e18108 Background: The incidence of early-onset (EO) head and neck squamous cell carcinoma (HNSCC) is increasing and appears to be associated with improved survival compared with average-onset (AO) disease, suggesting potential biological differences. However, data are limited. We compared demographics, primary tumor sites, metastatic patterns, and outcomes between EO and AO HNSCC. Methods: We performed a multicenter retrospective study using the TriNetX federated, de-identified electronic medical record network. Patients with HNSCC were identified with diagnosis as the index event. EO was defined as diagnosis before age 50 and AO as age ≥51. Primary and metastatic sites were identified using ICD-O and ICD-10 codes. Propensity score matching (1:1 greedy nearest-neighbor, caliper 0.1) was performed for sex, race, primary site, HPV status, and comorbidities. Kaplan–Meier survival analysis and comparative statistics were performed within TriNetX. Results: Among 468,496 patients, 41,596 (8.9%) had EO HNSCC. EO patients were more often female (43.1% vs 29.6%), Asian (12.2% vs 7.2%), and African American (8.2% vs 7.1%), and less often White (40.4% vs 61.7%) (all p<0.0001). Primary tumors were more frequently nasopharyngeal (15.0% vs 4.8%) and parotid (7.7% vs 5.3%), and less frequently tonsillar (5.3% vs 7.6%), oropharyngeal (4.6% vs 6.2%), and base of tongue (2.0% vs 5.7%) (all p<0.0001). After matching, each cohort included 39,535 patients. Median overall survival was not reached in the EO cohort (3,450 deaths, 8.7%) and was 6,011 days in the AO cohort (7,823 deaths, 19.8%) (HR 0.49, 95% CI 0.47–0.51; p<0.0001). Stage IV disease developed less frequently in EO patients (12.6% vs 16.5%, p<0.0001). EO patients had fewer lung (3.1% vs 4.0%), lymph node (11.4% vs 13.5%), liver (1.6% vs 2.1%) all p<0.0001, and bone metastases (3.5% vs 3.7%, p=0.03), with no difference in brain metastases. There was no difference in receiving radiation treatment and those that received surgery within 6 months of diagnosis. Conclusions: EO HNSCC differs significantly from AO disease in demographics, tumor site distribution, metastatic patterns, and survival. EO disease is associated with fewer metastases and superior overall survival, suggesting distinct tumor biology and supporting the need for further mechanistic studies.

172 Background: Lynch syndrome is the most common hereditary syndrome associated with colorectal cancer (CRC). Lynch syndrome-associated CRC is typically characterized by microsatellite instability-high tumors which exhibit favorable response to PD-1 immune checkpoint inhibitors (ICIs). Our aim was to identify clinical and demographic factors that influence overall survival (OS) in Lynch syndrome-associated CRC patients treated with pembrolizumab, a PD-1 ICI. Methods: We designed a multicenter retrospective study using TriNetX, a global database of de-identified electronic health records, to evaluate the impact of multiple covariates on OS in patients with Lynch syndrome and stage IV CRC treated with pembrolizumab. Patients who underwent colectomy were excluded. Using the Cox proportional hazards model, we explored the effect of sex, age at index, marital status, obesity, type 2 diabetes mellitus, chronic kidney disease, nicotine dependence, alcohol use, depression, and metastasis to lung, liver, bone, brain, peritoneum or retroperitoneum. Results: Of the 394 patients diagnosed with both Lynch syndrome and stage IV CRC receiving pembrolizumab, 44.7% were males. Increased mortality risk was observed in males compared to females [HR 1.558, 95% CI 1.085-2.235; p=0.016]. Additionally, peritoneal and retroperitoneal metastases were significantly associated with worse OS [HR 1.822, 95% CI 1.151-2.882; p=0.010]. Age at index, marital status, obesity, type 2 diabetes mellitus, chronic kidney disease, nicotine dependence, alcohol use, depression, and lung, liver, bone or brain metastases were not significantly associated with worse OS. Conclusions: Male sex and presence of peritoneal or retroperitoneal metastases are poor outcome predictors in Lynch-associated stage IV CRC treated with pembrolizumab. The latter adverse prognostic indicators emphasize the need for careful risk stratification when treating Lynch-associated stage IV CRC patients with pembrolizumab and further guide treatment decisions. Effect of several covariates on overall survival (OS) in patients with Lynch syndrome and stage IV colorectal cancer treated with pembrolizumab. Covariate Hazard Ratio Coefficient Standard Error z P > |z| 95% Confidence Interval Male 1.558 0.443 0.184 2.405 0.016 (1.085, 2.235) Age at Index 1.013 0.013 0.007 1.913 0.056 (1.000, 1.027) Overweight and obesity 0.728 -0.317 0.214 -1.479 0.139 (0.478, 1.109) Nicotine dependence 1.476 0.389 0.219 1.772 0.076 (0.960, 2.269) Alcohol use 0.000 -15.887 2330.127 -0.007 0.995 -- Married 0.980 -0.020 0.185 -0.111 0.912 (0.682, 1.407) Type 2 diabetes mellitus 1.444 0.368 0.205 1.789 0.074 (0.966, 2.160) Depression 0.974 -0.026 0.232 -0.113 0.910 (0.618, 1.536) Chronic kidney disease (CKD) 1.291 0.256 0.227 1.125 0.261 (0.827, 2.016) Secondary malignancy of retroperitoneum and peritoneum 1.822 0.600 0.234 2.563 0.010 (1.151, 2.882)

