Citations

3593 Background: CUB domain-containing protein 1 (CDCP1) is a transmembrane protein shown to be over-expressed in colorectal cancer (CRC), with an important role in tumor initiation, growth and metastasis. Through interactions with EGFR, CDCP1 promotes nuclear translocation of the key regulators of Wnt signaling, β-catenin and E-cadherin. High CDCP1 expression has been associated with poor survival outcomes in multiple solid tumors but data in CRC remains limited. We investigated associations between CDCP1 level and survival outcomes in patients with metastatic CRC (mCRC) in the phase III clinical trial CALGB/SWOG 80405 (Alliance). Methods: Data from 433 mCRC patients in the CALGB/SWOG 80405 (Alliance) trial were analyzed. Patients received bevacizumab (n = 226) or cetuximab (n = 207) plus chemotherapy as 1st-line treatment. Tumor RNA was extracted from FFPE samples and processed through the HiSeq 2500 (Illumina) platform. Overall survival (OS) and progression free survival (PFS) curves were evaluated in all treatment subgroups and stratified according to high or low CDCP1 expression. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using Cox proportional hazards multivariate models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, consensus molecular subtypes, and treatment arm. Results: Overall, low CDCP1 expression was associated with better OS compared to high expression (HR = 1.38; 95% CI 1.07-1.77; 35.8 vs 25.0 months, p = 0.045). Subgroup analysis re-demonstrated this pattern in males (HR = 1.64; 95% CI 1.64-2.28; 35.9 vs 23.6 months, p = 0.01), patients with MSS tumors (HR = 1.56; 95% CI 1.17-2.08; 36.7 vs 25.1 months, p = 0.0094), and patients treated with cetuximab+FOLFOX (HR = 1.79; 95% CI 1.16-2.77; 40.8 vs 24.0 months, p = 0.03). The effect of CDCP1 expression on PFS was less pronounced. Relative to high expression, low expression was associated with better PFS in males (HR = 1.49; 95% CI 1.10-2.03; 13.1 vs 9.8 months, p = 0.027) and left-sided tumors (HR = 1.50; 95% CI 1.10-2.04; 14.4 vs 10.1 months, p = 0.034). Conclusions: Our findings represent real-world data of the predictive role of CDCP1 in patients with mCRC undergoing anti-EGFR or anti-VEGF treatment. Consistent with studies of other cancers, we show that low CDCP1 expression is predictive of better survival outcomes, with subgroup analysis revealing associations in males, MSS tumors, and left-sided tumors. Among treatment groups, low CDCP1 expression is predictive of better OS in cetuximab+FOLFOX-treated patients, a key finding given CDCP1’s close mechanistic ties to EGFR. Further studies should explore whether these associations are seen in other treatment modalities and whether CDCP1 blockade could represent a viable strategy in patients with high expression.

3014 Background: Macrocyclic next-generation tyrosine kinase inhibitors (TKIs) have transformed outcomes in ALK- and ROS1-positive NSCLC; such creatively designed medicines are similarly needed to improve outcomes in EGFR-mutant NSCLC. Using a novel, mutant-selective macrocyclic structure, BH-30643 was designed for super-potency against driver EGFRm, largely sparing wildtype (WT) EGFR, and with unique invulnerability to resistance from C797S with or without T790M. Here we report emerging first-in-human dose-escalation data from the SOLARA trial (NCT06706076). Methods: Phase 1 dose escalation used a BOIN design with backfill at potentially efficacious doses. Expansion cohorts targeted populations of interest. Patients (pts) had advanced NSCLC with EGFR and/or HER2 mutations detected on local testing (tissue or plasma). Measurable disease was required; asymptomatic untreated brain metastases (BM) were permitted. Objectives included safety, PK, and RECIST response rate (ORR). Plasma NGS was performed at baseline and on treatment. Results: As of 01/05/2026, 72 pts enrolled into dose escalation and backfill across 7 dose levels at a total daily dose of 20mg -160mg, median age 62, 44% Asian, 65% with history of BM, median of 3 prior lines of treatment (range 1-12). EGFR mutations included classical (38 pts), exon20ins (14 pts) and other/atypical (18 pts) or HER2 mutations (2 pts). Plasma exposures at doses of 40mg BID and above achieved > 10x coverage