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Variable wavefronts of light beam caused by phase-polarization electro-optic modulation of BaTiO3 crystal thin-film waveguide

This work investigates the characteristics of a birefringence electro-optic (EO) modulator based on a c-axis barium titanate (BaTiO3) crystal film rib waveguide and a pair of electrodes embedded in the crystal film applying a modulation electric field along the x-direction via a drive voltage. We derive the wavefront dependence of the output light wave under phase-polarization modulation (PPM) on multiple parameters such as EO coefficient, birefringence, and electric–optic field interaction length, so both the phase and polarization of the output beam are simultaneously changed with modulation voltage. The numerical simulations show that the variable helical wavefronts of a full-wave are obtained under a drive voltage of 7.0 V with a sub-millimeter-scale interaction length and a high EO coefficient (∼600 pm/V). Furthermore, the elliptical wavefront is variable in both amplitude and principal axis orientation to form a tunable helical wavefront. Consequently, the PPM effect induced variable helical wavefront evolutions of output light beam are testified by experiments. This study systematically elucidates the phase-polarization modulation mechanism and quantitatively presents the correspondence among the drive voltage, phase shift, and polarization state of the output light beam.

From pollution to solution: Optimized UiO-66 based metal-organic framework for environmental cleanup

Multiobjective framework for hardware and quality aware approximate Gaussian filtering toward energy efficient ultrasound image denoising

HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures

Determinants of triple-negative breast cancer among African patients: Early results from The African Cancer Atlas.

1133 Background: Triple-negative breast cancer (TNBC) is disproportionately common among women of African ancestry and is associated with aggressive clinical behavior and limited therapeutic options. Understanding demographic and contextual determinants of TNBC across African countries is essential to improving prevention, early detection, and precision oncology strategies. Using harmonized data from The African Cancer Atlas (TACA)--an initiative of Yemaachi Biotech, we examined factors associated with TNBC across Côte d’Ivoire, Ghana, Kenya, Nigeria, and Seychelles. Methods: We analyzed 236 participants with complete immunohistochemistry data enrolled in TACA. Associations between TNBC and demographic variables were assessed using Wilcoxon rank-sum tests, Fisher’s exact tests, and multivariable logistic regression. Results: TNBC accounted for 38.1% of breast cancers in the cohort. TNBC had prevalence rates ranging from 21.1% in Kenya to 68.1% in Nigeria (p<0.001). Seychelles exhibited no TNBC cases (0/23). TNBC prevalence among females was 38.5% (89/231), compared with 20.0% (1/5) among the few male participants. Women in Nigeria had markedly higher odds of TNBC compared with Kenya (OR 10.4, 95% CI 3.72–31.4, p<0.001). Women in Ghana also demonstrated increased odds (OR 2.55, 95% CI 1.10–6.12, p=0.032). Age showed no significant association with TNBC (mean age 51.6 years for TNBC vs. 50.2 years for non-TNBC, p=0.6), though the 60–69 age group showed a modestly increased proportion of TNBC (38.1%, OR 0.26, 95% CI 0.07–0.93, p=0.042, relative to 50–59). Education level was significantly associated with TNBC (p=0.004). Women with no formal education had a 59.2% TNBC prevalence (29/49), compared with 26.9% among those with primary education (18/67, OR 0.69, 95% CI 0.26–1.85) and 33.3% among those with higher education (17/51, OR 0.77, 95% CI 0.28–2.14). Family history of cancer was also associated with TNBC (p=0.006). Among women reporting a positive family history, 23.8% had TNBC (15/63), compared with 76.2% with non-TNBC (48/63). Conclusions: TNBC prevalence in this multi-country African cohort was high and characterized by substantial geographic variation, with Nigeria demonstrating the highest burden. Lower educational attainment and family history of cancer were also associated with TNBC, independent of country. These findings highlight the importance of considering sociodemographic and contextual factors when designing TNBC-focused screening and treatment strategies and underscore the need for country-specific precision oncology approaches in African settings.

Genomic predictors of response to cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC): A real-world analysis from the PROMISE registry.

