Purpose: We compared the association of concurrent TP53 pathogenic variants (PV) with overall survival (OS) by driver status in non-small cell lung cancer (NSCLC). Patients and Methods: The discovery cohort included 3,295 patients with stage IV NSCLC treated at Kaiser Permanente Northern California. The validation cohort included 12,982 NSCLC from 37 public cBioPortal studies. Driver-positive disease was defined as presence of EGFR, ALK, or ROS1 alteration. We used Cox regression modeling to estimate hazard ratios (HRs) for mortality, adjusting for demographics and other factors. Results: Among the discovery cohort, TP53 PV was associated with worse OS among patients with an EGFR, ALK, or ROS1 alteration (HR = 1.80, [95% confidence interval (CI), 1.50-2.15]) but not among those without a driver mutation (HR = 1.08, [95% CI, 0.97-1.21]). Among the validation cohort, TP53 PV was associated with worse OS with HR of 2.27 [1.92-2.69], 2.42 [1.42-4.10], 1.30 [1.20-1.42], and 3.09 [95% CI, 1.47-6.47], for EGFR-activating, ALK-fusion, EGFR/ALK wild-type disease and RET-fusion respectively. The differential association was largest in EGFR exon 20 insertion tumors, in which TP53 PV carried HR = 4.68 [95% CI, 2.34-9.37], 3.9-fold that in driver-negative disease; the corresponding ratio for ERBB2 exon 20 insertions were 1.23 [95% CI, 0.75-2.02]. TP53 PV was not associated with OS in squamous carcinoma. Conclusions: Association of TP53 PV with OS in advanced NSCLC appears to depend on co-occurrence of other driver mutations. This driver-dependent effect modification informs interpretation of TP53 status and may be useful for risk stratification in clinical practice.

350 Background: Esophageal (EAC), gastroesophageal junction (GEJ) or gastric (GAC) adenocarcinoma share similar etiologies and treatment approaches. However, it is not clear if they possess similar or different prognostic and biological characteristics. We aimed to examine overall survival (OS) in associations of the common genomic alterations with these three anatomically closely linked adenocarcinomas. Methods: Eligible patients had recurrent or de novo metastatic GAC, GEJAC or EAC whose tumors had undergone next generation sequencing (NGS) performed from November 2017 to December 2023. We used Cox regression modeling to examine the association between GAC, GEJAC, EAC and OS, adjusting for demographics, performance status, Charlson comorbidity index, receipt of chemotherapy, and HER2 overexpression or amplification (HER2 positive), p53 (mutp53 ) , KRAS (mutKRAS), CDKN2A , PIK3CA co-mutations and MYC amplification. Results: Of 875 total eligible patients, 173 had EAC, 276 had GEJAC and 426 had GAC. GEJAC had substantially better OS than EAC (HR = 0.68, [95% CI, 0.54-0.86]), and modestly better OS than GAC (HR = 0.85, [95% CI, 0.67-1.09]). HER2 positivity was associated with substantially better OS among EAC (HR = 0.62; [95% CI, 0.40-0.96]) and GEJAC (HR = 0.59; [95% CI, 0.38-0.87]) but not among GAC (HR = 0.98; [95% CI, 0.78-1.23]) patients. In addition, p53 gain-of-function versus non-gain-of-function mutations were associated with substantially worse OS among GAC (HR = 1.41; [95% CI, 0.98-2.01]) but not among EAC or GEJAC. MutKRAS was associated with substantially worse OS among EAC (HR = 1.81; [95% CI, 1.10-2.99]) but not among GEJAC or GAC. Surprisingly, MYC amplification was associated with dramatically better OS among EAC (HR = 0.19; [95% CI, 0.08-0.42]) but substantially worse OS among GEJAC (HR = 1.98, 95% CI, 1.14-3.40]) and GAC (HR = 1.75; [95% CI, 1.10-2.80]). Conclusions: GEJAC, EAC and GAC possess substantially different OS that appears differentially associated with HER2 status, mutp53, mutKRAS and MYC amplification. These results suggest distinct prognostic and biological characteristics of these three anatomically closely linked adenocarcinomas that could have important implications in clinical practice and on further investigations on their biological and topological mechanisms.