e20660 Background: Immune checkpoint inhibitors (ICIs) are standard first-line therapy for metastatic non–small cell lung cancer (NSCLC) without targetable mutations. In real-world practice, the timing of ICI initiation varies and may reflect differences in clinical urgency and care pathways rather than treatment efficacy alone. We evaluated whether early versus delayed initiation of first-line ICIs is associated with survival and early healthcare utilization in metastatic NSCLC. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including electronic health records from approximately 170 healthcare organizations. Adults (≥18 years) with stage IV NSCLC who received first-line immunotherapy (pembrolizumab, nivolumab, atezolizumab, durvalumab, or cemiplimab) were included. Patients were stratified by time from metastatic diagnosis to ICI initiation: early (≤30 days) versus delayed (30–90 days). Propensity score matching was performed for demographics and comorbidities. To minimize immortal time bias, overall survival (OS) was indexed to the date of stage IV diagnosis, while 90-day outcomes, including mortality, emergency department (ED) visits, hospitalizations, and intensive care unit (ICU) admissions, were indexed to the date of ICI initiation. Kaplan–Meier analyses and hazard ratios were used to compare outcomes. Results: After propensity score matching, 1,424 patients were included in each cohort. When overall survival was indexed to the date of metastatic diagnosis, there was no significant difference between patients initiating first-line ICIs within 30 days versus 30–90 days (median OS 732 vs 819 days; HR 1.05, 95% CI 0.95–1.16; log-rank p=0.351). Ninety-day mortality following ICI initiation was similar between groups (14.5% vs 13.0%; p=0.217), as were rates of ED or observation visits (30.2% vs 30.8%; p=0.714). However, earlier ICI initiation was associated with lower rates of acute hospitalization (40.2% vs 44.7%; p=0.015) but higher rates of ICU admission within 90 days of treatment initiation (41.1% vs 35.3%; p=0.002). Conclusions: In this real-world analysis of metastatic NSCLC restricted to first-line immunotherapy, initiation of ICIs within 30 days versus 30–90 days of diagnosis was not associated with differences in overall survival when survival was indexed to metastatic diagnosis. Earlier initiation was, however, associated with increased ICU utilization shortly after treatment initiation, suggesting greater clinical instability at the time therapy is started. In practice, awaiting sequencing results before starting immunotherapy is essential and thus the effect of time to initiation of immunotherapy needs further assessment via larger retrospective studies in an attempt to eliminate confounding variables.