over target EC90 and exceeded exposure levels of most contemporary EGFR TKIs. Common TRAE ( > 10%) were WT EGFR-associated, including diarrhea (38%), rash (28%), fatigue (15%), stomatitis (13%), and were predominantly grade 1. Bilirubin elevation was seen in 26 pts (36%) related to off-target UGT1A1 inhibition (Gilbert’s-like). Grade 3 TRAE were seen in 15 pts (18%), most commonly bilirubin (8/15); DLTs included bilirubin increase and mucositis, occurring at doses ≥ 60mg BID. No pneumonitis was observed. Responses were observed across diverse EGFRm subsets, including in CNS. Including expansion pts, 28 pts enrolled with C797S on their most recent informative molecular testing (6 with concurrent MET+ or KRAS+), with 23 still on therapy. Of 17 with on-treatment scans, partial responses (confirmed or ongoing) were seen in 10 (59%); ORR was comparable with (50%) or without (66%) T790M. Of 9 pts with baseline C797S detected in ctDNA (3 with T790M), 7 had > 99% reduction of C797S VAF on treatment. Conclusions: Leveraging a novel macrocyclic scaffold, BH-30643 is the first TKI monotherapy to demonstrate clinical responses against C797S both with or without T790M. High plasma exposures combined with super-potency, CNS activity, and favorable safety offers potential for deep and durable EGFR inhibition. Enrollment into backfill and expansion cohorts is ongoing to better characterize activity in both TKI-naïve and resistant pts. Clinical trial information: NCT06706076 .

2089 Background: Central neurocytomas (CNs) are rare, WHO grade 2 brain tumors that can have relatively high recurrence rates following surgical resection. Owing to the rarity of CNs and limited robust data, the optimal use and timing of radiotherapy (RT) remain undefined, particularly in young adults with low mortality. Tumor proliferation index (Ki-67) may also predict CN recurrence rates, but there is no consensus on its utility in clinical practice. The present collaboration between Northwestern University and the Mayo Clinic describes long-term outcomes of CN as it relates to RT timing and Ki-67 level. Methods: Patients established between 1990-2025 with a tissue diagnosis of CN at Northwestern University and the Mayo Clinic were reviewed. Demographic, treatment, and tumor characteristics (histologic/molecular) were recorded. Recurrence free survival (RFS) and overall survival (OS) were calculated according to the Kaplan Meier-method. Results: Fifty-one patients with CN (51% male, 49% female)--with a median age of 26 years and 9.7 years median follow-up--were included. RFS at 2, 5, and 10 years for the cohort was 79%, 65%, and 59% respectively; OS at 10 years for the cohort was 94%, and no deaths were attributed to uncontrolled CN. Subtotal resection (STR) yielded 2- and 5-year RFS of 74% and 65%, while gross total resection (GTR) yielded 2- and 5-year RFS of 90% and 66%. Median Ki-67 of the cohort was 3%; RFS at 2 and 5 years for Ki-67 <3% was 82% and 76%, compared to 76% and 43% for Ki-67 ≥3% (p<0.02). In patients who underwent resection without adjuvant RT (n=35), those with STR had a 2- and 5-year RFS of 61% and 45%, and those with GTR had a 2- and 5- year RFS of 88% and 61%. Additionally, without adjuvant RT, RFS at 2 and 5 years for Ki-67 <3% was 73% and 64% versus 71% and 24% for Ki-67 ≥3%. Among patients without adjuvant RT and Ki-67 ≥3% (n=14), 2-year RFS was 60% after STR and 78% after GTR. Salvage RT after first recurrence (n=16) had a 5-year RFS of 81%, with a median follow-up of 4.1 years. Conclusions: We report one of the largest cohorts of CN with long-term follow-up. STR and/or Ki-67 ≥3% were associated with shorter RFS. Salvage RT at recurrence achieved durable long-term tumor control, and long-term (~10-year) mortality was low. In appropriately selected patients, observation after resection may be a reasonable initial strategy, with RT reserved for salvage. General cohort characteristics (n=51) with Ki-67 (n=39). Variable Number (%) Median Age (years) 26 (range: 5-57) Gender, Male:Female (M/F) 26:25 (51/49) Subtotal Resection 29 (57) Gross Total Resection 22 (43) Adjuvant Radiotherapy 16 (31) Salvage Radiotherapy 16 (31) No Radiotherapy 19 (38) Ki-67 ≥3 21 (56) Ki-67 <3 18 (44)