5066 Background: Cabazitaxel (Cabazi) is an important treatment for refractory mCRPC, but responses are heterogeneous. Homologous recombination repair (HRR) and tumor suppressor gene (TSG alterations (alt) can predict aggressive behavior in patients (pts) with mCRPC. We hypothesize that Cabazi has enhanced efficacy in pts with these aggressive alt. Methods: The multi-institutional PROMISE clinical-genomic database was queried for patients who had undergone tumor next-generation sequencing prior to initiating Cabazi monotherapy for mCRPC. We evaluated the association of select gene alt HRR ( BRCA1, BRCA2, ATM, BRIP1, CDK12, CHEK2, PALB2, RAD51, RAD51B/CD ), TSG ( RB1 , PTEN loss, TP53 ) and other common alt in mCRPC with PSA response and clinical Progression to Cabazi. Comparisons of PSA50 responses were made using Fisher’s exact tests, and associations between genetic alterations and both OS and PFS were conducted using log-rank tests. Results: Among 383 pts who met inclusion criteria median age was 61 years, with 283 (74%) Caucasian pts, 71 (19%) African-American/Black pts, 9 (2%) Asian pts, and 20 (5%) Hispanic pts. 302 (79%) had prior docetaxel, 23 (6%) had received PARP inhibitor, and 16 (4%) had received Lu-177 PSMA. The most frequent alt noted were: TSG in 204 (53%) pts, TP53 in 164 (43%), AR alt in 130 (34%) pts, and HRR alt in 91 (24%) pts. No significant difference was noted in PSA50 responses in pts with TSG or HRR alt relative to wild-type, though there was a difference noted in pts with PIK3CA alt (Table). Progression-free survival (PFS) on Cabazi was shorter in pts with TP53 alt [HR 1.55 (1.19 – 2.04), p=0.001), any TSG alt [HR 1.51 (1.15 – 1.98) p=0.003], RB1 [HR 2.34 (1.38 – 3.99), p-=0.005], and AR alt [HR 1.37 (1.04 – 1.79) p=0.03). There was no difference in pts with HRR alt [HR 0.83 (0.60 – 1.15), p=0.26)]. Overall survival (OS) was prolonged in pts with HRR alt [HR 0.69 (0.59 – 0.92), p=0.009)] and worse in pts with TP53 alt [HR 1.54 (1.20 – 1.98) p<0.001)], any TSG alt [HR 1.36 (1.07 – 1.74), p=0.01], or RB1 alt [HR 1.94 (1.18 – 3.18) p=0.02]. Conclusions: Common genomic alt including TSG, HRR, and PI3KA were not predictive of Cabazi response in mCRPC. TSG alt were associated with worse outcomes, consistent with aggressive disease biology. Improved OS in pts with HRR alt likely reflects PARP inhibitor or platinum use rather than Cabazi efficacy. Association between genomic alterations and cabazitaxel response in mCRPC. Genetic Alteration PSA50 Response PFS (HR) OS (HR) Any TSG 26.8% vs 25.4%(p=0.80) 1.51 (p=0.003) 1.36 (p=0.01) AR 20.8% vs. 28.6%(p=0.16) 1.37 (p=0.03) 1.19(p=0.19) Any HRR 31.8% vs. 24.6%(p=0.27) 0.83(p=0.26) 0.69 (p=0.009) PTEN 35.7% vs. 24.0%(p=0.09) 1.12(p=0.50) 0.98(p=0.92) PIK3CA 5.6% vs. 27.4% (p=0.05) 1.53(p = 0.22) 1.27(p = 0.36)

Viral vs non-viral combined hepatocellular–cholangiocarcinoma: Distinct genomic landscapes and survival outcomes.

e16292 Background: Combined hepatocellular–cholangiocarcinoma (cHCC-CCA) is a rare and biologically heterogeneous primary liver cancer. Prior literature has reported conflicting clinical outcomes and treatment responses. Given the established prognostic influence of viral hepatitis in hepatocellular carcinoma, understanding whether similar effects exist in cHCC-CCA may have therapeutic implications. We evaluated published clinical outcomes and genomic datasets to explore differences between viral and non-viral cHCC-CCA. Methods: A structured PubMed and Embase search identified case reports and series reporting viral status, demographics, treatment details, and overall survival (OS) in patients with cHCC-CCA. Studies lacking OS attribution or viral status were excluded. Due to heterogeneous follow-up and absence of standardized censoring, survival data were analyzed descriptively; differences in OS distributions between viral and non-viral etiologies were compared using a nonparametric Mann–Whitney U test. A complementary genomic cohort of annotated cHCC-CCA cases was identified in cBioPortal. Differences in OS were compared using Student’s t-test. Mutation frequency differences were evaluated to identify putative biologic distinctions. Results: Across published cases, median OS was 49.5 months in the viral cohort and 20.0 months in the non-viral cohort, with mean OS of 47.7 ± 18.5 and 29.6 ± 16.2 months, respectively. This difference was statistically significant by Mann–Whitney U testing (U = 14.5, Z = −2.27, p = 0.023). A crude hazard approximation derived from median OS ratios suggested lower mortality risk in viral cHCC-CCA (HR = 0.40), although formal time-to-event analyses were not feasible. In the cBioPortal cohort, viral cases similarly demonstrated longer OS compared with non-viral cases (mean 23.1 vs 13.0 months; p = 0.02). Genomic analysis identified 367 differentially mutated genes, with significantly enriched alterations in non-viral tumors including IDH , SLC16A1 , CLDN18 , HMCN1 , ADAMTS8 , BNC1 , YES1 , and TGFBR1 (all p < 0.05). Although not statistically significant, viral cases demonstrated higher frequencies of CTNNB1 , TERT , MYCT1 , and MYCBPAP alterations. Conclusions: Across published clinical series and genomic datasets, viral etiology in cHCC-CCA was associated with longer OS compared with non-viral disease. Non-viral tumors demonstrated enrichment of mutations associated with metabolic reprogramming, proliferative signaling, pathway escape, and metastatic biology, potentially contributing to poorer outcomes. These findings are hypothesis-generating and limited by retrospective reporting, selection bias, and absence of true time-to-event datasets. Larger prospective cohorts and standardized genomic annotation will be essential to validate whether viral and non-viral cHCC-CCA represent distinct disease subsets.