e23570 Background: Soft tissue sarcomas (STS) are rare, and metastatic disease confers a poor prognosis. There are limited treatment options for systemic disease, and standard chemotherapy is the first line for many subtypes. Given the success of ICI (immune checkpoint inhibitors) in many solid tumors, ICI has been investigated in STS as well. This retrospective observational study aimed to investigate the efficacy of ICI in STS. Methods: We queried the Global Collaborative Network, comprising 170 HealthCare Organizations, using the TriNetX research platform, a federated network of de-identified electronic medical records, for identifying patients with soft tissue sarcoma (STS) using ICD10CM as well as ICD-O codes. Population was divided into two cohorts based on receipt of ICI. Propensity score matching (1:1 greedy nearest-neighbor, caliper 0.1) was performed for age, race, gender, and comorbidities. Kaplan–Meier survival analysis and comparative statistics were performed. Using the Cox proportional hazards model, we explored the effect of covariates including sex, age at index, race, marital status, obesity, nicotine dependence, alcohol use. Results: 14,623 STS cases were identified, of which 363 received ICI. Patients who received ICI were older (61.2 ± 16.4 vs 56.1 ± 19.2 years, p< 0.001), predominantly whites (75% vs 50%, p < 0.001); no significant difference in gender (males: 54% vs 49%, p = 0.0785). Prior to PSM, median follow up period was 358.5 days in ICI group and 846 days in non-ICI group. Survival probability at the end of time window was lower in ICI group (10.57% vs 22.56%, p < 0.001). After PSM, the group which received ICI had lower survival probability (11.26% vs 29.31%, p < 0.001), with median OS of 520 days in ICI group compared to 3161 days in non-ICI group. On reviewing the cox proportional hazard models, it was seen that nicotine dependance (HR 1.266 (1.096, 1.462), p = 0.0013), being male (HR 2.977 (2.589, 3.423), p < 0.001), or older age at index (HR 1.148 (1.076, 1.224), p < 0.001) increased the risk of death, while being married (HR 0.877 (0.815, 0.945), p = 0.0005)) decreased the risk of death. Conclusions: Our study aids in providing real-world data regarding the use of ICI in STS. In literature, we have seen no significant difference between ICI and SOC with OS ranging from 6.1 - 17 months with ICI. Even though our study did not show any survival benefit compared to non-ICI cohort, the median OS of ~17 months in ICI group is equivalent to current literature. STS are heterogenous disease, and further studies are required to determine which histologic subtype would benefit most from ICI.

e23560 Background: Soft tissue sarcomas (STS) have historically been treated with surgery, radiation, or chemotherapy. Recent studies and clinical trials have investigated the use of immune checkpoint inhibitors (ICI) either alone or in combination with chemotherapy. Here we present a meta-analysis examining ICI use in STS. Methods: A systemic search with terms encompassing STS and ICI was conducted in PubMed and Embase on January 11, 2026. A total of 1494 records were identified, which were imported into Rayyan, and titles were screened independently by 2 reviewers. 134 records were relevant, and full texts were reviewed. Only studies in which ICI was utilized for STS treatments were included. RevMan was used for analysis, and the Binary Random-Effects (RE) model was used for Pooled Proportions (PP) analyses. Results: ICI cohort had a total of 4455 patients. Using the RE model, the pooled proportions of patients achieving Complete Response (CR) was 1.7% (1.3% - 2.1%, p < 0.001, I^2 0), Partial Response (PR) was 17.7% (15.5-20.0, p < 0.001, I^2 79.057), and Stable Disease (SD) was 43% (39% - 47.1%, p < 0.001, I^2 84.044) while no response was seen in 33.5% patients (28.4% - 38.6%, p < 0.001, I^2 91.06). Overall Response Rate, (not including SD) was estimated to be 23.1% (20.4%-25.8%, p < 0.001). There was substantial heterogeneity across studies (I^2 86.629) for ORR. Current literature shows that using chemotherapy, mainly anthracycline based, has CR < 10%, PR 15-30%, and ORR 20-40%. Conclusions: Pooled data using ICI in sarcoma shows good overall response rates, especially the partial response rates. Current literature shows that using chemotherapy, mainly anthracycline based, has CR < 10%, PR 15-30%, and ORR 20-40%. Our data is very comparable to chemotherapy regimens. While meta-analysis results can be confounded by heterogeneity between studies, results of ongoing clinical studies that may result in near future may help better answer this question.

Patients with metastatic breast cancer and tumor mutational burden (TMB) ≥10 mutations/megabase are eligible for immunotherapy, but clinical and genomic characteristics and outcomes of patients with ultra-high TMB (UHTMB) ≥20 mutations/megabase remain under-characterized. In this retrospective cohort and comparative effectiveness study we examined comprehensive genomic profiling assessed on tumors as part of routine care. Real-world time to next treatment (TTNT), and overall survival (rwOS) data were collected from the Flatiron Database. 45/2049 (2.2%) patients had UHTMB; patients with UHTMB were more likely to have estrogen receptor-positive disease (86.6% vs. 70.0%), lobular histology (40.0% vs. 14.5%), and PIK3CA mutation (81.8% vs. 37.9%) vs. patients with TMB ≤ 20. Patients with UHTMB who received immunotherapy had longer TTNT (4.9 vs. 2.6 months, hazard ratio (HR) = 0.49, 95% confidence interval (CI):0.26-0.91,p = 0.025) and longer rwOS (14.1 vs. 3.2 months, HR = 0.37, 95%CI:0.18-0.76,p = 0.007) than patients with TMB <10. Single agent immunotherapy is an important treatment option for patients with UHTMB.

