Citations

Background: Rare, functionally deleterious genetic variants have been implicated as having substantially larger effect sizes than common variants, potentially accounting for much of the missing heritability in lung cancer (LC). Over 25 years, the Genetic Epidemiology of LC Consortium (GELCC) has curated an invaluable resource of specimens and data from individuals with a strong family history of LC. Methods: Whole-genome and exome sequencing data were analyzed in 129 high-risk familial LC (FLC) families, defined as having two first-degree relatives or three or more second-degree relatives affected by LC (177 affected FLC and 309 unaffected relatives). The discovery focused on rare (allele frequency < 1% in gnomAD global population) and deleterious variations (missense, stop-gained, frameshift) enriched in FLC. Promising candidates were further external validated in 2,408 sporadic lung cancer (SLC) cases and 885 population controls from the International Lung Cancer Consortium. Results: We identified 168 variants with moderate-to-large effects on FLC risk, 100 of which were validated for SLC risk (Table 1 Table 1. Top 20 candidates Gene Rare (MAF < 1%), deleterious variants No. of variant carrier counts Odds Ratio, LC vs Control FLC | Relative | SLC | Control FLC+SLC SLC Oncogene ERBB3 / HER3 p.A1131T 3 | 1 | 2 | 0 35 15 JAK p.V651M 2 | 3 | 7 | 0 62 51 NOTCH3 p.R1560P 3 | 1 | 4 | 0 48 29 ROS1 p.N785X 6 | 4 | 10 | 0 110 74 USP6 p.R522 fs del 3 | 6 | 6 | 0 62 45 Tumor suppressor gene ATM p.L2332P 3 | 2 | 8 | 0 76 59 LZTS2 p.K458R 4 | 4 | 18 | 0 152 133 NPIPB13 p.V270 fs del 13 | 14 | 10 | 0 159 74 PARK2 / PRKN p.P153R 3 | 3 | 8 | 0 76 59 RB1 p.A525G 3 | 0 | 6 | 0 62 45 SLX4 p.S1716T 3 | 2 | 9 | 0 83 66 SYNE1 p.M6566I 2 | 0 | 7 | 0 62 52 TGFBRAP1 p.T301R 5 | 0 | 11 | 0 110 82 WNK1 p.K583 fs del 4 | 0 | 23 | 0 187 171 Other cancer-associated gene CFTR p.R74W 4 | 2 | 4 | 0 55 30 FLG p.R3404 fs del 7 | 2 | 4 | 0 69 30 LTN1 p.R349H 6 | 1 | 10 | 0 110 74 MLNR p.Q334 fs del 3 | 2 | 19 | 0 152 134 SLC39A11 p.R38Q 4 | 2 | 13 | 0 117 96 TTYH2 p.R493C 5 | 4 | 14 | 0 131 104 Dose effect of the top candidates No. candidates 0 variant allele 67 | 194 | 1911 | 834 reference reference 1 variant allele 50 | 66 | 363 | 50 3.5 (2.6 - 4.7) 3.2 (2.3 - 4.3) 2 variant alleles 15 | 18 | 62 | 1 32 (4.5 - 230) 27 (3.8 - 195) 3+ variant alleles 45 | 31 | 72 | 0 98 (6 - 1506) 62 (3.9 -1012) lists 20 top hits). Among these, 15 variants mapped to our previously identified lung cancer linkage locus at 6q23-25 (ROS1, PARK2, SYNE1). Others were enriched in oncogenes (ERBB3, JAK1, MET), tumor suppressor genes (ATM, BRCA2, RB1), and genes involved in the extracellular matrix (COL6A3, FLG, MUC5B). Importantly, individuals carrying more than two combinations of these variants exhibited exceptionally strong dose effects, with odds ratios (OR) exceeding 27. Conclusion: Our findings underscore the significant role of rare, high-penetrance variants in FLC etiology and highlight promising targets for early detection and personalized treatment. Future in-depth mechanistic studies are planned to evaluate the pathogenic effects of these specific alleles. Citation Format: Yanhong Liu, Claudio Pikielny, Xiangjun Xiao, Bo Peng, Yafang Li, Jinyoung Byun, Chao Cheng, Dakai Zhu, Spiridon Tsavachidis, Colette Gaba, Elena Kupert, Ellen L. Goode, Erin L. Crawford, Kristen Purrington, Marshall Anderson, Michael Cole, Paul Brennan, Geoffrey Liu, James McKay, John K. Field, Rayjean J. Hung, David C. Christiani, Diptasri Mandal, James C. Willey, Ann Schwartz, Joan Bailey-Wilson, Susan M. Pinney, Christopher I. Amos. High-penetrance rare variants underlying familial lung cancer risk: Insights from the Genetic Epidemiology of Lung Cancer Consortium [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 3815.

