11184 Background: Baseline systemic corticosteroids are often prescribed to patients with non-small cell lung cancer (NSCLC) initiating immune checkpoint inhibitors (ICIs). Prior studies associating steroids with reduced ICI efficacy have largely treated steroid exposure as binary without accounting for indication. We evaluated outcomes following baseline steroid use by indication. Methods: We conducted a retrospective cohort study using TriNetX, a federated research network of de-identified electronic medical records. Using approximately 7,000-12,000 patients per stratum, NSCLC patients initiating ICIs were stratified by presence of systemic steroid prescriptions within 30 days prior to ICI initiation by indication: brain metastases (BM), pulmonary disease (PD), autoimmune disease (AI), and palliative indications (PI). In each stratum, steroid-exposed patients were compared with propensity-matched steroid-naive controls adjusting for demographics, non-brain metastases, comorbidities, substance use, and prior cancer treatments. Outcomes included mortality, ICU admission, and infection at 1 month. Results: Baseline steroid use was associated with worse 1 month outcomes in an indication dependent manner. Among patients receiving steroids for BM, mortality was higher compared with controls (8.75% vs 5.46%; HR 1.62, 95% CI 1.44-1.82; p < 0.001), as were ICU admission (5.06% vs 2.80%; RR 1.81, 95% CI 1.53-2.14; p < 0.001) and infection (6.81% vs 4.20%; RR 1.62, 95% CI 1.40-1.88; p < 0.001). Similarly, among patients receiving steroids for PI, steroid use was associated with increased mortality (9.68% vs 5.29%; HR 1.87, 95% CI 1.69-2.06; p < 0.001), ICU admission (4.83% vs 2.65%; RR 1.82, 95% CI 1.57-2.12; p < 0.001), and infection (7.50% vs 4.21%; RR 1.78, 95% CI 1.56-2.03; p < 0.001). In contrast, steroid use for PD or AI was not associated with increased mortality. PD was associated with higher ICU admission (3.35% vs 2.61%; RR 1.29, 95% CI 1.10-1.51; p = 0.0027) and infection (6.31% vs 4.23%; RR 1.49, 95% CI 1.31-1.70; p < 0.001), while AI was associated with increased ICU admission (3.63% vs 2.68%; RR 1.36, 95% CI 1.11-1.65; p = 0.0039) but not increased infection risk. These survival patterns persisted at longer follow-up, with higher mortality among patients with BM and PI at 6 months (BM HR 1.40, 95% CI 1.32-1.48; p < 0.001; PI HR 1.40, 95% CI 1.33-1.47; p < 0.001), 1 year (BM HR 1.40, 95% CI 1.33-1.47; p < 0.001; PI HR 1.36, 95% CI 1.31-1.42; p < 0.001), and 5 years (BM HR 1.30, 95% CI 1.24-1.35; p < 0.001; PI HR 1.32, 95% CI 1.27-1.37; p < 0.001), while no long-term survival decrement was observed for PD or AI. Conclusions: Baseline steroid use prior to ICI initiation is associated with increased early and long-term mortality in NSCLC in BM and PI but not PD and AI. Accounting for clinical indication is important to understand real-world ICI outcomes of patients using steroids.