e12669 Background: Neoadjuvant endocrine therapy (NET) and neoadjuvant chemotherapy (NCT) are accepted treatment strategies for postmenopausal women with hormone receptor–positive (HR+), HER2-negative invasive breast cancer (IBC). Contemporary comparisons of surgical outcomes and survival remain limited. Methods: Women aged ≥50 years with stage II–III, HER2-negative (IHC 0–1+ or 2+/FISH-negative), HR+ IBC diagnosed from 2010–2017 were identified from the NCDB. Patients received NET or NCT followed by surgery and adjuvant endocrine therapy were included. Overall survival (OS) was analyzed using Kaplan–Meier methods and multivariable Cox regression Results: Among 6,857 patients, 1,619 (23.6%) received NET and 5,238 (76.4%) received NCT. NET was independently associated with older age, higher comorbidity burden, government insurance, greater travel distance ( > 200 miles), and T2 tumors, while NCT was associated with community facility treatment, higher tumor grade, and greater nodal involvement. NET was associated with lower odds of mastectomy compared with NCT (19.4% vs 80.6%; adjusted odds ratio [aOR] 0.63, 95% CI 0.53–0.75). Adjuvant radiation use did not differ after adjustment. NET was associated with lower odds of achieving at least a partial response (aOR 0.58, 95% CI 0.44–0.76), although longer NET duration ( > 115 days) was associated with reduced mastectomy rates. Median follow-up was 178 months with similar median OS; 5 yr survival at 94.6% vs 95.2%, 9 yr survival at 48.6% vs 52.1% for NET vs NCT respectively. NCT conferred a modest survival advantage in the full cohort (adjusted hazard ratio [HR] 0.89, 95% CI 0.81–0.98; p = 0.016) and in ER+/PR+ tumors (HR 0.85, 95% CI 0.77–0.94; p = 0.002), with no difference in single HR-positive disease. Conclusions: NET is preferentially used in older, more comorbid patients and those with geographic or socioeconomic barriers and is associated with lower mastectomy rates and largely comparable survival to NCT. Interpretation is limited by the retrospective design, potential selection bias, availability of Oncotype DX only in subset of pts, and lack of specific therapy used.

BACKGROUND:Sitosterolemia is a rare inherited condition caused by elevated levels of plant sterols in the plasma, characterized by mutations in ABCG5 and ABCG8 genes. A scarce occurrence in this condition are hematological abnormalities such as hemolytic anemia, stomatocytosis, and macrothrombocytopenia. We conducted a meta-analysis and systematic review to answer these questions regarding patients who have hemolytic anemia and ABCG8 mutation. METHODS:13 reports were shortlisted for the final analysis (Observational studies-6, case series-4, case reports-3). Descriptive statistics were utilized to study the patient characteristics. RESULTS:From the 13 reports that we found in available literature, we identified 19 cases of ABCG8 mutation and anemia. From the random-effects proportions model, the chance of this event occurring among patients with sitosterolemia was 6.8% [0.068, 95% Confidence Interval (CI) 0.016-0.120, P=0.010] (I2 24.68%) (14/145). Thrombocytopenia and stomatocytosis were frequently reported. Splenomegaly and xanthomas were other common associations. CONCLUSIONS:To the best of our knowledge, we provide the first report of the prevalence of anemia, specifically in patients with sitosterolemia caused by a mutation in the ABCG8 gene. At 6.8%, this is an extremely rare occurrence in an already infrequent disease.