HIPEC combined with PD-1 inhibitor, chemotherapy in conversion therapy for advanced gastric cancer with peritoneal metastasis: Results from a single-arm phase II clinical study.

e16077 Background: Patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) accompanied by peritoneal metastasis have an extremely poor prognosis, with limited treatment options and suboptimal outcomes from conventional systemic chemotherapy. Local therapy centered on hyperthermic intraperitoneal chemotherapy (HIPEC), combined with systemic treatment , has emerged as a promising approach for conversion therapy. This study aimed to evaluate the efficacy and safety of HIPEC combined with camrelizumab (a PD-1 inhibitor), paclitaxel, and S-1 in conversion therapy for patients with HER2-negative advanced GC/GEJC and peritoneal metastasis. Methods: This was a prospective, multicenter, single-arm phase II clinical study. Eligible patients had histologically confirmed advanced GC/GEJC with peritoneal metastasis (Peritoneal Carcinomatosis Index [PCI] score ≤20) as verified by laparoscopic exploration and no evidence of other distant metastases. All participants received conversion therapy: first, diagnostic laparoscopy followed by one cycle of HIPEC (paclitaxel 75 mg/m², days 1 and 3) within 72 hours post-surgery, along with concurrent oral S-1; subsequently, they received four cycles of systemic therapy (camrelizumab 200 mg IV on day 1 every 3 weeks + paclitaxel 150 mg/m² IV on day 1 every 3 weeks + oral tegafur on days 1–14 every 3 weeks). Radiological assessments were performed every 6 weeks. After completing five cycles of treatment, surgical feasibility was evaluated by a multidisciplinary team. Patients achieving R0 resection proceeded to receive four additional cycles of adjuvant therapy (following the same systemic regimen). The primary endpoint was the R0 resection rate; secondary endpoints included OS, PCI response rate, and safety. Results: A total of 46 patients were enrolled . Efficacy results demonstrated a conversion surgery rate of 67.4% (31/46), among whom 90.3% (28/31) achieved R0 resection, yielding an overall R0 resection rate of 60.9% (28/46). Additionally, the peritoneal carcinomatosis index (PCI) response rate (reduction in PCI score) was 69.6% (32/46). For survival outcomes, the median OS was 30 months in the surgery group versus 9.5 months in the non-surgery group (HR 0.09387; 95% CI: 0.03431 to 0.2568; p < 0.0001).Safety analysis indicated that the overall treatment regimen was tolerable: grade ≥3 TRAEs occurred in 19.6% (9/46) of patients, while the total incidence of grade 1–2 TRAEs was 73.9% (34/46). Common adverse events included hematological toxicities, gastrointestinal reactions, and irAEs such as reactive cutaneous capillary endothelial proliferation. Conclusion: HIPEC combined with camrelizumab, paclitaxel, and S-1 demonstrated promising conversion surgery and R0 resection rates, significantly improved survival outcomes in surgical patients, Clinical trial information: NCT04889768 .

Assessing adoption of neoadjuvant therapy in early-stage resectable non–small cell lung cancer: A retrospective review.

e20081 Background: Neoadjuvant therapy (NAT) has become standard of care for selected patients with resectable non–small cell lung cancer (NSCLC). Accurate and timely preoperative staging is essential to identify patients who may benefit from NAT prior to curative-intent surgery. We sought to evaluate real-world implementation of guideline-informed staging and treatment decisions in early-stage NSCLC and to identify potential barriers to appropriate NAT utilization. Methods: We conducted a retrospective chart review of patients with stage IB–IIIB NSCLC who underwent curative-intent surgical resection at an academic community medical center within our health system between April 1, 2023, and October 1, 2024. All included patients underwent preoperative staging with PET-CT. Clinical stage at diagnosis was compared with final pathologic stage at surgery. Time from first imaging suspicious for lung cancer to surgery (time to surgery; TTS) was calculated and compared between patients who were upstaged versus those whose stage remained unchanged. Results: Thirty-nine patients met inclusion criteria. Pathologic staging was unchanged in 20 patients (51%), while 19 patients (49%) were upstaged to stage IIA or higher at surgery. Among upstaged patients, upstaging occurred due to increased T stage in 8 patients, nodal positivity in 9 patients, and both T and N stage changes in 2 patients. The overall mean TTS was 96 days (median 75 days). Mean TTS was similar between patients with unchanged pathologic stage (mean 94 days; median 61 days) and those who were upstaged (mean 97 days; median 78 days). Staging changes are summarized in Table 1. Conclusions: Nearly half of patients with resected early-stage NSCLC were found to have more advanced disease at surgery than suggested by preoperative PET-CT, representing missed opportunities for consideration of standard-of-care NAT. These findings highlight limitations in current diagnostic staging and/or delays between imaging and surgery. Improved accuracy and timeliness of preoperative staging are critical to ensure appropriate multidisciplinary evaluation and optimal delivery of neoadjuvant therapy for eligible patients. Changes between preoperative clinical stage and final pathologic stage. Staging Outcome Number of Patients (n=39) Pathologic stage unchanged 20 Pathologic upstaging (any) 19 Upstaged by T stage only 8 Upstaged by N stage only 9 Upstaged by both T and N stage 2

SOLAR: A post-approval study evaluating longitudinal performance of a blood-based test for screening individuals at average risk for colorectal cancer (CRC).