Background/Objectives: Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has undergone rapid therapeutic evolution. However, heterogeneous outcomes persist, driven by mutations, central nervous system (CNS) involvement, and dynamic tumor burden reflected in part by circulating tumor DNA (ctDNA). As such, this review aims to summarize the most recent risk stratification frameworks in treating EGFR-mutant NSCLC, evaluate evidence supporting treatment intensification strategies and managing adverse effects, and explore the evolving role of ctDNA in guiding personalized therapy. Methods: A comprehensive literature search was conducted using major medical databases with a focus on key relevant studies on the workup and management of EGFR-mutant NSCLC. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Molecular co-alterations, such as TP53 and RB1, as well as central nervous system (CNS) involvement, are consistently associated with inferior outcomes, supporting consideration of upfront treatment intensification. Combination strategies, including osimertinib plus chemotherapy or amivantamab-based regimens, demonstrate improved progression-free survival and delayed CNS progression when compared against osimertinib monotherapy. Intensification, however, is associated with a higher risk of increased toxicity, including dermatologic adverse events and infusion-related reactions. Finally, the utilization of circulating tumor DNA (ctDNA) has emerged as a strong prognostic marker, with ongoing trials investigating its predictive role for both escalation and de-escalation of therapy. Conclusions: The treatment paradigm for EGFR-mutant NSCLC is gradually evolving beyond first-line osimertinib to include a more integrated approach that considers molecular features, CNS involvement, and early ctDNA response. Although intensified regimens offer meaningful efficacy gains for high-risk patients, proactive toxicity management is essential to preserving quality of life. ctDNA-guided strategies represent a new and promising frontier for escalation and de-escalation of therapy, with results from ongoing trials poised to further refine personalized treatment algorithms.

Background:Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for non-small cell lung cancer, but the role of race/ethnicity is not well understood. Design:This is a retrospective study of non-small cell lung cancer (NSCLC) patients receiving ICI. Objective:We evaluated the role of race/ethnicity in ICI response and immune-related adverse events (irAEs) in NSCLC patients. Methods:NSCLC patients treated with ICIs from 2014 to 2022 at Los Angeles General Medical Center and Norris Comprehensive Cancer Center were included. Primary endpoints were irAE incidence, time on ICI treatment (TOT), overall survival (OS), and progression-free survival (PFS). TOT, OS, and PFS were evaluated using the Kaplan-Meier method. Landmark analysis was performed of patients receiving >6 month ICIs. Fisher's exact test was performed for analysis of variables between groups. Results:In total, 211 NSCLC patients receiving ICIs were analyzed, including 86 (40.8%) Asian American/Pacific Islander (AAPI), 65 (30.8%) non-Hispanic White/Caucasian (NHW), 37 (17.5%) Hispanic/Latino (HIS), and 23 (10.9%) African American/Black (AA). Among stage IV patients, median OS for AAPI was 23.2 months (95% confidence interval (CI) 16.0-not reached (NR)), 23.6 months (95% CI 6.9-38.8) for NHW, 12.7 months for AA (95% CI 2.2-37.0), and 11.0 months (95% CI 4.8-14.8) for HIS (p = 0.008). Median TOT and PFS were similar among race/ethnicities. 48.3% of AAPI developed irAE versus 27.3% for AA, 27.0% for HIS, and 39.4% for NHW. Landmark analysis showed that AAPI had longer median OS 60.6 months (95% CI 20.6-NR), while HIS had shorter median OS 15.4 months (95% CI 8.9-NR; p < 0.01). Among patients who experienced irAEs, median OS for AAPI was 60.6 months (95% CI 20.6-NR), compared to NHW at 48.4 months (95% CI 20.5-NR), AA at 35.7 months (95% CI 2.2-NR), and HIS at 15.2 months (95% CI 6.3-31.0; p = 0.0211). There was no difference in median OS among patients who did not experience irAEs. Multivariate analysis for OS in stage IV patients showed that HIS versus AAPI (hazard ratio: 2.27; 95% CI 1.30-3.95) was a significant variable. Conclusion:Our study demonstrates that AAPIs and NHW had higher irAE incidence and longer OS. Validation studies evaluating the role of race/ethnicity in ICI response and toxicity are merited.