Background: Sickle cell disease (SCD) is hereditary blood disorder leading to anemia, vaco-occlusive crises, organ damage. Its treatment remains challenging. There are various reports of utilization of Erythropoietin Stimulating Agents (ESAs) in sickle cell patients along with hydroxyurea showing some benefit in decreasing sickle cell crisis.[1-3] Here, using global research network dataset, we evaluate outcomes of using ESAs in SCD. Methods: Trinetx, a global federated research network that provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients with age >18 years, who had SCD without crisis or sickle cell/thalassemia disease or sickle cell/Hb-C disease (ICD 10 codes D57.1, D57.2, D57.4, D57.80) and Hemoglobin levels between 7 and 10 gm/dl. The population was divided into two cohorts based on receipt of ESAs (EPO, Epoietin alfa, Darbepoetin alfa). Propensity Score matching (PSM) was carried to match age, sex, race, chronic heart failure, chronic lung disease, neoplasms, chronic kidney disease stages 4 and 5, use of hydroxyurea and crizanlizumab. Outcomes of all-cause mortality (ACM), sickle cell crisis, ischemic stroke, cardiac ischemia and other arterio-venous thrombosis were evaluated. Results: 19,143 patients with SCD were identified, of whom 9.14% (n=1750) patients received EPO. The patients who received EPO were older (49 ± 18.2 vs 32.2 ± 17.4 years, p<0.0001), with more males receiving EPO (10.01% vs 8.81%, p=0.019). Use of hydroxyurea was found to be more in EPO group (37% (n=629) vs 16% (n=1568), p<0.0001). The median follow- up period was 887.5 days in EPO group and 1078 days in non-EPO group. All-cause mortality was high for patients receiving EPO (31.94% (544) vs 8.94% (1499), p<0.0001, OR = 4.78 (4.26, 5.36) with Hazard ratio 4.21 (3.82, 4.65; log-rank test = p<0.0001)). Sickle cell crisis risk was less in patients receiving EPO (14.86% (129) vs 36.34% (3521), p<0.001, OR=0.31 (0.25,0.37) with HR 0.34 (0.28,0.41)). The risk of developing stroke (11.56% vs 6.52%, p<0.0001), cardiac ischemia (17.91% vs 5.15%, p<0.0001), and other arterio-venous thrombosis (19.62% vs 9.36%, p<0.0001) was high in EPO group. After PSM, the all-cause mortality was still high in EPO group (29.22% vs 20.21%, p<0.0001, OR=1.63 (1.33,1.99), HR=1.3 (1.09,1.55)) with no significant difference in sickle cell crisis (20.25% vs 19.19%, p=0.6607, OR=1.07 (0.79,1.44)). The risk of cardiac ischemia (15.03% vs 9.16%, p<0.0001), and other arterio-venous thrombosis (18.86% vs 11.58%, p<0.001) remained higher in EPO group, while there was no significant difference in risk of stroke (10.71% vs 8.59%, p=0.1233). Conclusion: This real-world data shows that ESAs use does increase the utilization of hydroxyurea, but its significance in improving survival and sickle cell crisis still needs to be evaluated with prognostic studies. The study also highlights potential risks of arterio-venous thrombosis with the use of ESAs. Reference:Obeagu EI. Maximizing longevity: erythropoietin's impact on sickle cell anaemia survival rates. Ann Med Surg (Lond). 2024 Jan 24;86(3):1570-1574. doi: 10.1097/MS9.0000000000001763. PMID: 38463100; PMCID: PMC10923353.Santosh Saraf, Robert Molokie, Michel Gowhari, Johara Hassan, Victor R. Gordeuk; Clinical Efficacy and Safety of Erythroid Stimulating Agents in Sickle Cell Disease. Blood2012; 120 (21): 3218. doi:Little JA, McGowan VR, Kato GJ, Partovi KS, Feld JJ, Maric I, Martyr S, Taylor JG 6th, Machado RF, Heller T, Castro O, Gladwin MT. Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review. Haematologica. 2006 Aug;91(8):1076-83. PMID: 176885048; PMCID: PMC3522485.

The RxPONDER trial showed improved outcomes in premenopausal hormone positive breast cancer (BC) with 1–3 nodes and OncotypeDx (RS) score ≤ 25 with adjuvant chemotherapy (Chemo) use. This study aims to determine whether adjuvant chemotherapy improves survival outcomes in young women (≤ 50 years) with node positive, hormone receptor-positive breast cancer and oncotypeDx score ≤ 25. The 2010–2018 National Cancer Database was used to include M0 BC patients aged ≤ 50 years with N1-N3 lymph nodes stages, any T stage, and RS ≤ 25. Kaplan-Meier (KM) and multivariate (MV) propensity score (PS) weighted Cox model was used to compare survival between patients without and with chemo. 8628 women were included of which 3519 (40.8