Background: Deciding to use oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF) is complex. For many, the decision between treatment and non-treatment requires a primary tradeoff between the risks of potential stroke and increased bleeding. Hypothesis: We hypothesized that patient values and empiric stroke risk measured by CHA 2 DS 2 -VASc score would influence OAC decisions. Methods: We conducted a secondary analysis of a randomized clinical trial where eligible clinicians and patients were independently randomized to one of two decision aids (DAs) – a patient decision aid and/or an encounter decision aid. Eligible patients were adults with AF with CHA 2 DS 2 -VASc≥1 for men or ≥2 for women. Patients newly prescribed (OAC-naive subgroup) or already taking OAC (OAC-experienced subgroup) were included. We assessed patient values using a 5-point Likert scale between stroke prevention and bleeding risk after SDM during a clinical encounter. We report preliminary results using descriptive statistics and adjusted analysis to investigate the effects of CHA 2 DS 2 -VASc and expressed values on OAC use. Results: 1005 patients were included in the analysis. 828 (82%) patients valued stroke prevention over bleeding risk. Among the OAC-naive group, 175 (63%) valued stroke prevention more than bleed avoidance, 58 (20%) valued bleed avoidance more than stroke prevention, and 47 (17%) were neutral. In the unadjusted analysis, patients were more likely to value stroke prevention if they were OAC-experienced (p<0.001), older (p<0.001), female (p< 0.001), had patient-reported bleeding (p=0.003), or if CHA 2 DS 2 -VASc ≥ 2 if male, ≥3 if female (p<0.001) Table 1 . After adjustments, there were significant associations for OAC use among patients who valued stroke prevention (OR 5.35, 95%CI 3.13-9.13, p<0.001) or had higher CHA 2 DS 2 -VASc (OR 2.03, 95%CI 1.26-3.27, p=0.004). Patients who valued bleed avoidance had an opposing association not to use OAC (OR 0.23, 95%CI 0.11-0.48, p<0.001). Conclusions: Patients with elevated risk (CHA 2 DS 2 -VASc score, age, and female), and those who reported a prior bleeding event valued stroke prevention more than bleeding avoidance. Both empiric stroke risk and patient values were associated with the decision to use OAC. While the tradeoff between stroke prevention and bleeding risk is only one aspect of the decision-making process, these results indicate variability in patient values may influence OAC use.

Introduction: It is unknown how comorbid diagnoses affect patients’ disease-specific knowledge or how patients’ health literacy or numeracy affects this relationship. In patients with atrial fibrillation (AF), comorbidities can be quantified by the CHA 2 DS 2 -VASc score. We explore the association of AF/stroke knowledge with CHA 2 DS 2 -VASc score, health literacy, and numeracy for usual care participants in the multi-center Randomized Evaluation of Decision Support Interventions for Atrial Fibrillation (RED-AF) trial evaluating decision aids to initiate (initiation cohort) or continue (monitor cohort) oral anticoagulation (OAC) in AF patients. Methods: This study was conducted at six academic medical centers in the United States. Participants were aged ≥18, diagnosed with non-valvular AF, and at risk for stroke (CHA 2 DS 2 -VASc ≥1 for men, ≥2 for women). Patient demographics were obtained via questionnaires after a baseline clinical encounter; knowledge was evaluated by patient responses to 7 questions about OAC and AF. Health literacy was measured by a validated self-reported screening tool; numeracy by a validated subjective numeracy scale; CHA 2 DS 2 -VASc was calculated from medical records. We applied generalized estimating equations for a binomial outcome to jointly relate patient knowledge to CHA 2 DS 2 -VASc score, health literacy and numeracy, controlling for 5 additional patient factors and accounting for clustering by clinician. Results: We report on 306 patients randomized to the usual care group across six participating sites. Average age 68.7 9, 61.6% male, mean CHA 2 DS 2 -VASc 2 1.5. Patient knowledge was independently associated with numeracy (5% higher odds of correct response per 1 unit increase in numeracy, 95% CI 0-10%, p=0.05) and membership in the monitor cohort (40% odds of correct response, 4-89%, p=0.03) but not health literacy or increased stroke risk. Conclusion: In the RED-AF study , although health literacy and increasing stroke risk were not independently associated with patient knowledge about AF, numeracy had a minimal positive association. Those already on OAC had greater disease knowledge than patients newly starting OAC. These results suggest a need to broadly increase patient education regardless of baseline comorbidity burden and degree of health literacy. Future studies should be performed to better understand other factors that drive patient knowledge regarding AF and stroke.