e13672 Background: There are widespread disparities in access to rapid, expert-level second opinions worldwide. We assessed the feasibility and early adoption of an anonymized, human-in-the-loop AI decision-support platform (PrecisCa.AI) that analyzes cases in 2-3 minutes and offers optional expert faculty over-read on request. Methods: After a real-time demonstration during international breast cancer tumor boards (December 2025), we collected provider-submitted, de-identified cases. Feasibility measures included successful case processing and measured time to response. Secondary measures included clinician uptake, location of submitted cases, tumor of origin, referral sources, and in-app feedback. AI consults are undergoing expert review and scoring from 1-5 (5 being the highest) on 6 attributes: clarity, completeness, menu of options, recency, reasoning, and relevance. An in-app survey asked if the response was helpful. Results: Across the observation window, from 12/10/2025-1/23/2026, 256 cases were submitted by 89 unique active providers (mean 2.9 cases/provider) after 125 new sign-ups (100% registration completion). Processing success was 100% (0/256 failed), with mean turnaround time of 149 seconds. Submissions originated from North and South America, Europe, Middle East, Africa, and Asia. Breast cancer cases (58%) were most common followed by thoracic 13%, hematologic 9%, GI 8%, GU 5%, gynecologic 3%, head & neck 2%, and skin 1%. Referrals were most commonly from a colleague (45%) followed by referrals from a conference 32%, email 7%, social media 6%, Google 3%, and other 7%. In-app survey response rate was 16.8% (43/256) with mean score 3.7/5. 33% of survey responses contained free-text comments. Multiple adjudicator large language models were available and used (most commonly recent Gemini and ChatGPT). Conclusions: An anonymized, clinician-submitted, human-in-the-loop AI platform achieved feasible global use shortly after a public demonstration, with 100% processing success and short mean turnaround time across diverse tumor types and referral channels. Optional expert faculty over-read was available, and AI consults will now be expert-rated (1-5) on clarity, completeness, menu of options, recency, reasoning, and relevance. Detailed analyses of expert ratings and comparative model performance will be presented.

Pure ground-glass and part-solid lung nodules are becoming increasingly appreciated as harbingers of malignancy. However, occasionally diagnostic biopsies can demonstrate unexpected findings that may lead to a misleading diagnosis and clinical confusion. Here we present the case of a 70-year-old Taiwanese man with a light smoking history (10-20 pack years), emphysema, and childhood-treated tuberculosis who presented with a part-solid nodule that was diagnosed as a very rare case of adenocarcinoma of the lung with desquamative interstitial pneumonia (DIP)-like microscopic morphology. DIP is a non-neoplastic interstitial lung disease which presents as a diffuse and bilateral process and primarily occurs in smokers. When the morphologic pattern of DIP presents as a focal process, usually around bronchioles, it is labeled respiratory bronchiolitis. (RB)- a very common entity and almost universal in patients with significant smoking history. We describe this case to help educate and guide pathologists on the existence of this very rare entity and to consider performing lung cancer immunohistochemical markers whenever faced with this unexpected histological pattern in a pulmonary nodule.

Background/Objectives: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid proliferation, early metastasis, and near-universal relapse after initial therapy. While chemo-immunotherapy modestly improves first-line outcomes, survival after progression remains poor and highlights the urgent need for biomarker-directed strategies. Methods: A comprehensive literature search was conducted using major medical databases looking at key relevant studies on SCLC antibody studies. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Recent advances in antibody-drug conjugates (ADCs) and T-cell engagers (TCEs) have transformed therapeutic development by targeting antigens selectively expressed on SCLC cells, enabling more precise and potentially durable tumor control. DLL3 has emerged as the most clinically relevant target to date, with the bispecific TCE tarlatamab demonstrating meaningful and durable response, manageable cytokine-release toxicity, and ultimately achieving accelerated FDA approval for previously treated extensive-stage SCLC. Concurrently, DLL3-directed ADCs have shown variable efficacy, underscoring the importance of payload selection, linker chemistry, and antigen density. Beyond DLL3, next-generation ADCs targeting TROP2, B7-H3, and SEZ6 have reported encouraging early-phase activity, including response rates exceeding those of existing second-line cytotoxic options, though myelosuppression, interstitial lung disease, and hepatic toxicity remain key considerations. Conclusions: Collectively, these emerging immunotherapies illustrate a shift toward antigen-specific targeting in a disease historically defined by limited therapeutic innovation. Continued optimization of antigen selection, payload and linker engineering, and biomarker-driven trial design will be critical for translating early promise into durable clinical benefit and reshaping the treatment landscape for SCLC.