11078 Background: Unmet essential needs, such as food, transportation, and housing insecurity, can create barriers to timely cancer treatment. Delayed or prolonged courses of definitive radiotherapy (RT) can compromise cancer outcomes like recurrence and survival. There are limited prospective data testing interventions to improve timely cancer treatment completion by meeting essential needs. Methods: We conducted a pragmatic single-arm pilot study testing an enhanced financial assistance intervention for unmet needs during RT. Eligibility criteria included adults with a cancer diagnosis and unmet social needs (via social risk screening and/or social worker evaluation) who were prescribed or undergoing a course of RT with > 10 fractions remaining. Participants received standard institutional assistance (e.g., limited support for travel/lodging with strict eligibility criteria) plus the enhanced assistance intervention, including needs assessments prior to and during RT and up to $2000/patient of tailored unconditional monetary transfer via gift cards for all essential needs identified. The primary outcome was delay-free completion of RT (DFC: completing all prescribed RT fractions and delaying < 5 fractions). The study was powered (power = 80%, 1-sided alpha = 0.2 for this pilot study) to detect a 10-percentage point increase in % DFC relative to a historic benchmark of 83% (based on similar patients from our institution), with required sample size of N = 33. Due to delays in gift card administration (on average ~2 weeks after consent), we also present per protocol analysis, limited to patients who had > 10 fractions remaining after first receiving financial assistance. Post-hoc analyses using generalized linear mixed models evaluated percentages of delayed fractions prior to and after an individual’s receipt of financial assistance. Results: 35 met inclusion criteria and were approached, 33/35 enrolled. Participants received median assistance of $1800 ($700-2000) and had a median of 27 RT fractions after consent (range: 12-35) and 17 (3-34) after receiving assistance. In the overall cohort, 1 patient did not complete RT and 2 patients had ≥5 delayed fractions, leading to 30/33 achieving DFC (90.9%, 80% CI = 83.9 – 100), significantly higher than the 83% benchmark. In the per protocol analysis, 27/28 achieved DFC (96.4%, 80% CI = 89.7–100, P = .037). Among the 27 patients who started RT prior to receiving assistance, mixed model analysis showed more delayed fractions prior to (7.1%) vs. after (3.0%) receiving assistance (OR 2.84, 95% CI = 1.43-5.80, P = .003). Conclusions: In this prospective pilot study, a tailored enhanced financial assistance intervention for unmet essential needs led to improved delay-free completion of RT over a historic benchmark. Further analysis on patient-reported quality of life and financial toxicity will be reported in the future. Clinical trial information: NCT06582849 .

1056 Background: Resistance to HER2-directed therapies remains a major challenge in HER2-positiveMBC. In preclinical models, HER2+ tumors overexpress poly (ADP-ribose) polymerase (PARP), and PARP inhibition induces apoptosis through NF-κB suppression even in the absence of pathogenic mutations in BRCA 1/2 . We evaluated the safety, efficacy, and translational correlates of niraparib combined with trastuzumab in patients (pts) with refractory HER2+ MBC. Methods: This open-label Phase 1b/2 trial (NCT03368729) enrolled pts with HER2+ MBC (IHC 3+ and/or FISH amplified), measurable disease, LVEF ≥50%, and progression on ≥1 prior HER2-targeted therapy; stable CNS disease was allowed. Pts with germline BRCA1/2 mutations or prior PARP inhibitor exposure were excluded. Niraparib 300 mg orally was administered on Days 1–21 of a 21-day cycle with trastuzumab 6 mg/kg IV every 3 weeks (loading dose 8 mg/kg on cycle 1). The Phase 2 portion used a Gehan/Simon two-stage design with early stopping for futility (P0=24%); ≥1 response among the first 20 patients triggered expansion to 40 patients. ORR was assessed by RECIST v1.1, meeting the primary endpoint and allowing response rate estimation with <7% standard error and a two-sided 95% exact CI width of 0.28. Gene expression profiling of paired tumor tissue and peripheral blood mononuclear cells (PBMCs) was