Background Flow-diverter stents (FDS) have become the standard of care for a wide range of intracranial aneurysms, but their efficacy/safety in the context of recurrent/recanalized aneurysms following stent-assisted coiling (SAC) is not well established. We evaluate the outcomes of FDS retreatment in a large multicenter cohort. Methods We retrospectively analyzed data from 118 patients across 22 institutions who underwent FDS retreatment for recurrent/persistent aneurysms after SAC (2008–22). The primary outcome was angiographic occlusion status at last follow-up, categorized as complete (100%), near-complete (90–99%), or incomplete (<90%) occlusion. Secondary outcomes included procedural complications and clinical outcomes measured by the modified Rankin Scale (mRS). Results A total of 118 patients (median age 57, 74.6% female) with median follow-up of 15.3 months were identified. Complete occlusion was achieved in 62.5% and near-complete occlusion in 25%. FDS deployment within the pre-existing stent was successful in 98.3% of cases. Major complications occurred in 3.4% of cases, including postoperative aneurysmal rupture with resultant mortality (1.6%) and thromboembolic events with long-term disability (1.6%). Favorable clinical outcomes (mRS 0–2) were observed in 95.1% of patients. Wider aneurysm neck diameter was a significant predictor of incomplete occlusion (adjusted OR (aOR) 1.23 per mm, P=0.044), with male sex trending towards association with non-occlusion (aOR 3.2, P=0.07), while baseline hypertension was associated with complete occlusion (aOR 0.32, P=0.048). Conclusions FDS treatment for recurrent/residual aneurysms after SAC represents a viable treatment option for these challenging cases with acceptable safety and reasonable occlusion rates, although lower than de novo FDS occlusion rates.

ABSTRACT Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695 , a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

114 Background: Oncologists have traditionally relied upon serial assessments of PSA and periodic imaging (i.e., every 2 to 3 cycles) to monitor treatment response. Early identification of disease progression allows for faster transitions to alternative therapies that might be more effective. In this study, we evaluated the utility of post-treatment SPECT/CT for earlier detection of treatment failure in patients receiving Lutetium-177–PSMA-617 (LuPSMA). Methods: We queried an IRB-approved registry including all patients starting LuPSMA at Mayo Clinic, MN, in the interval of March 2022 to March 2023. Those receiving fewer than 2 cycles of treatment and missing SPECT/CT data were excluded. We reviewed clinical notes to document the date and reason(s) for treatment discontinuation. The assembled cohort consists of patients stopping LuPSMA for progressive disease ([PD], categorized as biochemical, radiographic, or both). Results of the prior SPECT/CT imaging reports were reviewed. At our institution SPECT/CT images are typically acquired on the day after each infusion. Metrics collected from the radiology reports included: new foci of PSMA localization since the prior PSMA PET or SPECT/CT, suspicion for new non-PSMA avid disease, and a visual determination of PSMA-avid tumor volume. Results: A total of 256 patients received an initial cycle of LuPSMA. SPECT/CT imaging data for at least 2 consecutive treatment cycles was available for 68 patients who developed PD after a median (IQR) of 3 (2-4) cycles. There were 55 patients (81%) with both biochemical and radiographic evidence of PD, 7 (10%) with biochemical only progression, and 6 (9%) with radiographic only progression. The most used imaging modality for response assessment was PSMA PET/CT (n=46, 67%), followed by conventional imaging (n=9, 13%), and choline PET/CT (n=5, 7%). The median time between most recent post-therapy SPECT/CT and determination of PD was 39 days. The prior SPECT/CT had detected new foci of PSMA avid disease in 12 (18%) cases and new non-PSMA avid disease in 5 (7%) cases. Two patients had both new PSMA-avid and non-PSMA avid lesions. The most common sites of new PSMA-avid disease on SPECT/CT were bone (n=10) and liver (n=2). A total of 20 (29%) patients had visually increased tumor volume on SPECT/CT, 9 (45%) of which had no new lesions. In total, 24 of 68 patients (35%) had early detection of treatment futility detected by SPECT/CT. At a median (IQR) follow-up time of 8 (6.4-12) mo, the median OS [95% CI] was similar for patients with PD detected on SPECT/CT (7.8 [6.6 – 9] mo) compared to those without clear evidence of PD on SPECT/CT(8.4 [6.4-10.3] mo, p=0.885). Conclusions: Post-treatment SPECT/CT imaging may complement traditional forms of response assessment and provide an earlier warning of treatment failure through identification of new PSMA-avid lesions, non-PSMA avid disease, and increased tumor volume.