Supplementary Figure S5: Gene Ontology enrichment analysis of co-occurring alterations in NC. Bar plots displaying the top enriched Gene Ontology (GO) terms generated using the SRplot online platform. GO categories include (A) Biological Process, (B) Molecular Function, and (C) Cellular Component.

Supplementary Figure S4: Tumor mutation burden and PD-L1 expression among cases with DNA NGS testing. (A) Box-and-whisker plot showing tumor mutation burden (B) Bar chart showing the distribution of PD-L1 expression levels, stratified by tumor proportion score and combined proportion score. Expression levels are grouped into <1%, 1–49%, and ≥50%.

PURPOSE:Diagnostic delays are common for patients with NUT carcinoma (NC), a cancer driven by NUT fusion oncoprotein. Rapid diagnosis is crucial for the best outcomes. We investigated NC's presenting features and associations with diagnostic delays. METHODS:We manually reviewed medical records from US participants in the NC Registry (2007-2024). Baseline features were analyzed descriptively, and multivariable logistic regression was used to examine odds ratios for delays. RESULTS:We analyzed 132 patients (median age 37 years). At presentation, 55% had metastatic disease and 64% had a thoracic primary. The median interval from symptom onset to diagnosis was 10 weeks (range, 1-165 weeks). The initial histopathologic diagnosis was poorly differentiated/squamous cell cancer in 52%, insufficient malignant cells in 14%, carcinoma in 12%, and NC in 22%. Immunohistochemistry (IHC) testing revealed NUT in 100%; 93% were keratin+, 88% p63+, 89% p40+, and 72% had Ki-67 ≥50%. IHC was used to diagnose NC in 79%. Nonthoracic primaries were associated with a longer time between symptom onset and NC diagnosis (odds ratio, 3.25). Of 32 patients who started treatment before diagnosis, 78% were on agents appropriate for NC. After a diagnosis of NC, 33% participated in clinical trials. CONCLUSION:NC almost always presents as squamous/poorly differentiated non-small cell lung or head and neck cancer. Overall, 78% of patients were initially diagnosed as non-NC. Efforts to raise awareness, recognition, and rapid diagnosis of NC by both oncologists and pathologists are critical if we are to improve outcomes.

