4554 Background: Some studies have demonstrated that Latino patients (pts) with mccRCC have worse clinical outcomes than NHW pts. It is unclear if this disparity is related to biological differences and/or social determinants of health (SDOH). Herein, we investigate clinical-genomic features and outcomes among Latinos and NHW pts with ccRCC. Methods: Pts with mccRCC treated at UCSD were retrospectively identified from an institutional database. Pts with genomic sequencing on tumor tissue samples were included. Pts were categorized as Latino or NHW based on self-identification. Logistic regression was applied for the presence of divergent frequencies of somatic mutations. Cox regression models evaluated the effect of additional factors, including tumor genomic alterations and clinical features, on overall survival (OS). Results: The analysis included 135 pts with mccRCC, of whom 62 were Latinos. There were no significant differences in age at diagnosis (61 vs 62 years), BMI (28 in both), sex (76% vs 71% males), presence of sarcomatoid/rhabdoid features (38% vs 30%), and number of metastatic sites (71% vs 68% with >1 site). Compared to NHW, Latino pts had higher rates of IMDC intermediate/poor risk disease (85% vs 59%, p<0.01) and synchronous metastatic disease (60% vs 41%, p=0.04). Latino pts were also more likely to have public health insurance (42% vs 8%, p <0.01), and reside in areas with higher deprivation indexes (43% vs 20%, p<0.01). BAP1 (26% vs 10%, p=0.02) and ATMmutations (10% vs 0%, p <0.01) were more common in Latino pts, whereas SETD2 (32% vs 8%, p <0.01) and TERT alterations (19% vs 6%, p=0.04) were more prevalent among NHWs. VHL(84% vs 78%), PBRM1 (27% vs 36%) and TP53 (10% vs 14%) mutation rates were comparable between Latino and NHW pts. The use of first-line immune checkpoint inhibitor (ICI) based combination therapy was similar between groups (47% in both). In those receiving first-line ICI-based therapy, 2-year OS was shorter among Latino pts compared to NHW pts (HR 4.05, p=0.04). Similarly, Latino pts had a significantly reduced 2-year OS when treated with first-line tyrosine kinase inhibitor (TKI) monotherapy compared to NHW pts (HR 9.25, p=0.03). On multivariable analysis, there was a significant difference in OS between Latino and NHWs (HR 2.7, 95%CI 1.18-6.36, p=0.02) after adjusting for age, nephrectomy status, IMDC risk group, sarcomatoid features, synchronous disease, sites of metastasis, and BAP1, PBRM1, SETD2, TP53, TERT, and KDM5C mutations. Conclusions: Our study demonstrates that, within our local healthcare system, Latino pts with mccRCC present with different clinical-genomic features and worse survival outcomes. These findings underscore the complex interplay between tumor biology and SDOH. Our study emphasizes the unmet need to promote diversity in future research as well as understand and bridge disparities gaps across varied ethnicities with RCC.

4533 Background: Next generation sequencing (NGS) of ctDNA can complement tissue NGS and is a non-invasive test that can be conducted serially, with the potential to enhance assessment of spatial and temporal molecular tumor heterogeneity. Here, we investigated mutations in RCC patients from ctDNA and matched tissue genomic profiling. Methods: From the Tempus multimodal database, we retrospectively analyzed de-identified NGS data from patients (pts) with RCC that had dual tissue (Tempus xT, 648 genes) and ctDNA testing (Tempus xF, 105 genes). Pts with matched samples (collected +/- 90 days of one another) were included. Clinical characteristics and select pathogenic somatic short variants (PSSV) and copy number variants [(amplifications and deletions, two copy number losses (CNL)] were evaluated. Concordance analyses were restricted to the 105 genes tested on the ctDNA panel and further restricted to short variants, with the exception of amplifications and CNL detected by both xF and xT. Results: Among all pts (n=393), the median age was 61 years and 71% were male. Median time from tissue to blood collection was 21 days (IQR, 7, 39). 67% (n=265) and 68% (n=266) had metastatic disease at the time of tissue and blood collection, respectively. The most common tissue sites were kidney (49%, n=189), bone (11%, n=43), lung (9%, n=34), lymph node (8%, n=29), liver (6%, n=23), and brain/CNS (4%, n=17). Genes harboring the most common PSSV in tissue included VHL (59% n=232), PBRM1 (31%, n=123), SETD2 (23%, n=91), and TP53 (14%, n=54). Genes with common PSSV in ctDNA included TP53 (23%, n=91), VHL (18%, n=69), BAP1 (6%, n=23), and PBRM1 (5%, n=21). The combination of tissue and ctDNA testing increased detection of mutations (Table). There was higher concordance between somatic alterations in select genes among patients with metastases. Conclusions: This analysis shows that ctDNA profiling is complementary to tissue based NGS in RCC and can increase the detection of mutations. Concordance between ctDNA and tissue profiling increased in individuals with metastatic disease. Future research is warranted to understand how longitudinal ctDNA analysis can define biomarkers of response and resistance at the mutation and ctDNA fraction levels. [Table: see text]