Cryotherapy with taxane infusion is a noninvasive strategy for preventing peripheral neuropathy (PN), but the efficacy of this approach has not been proven. A systematic search was conducted, and 477 records were initially identified. The titles were screened independently by 2 reviewers. Fourteen studies were ultimately included for meta-analysis, which was conducted using the meta package in the R software. Only studies that analysed cryotherapy use in breast cancer patients who received paclitaxel or nab-paclitaxel were included. Relative risks (RRs) were calculated using the random effects model to compare the occurrence of PN between the paclitaxel and nab-paclitaxel groups. The incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 PN was 24.85

Immune checkpoint inhibitors (ICI) have become integral to treatment of non-small cell lung cancer (NSCLC). However, reliable biomarkers predictive of immunotherapy efficacy are limited. Here, we introduce HistoTME, a novel weakly supervised deep learning approach to infer the tumor microenvironment (TME) composition directly from histopathology images of NSCLC patients. We show that HistoTME accurately predicts the expression of 30 distinct cell type-specific molecular signatures directly from whole slide images, achieving an average Pearson correlation of 0.5 with the ground truth on independent tumor cohorts. Furthermore, we find that HistoTME-predicted microenvironment signatures and their underlying interactions improve prognostication of lung cancer patients receiving immunotherapy, achieving an AUROC of 0.75[95% CI: 0.61-0.88] for predicting treatment responses following first-line ICI treatment, utilizing an external clinical cohort of 652 patients. Collectively, HistoTME presents an effective approach for interrogating the TME and predicting ICI response, complementing PD-L1 expression, and bringing us closer to personalized immuno-oncology.

7066 Background: Three CAR-T cell therapies i.e. axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel are currently approved for relapsed refractory DLBCL after 2 or more prior lines of treatment. Landmark trials have shown promising efficacy however, a notable concern with CAR-T therapy is the potential development of secondary primary malignancies. Methods: A retrospective study was performed using TriNetX, a global research de-identified database with data from 145 health care organisations as of January 2025. ICD-10 codes were used for associated diagnosis and medications. The database was queried to identify RR-DLBCL patients who had received any of axi-cel, tisa-cel or liso-cel. These treatments were set as the index event for outcome analysis. Demographics and prevalence of comorbidities were extracted. Outcome analysis queried for several hematological and solid tumor malignancies. The Measure of Association Analysis was used to calculate Odds Ratio. Results: 1842 adult patients with RR-DLBCL received one of the 3 CAR-T cell treatments as listed above and 12,431 patients with RR-DLBCL did not receive any of the 3 treatments. There were 1:1 propensity score matched adjusting for age, race, sex and tobacco use. Final number for both groups was 1842. For both cohorts, 1367 (73.8%) were white, 1055 were male (57%). The cohort had a mean follow up of 497 days, median follow up of 331.5 days. The CAR-T group had higher rates of MDS (3.9% vs 0.8%, p=<0.001) and AML (3.2% vs 1.2%, p=<0.001) in our database review of the US population. It did not show higher rates of other reported SPMs like Mature T/NK cell lymphoma, Hodgkin's lymphoma, multiple myeloma or solid tumours like lung, breast, prostate primary or malignant melanoma. Data on other SPMs is shown in Table 1. Conclusions: In our retrospective study of real-world population, RR-DLBCL patients who received CAR-T cell therapy with any of axi-cel, tisa-cel or liso-cel showed higher rates of MDS and AML compared to propensity matched patients with RR-DLBCL who did not receive CAR-T cell therapy while rates of other reported SPMs were not significantly different. Frequency of SPMs in CAR-T receiving and no CAR-T receiving patients with RR-DLBCL. SPM Received CAR-T cohort (%) Did not receive CAR-T cohort (%) Odds Ratio p-value MDS 3.9 0.8 4.852 (2.767-8.507) <0.001 AML 3.2 1.2 2.668 (1.624-4.382) <0.001 Mature T/NK cell lymphoma 0.7 1.5 0.466 (0.238-0.909) 0.022 Hodgkin's lymphoma 0.9 1.9 0.469 (0.257-0.854) 0.011 Follicular lymphoma 3.8 3.6 1.055 (0.721-1.545) 0.781 Mantle cell lymphoma 1.0 0.5 1.792 (0.825-3.893) 0.135 Multiple Myeloma 1.4 2.4 0.566 (0.341-0.938) 0.025 Primary Lung site 0.7 0.5 1.292 (0.565-2.954) 0.543 Primary Breast site 0.5 0.7 0.815 (0.351-1.892) 0.634 Prostate cancer 0.5 0.6 0.902 (0.382-2.129) 0.814