1051 Background: Hispanics or Latinos (HL) and African Americans or Black (AA) have a higher prevalence of advanced-stage breast cancer (BC) at diagnosis compared to Non-Hispanic Whites (NHW). To understand the role of immune system, we evaluated the tumor immune microenvironment (TIME) by race/ethnicity among HL, AA, and NHW BC patients. Methods: 15544BC samples were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). Race/ethnicity data is self-reported. Immune cell were estimated using WTS deconvolution (Quantiseq). Gene expression profiles were analyzed for T-cell inflammation score (TIS) and interferon-gamma (IFN-gamma) score. Real-world overall survival (OS) was obtained from insurance claims and calculated from date of tumor biopsy to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p -values adjusted for multiple comparisons (q < .05). Results: 7170 NHW (35.3%, N = 2528) biopsied (bx) from primary breast cancer (pBC), 64.7% (N = 4642) metastatic bx (mBC), 1,508 AA (pBC 39.3% N = 592, mBC 60.7% N = 916), and 1,754 HL (pBC 44.1% N = 774, mBC 55.9% N = 980) cases were included. By subtype, there were 1,956 (60.4% NHW, 20.7% NHB, 18.9% HL) TNBC, 3425 HR+/HER2- (72.6% NHW, 11.9% NHB, 15.6% HL), and 694 HER2+ (64.6% NHW, 15.7% NHB, 19.7% HL). Across all cases, AA (20.5%) and HL (20.4%) had greater incidence (%) of PD-L1+ cases versus (vs) NHW (17.4%), all q < .05. TMB-High (³10 mut/Mb) was similar in NHW (11.5%), AA (10.8%), and HL (10.9%). AA tumors had lower median % cell infiltration of M2-like macrophages (M2 Mφ), B cells, and neutrophils vs NHW (Table). HL had a lower fraction of M2 Mφ and higher CD8+ T cells (Table). AA had lower TIS (-8 vs 1, p = .02) while HL had lower IFN-gamma (-0.38 vs. -0.35, q < .05) vs NHW. By subtype, AA had lower neutrophils (4% vs 4.3%) and increased DC fractions (3.1% vs 2.8%) in TNBC vs NHW, all q < .05; no significant changes seen in HL vs NHW. AA had worse mOS than NHW overall (31.8 vs 36.8 months (mo)), HR 1.1, 95% CI 1 – 1.2, p = < .01), in pBC (40.3 vs 49.9 mo, HR 1.3, 95% CI 1.1 – 1.5, p = < .01), but not mBC (27.4 vs 29.1 mo, HR 1, p = 0.2). HL had similar mOS vs NHW overall (37.4 vs 36.8 mo, HR 0.9, p = 0.9) and in mBC (29.1 vs 31 mo, HR 0.96, p = 0.4), but worse mOS in pBC (44.7 vs 50.0 mo, HR 1.1, 95% CI 1 – 1.3, p = .01). Conclusions: Our study shows worse mOS in AA and HL pBC cases vs NHW, possibly from a less inflamed TIME in AA and HL and lower fraction of neutrophils and M2 Mφ despite higher % of PD-L1+. Targeting Mφ and CD8+ T cells and converting cold to hot TIME may lessen race/ethnic disparities, especially in early-stage BC. Immune cell fraction of NHW, AA and HL BC. NHW (median %) AA (median %) HL (median %) q-valueNHW vs AA q-value NHW vs HL B cell 5.2 4.8 5.0 <.05 0.7 DC 2.6 2.7 2.6 0.08 0.4 M1 Mφ 2.5 2.4 2.4 0.4 0.9 M2 Mφ 4.6 3.7 4.2 <.05 <.05 Neutrophils 3.7 3.5 3.4 <.05 <.05 NK cell 2.9 2.9 2.9 0.7 0.6 CD8+ T cell 0.1 0.15 0.26 0.8 <.05 Treg 1.5 1.5 1.6 0.6 <.05

Immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), prevent tumor infiltrating-lymphocytes (TILs) from mounting an anti-tumoral immune response in solid tumors, including breast cancer. Even though genetic factors, such as race and ethnicity, are suspected to contribute to immunosuppression, social determinants of health—non-medical factors including economic stability, education access and quality, health care access and quality, neighborhood and built environment, and social and community context—may also contribute to observed differences in tumor growth and therapeutic response across different racial and ethnic groups. We hypothesized that the combined effects of Hispanic/Latina origin and higher social deprivation contribute to an increased proportion of immunosuppressive cells in circulation. In this study, our IRB-approved cohort consisted of 131 patients with varied histologic subtypes and stages of breast cancer including 71 Hispanic/Latina (H/L), 37 Non-Hispanic White (NHW), 15 Asian, and 8 African American/Black (AAB) individuals. To assess the proportion of immunosuppressive cells in circulation, we performed flow cytometry analysis of peripheral blood mononuclear cell (PBMC) samples obtained from our cohort. To study social determinants of health across racial and ethnic groups, we utilized the Social Deprivation Index (SDI) as a proxy using each patient’s ZIP Code and stratified SDI values into quartiles (where lower quartile indicates less social deprivation). Preliminary data suggested that H/L groups have a greater percentage of circulating suppressive granulocytic (G)-MDSCs (0.31% vs. 0.14%) compared to NHW groups. A similar trend was noted for regulatory T cells with 1.51% in H/L and 1.22% in NHW. This finding also appeared to continue when further adding social deprivation, where groups with both higher social deprivation and H/L origin demonstrated a trending increase in G-MDSCs and monocytic (M)-MDSCs. Preliminary differences in circulating immune cells in in the H/L group could be driven by genetic differences in one or more of the ancestral components and/or by specific exposures that may be more prevalent among H/L women, such as stress, environmental exposures, or others. We are investigating additional data from patient surveys to further inform the observed correlations between SDOH and immune cell differences. Studies are also underway to examine differences in intratumoral immune suppressive cell types in a subset of 13 tumor specimens from 3 H/L and 9 NHW patients with early-stage hormone receptor positive breast cancer. These findings demonstrate the importance of further investigation of the multi-level determinants of response to treatment, especially in patients receiving immune checkpoint inhibitors across diverse racial and socioeconomic populations. Elexa P. Rallos, Sabrina Carrel, Michelle Li, Batul Al-Zubeidy, Edgar Gonzalez, Aaron G. Baugh, Matthew Jacobo, Cheol Park, Robert Hsu, Dominic Zavala, Steven Do, Michael F. Press, Ming Li, Anastasia Martynova, Priya Jayachandran, Daphne Stewart, Chanita Hughes-Halbert, Mariana C. Stern, Evanthia T. Roussos Torres. The relationship between social deprivation and immune suppression in Hispanic/Latina patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7100.