TPS10632 Background: CRC is a leading cause of cancer-related mortality; CRC screening has been shown to reduce mortality through detection of early-stage disease, yet adherence to recommended screening remains suboptimal. Shield is a methylation partitioning cell-free DNA (mp-cfDNA) blood-based test indicated for CRC screening in average-risk adults age 45 years or older. This test achieved 83% sensitivity for CRC and 90% specificity for advanced neoplasia in a prospective, observational study that enrolled over 20,000 patients (ECLIPSE), and became the first blood-based screening test approved by the FDA as a primary CRC screening option in July 2024. SOLAR is an FDA-mandated, post-approval study to evaluate longitudinal performance of the blood-based mp-cfDNA test in the intended use population. Methods: SOLAR (NCT06880055) is an observational, prospective study supplemented with real-world data to evaluate the mp-cfDNA test following a second round of CRC screening. Patients will receive an initial mp-cfDNA test (Shield, Guardant Health, Palo Alto, CA) at baseline (T0). Deidentified healthcare claims data will be collected to assess overall health and any development of disease at 1 and 2 years following the baseline test (T1 and T2, respectively). Patients with a negative screening result at T0 will receive a screening colonoscopy alongside a blood draw approximately 3 years after baseline screening (T3). Patients with a positive result at T0 will be recommended to receive diagnostic colonoscopy. Individuals aged 45-81 years at average-risk for CRC are eligible for the trial. Individuals who have a personal/family history of CRC or are at high risk for CRC are excluded. Those with a positive result from any of the following CRC screening tests are also excluded: fecal occult blood test or fecal immunochemical test within the last 12 months, multi-target stool DNA test within the last 36 months, mp-cfDNA test within the last 36 months, or another CRC screening method within the last six months. Primary outcome is the performance of the mp-cfDNA test at T3, including sensitivity for CRC or advanced adenoma detection and specificity for advanced neoplasia detection. Enrollment began July 2025. There are currently 29 active study sites across the US. Clinical trial information: NCT06880055 .

The association between cardiovascular disease risk and breast arterial calcifications identified on screening mammography: A retrospective study.

12026 Background: Screening mammography enables early breast cancer detection and improves outcomes. Breast cancer and cardiovascular disease (CVD) share several overlapping risk factors in women. Breast arterial calcifications (BACs) are non-occlusive calcifications of the medial layer of small to medium-sized arteries in the breast that can be identified on mammography. Prior studies have demonstrated an association between BACs and increased cardiovascular risk with growing evidence suggesting that BACs may serve as a non-invasive, low-cost screening tool for CVD. Currently, routine screening for BACs is not uniformly performed. This study aimed to evaluate the prevalence of BACs in screening mammograms, and to characterize associated atherosclerotic cardiovascular disease (ASCVD) risk scores and cardiovascular risk factors among individuals with BACs. Methods: We performed a retrospective analysis of 650 individuals undergoing screening mammography at our institution from 2023 to 2025. Data collected included patient demographics, medical and social history, and cardiovascular risk factors, including blood pressure, diabetes mellitus, and lipid profiles. ASCVD risk scores were calculated for each individual. Statistical analyses, including chi-square test and T-test, were performed to evaluate associations between the presence of BACs, cardiovascular risk factors, and ASCVD scores. Results: Among the 650 women who underwent screening mammography, n = 641 had BI-RADS 1 (negative) or 2 (benign) results, while n = 9 had an abnormal mammogram that subsequently led to a breast cancer diagnosis. BACs were identified in 15.1% of the participants (n = 98). BAC prevalence increased significantly with age: 2.3% among women aged 40-49 years, 8% in those aged 50-59 years, 18.4% in those aged 60-69 years, and 42.2% among women aged 70 years and older (p < 0.001). Among participants with available ASCVD risk data (n = 429), BAC-positive patients had a significantly higher mean 10-year ASCVD risk when compared with BAC-negative patients (14.0% vs 5.23%, p < 0.001). Among the BAC-positive patients, 61.2% were categorized as ASCVD intermediate or high risk versus 20.8% of BAC-negative patients (p < 0.001). BAC-positive patients also exhibited higher mean systolic blood pressure (123.76 vs 120.66 mm Hg, p = 0.042). Hemoglobin A1c, total cholesterol, diastolic blood pressure, and smoking status did not differ significantly between the two groups. Conclusions: Breast arterial calcifications identified on screening mammograms were significantly associated with less favorable cardiovascular risk profiles. Implementation of routine BAC reporting may enable opportunistic CV risk detection during breast cancer screening, potentially leading to earlier preventive interventions.

RALLY-MF: Initial efficacy of a phase 2 study of DISC-0974, an anti-hemojuvelin antibody, to treat anemia in myelofibrosis.