performed using the NanoString nCounter Tumor Signaling 360 panel at pretreatment compared to cycle 2. Results: Forty-six pts were enrolled (9/2019–2/2025); 41 were evaluable for response. Pts were heavily pretreated (median 3 prior regimens), including trastuzumab deruxtecan in 22 pts; 33% had brain metastases. Treatment-related adverse events were predominantly grade 1–2 and manageable. Clinical benefit rate (CBR) was 44% (18/41) including 1 complete response, 2 partial responses, and 15 stable disease. Eleven patients achieved disease control ≥ 6 months; 1 patient remained on treatment at data cutoff. Tumor profiling revealed enrichment of a B-cell–driven tertiary lymphoid structure signature with reduced hypoxia signaling in responders. Matched PBMC analyses demonstrated coordinated downregulation of interferon signaling, DNA damage response, metabolic activation, angiogenesis, and resistance pathways in clinical responders, whereas non-responders retained signatures of chronic stress and immune exhaustion. Conclusions: Niraparib plus trastuzumab demonstrated a favorable safety profile and durable clinical benefit in heavily pretreated HER2+ MBC. Integrated tumor and blood-based analyses identify immune-organized tumor microenvironments and systemic immune normalization as key correlates of prolonged response, supporting further investigation of PARP inhibition strategies. Clinical trial information: NCT03368729 .

1042 Background: The primary analysis of the phase 3 HER2CLIMB-05 study (NCT05132582) showed the addition of TUC to 1L maintenance HP yielded a statistically significant improvement in progression-free survival (per investigator) versus control treatment (hazard ratio: 0.641, P < 0.0001) in patients with HER2+ MBC. Here we report our findings from an in-depth safety analysis of HER2CLIMB-05. Methods: Patients with centrally confirmed HER2+ MBC without evidence of progression following chemotherapy-based induction treatment (taxane + HP) were randomly assigned 1:1 to TUC (300 mg) or placebo (PBO) BID, both in combination with HP. The safety analysis set included all randomly assigned patients who received ≥1 dose of any study treatment. Treatment-emergent adverse events (TEAEs), laboratory values, and TUC/PBO dose modifications and discontinuations were examined. Results: Among patients in the safety analysis set (TUC arm = 326; PBO arm = 324), median treatment durations of TUC and PBO were 17.1 months (range: 0.4–36.5) and 15.5 months (range: 0.5–41.3), respectively. Grade (G) ≥3 TEAEs occurred in 42.3% of patients in the TUC arm and 24.4% in the PBO arm; the most frequent G ≥3 TEAEs in the TUC arm were elevated alanine aminotransferase (ALT; 13.5%) and aspartate aminotransferase (AST; 7.1%). TUC was discontinued in 13.5% of patients due to a TEAE. Cardiac TEAEs were similar between TUC and PBO arms (4.3% vs 6.2%). TEAEs of hepatic events (43.6% vs 15.7%) and diarrhea (72.7% vs 51.2%) occurred at higher incidence in the TUC arm versus the PBO arm (Table). In the TUC arm, increased ALT (28.2%) and AST (25.8%) accounted for the majority of hepatic TEAEs. Most hepatic and diarrhea TEAEs were managed with TUC dose modifications and/or discontinuation; 7.7% of patients discontinued TUC due to hepatic TEAEs and 1.5% discontinued due to diarrhea (Table). Among the patients with a TEAE of diarrhea, 57.7% and 29.9%, respectively, in the TUC and PBO arms used antidiarrheals; the most used medication was loperamide. Further details of the in-depth safety analysis will be presented. Conclusions: TUC addition to 1L HP maintenance therapy may be an effective option for HER2+ MBC with a clinically manageable safety profile. Clinical trial information: NCT05132582 . TEAEs* Any Any hepatic Increased ALT/AST Diarrhea Arm TUC PBO TUC PBO TUC PBO TUC PBO Any G, % 99.1 96.6 43.6 15.7 28.2/25.8 7.1/9.0 72.7 51.2 G ≥3 42.3 24.4 18.1 1.2 13.5/7.1 0.6/0.6 6.1 4.0 Any G: Median time to onset (days) 34.5 85.0 11.0 32.0 Median time to resolution (days) 25.0 22.0 2.0 5.0 Any G: TUC/PBO dose hold, % 49.4 25.3 19.3 2.5 12.6/4.0 0.6/0.6 8.6 3.4 TUC/PBO dose reduction, % 29.1 11.1 16.3 0.9 11.7/2.8 0.3/0.6 6.4 3.1 TUC/PBO discontinuation, % 13.5 2.2 7.7 0 4.0/0.3 0/0 1.5 0.9 *As of data cutoff, Sep 5, 2025.