8071 Background: BTRx improves survival of pts with resected early-stage NSCLC, making thorough biomarker testing critical in this setting. Disparities in testing and receipt of guideline-supported BTRx may adversely impact outcomes. We evaluated rw biomarker testing patterns, outcomes, and receipt of BTRx in pts with resected NSCLC. Methods: This was a retrospective US cohort study of Flatiron Health data from pts with stage IB–IIIB (T3N2) NSCLC diagnosed during 2021–2023, who had surgical resection. Biomarker testing, BTRx rates, and clinical outcomes (rw recurrence-free survival [rwRFS]; overall survival [OS]) were evaluated and compared across clinical and sociodemographic groups. BTRx was defined as 1) osimertinib for EGFR+ (Ex19del/L858R) NSCLC; 2) atezolizumab or pembrolizumab (per PD-L1 status) for EGFR- and ALK-negative (-) NSCLC. Results: In this cohort (N=885), biomarker testing rates were lower among stage I (75%) vs III (93%), older (83%) vs younger (87%), non-Hispanic Black (74%) vs White (84%), and pts with smoking (83%) vs no smoking history (89%) (Table). 539 (61%) pts received adjuvant therapy; 231 (43%) had actionable biomarkers, of whom 137 (59%) received BTRx, with rates highest for pts with EGFR+ disease (85%) and lowest for pts with EGFR-/ALK- disease (49%). BTRx was received more often by pts who never smoked (76% vs 55% of pts who smoked) and pts of Asian ethnicity (100% vs 56% White) (all p<0.05). At 24 months, 90% of pts who had BTRx were alive vs 77% who did not (p<0.05). Median rwRFS was 35 months for BTRx vs 28 months for non-BTRx cohort (p<0.05). In multivariable analysis among pts who had BTRx, younger age was significantly associated with OS. Conclusions: In this large rw analysis, BTRx was significantly associated with OS in early-stage NSCLC, irrespective of age, stage and sex. Ensuring biomarker testing and BTRx for all pts may reduce outcomes disparities in NSCLC. Table Overall Stage IB Stage IIIB <65 yrs ≥65 yrs Male Female Non-Hispanic White Non-Hispanic Black Smoked Never smoked SES Quintile 1 SES Quintile 5 ≥1 Biomarker test after diagnosis, % 84 75 93* 87 83 85 83 84 74 83 89 80 86 Received adjuvant Rx (n=539), % 61 31 90* 74 56* 59 63 62 60 60 64 63 65 BTRx rate in pts with actionable bioms (n=231), % 59 64 73 57 60 63 57 56 61 55 76* 51 68 24-mo OS, % (95% CI) (all pts) 84 (81–87) 87 (80–92) 72(46–87)** † 92 (86–96) 81 (77–85)** † 81 (75–85) 87 (82–90)** † 86 (82–89) 88 (70–96) 83 (80–87) 89 (79–94) 85 (74–92) 88(80–93) 24-mo OS, % (95% CI) (pts with BTRx) 90 (80–95) 91 (51–99) NR 100 (100–100) 86 (71–93)** 83 (58–94) 94 (82–98) 88 (73–95) 100 (100–100) 89 (76–95) 95 (68–99) 80 (41–95) 86* (53–96) *χ2-test p<0.05. **Log-rank p<0.05, for comparisons within stage and sociodemographic groups. † Results significant in multivariable Cox regressions adjusted for age, sex, stage and practice type. NR, not reached.

