/African American race along with obesity seem to be associated with an increased risk of more aggressive Luminal B breast carcinomas.

e12568 Background: Genomic risk of recurrence assays provide prognostic information that aids treatment recommendations for patients with early breast cancer (EBC). The 70-gene signature (MammaPrint/MP) and the 21-gene assay (Oncotype DX/ODX) were both validated by large prospective, randomized clinical trials. Previous studies have directly compared the performance of these assays, with moderate discordance widely observed. Recent work showed poor prognostic performance of the ODX in African American (AA) EBC patients (Hoskins et al., 2021). Here, we compare the concordance of two genomic tests in an AA cohort. Methods: This retrospective analysis included a subset of self-reported AA patients from the prospective, observational PROMIS (n = 66, NCT01617954) and FLEX (n = 29, NCT03053193) registry trials, for whom both MP and ODX RS results were available. Patients were enrolled from 2012 to present. The PROMIS trial enrolled patients with intermediate ODX RS (18-30). MP results were obtained from standard testing performed centrally by Agendia, Inc. (Irvine, CA); ODX testing was performed by Genomic Health, Inc. (Redwood City, CA) and results were collected from patient case report forms. Results: AA patients (n = 95) included in this sub-analysis were 77% post-menopausal with a median age of 60 years. 28% of patients were aged ≤ 50 years. Of patients with metabolic data (n = 49), 63% were obese by body mass index (BMI > 30), and 23% had type 2 diabetes mellitus (T2DM). Tumors were predominantly invasive ductal carcinoma (82%), T1 (73%), grade 2 (53%), ER+ (99%), HER2-negative (94%), lymph node-negative (86%), and MP High Risk (66%). By ODX clinical RS, 17% of tumors classified as low (0-17), 80% intermediate (18-30), and 3% high (31-100) risk. As expected, the large intermediate RS group reflects the inclusion of PROMIS patients. By TAILORx RS ranges, 76% of tumors were low risk (≤25). Of these, 61% (n = 44/72) classified as MP High Risk. Notably, 62% (n = 41/66) of tumors with TAILORx intermediate RS (11-25) were MP High Risk. Conclusions: The overall discordance between MP and ODX was 51% in these AA patients. Discordance was more frequent (61%) in ODX low risk (RS≤25) cases. Notably, of tumors with TAILORx intermediate RS (11-25), the majority (62%) classified as MP High Risk. Combined with previously published data in AA patients (Nunes et al., 2016), this results in a total of 57% (n = 52/91) of ODX low RS (≤25) tumors classified as MP High Risk. Recent data indicate that AA patients who receive a low (≤10 or ≤25) or intermediate RS (11-25) have higher recurrence rates and lower survival than White/Caucasian EBC patients with the same RS. In the current study, clinical outcomes are forthcoming; however, these data suggest the majority of AA patients are more likely to receive a MP High Risk result, which may capture the diversity of pathways driving tumor metastasis. Clinical trial information: NCT01617954, NCT03053193.

556 Background: Genomically basal-type breast cancer is a heterogenous subtype that occurs at higher frequencies in non-Caucasian patients. Triple negative breast cancer (TNBC) has been refined into distinct transcriptomic groups including the basal-like immunoactive (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES) subtypes. Here we report the distribution of triple negative subtypes in genomically basal cancers from Caucasian (CA), African American (AA), and Latin American (LA) patients and the association of clinical estrogen receptor (ER) status. Methods: The FLEX Registry (NCT03053193) is an ongoing, prospective study evaluating primary tumors from patients with stage I-III breast cancer who receive the 70-gene signature and 80-gene signature (80-GS) molecular testing and consent to clinically annotated full transcriptome data collection. This sub-analysis evaluated 143 80-GS Basal type tumors from patients with self-reported ethnicity (60 CA, 59 AA, 24 LA). TNBC subtypes BLIA, BLIS, LAR, and MES were derived using an adjusted version of the 80-gene centroid signature published by Burstein and colleagues (2015). Differences in clinical ER expression between ethnicities were assessed by Fisher’s exact test. Results: Basal indices from 80-GS were not influenced by patient ethnicity (one-way ANOVA, p = 0.182). The frequency of BLIA, BLIS, LAR, and MES subtypes did not vary significantly by ethnicity (Fisher’s exact test, p = 0.671). The majority of tumors in all ethnic groups were BLIS (67% CA, 75% AA, 63% LA), followed by BLIA (22% CA, 22% AA, 25% LA), with low frequency of LAR (5% CA, 1.7% AA, 8.3% LA) and MES (5% CA, 1.7% AA, 4.2% LA) subtypes. Nearly one third (31%) of Basal type tumors were defined by IHC as ER positive and were present in all TNBC subtypes (39% BLIA, 29% BLIS, 33% LAR, and 20% MES); ER receptor expression ranged from 1-90% and was not associated with specific basal subtype (p = 0.8) nor ethnicity (P = 0.76). Progesterone receptor expression ranged from 1-50%. Conclusions: This analysis demonstrated that genomic Basal type tumor classification by 80-GS encompasses all TNBC subtypes evaluated regardless of ethnicity. Additionally, we show that IHC ER positive tumors occur in all TNBC subtypes assessed. These findings confirm the heterogeneous nature of basal breast tumors in CA, AA, and LA patients and highlight the clinical need to delineate basal biology in the ER+ cohort to advance treatment for basal-like tumors. Clinical trial information: NCT03053193 .