Chronic hepatitis B (CHB), a major global public health burden, is characterized by the presence of high circulating levels of non-infectious subviral particles (SVPs). These SVPs are mainly composed of small hepatitis B surface antigen (SHBs) and are associated with a dysfunctional HBV-specific immune response. Previous studies exploring the cellular mechanisms and molecular pathways by which SVPs are secreted from hepatocytes have utilized either non-hepatic cells or whole-genome HBV-integrated hepatoma cell lines in which SHBs can also be secreted as a component of the virion envelope. In this study, we provide a detailed examination of SHBs trafficking using biochemical approaches coupled with high-resolution confocal microscopy and live-cell imaging via a novel fluorophore-tagged SHBs probe in both HepG2 and primary human hepatocytes stably expressing SHBs. Our results provide evidence that SHBs utilize a modified ER-Golgi secretory pathway with transit from the ER to the multivesicular body and lysosomal/late endosomal compartments. Importantly, we identified the autophagy adapters ATG5 and LC3B, and the ER-phagy protein atlastin 3 (ATL3), central to mediating SHBs secretion. These findings suggest that SHBs is trafficked through a non-canonical path for secretion and provides new potential therapeutic targets for the treatment of CHB.

Abstract Background Ultra‐high‐field 7 Tesla (7T) magnetic resonance imaging (MRI) provides improved resolution and signal‐to‐noise ratio (SNR) over standard clinical field strengths (1.5T, 3T). However, 7T scanners are costly, scarce, and introduce additional challenges such as susceptibility artifacts. Purpose We propose an efficient transformer‐based model (7T‐Restormer) to synthesize 7T‐like MRI (quantitative T1 MP2RAGE maps) from routine 1.5T or 3T T1‐weighted (T1W) images. Methods The proposed method leverages an efficient restoration transformer backbone and spatial attention layers to capture long‐range dependencies and generate high‐quality 7T‐like images. Our model was validated on an institutional dataset, comprised of 35 1.5T and 108 3T T1w MRI paired with corresponding 7T T1 maps of patients with confirmed multiple sclerosis (MS). A total of 141 patient cases (32 128 slices) were randomly divided into 105 (25 1.5T and 80 3T) training cases (19 204 slices), 19 (5 1.5T and 14 3T) validation cases (3476 slices), and 17 (5 1.5T and 12 3T) test cases (3145 slices). The synthetic 7T T1 maps were evaluated by comparing their similarity to the ground truth volumes using peak signal‐to‐noise ratio (PSNR), structural similarity index measure (SSIM), and normalized mean squared error (NMSE), and were compared against ResViT and ResShift. In addition, a blinded reader study was performed in which three clinicians scored the diagnostic image quality of each method on a 5‐point Likert scale (1 = non‐acceptable, 5 = excellent). Statistical significance ( α = 0.05) was assessed using two‐sided paired t ‐tests with Holm correction for multiple comparisons and Wilcoxon signed‐rank tests with Holm correction for reader scores. Effect sizes (Cohen's for paired data) were also computed to quantify practical significance. We interpreted and as small, medium, and large effects. Results For 1.5T inputs, 7T‐Restormer achieved an NMSE of 0.018 ± 0.003, PSNR of 25.0 ± 0.6 dB, and SSIM of 0.870 ± 0.019; for 3T inputs, the corresponding values were 0.019 ± 0.006, 24.5 ± 1.2 dB, and 0.874 ± 0.027. Across both field strengths, 7T‐Restormer provided the lowest NMSE and highest PSNR and SSIM among the three methods, reducing NMSE by approximately 5% and 25% relative to ResShift and ResViT at 1.5T and by 14% and 24% at 3T, respectively, and increasing PSNR by 0.5–1.5 dB (Holm‐adjusted p < 0.05, paired Cohen's = 1.37–6.84). Training on mixed 1.5T+3T data improved performance for 1.5T inputs compared with 1.5T‐only training (e.g., NMSE 0.018 vs. 0.019; p = 0.001, ), without degrading performance for 3T inputs ( p = 0.630, for NMSE). In the blinded reader study, 7T‐Restormer received higher diagnostic quality scores (3.50 ± 0.28) than ResShift (3.00 ± 0.27) and ResViT (2.33 ± 0.27), corresponding to mean improvements of 0.5–1.2 points on the 5‐point scale (Holm‐adjusted p = 0.014 and 0.004; paired Cohen's and 3.24, respectively). Conclusion We propose a novel method for predicting quantitative 7T MP2RAGE maps from 1.5T and 3T T1W scans with higher quality than existing state‐of‐the‐art methods. Future development and application of our approach may enhance diagnostic accuracy, treatment planning, and facilitate downstream tasks by making the benefits of 7T MRI more accessible to standard clinical workflows.