Supplementary Figure S3: Kaplan–Meier curve of overall survival from time of diagnostic testing. Survival curve showing overall survival from the date of the positive test that led to the diagnosis of NUT carcinoma. The y-axis indicates overall survival (%) and the x-axis represents time in months since testing.

PURPOSE:NUT carcinoma (NC) is an underdiagnosed, poorly differentiated squamous cell cancer with a median survival of 6.7 months. Defined by NUTM1 fusions, NC enhances oncogene transcription, including MYC. We investigated the ability of standard next-generation sequencing (NGS) to identify NUTM1 fusions and describe additional molecular features of NC. EXPERIMENTAL DESIGN:This study included 116 patients with NC whose tumors underwent broad-panel NGS (>80 genes) of DNA, ctDNA, and/or RNA fusion sequencing between 2013 and 2024. NGS reports and medical records were manually reviewed. RESULTS:Of 116 patients (median age, 38; 40.5% female), 84.5% had DNA, 12.1% had ctDNA, and 51.7% had RNA fusion testing. In a subset of 100 patients with DNA/ctDNA testing, 92.9% (n = 79/85) had <10 pack-years/never-smoking history, and 58.8% (n = 47/80) had a BRD4::NUTM1 fusion. The median tumor mutational burden was 1.0 mut/Mb (range 0.0-16.0; n = 71 known), and 19.7% (n = 13/66) had PD-L1 expression ≥1%. DNA, ctDNA, RNA fusion, NUT IHC, and NUTM1 FISH detected NC fusions in 21.6%, 21.4%, 83.9%, 100.0%, and 91.9% of tests, respectively. Co-occurring pathogenic mutations included oncogenes PIK3CA, RET, and FGFR3 and tumor suppressors ATM and BRCA1 (n = 1 each). Secondary genes altered in >5% of NCs included LDL receptor-related protein 1B (LRP1B; 10.4%), histone-lysine N-methyltransferase 2D (KMT2D; 8.0%), and FAT atypical cadherin 1 (FAT1; 5.5%); common pathways with mutated genes were epigenetic (57.0%), cell cycle (26.0%), and DNA repair (24.0%). CONCLUSIONS:Standard DNA NGS detects less than a quarter of NCs; RNA-based fusion testing, or NUT IHC/NUTM1 FISH, should be routine for suspected NC. NCs are enriched in co-occurring epigenetic, cell cycle, and DNA repair alterations, warranting further evaluation.