6501 Background: Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell (RBC) production and contributes to anemia onset and severity. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Methods: RALLY-MF (NCT05320198) is an ongoing Phase 2, open-label study conducted in the US. The primary aim is to evaluate DISC-0974 efficacy in participants with MF and anemia. Secondary aims include evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD). Eligible participants are ≥18 years of age with primary or secondary MF and hemoglobin (Hgb) <10 g/dL or RBC transfusion requirement. Participants enroll into 3 cohorts based on RBC units transfused in the 84 days prior to screening: non-transfusion dependent (nTD, 0 units and Hgb <10 g/dL), low transfusion burden (TD low, 1-2 units), high transfusion burden (TD high, 3-12 units). Stable dose of concomitant Janus kinase inhibitor (JAKi) is allowed. DISC-0974 is administered subcutaneously at 50 mg monthly for up to 6 doses, with escalation to 75 mg for inadequate or lost response. Primary endpoints include major hematologic response defined as transfusion independence (TI) during any consecutive 16 weeks (TD low) or 12 weeks (TD high), or a mean Hgb increase of ≥1.5 g/dL from baseline for ≥12 weeks (nTD). Secondary endpoints include PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results: At data cut (16 Oct 2025), 47 participants enrolled in the nTD (n=30), TD low (n=10), and TD high (n=7) cohorts, with 53% on concomitant JAKi therapy. DISC-0974 led to sustained hepcidin reduction and iron mobilization across cohorts. DISC-0974 resulted in meaningful hematologic responses among evaluable participants: 50% of nTD participants achieved a mean Hgb increase of ≥1.5 g/dL for ≥12 weeks, 71% of TD low participants achieved TI for ≥16 weeks, and 67% of TD high participants experienced a ≥50% reduction in transfusion burden, with follow-up ongoing. Major hematologic response rates were 50% for participants on and off concomitant JAKi therapy (n=18 and n=16, respectively). DISC-0974 was associated with meaningful improvement in FACIT-Fatigue scores for nTD and TD low participants. Serious adverse events (AEs, n=9) and ≥Grade 3 AEs (n=16) were considered unrelated to DISC-0974. There were no early withdrawals due to AEs. Conclusions: DISC-0974 was well tolerated and shows a favorable safety profile. Anemia response and fatigue scores improved across patients with MF and anemia, including those receiving JAKi therapy. These data validate hepcidin reduction as a promising approach to treating anemia in MF. Clinical trial information: NCT05320198 .

Circulating tumor DNA <i>NRAS</i> and <i>TP53</i> mutations to identify ultra-high-risk primary refractory myeloma patients.

7557 Background: Approximately 5% of newly diagnosed multiple myeloma (MM) patients progress on bortezomib-containing first-line (1L) therapies and develop primary refractory disease (1REF). These patients have unacceptably poor outcomes. Underlying drivers of 1REF remain unclear. We hypothesized that circulating tumour DNA (ctDNA) profiling would identify the genetic drivers of 1REF. Methods: We analyzed plasma ctDNA, bone marrow (BM) MM cells from 89 patients, comprising 33 1REF and 56 contemporaneous 1L-responsive (RES) patients. ctDNA was available for all patients; BM was available for 63% (18 1REF and 38 RES). Ultra-deep targeted sequencing used a 21-gene panel enriched for MM drivers. High-confidence pathogenic variants were defined as variant allele frequency ≥1% with ≥15 supporting reads. Genomic enrichment analyses used Fisher's exact test. Survival outcomes (progression-free survival, PFS and overall survival, OS) were available for 27 1REF patients and analyzed using Kaplan–Meier methods. Results: Interrogation of BM showed more mutations in 1REF versus RES (67% vs 34%; p=0.04) with RAS/RAF predominating (67% vs 26%; p=0.007). Mutation patterns in 1REF versus (vs) RES comprised predominantly KRAS (44% vs 21%), followed by NRAS (22% vs 8%). BRAF was detected exclusively in 1REF (17% vs 0%) and TP53 showed no difference (6% vs 8%). ctDNA profiling revealed pathogenic variants in 18% of patients, enriched in 1REF vs RES (30% vs 11%; p=0.02), with RAS/RAF pathway mutations predominating (24% vs 2%; p=0.001), in line with BM observations. However, ctDNA RAS/RAF mutation patterns differed strikingly from BM. In 1REF vs RES, these comprised mainly NRAS (12% vs 0%; p=0.01) and BRAF (9% vs 0%; p=0.04), detected exclusively in 1REF, and KRAS (6% vs 2%). TP53 did not co-occur with RAS/RAF and were comparable across both cohorts (6% vs 5%). Mutation-survival associations in 1REF patients also revealed differences between BM and ctDNA. BM mutations lacked prognostic value while ctDNA mutations predicted survival, suggesting ctDNA captures treatment-resistant systemic disease. Patients with any ctDNA mutations had significantly shorter PFS and OS compared to those without (PFS: 8.5 months vs not reached [NR], p=0.0005; OS: 12.0 months vs NR, p=0.004). Patients with NRAS mutations showed consistently poor outcomes, while the impact of BRAF varied. The worst outcome was seen in an ultra-high-risk subset (15%, 4/27) with TP53 or NRAS , with all patients demonstrating an early fatal outcome (PFS 5.3 and OS 5.6 months; both p&lt;0.0001). Conclusions: ctDNA TP53 or NRAS identify a high-risk subset of 1REF patients with exceptionally poor outcomes, demonstrating that liquid biopsy, not BM evaluation, captures treatment-resistant systemic biology. These findings establish ctDNA as superior for risk stratification in 1REF MM and highlight an urgent need for alternative therapies in these patients.