BACKGROUND:Advanced esophageal (EAC), gastroesophageal junction (GEJAC) and gastric (GAC) adenocarcinomas with HER2 amplification or overexpression (HER2+) are routinely treated with trastuzumab. However, it remains unclear if HER2+ is associated with superior overall survival (OS). METHODS:The cohort included recurrent or de novo metastatic GAC, GEJAC and EAC from Kaiser Permanente Northern California. We used Cox regression modelling to examine association between HER2+ and OS, adjusting for demographics, performance status, CCI, receipt of chemotherapy and p53 (mutp53), KRAS (mutKRAS), CDKN2A, PIK3CA co-mutations and MYC amplification. RESULTS:Of 875 total eligible patients, 173 had EAC, 276 had GEJAC and 426 had GAC. HER2+ was associated with better OS among the full cohort (HR = 0.74, 95% CI [0.60-0.93]), among EAC (HR = 0.62; [95% CI, 0.40-0.96]) and GEJAC (HR = 0.59; [95% CI, 0.38-0.87]), but not among GAC (HR = 0.89; [95% CI, 0.59-1.35]) patients. GEJAC had better OS than EAC (HR = 0.68, [95% CI, 0.54-0.86]). Trastuzumab treatment was associated with better OS (HR = 0.40, 95% CI [0.21-0.77]). In addition, HER2+ was associated with better OS across the molecular subgroups except that of KRAS mutation (mutKRAS). Our data also show that GEJAC, EAC and GAC were differentially associated with mutp53, mutKRAS and MYC amplification. CONCLUSION:HER2+ and treatment with trastuzumab in HER2+ patients were associated with superior OS in upper gastrointestinal adenocarcinomas across molecular subgroups except that of mutKRAS. These results reaffirm the importance of anti-HER2 treatment in HER2+ patients and provide insight on the prognostic and biological divergence among these anatomically linked upper gastrointestinal adenocarcinomas.

PURPOSE:To examine potential overall survival (OS) differences between males and females with advanced gastric (GAC), gastroesophageal junction (GEJAC) and esophageal (EAC) adenocarcinoma. PATIENTS AND METHODS:The study included patients from Kaiser Permanente Northern California with de novo metastatic or relapsed EAC, GEJAC and GAC. We used Cox regression modeling to examine association of sex with OS adjusting for demographics, performance status, Charlson comorbidity index, histology (Lauren's classification), receipt of chemotherapy, and HER2 amplification or overexpression, p53, KRAS, CDKN2A, PIK3CA co-mutations and MYC amplification. RESULTS:Of 875 total eligible patients, 426 had GAC, of whom 224 were male and 202 were female. Among patients with GAC, males had better OS than females (HR = 0.73; [95% CI, 0.59-0.92]), and this OS difference was preserved across the molecular subgroups except mutKRAS. Intriguingly, among GAC patients with a p53 mutation, males versus females had better OS if tumor carried a non-gain-of-function mutation (non-GOF, HR = 0.59; [95% CI, 0.40-0.85]) but worse OS if tumor carried gain-of-function mutation (GOF, HR = 1.80; [95% CI, 0.83-3.99]). Sex was not associated with OS among patients with GEJAC (HR = 1.14); (95% [CI, 0.77-1.67]) or EAC (HR = 1.0; [95% CI, 0.57-1.74]). These results remained similar when separate analyses were performed among patients who received and among patients who did not receive chemotherapy. CONCLUSIONS:Males had better OS than females among patients with advanced GAC. In addition, among GAC patients with a mutp53, sex and OS association was inversely driven by the presence of GOF versus non-GOF. Our data reveal a previously unappreciated sex disparity in survival outcomes among patients with advanced GAC. If confirmed, this finding could have important implications for clinical practice and for further understanding the biology of GAC.