Breast cancer is the leading cause of cancer-related death among Hispanic/Latinx (H/L) women in the U.S. Compared to Non-Hispanic White (NHW) women, H/L patients are more likely to be diagnosed before age 50 (29% vs. 15%), to present with larger tumors (>2.0 cm in 45% vs. 38%) and to have estrogen receptor (ER)-negative subtypes (18% vs. 14%). All patients with breast cancer have low levels of anti-tumor immunity as a result of intrinsic immune suppression, affecting response to standard therapies, including immunotherapy. We hypothesize that biological and social factors interact to shape an immunosuppressive tumor microenvironment, which can lead to disparities in clinical outcomes. Preliminary investigation of circulating and intratumoral immune cells in parallel with social determinants of health (SDOH) assessments suggest possible correlations between disparities in SDOH and preliminary differences in anti-tumor immunity. Bulk RNA sequencing (for immune cell fractions), whole exome sequencing (for common mutations), PD-L1 status (for combined positivity scores), and self-reported race and clinical outcomes (by disease biopsy site and histological subtype) were collected for 7,000 patients via collaboration with Caris Life Sciences. We performed multiparametric flow cytometry of peripheral blood samples to characterize circulating immune populations from an additional 130 patients. Spatial transcriptomics were used to profile intratumoral immunity on 13 patients via Visium 10X. A social deprivation index (SDI) was calculated based on patient zip codes and additional demographic factors for 130 patients. Descriptive statistics were used to summarize demographics, tumor characteristics, and SDI components. H/L patients exhibited shorter overall median survival, higher PD-L1 positivity, and higher interferon-gamma score in those whom primary breast tumors were examined. Moreover, we observed an enrichment of circulating myeloid-derived suppressor cells (MDSCs), exhausted CD8+ T cells, and M2-polarized macrophages, consistent with an immunosuppressive immune profile. Spatial localization and transcriptomic data from H/L patients showed greater intratumoral lymphocyte infiltration. SDI scores were higher among H/L patients, relative to NHW. Across both H/L and NHW groups, higher SDI correlated with increased circulating G-MDSCs and regulatory T cells. Within the H/L group, circulating CD8+ and CD4+ T-cell levels also increased with greater deprivation. Poorer clinical outcomes were observed in H/L patients who also demonstrated higher levels of pro- and anti-tumor immune activation. These immune-related disparities are likely influenced by both biological mechanisms and contextual social disadvantage. Ongoing work includes validating these findings in larger genomic datasets and stratifying by histologic subtype. Addressing differences in tumor immune microenvironment and social vulnerability is essential to providing personalized treatment options to improve outcomes in patients with breast cancer. Nana A. K. Gyabaah-Kessie, Elexa Rallos, Sachin Kumar Deshmukh, Joel Sanchez Mendez, Diego I. Alvarez-Lopez, Dominic Zavala, Batul Al-Zubeidy, Matthew Jacobo, Michelle Li, Sabrina Carrel, George Sledge, David Conti, Robert Hsu, Mariana C. Stern, Evanthia T. Roussos Torres. Evidence of more highly activated anti-tumor immunity in Hispanic/Latinx patients with breast cancer and associated social determinants of health [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C072.

BACKGROUND:Anaplastic thyroid carcinoma (ATC) is a highly aggressive cancer historically associated with a median survival of about 5 months. Recent advances in tumor genomic testing have identified targetable BRAF mutations in about 35-40% of ATC cases and have shown high levels of programmed death ligand-1 (PD-L1) expression in ATC. These observations have led to clinical trials showing favorable outcomes with targeted therapy and immunotherapy for ATC. OBJECTIVE:We aimed to evaluate treatments and outcomes of patients diagnosed with anaplastic thyroid cancer treated at our institution in order to determine the impact of targeted therapy and immunotherapy. METHODS:A retrospective review of ATC patients at a single institution was performed. Data were collected from institutional electronic medical records, including demographic information, treatments administered, and outcomes including survival. RESULTS:A total of 28 patients were identified within the period under study. Systemic therapy was initiated in 61% of patients. The median overall survival for all patients was 7.3 months. There was a statistically significant improvement in overall survival for patients who received targeted therapy or immunotherapy compared to those who did not. CONCLUSIONS:In this single-institution cohort of 28 patients with ATC, patients who received either targeted therapies or immunotherapy demonstrated markedly improved outcomes. Further clinical trials are required to determine the optimal systemic therapy for this patient population.