Determinants of accrual speed in U.S. phase III therapeutic cancer clinical trials.

e23001 Background: Patient accrual remains the dominant rate-limiting step in cancer clinical trials, driving underpowering, escalating costs, and delayed access to practice-changing therapies. Despite prior efforts, effective trial accrual strategies are limited due to a lack of generalizable, trial-level evidence to understand factors associated with accrual speed in the modern cancer clinical trial ecosystem. We sought to identify these trial-level factors associated with faster accrual speed in completed phase III adult cancer trials conducted in the U.S. Methods: We identified 517 U.S based phase III, adult, interventional therapeutic oncology trials from clinicaltrials.gov, initiated after 1/1/2000, last updated after 1/1/2010, and successfully completed before 1/1/2025. Accrual speed was defined as patients per site per month (PPSM). We conducted a trial-level case-control study, classifying trials as fast (top PPSM quintile) or slow (others) groups. We assessed temporal trends in PPSM with linear regression and compared trial characteristics between groups. Results: PPSM decreased over time (start year: β=−0.038, p=.003). Majority trials had low accrual rates while a small proportion accrued rapidly (normality test p&lt;.001). Of the 517 trials, 104 (20%) were defined as fast accruing (mean PPSM±SD: 4.5±9.6) and 413 (80%) as slow accruing (mean PPSM±SD: 0.1±0.1). Compared with the slow group, fast-group trials were more likely to be single-site (52.9% vs 1.5%, p&lt;.001), with small-to-medium enrollment (≤150 patients, 38.5% vs 13.6%, p&lt;.001), primary sponsorship by non-industry institutions (65.4% vs 20.6%, p&lt;.001), and least restrictive eligibility (lowest quintile by criteria count, 31.7% vs 19.6%, p=0.011). Accrual speed was not associated with cancer type (p=.197), and major cancer types (breast, prostate, lung, and colorectal) were not overrepresented among fast-accruing trials. Conclusions: Accrual speed in phase III cancer trials is unevenly distributed, with few fast-accruing trials and many slow-accruing trials. Fast accrual was associated with single trial site, non-industry sponsorship, smaller enrollment size, and lower eligibility restrictions. These findings support systematic evaluation of factors underlying rapid accrual to inform future trial optimization. Accrual speed (PPSM) group (n, %)　 Fast (104, 20%) Slow (413, 80%) P PPSM, mean (SD) 4.5 (9.6) 0.1 (0.1) &lt;.001 Single-site 55 (52.9) 6 (1.5) &lt;.001 Enrollment ≤150 40 (38.5) 56 (13.6) &lt;.001 Randomized 95 (91.3) 381 (92.3) .918 Double/triple blind 34 (32.7) 157 (38.0) .373 Non-industry sponsored 68 (65.4) 85 (20.6) &lt;.001 Least restrictive eligibility (lowest quintile by criteria count) 33 (31.7) 81 (19.6) .011 Cancer Type Breast 13 (12.5) 54 (13.1) 1.000 Prostate 11 (10.6) 28 (6.8) 0.270 Lung 11 (10.6) 55 (13.3) 0.559 Colorectal 3 (2.9) 21 (5.1) 0.441

G8 screening-defined geriatric vulnerability as a predictor of survival and quality of life in older patients with advanced cancer treated with novel therapies.