Background: It has been hypothesized that RS score has lower prognostic accuracy in AA, compared to Caucasians. This study evaluates this difference using the NCDB, focusing on premenopausal, node-negative patients with RS ≥ 26 or MP high risk. Methods: The 2021 NCDB PUF was used to include premenopausal female BC patients aged 18-50 years. Inclusion criteria were N0, M0 patients with T1-4, RS ≥ 26 or MP high risk, estrogen and/or progesterone receptor-positive, and HER2-negative. Patients were stratified by their recorded race (Caucasians and AA). Univariate analysis was used after distributing the groups based on chemotherapy receipt. Kaplan-Meier analysis (KM) was used to evaluate survival rates. Results: 8,842 patients had RS ≥ 26 [Caucasians-7,412(83.83%), AA-1,430(16.17%)] of which 7,699 (87.07%) received chemotherapy [Caucasians-6495(84.36%), AA-1204(15.64%)] and 7,910 (89.46%) received hormonal therapy [Caucasians-6,663(89.89%), AA-1,247(87.20%)]. In the high-risk MP category, 1,524 patients were identified [Caucasians: 1,278 (82.99%), AA: 262 (17.01%)]. Among these, 1,259 (82.61%) received chemotherapy [Caucasians: 1,051 (82.24%), AA: 208 (79.39%)] and 1,365 (89.57%) received hormonal therapy [Caucasians: 1,141 (89.28%), AA: 224 (85.50%)]. The KM survival curve showed similar survival rates in Caucasians and AA among RS ≥ 26 patients who received chemotherapy [5 years – Caucasians 95.9(95.3-96.5)%, AA 95.1(93.4-96.4)%; 10 years – Caucasians 90.1(88.8-91.3)%, AA 89.2(86.0-91.7)%]. Numerically, survival rates were lower in AAs among RS ≥ 26 patients who did not receive chemotherapy [5 years – Caucasians 94.9(92.9-96.4)%, AA 90.4(84.4-94.2)%; 10 years – Caucasians 88.0(83.9-91.1)%, AA 80.2(66.1-88.9)%]. In the high-risk MP group, the 5-year survival rate with chemotherapy was 97.0% (95.5-98.1) for Caucasians and 93.9% (88.4-96.9) for AAs. Without chemotherapy, the 5-year survival rate was 95.5% (88.6-98.3) for Caucasians and 94.7% (68.1-99.2) for AAs. Conclusions: Our study shows that among high genomic risk, node-negative, premenopausal patients, the survival rates are numerically similar between Caucasians and African Americans (AAs) when chemotherapy was administered. However, when chemotherapy was omitted, there were numerical differences in the survival rates within the high-risk RS population. This trend was not observed with the MP cohort. The analysis also highlights that approximately 13% of patients with RS ≥ 26 and 17% of high-risk MP patients did not receive chemotherapy. Citation Format: Devashish Desai, Prashanth Ashok Kumar, Dongliang Wang, Abirami Sivapirasgasam. Prognostic Value of high-risk Oncotype Recurrence Score (RS) and MammaPrint (MP) assay in Premenopausal African American (AA) Patients with Hormone-Positive (HR+), Node-Negative Breast Cancer (BC): A Study of the National Cancer Database (NCDB) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-11-22.