Predictive biomarkers for multiple ADCs/tumor types (beyond 3+ HER2 IHC) are lacking. We previously reported the discovery of ADC TRS—an algorithm combining individual ADC target expression, proliferation, and adhesion by RNAseq to predict ADC clinical benefit across tumor types/targets—and association with OS after ADC treatment (Abstract 3140, ASCO 2024). Here we evaluated the final ADC TRS biomarker (ADC-specific; tuned on >100 tumor type/ADC RRs) by a qRT-PCR based clinical trial assay (CTA) for predicting ADC clinical benefit. Adults in the Kaiser Permanente Northern California (KPNC) system with advanced bladder or breast cancer in an observational trial (NCT03061305) who were treated with an approved ADC (enfortumab vedotin [EV], sacituzumab govitecan [SG] or trastuzumab deruxtecan [T-DXd]; first dose by Apr. 21, 2023) with valid CTA TRS results from FFPE tissue (collected prior to 1st ADC treatment) were eligible; patients with prior trastuzumab or hormonal (between tissue collection/ ADC start) treatment were excluded. KPNC oncologists (blinded to ADC TRS status) determined best response to therapy from chart review. ADC TRS status (+ vs. -) / response data were merged by the KPNC statistician and analyzed per a prespecified plan. A total of 117 KPNC patients with advanced bladder (n=58 [50%]) or breast (n=59 [50%]) cancer treated with an approved ADC (n= 56 [48%], 47 [40%], and 14 [12%] EV, SG, and T-DXd, respectively) were evaluable for TRS and RR. As shown in the Table, TRS+ status was associated with significantly higher RR and longer PFS and OS for approved ADC treatment; results were generally similar across ADCs and tumor type. By a qRT-PCR based CTA, TRS+ status was associated with improved RR, PFS and OS for approved ADCs in an observational cohort of patients with advanced bladder or breast cancer. Prospective validation for approved and/or investigational ADCs is warranted. Sachdev P. Thomas, Laurel A. Habel, Jennifer M. Suga, Ninah Achacoso, Joshua R. Nugent, Chen Jiang, Elaine Chung, Stephanie Bush, Michael D. Nitchie, Katarina M. Robinson, Jasie Inman, Ryan White, Komal Plouffe, Daniel R. Rhodes, Scott A. Tomlins, Bryan Johnson. Antibody Drug Conjugates Treatment Response Score (ADC TRS) for predicting ADC treatment response [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 2038.

809 Background: Gene fusion/rearrangements occur at a frequency of 0-15% in GI system cancers. Detection and treatment of fusion genes such as NTRK, FGFR2, NRG1 and RET fusions are included in NCCN guidelines and are commonly detected using next generation sequencing (NGS). NGS panels have continued to expand over time, which should result in increases in the identification of gene fusions. The aims of this study were to describe the percent of patients with advanced GI tumors undergoing NGS with identified gene rearrangements across time as panels expanded. Methods: The study included 7237 patients in the Kaiser Permanente Northern California Integrated Health System receiving care for advanced GI cancers from 2017 to Aug 2024, whose tumors samples were evaluated using NGS (Stomach=926, Colorectal=2792, Gallbladder=569, Esophagus=761, liver=218, Pancreas=1971). Results: A total of 231 patients (3.2%) were identified with a gene rearrangement, including 4.6% in stomach(N=43), 2.8% in colorectal(N=78), 8.9% in gallbladder(N=24), 5.3% in esophagus(N=40), and 1.9% in pancreatic (N=38 ). Rearrangements included NTRK1/2/3, FGFR2/3, NRG, ALK, ROS, CLDN18-ARHGAP, RSPO2/3, DNAJB1-PRKACA, BRAF, MET and RET. The numbers per year were (see table). Conclusions: The use of more comprehensive NGS panels such as WES did not appear to increase the detection rate for fusion/rearrangements. In resource limited settings, limited panels may suffice. The number of GI cancer patients getting NGS testing has increased over time. Gene rearrangements/fusions identified per year. YEAR 2018 2019 2020 2021 2022 2023 2024 (Jan – Aug) Gene Rearrangement identified 29 37 43 55 54 62 38 TOTAL GI Cancer Samples Sequenced 610 858 900 1047 1249 1181 785 Percentage 4.75% 4.31% 4.78% 5.25% 4.32% 5.25% 4.84%