1663 Background: Older patients with advanced cancer are a highly heterogeneous population, in whom geriatric vulnerability may significantly influence survival, treatment tolerance, and patient-reported outcomes. The G8 screening tool is a validated instrument designed to identify geriatric vulnerability and select patients for comprehensive geriatric assessment; however, its prognostic and longitudinal impact on quality of life in patients receiving novel anticancer therapies remains poorly explored. Methods: The ONC-OLD study prospectively enrolled patients aged ≥70 years with advanced cancer treated with novel therapies across six referral centers. The primary objective was to assess the prognostic impact of baseline G8-defined geriatric vulnerability on overall survival (OS). Geriatric vulnerability was assessed at baseline using the G8 screening tool (≤14 vs &gt;14). Health-related quality of life (HRQoL) was assessed using the EORTC QLQ-C30 and QLQ-ELD14 at baseline, after 3 months, and at disease progression. Baseline associations were analyzed using multivariable regression models, while longitudinal HRQoL changes were assessed using ANCOVA adjusted for baseline scores and relevant clinical covariates. Results: A total of 143 patients were included (median age 78 years, IQR 75-82); 78% had ECOG performance status (PS) 0-1, and 73% had G8 ≤14. Treatments consisted mainly of immunotherapy, either as monotherapy (31%) or in combination (36%), and targeted therapy (30%). At baseline, patients with G8 ≤14 were older (≥80 years: 46% vs 20%, p=0.019), more frequently female (42% vs 16%, p=0.016), and had worse ECOG PS (PS ≥2: 25% vs 0%, p=0.005) compared with those with G8 &gt;14, with a different distribution of primary tumor types (lung cancer: 67% vs 29%, p=0.001). Median OS was 16.1 months (95% CI, 13.4-not reached) and was significantly shorter in patients with G8 ≤14 compared with those with G8 &gt;14 (14.2 vs not reached; p=0.019). G8 ≤14 was independently associated with an increased risk of death (HR 2.71, 95% CI 1.01-7.24; p=0.047), after adjustment for ECOG PS, number of metastatic sites, treatment line and type. G8 ≤14 was associated with a trend toward a higher risk of grade ≥3 adverse events (OR 2.00, 95% CI 0.69-7.25; p=0.23), without specific treatment-related safety signals. At baseline, patients with impaired G8 reported worse global health, physical and role functioning, fatigue, pain, and mobility (all p≤0.01). In longitudinal analyses adjusted for baseline HRQoL and clinical covariates (ECOG PS, age, treatment), G8 remained significantly associated with higher fatigue (+12.6 points; p=0.039). Conclusions: Baseline G8 impairment is associated with poorer survival, worse baseline HRQoL, and a higher risk of severe toxicity, supporting the clinical value of G8 screening in older patients treated with novel therapies.

Integrating AI-derived lung cancer risk and social determinants of health to improve risk stratification in a safety net lung cancer screening program.

11081 Background: Lung cancer screening (LCS) outcomes remain inequitable, with social and environmental determinants of health (SDOH) influencing lung cancer risk, screening adherence, and cancer detection. Sybil is a validated deep learning model that predicts future lung cancer risk from a single low-dose CT (LDCT) scan using imaging features alone, without demographic or clinical inputs created by MIT/MGH. Its relationship to SDOH in real-world, safety-net screening populations has not been well characterized. Methods: We analyzed 2,645 individuals enrolled in the UI Health LCS program with baseline LDCT imaging and available Sybil risk scores. Scores were generated using the publicly available model applied exclusively to volumetric LDCT images, without retraining or incorporation of demographic, clinical, or SDOH variables. Individual-level clinical data were linked to census- and community-level SDOH measures. Sybil scores were log₁₀-transformed and analyzed as continuous and categorical variables. Associations between Sybil risk, SDOH, and lung cancer diagnosis were assessed using multivariable logistic regression. Results: Mean baseline Sybil score was 0.014 (median 0.002). Ninety-six individuals (3.6%) were diagnosed with lung cancer. Sybil scores were significantly higher among individuals later diagnosed with cancer (mean log score −1.52 vs −2.48; p&lt;0.001). In multivariable models, Sybil risk was the strongest independent predictor of lung cancer diagnosis (OR 6.12 per log-unit increase, 95% CI 4.31–8.83; p&lt;0.001), independent of BMI and SDOH. High Sybil risk remained strongly associated with cancer diagnosis across multiple thresholds (all p&lt;0.001). Census-level area deprivation and community-level measures of food insecurity, vehicle access, and neighborhood conditions were also independently associated with cancer diagnosis (Table 1). Conclusions: In a large safety-net LCS cohort, AI-derived Sybil risk robustly predicted lung cancer diagnosis and remained informative despite relying solely on imaging data. Integrating AI-based risk prediction with SDOH context may support more equitable, precision-guided lung cancer screening strategies. Association of Sybil AI-risk scores and social determinants of health with lung cancer diagnosis in the UI Health lung cancer screening cohort. Predictor Comparison / Scale Adjusted OR (95% CI) P value Sybil score Log10 continuous 6.12 (4.31–8.83) &lt;0.001 Sybil score High vs Low (median cutoff) 4.18 (2.38–7.79) &lt;0.001 Sybil score High vs Low (75th percentile) 5.10 (3.08–8.57) &lt;0.001 Sybil score High vs Low (tertiles) 8.02 (3.90–18.72) &lt;0.001 BMI Per unit increase 0.93 (0.89–0.96) &lt;0.001 Area Deprivation Index Census-level 1.02 (1.00–1.04) 0.02 Food insecurity Community-level (%) 1.08 (1.02–1.15) 0.01 No vehicle access Community-level (%) 1.05 (1.02–1.09) 0.003

Atrial fibrillation mortality among patients with neoplasms: National trends and deep learning forecast through 2038.