112 Background: We now have more than a decade of experience using Androgen Receptor Pathway Inhibitors (ARPIs) across various disease states of prostate cancer, and the safety of their combination with Lutetium-177–PSMA-617 has been demonstrated in VISION and other large randomized clinical trials. However, real-world data on treatment patterns and outcomes involving combination therapies with 177 Lu-PSMA-617 remain limited. Methods: For this analysis, we utilized the Mayo Clinic Rochester radiopharmaceutical database, a prospectively maintained retrospective database containing all patients who received 177 Lu-PSMA-617 at our institution. We focused on patients who started treatment from March 2022 to March 2023. Patients receiving an ARPI (abiraterone acetate, enzalutamide, apalutamide, or darolutamide) during the course of 177 Lu-PSMA-617 treatment were identified, inclusive of patients who continued using an ARPI prescribed as a prior line of treatment and those who started (i.e., switched) to a new ARPI. Baseline clinicopathologic and imaging characteristics were abstracted and compared using the Mann-Whitney U and Chi-square tests. Best PSA response during treatment was reported as a percent decline from baseline. Survival was calculated from the date of the first cycle of 177 Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (concurrent use of ARPI vs. 177 Lu-PSMA-617 alone) were compared using the Chi-square test and Kaplan-Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Results: An ARPI was prescribed to 106 of the 256 patients (41.4%) starting 177 Lu-PSMA-617 in the interval of March 2022 to March 2023. With regards to baseline characteristics, those receiving an ARPI concurrently with 177 Lu-PSMA-617 had a lower PSA (3.4 vs 29.7 ng/mL, p < 0.001) and a lower frequency of bone (77.4% vs. 87.4%, p = 0.035) and visceral metastases (18.9 vs 34%, p = 0.008) at start of treatment. Median follow-up for the overall cohort (IQR) was 19.1 months (8.7 – 23.6). Patients receiving an ARPI plus 177 Lu-PSMA-617, as compared to 177 Lu-PSMA-617 alone, were more likely to complete all 6 planned doses of treatment (63.2% vs. 48.7%, p < 0.001), though the PSA50 response rate was similar (49.1% vs 47.3%, p = 0.786). Median OS [95% CI] for the overall cohort was 21.3 [16.7 – 25.9] months and significantly longer for those receiving ARPI with 177 Lu-PSMA-617 (NR [NE – NE]) as compared to 177 Lu-PSMA-617 alone (15.3 mo [11.6 – 19.1], p < 0.001). However, on multivariate analysis including known prognostic variables, use of ARPI was not independently associated with improved survival (HR = 1.03 [CI: 0.68 to 1.55], p = 0.891). Conclusions: Patients receiving an ARPI with 177 Lu-PSMA-617 were more likely to complete all 6 cycles of treatment, but no clear differences in survival were observed on multivariate analysis.

129 Background: Few studies have explored the use of focal therapies to address select sites of resistant disease in men receiving 177-Lu-PSMA-617 for metastatic castrate resistant prostate cancer (mCRPC). Our institutional practice is to offer SBRT for patients with up to 5 sites of oligoprogression or non-responding lesions while undergoing 177Lu-PSMA-617 (every 6 weeks for 6 cycles total). This is determined by PSMA or choline PET imaging during the course of 177Lu-PSMA-617. Herein, we evaluated the safety of adding target SBRT during treatment with 177Lu-PSMA-617. Methods: This retrospective single institution analysis was conducted via systematic chart review to evaluate for adverse events during or after treatment. Grading of treatment-related adverse events was conducted using Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5). Results: Thirty-one patients receiving 177Lu-PSMA-617 with 51 sites of oligoprogressive or non-responding metastatic disease were treated with SBRT. The median number of sites treated was 1 (range 1-4). Most patients received SBRT immediately after cycle 6 (32%) or after cycle 3 or 4 (42%). Bone was the most commonly treated site of disease (90%) with the majority (54%) of bone sites being spine or sacrum, followed by lymph nodes (10%). Ultimately, 84% of patients completed all 6 cycles of 177Lu-PSMA-617 (range 4-6). The median follow-up time was 19.1 months (IQR 15.5-22.4) after 177Lu-PSMA-617 therapy start. A total of 2 patients experienced a pathologic fracture within the SBRT treatment field that could possibly be related to radiotherapy. One patient experienced a grade 2 neuropathy which may have been related to radiation therapy. Other potential adverse events are listed (Table). Conclusions: Our data demonstrates a low rate of significant toxicity with the use SBRT during treatment with 177Lu-PSMA-617. Further study is indicated to determine the oncologic efficacy and potential late side effects of this treatment strategy. Adverse events. Event All Grades Grade > 3 Any Adverse Event 104 2 Anemia 29 (94%) 0 Low Platelets 11 (35.5%) 1 (3.2%) Any Pathologic Fracture 7 (22.5%) 1 (3.2%) Possible SBRT-related Pathologic Fracture 2 (6.5%) 1 (3.2%) Bone Pain Flare 3 (9.6%) 0 Neuropathy 1 (3.2%) 0

PURPOSE Off-the-shelf, allogeneic CD19 chimeric antigen receptor (CAR) T-cell products may improve access to treatment versus autologous ones. We report the phase I experience of the allogeneic CD19 CAR T-cell product cemacabtagene ansegedleucel (cema-cel) and its predecessor, ALLO-501, in CD19 CAR T-naïve patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). METHODS In the ALPHA2/ALPHA studies, the safety and efficacy of allogeneic CD19 CAR T cells were evaluated in CD19 CAR T treatment-naïve patients with R/R LBCL. Patients received healthy donor-derived, human leukocyte antigen–unmatched cema-cel/ALLO-501 following a 3-day lymphodepletion regimen of fludarabine (30 mg/m 2 once daily), cyclophosphamide (300 or 500 mg/m 2 once daily), and escalating doses of the anti-CD52 monoclonal antibody, ALLO-647. RESULTS As of September 26, 2024, 33 CD19 CAR T-naïve patients with LBCL (median age, 66 years; median number of previous therapies, 3) received allogeneic CAR T cells. CAR T-cell expansion was observed following infusion, with persistence observed up to 4 months. The overall and complete response (CR) rates were 58% and 42%, respectively; the median duration of response in patients with a CR was 23.1 months. The most common treatment-emergent adverse events were hematologic toxicities. No cases of graft-versus-host disease, immune effector cell–associated neurotoxicity syndrome, or grade ≥3 cytokine release syndrome were reported. CONCLUSION Allogeneic CD19 CAR T cells demonstrated promising overall and durable CR rates with a manageable safety profile in CD19 CAR T-naïve patients with R/R LBCL, supporting additional evaluation of cema-cel in patients with LBCL.

AbstractBackgroundAcute lymphoblastic leukemia (ALL) in adults is aggressive, with long‐term outcomes impacted by treatment resistance and toxicity. CD52 is expressed in most cases of B‐ and T‐lineage ALL. Alemtuzumab, a humanized immunoglobulin G1 monoclonal antibody that targets CD52, was identified as a potential agent to improve treatment efficacy without increasing toxicity.MethodsIn this phase 1/2 study (Cancer and Leukemia Group B [CALGB] 10102, NCT00061945), a course of single‐agent alemtuzumab was intercalated into CALGB 19802 backbone chemotherapy after the third course of intensive chemotherapy in those who were CD52+ at diagnosis. Phase 1 tested three dose levels of subcutaneous alemtuzumab (10, 20, and 30 mg 3 times weekly for 4 weeks/12 doses) and demonstrated that 30 mg was tolerable. Phase 2 established feasibility.ResultsThe study enrolled 295 evaluable patients (115 in phase 1, 180 in phase 2); 206 (69.8%) were CD52+. Among evaluable CD52+ patients, 43.7% (90/206) completed the first three treatment modules; 97.8% (88 of 90) were treated with alemtuzumab. Alemtuzumab was associated with cytomegalovirus viremia, which occurred in 23.3% (14 of 60) of patients during and 29.2% (19 of 65) after alemtuzumab treatment. With a median follow‐up of 101.2 months, median overall survival (OS) was 26.3 months (3‐year rate, 44%; 5‐year rate, 36%; 10‐year rate, 31%). Landmark analysis at the start of the fourth course of treatment demonstrated no difference in OS or disease‐free survival between patients who did and who did not receive alemtuzumab.ConclusionAlemtuzumab was feasible to administer in adults with ALL receiving intensive chemotherapy, but was without evidence of benefit.