Background: Exogenous and endogenous polyamines are critical for gastrointestinal (GI) barrier integrity, of which putrescine, spermidine and spermine are most well studied. Our recent work shows n-acetylputrescine, a putrescine derivative, correlates with increased intestinal permeability and loss of microbial diversity. Despite this, bacterial mechanisms of n-acetylputrescine production or direct effects on barrier integrity are unknown. Aim: Determine the role of microbiota in shaping n-acetylputrescine abundance and the effect on barrier integrity. Methods: N-acetylputrescine effects on barrier were assessed both in vitro using Caco-2 and ex vivo in Ussing using colonic strips from conventional mice. Germ-free (GF) mice were monocolonized with wild-type E. coli (SK929) or E.coli SK930 (2-weeks, n=4mice/group), strains given by Dr. Shin Kurihara. E. coli SK930 is deficient in SpeC, SpeF and SpeB, genes generating putrescine, required for n-acetylputrescine production. Untargeted metabolomics (Metabolon) was performed on fecal pellets. Targeted isotope tracing with [13C6, 15N4]-arginine delivered via enema was done to track bacterial production of n-acetylputrescine by Fusobacterium varium, a known producer, in vivo with isotopolog labeling measured by LC/HRMS. Results: In vitro n-acetylputrescine (100mM) addition to Caco-2 monolayers caused significant barrier disruption compared to controls (%Baseline TER, 13.7±6.7 vs 102.8±9.4, 3h postexposure, n=3 p=0.0002), not seen at lower (10mM) concentration. N-acetylputrescine caused increased flux of 300Da fluorescein (12.6±2.0 vs 6.0±0.2 mg/mL, n=3 p=0.004) and 4kDa FITC-Dextran flux on Ussing compared to untreated controls (999±94 vs 562±121 ng/hr/cm2, n=3 p= 0.01). Mutant E. coli SK930 monocolonized mice had similar fecal n-acetylputrescine to GF animals. In contrast, wild type E. coli SK929 monocolonization led to significantly greater n-acetylputrescine (5-fold, FDR< 0.001) compared to SK930, indicating a bulk of n-acetylputrescine production is driven by bacterial mechanisms. Pathway enrichment analysis predicted decreased spermidine and spermine biosynthesis in SK930 monocolonization, indicative of impaired polyamine metabolism, compared to SK929 (FDR< 0.01). Targeted metabolomics on fecal pellets showed a shift in the production of isotopolog [13C1, 15N0]-N-acetylputrescine to increased isotopolog [13C4, 15N2]-N-acetylputrescine concentration after monocolonization with F. varium compared to GF mice (5.9±5.0 vs. 2.1±3.6 pg/mg stool, n=3mice/group p=0.05) suggesting microbiota driven shifts in n-acetylputrescine metabolism. Conclusion: Luminal n-acetylputrescine production and profile is driven by bacteria in the GI tract. Concentration dependent effects of n-acetylputrescine suggest insufficient regulation by intestinal microbiota can lead to accumulation of n-acetylputrescine and the intestinal barrier disruption seen in human studies. Ongoing studies aim to identify bacterial taxa critical for n-acetylputrescine suppression, the mechanisms involved, and impact on GI health. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.