e24027 Background: Atrial fibrillation (AFib) is the most common cardiac arrhythmia globally and has emerged as a prevalent cardiovascular comorbidity in patients with neoplasms. Although prior studies have reported an association between AFib and neoplastic diseases, national trends in AFib-related mortality within this population remain poorly characterized. Methods: This population-based retrospective study utilized CDC WONDER mortality data. Decedents with cardiovascular disease listed as the underlying cause of death and with listed diagnoses of AFib and neoplasms were included. Age-adjusted mortality rates (AAMRs) were calculated using the 2000 U.S. standard population. Temporal trends were assessed using joinpoint regression to identify significant inflection points and estimate annual percent changes (APCs). GRU-based deep learning models were used to forecast mortality through 2038. Results: Among 478,881 deaths, AFib-related mortality in individuals with neoplasms increased from 4.3 per 100,000 in 1999 to 11.0 in 2022 (APC: 3.93%; 95% CI: 3.49–4.37; p &lt; 0.00001). Significant joinpoints were identified in 2014, 2018, and 2021, with the steepest APC of 10.24% observed between 2018 and 2021. Mortality was higher in males but rose similarly across both sexes. Racial disparities were evident, with White and Black individuals exhibiting the highest AAMRs, while Hispanic individuals experienced the fastest rate of increase (AAPC: 5.05%). The majority of deaths occurred in medical facilities (37.7%) and 94.3% of AFib-related deaths were attributable to malignant neoplasms.. Forecasting analysis projected a 27% rise in AAMR by 2038, with upward trends across all sex and racial groups. Conclusions: AFib-related mortality among individuals with neoplasms has nearly tripled over the past two decades, marked by distinct periods of acceleration, persistent demographic disparities, and concerning future projections. These trends may be related to prolonged survival among cancer patients, improvements in overall survival, and the increasing number and complexity of oncologic and cardiovascular medications.

Utilization of CEACAM7 as a novel diagnostic biomarker of pancreatic cancer.

e16421 Background: The trends of pancreatic cancer (PanCa) incidence and mortality are on a rising pattern. Pancreatic ductal adenocarcinoma (PDAC), a major form of PanCa, exhibits a grim prognosis as the mortality rate is very close to the incidence rate, due to a lack of early detection methods and effective therapeutic regimen. Late diagnosis of PanCa is a major concern for health care professionals. Unfortunately, no early and FDA-approved tumor-specific biomarker for PDAC is available at present. Currently, multidetector computed tomography (CT) and the serum level of carbohydrate antigen 19-9 (CA19-9) are used for PDAC diagnosis, but both have their own limitations. CA19-9 has a broad range of cross-immune-reactivity in multiple malignancies and nonmalignant indications, such as chronic pancreatitis and liver cirrhosis. Thus, reliable specific molecular signals capable of predicting the primary detection and prognosis of PDAC are highly desired to upgrade the narrow diagnostic portfolio against PanCa. Methods: Considering this situation, our group has identified a novel oncogenic protein, Carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7). CEACAM7 is a member of the carcinoembryonic antigen (CEA) family. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) belong to the immunoglobulin (Ig) family with differential expression over the surfaces of cells. The functional-cellular processes of CEACAMs are quite diverse, like cell adhesion, tumor progression, proliferation, signal transduction, and phagocytosis. We performed deep data mining bioinformatics analysis to investigate expression profile of CEACAM7 in different cancers. To determine the translational potential, concentration of CEACAM7 in various PDAC cell lines was evaluated. Expression of CEACAM7 was also examined in pancreatic tumor tissues, normal pancreatic tissue, and blood samples from PanCa patients and healthy individuals. Results: Observations from our laboratory show that CEACAM7 is differentially expressed in PanCa compared to healthy individuals. Bioinformatics analysis showed that pancreatic cancer (PAAD) was the only cancer that showed higher CEACAM7. Among PDAC cell lines, HPAF-II showed the highest CEACAM7 protein concentration (704.435 pg/ml), followed by SU86.86 (583.806 pg/ml), PANC1 (329.8719 pg/ml), and HPNE (231.237 pg/ml). We also found strong expression of CEACAM7 in pancreatic tumor tissues, while normal pancreatic tissue showed no expression. More importantly, our studies detected measurable CEACAM7 protein in the blood of PanCa patients but not in healthy individuals. Conclusions: These data clearly suggest that CEACAM7 might be an excellent and highly specific biomarker for the early diagnosis of pancreatic cancer and monitoring treatment response. If successful, it can be a good replacement for CA19.9 for monitoring therapy response.

Fair inclusion in clinical trials: Updated Good Pharma Scorecard evaluations of FDA oncology drugs approved by the FDA, 2018-2023.

11030 Background: Adequate representation of demographic subgroups in clinical trials is essential for understanding the safety and efficacy of novel therapies. We previously developed and piloted the “fair inclusion” measure, which assesses (1) transparency in participant demographics and (2) demographic representation. These metrics were incorporated into the Good Pharma Scorecard, a system evaluating pharmaceutical company performance in bioethics and social responsibility, with sponsors ranked by fair inclusion scores. However, it remains unclear whether sponsors have improved fair inclusion of women, older adults, and racial and ethnic minorities in pivotal trials since the most recent Scorecard. Methods: For transparency, we assessed 6 measures [whether the number of (1) women, (2) older adults, (4) Black, (5) Asian, and (6) Latinx participants were publicly reported], and for representation, 5 measures [whether the proportion of enrolled (1) women, (2) older adults, (3) Black, (4) