Shen, John P

e16479 Background: Recent genomic data has demonstrated SBA to be a molecularly unique entity when compared to colon or gastric cancers. The ongoing SWOG 1922 randomized clinical trial is comparing FOLFIRI to ramucirumab/paclitaxel as the second-line treatment for metastatic SBA. We sought to further define the activity of taxane-based therapy in the largest collection of SBA patients treated with this therapy. Methods: A retrospective review of SBA patients treated with taxane-based chemotherapy from 1994 to 2024 at MD Anderson Cancer Center was performed. All patients had pathologic confirmation, received > 1 cycle of therapy, and had documented tumor response evaluation. Response was assessed by the treating physician based on the imaging studies and categorized as response, stable disease or progression. Patient demographics, clinical parameters, molecular data, and taxane treatment was reviewed. Kaplan-Meier survival analysis was performed to calculate time to progression (TTP) and overall survival (OS). Results: 70 SBA patients treated with taxane-based therapy were identified. The median age at diagnosis was 57 years (range 33-80 years), majority being male (59%) with primary tumor located at duodenum (44%), Jejunum (34%), Ileum (16%). The most common presenting metastatic site was peritoneum (39%), followed by liver (31%). The genomic status revealed mutations in the following genes: 62% TP53, 47% KRAS, 24% SMAD4, and 15% APC. Taxane treatment was single agent (nab-paclitaxel, paclitaxel, or docetaxel) in 29%, gemcitabine and taxane combination in 61% and other taxane-based combinations in 10%. Therapy was given in the metastatic setting as 2nd-line in 40%, 3rd-line in 33% and 4th-line or greater in 20%. Response status was response in 24%, stable disease in 26%, and progression in 50%. Median TTP was 3.1 months (95%CI: 2.0-4.2 months), and median OS was 8.7 months (95%CI: 7.4-10.1 months). Median TTP was similar between single agent (2.6 months) and gemcitabine-based combination (2.5 months) (p =0.75). Efficacy did not differ by line of therapy nor primary tumor site. Efficacy differed by TP53 mutation status: TP53 mutated vs wildtype (response 21% vs 43%, p = 0.02; median TTP 2.4m vs 4.9m, p = 0.013; median OS 7.3m vs 10.6m, p = 0.004). Conclusions: This retrospective study of 70 SBA patients confirms the activity of taxane-based therapy demonstrating a response rate of 24% and median TTP of 3.1 months. Though limited by sample size, TP53 mutations may represent a negative predictive marker for taxane-based therapy in SBA patients. These findings support the ongoing SWOG 1922 trial investigating taxane-based therapy as a second line for metastatic SBA.

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal–regulated kinase (ERK)–dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

260 Background: NGS to identify HRR mutations (mut) is indicated in advanced prostate cancer (aPC); samples for testing may be tissue or plasma. In a large real-world (RW) database, we determined concordance between plasma ctDNA and primary tumor tissue (PT) and/or metastatic tissue (MT) for BRCA1, BRCA2, and ATM mut in PC patients (pts) who received both LB and tissue NGS any time during standard of care (SOC) management. The study objective was to assess the utility of LB to detect actionable mut in these HRR genes and demonstrate the utility of combined LB and tissue testing. Methods: We examined de-identified data from pts who had NGS using both Tempus xF (105 genes-LB) and Tempus xT (648 genes-tissue) during SOC for aPC. Analyses included 1) PT and LB and 2) MT and LB. The results from the pts’ earliest PT or MT and earliest LB were used for paired analyses. The prevalence of a pathogenic/likely pathogenic germline and/or somatic mut in BRCA1, BRCA2, or ATM was reported as N (%), 95% CI. The sensitivity of the LB to identify observed HRR mut in tissue was also reported as N (%), 95% CI. Concordance between pairs was evaluated by Cohen’s kappa statistic with 95% CI. Results: HRR results are show for 1074 PC pts who had NGS performed on PT and LB and 451 PC pts with NGS on both MT and LB. In the PT and LB analysis, HRR mut were found in 6.2% (95% CI: 4.9%-7.9%) of LB and 8.8% (95% CI: 7.2%-11%) of PT. The sensitivity of LB to detect HRR mut in the PT was 53% (95% CI: 43%-64%). Cohen’s kappa statistic was 0.59, 95% CI=0.50-0.68, between PT and LB. In the MT and LB analysis, HRR mut were found in 10% (95% CI 7.8%-14%) of LB and 10% (7.6%-13%) of MT. The sensitivity of LB to detect HRR mut in the MT was 70% (95% CI: 54%-82%). Cohen’s kappa statistic was 0.65, 95% CI=0.54-0.77, between MT and LB. Conclusions: In this large RW dataset, plasma ctDNA-based analysis of BRCA1, BRCA2, and ATM mut showed greater concordance between LB and MT than LB and PT, and may be used as an initial tool for HRR mut detection. When LB results are negative, further exploration with tissue-based testing may identify HRR mut to guide clinical decisions. [Table: see text]