e20674 Background: Dato-DXd is an antibody-drug conjugate with a TROP2-directed monoclonal antibody. Recent trials have demonstrated promising efficacy for Dato-DXd in pre-treated advanced NSCLC compared to 2nd line chemotherapy. Methods: A systematic search using terms encompassing Dato-DXd and NSCLC was conducted in PubMed, Embase, Cochrane and Scopus. A total of 2866 records were identified and imported into Rayyan. These were screened independently by two reviewers, and a third independent reviewer resolved conflicts. 56 studies were included for full text screening subsequent to which 5 studies were included for final analysis. All 5 studies were randomized controlled trials that studied Dato-DXd. 3 were full text articles, and 2 were abstracts. Binary Random-effects (RE) model pooled proportions (PP) using DerSimonian-Laird method was performed using OpenMeta. Results: A total of 756 patients were included from 5 studies. All studies included patients with advanced stage NSCLC who had received 1-5 prior lines of therapy. 4 studies used a standard Dato-DXd dose of 6mg/kg every 3 weeks while one study divided patients into 4mg/kg, 6mg/kg and 8mg/kg every 3-weeks groups. Disease Control Rate (DCR) ie CR+PR+SD was seen in 77.1% [(74.2-80.1) I2=0%]. Overall Response Rate (ORR) ie CR+PR was seen in 30.8% [(26.8-34.9) I2=24.4%]. Mortality rate was 62.8% [(49.7-76.0) I2=89.3%]. Pooled mean OS was 12.1 months (8.4-15.3), PFS was 5.5 (3.4-7.2). Pooled mean for median time to response was 1.4 months (1.2-9.7), median duration of response (DOR) was 9.6 (4.6-18.2). Stomatitis was seen in 55.5% [(50.0-60.9) I2=50.7%]. Pneumonitis was seen in 5.4% [(2.2-8.6) I2=78.8%]. Drug discontinuation due to adverse effects occurred in 11.5% [(6.7-16.2) I2=70.6%]. Rest of analytic statistics shown in Table 1. Conclusions: Pooled data for Dato-DXd in the subsequent line setting demonstrated a robust overall response rate and disease control rate.In comparison DCR for docetaxel and ramucirumab in the REVEL study was 67%. Based on this, Dato-DXD could be a subsequent line treatment option in metastatic NSCLC. While meta-analysis results can be confounded by heterogeneity between studies, results of ongoing clinical studies on Dato-Dxd that may result in the near future may help better answer this question. Pooled proportion metrics for Dato-DXd in pretreated advanced NSCLC. Dato-DXd in pretreated NSCLC % (95% CI) I 2 Partial Response (PR) 27.7% (22.4-32.9) 48% Complete Response (CR) 1.4% (0.5-2.3) 0% Stable Disease (SD) 47.2% (42.2-52.2) 27.5% Progressive Disease (PD) 14.3% (11.5-17.0) 0% Overall response rate (ORR) 30.8% (26.8-34.9) 24.4% Disease Control rate (DCR) 77.1% (74.2-80.1) 0% Grade 3 or worse adverse effects (AE) 38.8% (28.3-49.4) 88.9% Pneumonitis 5.4% (2.2-8.6) 78.8% Stomatitis 55.5% (50.0-60.9) 50.7%

BackgroundFusion of the RET gene resulting in clinically significant Genomic Alteration (GA) occur in 1-2% of NSCLC in the United States and has emerged as a major target for RET inhibitors which are first line treatment options in the Stage 4 setting. RET fusions have also been well-described as acquired resistance mutations in cases of EGFR-driven NSCLC treated with anti-EGFR tyrosine kinase inhibitors including erlotinib and osimertinib. The aim of this study was to determine whether RET fusion positive (RETfus+) NSCLC represents a unique histologic subtype of the disease with a unique genomic profile.MethodsWe selected 503 of 72,596 (0.7%) total NSCLC that were reported as RETfus+ from the Foundation One database. The cases were centrally evaluated for predominant histology and underwent hybrid capture based CGP to evaluate diverse GA. Cases with EGFR mutations were excluded. PD-L1 expression was determined by Immunohistochemistry (IHC) (Dako 22C3) with Tumor Proportion Score (TPS) ≥50% = high expression. For statistical comparisons, the false discovery rate was corrected using Benjamini/Hochberg adjustment.ResultsPotentially targetable GAs found less frequently in the RETfus+ group included BRCA1, BRAF, FGF12, FGFR1, KEAP1, KMT2D, KRAS, MDM2, MET, NF1, NSD3, PIK3CA, RB1, AND TP53. The presence of HRD, APOBEC and Tobacco gene signatures were also lower in frequencies in the RETFus+ NSCLC cases. SETD2 was the only GA found to be higher in the RETfus+ group. While markers predictive of checkpoint therapy response including TMB high level was more frequent in the RETfus- cases, PD-L1 high expression was more in RETfus+ samples. Surgical pathology analysis revealed that the high grade solid non-acinar pattern at 32% was the most frequent histologic subtype.ConclusionsRETfus+ NSCLC features a unique genomic signature which can further impact therapy selection. With recent expanded approval of more specific RET kinase targeting inhibitors (selpercatinib and Pralsetinib) in the pan-cancer treatment setting, further study of RETfusion+ NSCLC histology and genomic/biomarker status appears warranted.