715 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results from a cohort of pts with PC with BRCA1/2 mut treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site-selected labs. Most genomic tests did not distinguish between germline or somatic mut. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease of at least 16 wks duration (SD16+). CR is based on radiographic assessment. CA 19-9 levels were not collected. Simon 2-stage design tested null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled; otherwise, the cohort is closed. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and SD, and safety. DOR is defined as time from pt’s first documented OR to progressive disease. Results: 32 pts with PC with BRCA1 (n=8), BRCA2 (n=22) or both BRCA1/2 (n=2) were enrolled between October 2017 and March 2023. 4 pts were not evaluable for efficacy. Pts had adenocarcinoma (n=29), acinar cell carcinoma (n=2), and poorly differentiated carcinoma (n=1). Table shows demographics and outcomes. 1 CR, 3 PR and 4 SD16+ were observed for a DC rate of 31% (90% CI, 18 to 100) and OR rate of 14% (95% CI, 4 to 33). The pt with CR had a BRCA1 mut, the pts with PR had BRCA1 (n=1) and BRCA2 (n=2) muts, and the pts with SD16+ had BRCA1 (n=2) and BRCA2 (n=2) muts. The null DC rate was rejected (p=0.04). The pt with CR remains on tx with a DOR of 311 wks as of May 2024. 15 pts received prior tx with olaparib and 1 of those pts had SD16+ on this study. 17 pts had ≥1 drug-related grade 3-4 adverse event (AE) or serious AE. All were consistent with N+I labels except generalized muscle weakness and lymphopenia. Conclusions: N+I shows antitumor activity in pts with PC with BRCA1/2 mut and warrants further study. Clinical trial information: NCT02693535 . Demographics (N=32) and efficacy outcomes (n=28). Median (Med) age, years (range) 66 (37-80) ECOG PS, % 0-12 31 (97)1 (3) Prior systemic regimens, % 0-2≥3 10 (31)22 (69) DC rate, % (OR and SD16+) (90% CI) 31 (18, 100) OR rate, % (95% CI) 14 (4, 33) Med PFS, wks (95% CI) 9 (7, 16) Med OS, wks (95% CI) 34 (14, 46)

Demographics of patients with wt and mut TP53.

OS comparison between Stanford and KPNC cohort

Demographics of patients with wt and mut ATRX.

Demographics of patients wt and mut Rb1.

Background We aimed to examine whether PTEN pathogenic variants (mutPTEN) were associated with overall survival (OS) in patients with advanced soft tissue sarcoma (STS) with the presence of one or more of the most common genomic alterations including p53, CDKN2A, RB1 , and ATRX pathogenic variants. Methods This study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 or higher locally advanced and metastatic STS. Results A total of 174 patients had leiomyosarcoma (LMS), 136 had undifferentiated pleomorphic sarcoma (UPS), 78 had Liposarcoma (LPS), and 214 had other histology subtypes (Others). Among all patients with STS, OS was worse for those with mutPTEN versus wild-type PTEN (wtPTEN, adjusted HR [aHR] = 1.58 [95% CI, 1.11–2.23]), mutCDKN2A vs wtCDKN2A (aHR = 1.33 [95% CI .99–1.80]), and mutRB1 vs wtRB1 (aHR = 1.26 [95% CI 0.93–1.70[), while OS was similar for mutp53 vs wtp53 and mutATRX vs wtATRX. MutPTEN versus wtPTEN was consistently associated with worse OS in histologic subtypes including LMS and UPS and molecular subgroups. Conclusion MutPTEN vs wtPTEN was associated with worse OS in advanced STS. If confirmed, our findings could be helpful for prognostic stratification in clinical practice and for further understanding the molecular mechanisms of STS.

Demographics of patients with wt and mut CDKN2A.

3140 Background: Several ADCs are FDA-approved for patients with advanced solid tumors; dozens more are in trials. Predictive biomarkers are lacking, with ADC target expression alone performing poorly across ADCs/tumor types. We previously described the development of ADC Treatment Response Scores (ADC-TRS)—a tissue-based multivariate gene-expression test combining individual ADC target expression with proliferation and adhesion—with high correlation of per-ADC/tumor type biomarker frequency (TRS-High) with corresponding clinical trial ORRs for 9 ADCs (PO1-14-04; SABCS 2023). Here we evaluated ADC-TRS in two cohorts of patients treated with approved ADCs. Methods: Adults with advanced solid tumors from an observational trial (NCT03061305) treated with an ADC with TRS results from FFPE tissue (collected prior to 1 st ADC treatment) were eligible; HER2+ patients previously treated with trastuzumab or with hormonal therapy treatment between sample collection/first ADC treatment were excluded. Kaiser Permanente Northern California (KPNC; limited to breast [BR] and bladder [BL] cancer) patients and non-KPNC patient (pan-solid tumor) cohorts were analyzed separately. We evaluated whether treatment-matched ADC-TRS status (High or Low) was significantly associated with overall survival (OS) after ADC treatment initiation by Cox proportional hazards models (adjusting for age, indication, and years since tissue collection). Additional analyses in the non-KPNC cohort evaluated whether proliferation/adhesion-related gene expression provided information on outcomes beyond ADC target expression only and predictive/prognostic effect. Results: Patients treated with an approved ADC were included in the non-KPNC (n=72; 5 ADCs/9 tumor types); most frequent sacituzumab govitecan/BR [43%]) and KPNC (n=127; 3 ADCs/two tumor types; most frequent enfortumab vedotin/BL[50%]) cohorts, respectively. In both cohorts, ADC TRS status was significantly associated with OS (High vs. Low, median OS 22.8 vs. 8.7 months [mo.], aHR 0.15, p=0.005, and median OS 15.3 vs. 8.3 mo., aHR 0.58, p=0.011, respectively). In the non-KP cohort, ADC-TRS significantly improved model fit for OS beyond target gene expression alone (likelihood ratio test [LRT] p=0.0008). A predictive biomarker effect was confirmed by lack of ADC-TRS status association with OS from systemic chemotherapy start in indication-matched patients not treated with an ADC (n=126, aHR 0.43-2.79, p=0.11-1.0 for the 9 individual TRS). In a 15,108 patient pan-tumor cohort (regardless of treatment), 26.7% were ADC-TRS High for at least 1 approved ADC outside approved indications. Conclusions: Results support ADC-TRS as a multivariate gene-expression-based biomarker that predicts ADC OS across tumor types and targets. More than 25% of all patients with advanced solid tumors have a greater likelihood of being responsive to one or more approved ADCs outside of approved indications.

AbstractPurpose: To examine whether overall survival (OS) differs for male and female patients with advanced soft-tissue sarcoma (STS). Experimental Design: The study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 and 3 locally advanced or metastatic STS whose tumor underwent next-generation sequencing. We used Cox regression modeling to examine association of sex and OS adjusting for other important factors. Results: Among 388 eligible patients, 174 had leiomyosarcoma (LMS), 136 had undifferentiated pleomorphic sarcoma (UPS), and 78 had liposarcoma. OS for male versus female patients appeared to be slightly better among the full cohort [HR = 0.89; 95% confidence interval (CI), 0.66–1.20]; this association appeared to be stronger among the subsets of patients with LMS (HR = 0.76; 95% CI, 0.39–1.49) or liposarcoma (HR = 0.74; 95% CI, 0.32–1.70). Better OS for male versus female patients was also observed among all molecular subgroups except mutRB1 and mutATRX, especially among patients whose tumor retained wtTP53 (HR = 0.73; 95% CI, 0.44–1.18), wtCDKN2A (HR = 0.85; 95% CI, 0.59–1.23), wtRB1 (HR = 0.73; 95% CI, 0.51–1.04), and among patients whose tumor had mutPTEN (HR = 0.37; 95% CI, 0.09–1.62). OS also appeared to be better for males in the MSK-IMPACT and TCGA datasets. Conclusions: A fairly consistent pattern of apparent better OS for males across histologic and molecular subgroups of STS was observed. If confirmed, our results could have implications for clinical practice for prognostic stratification and possibly treatment tailoring as well as for future clinical trials design.

Demographics of patients with wt and mut PTEN.

Supplementary Table S4 shows the characteristics of the patients used in the case cross-over analysis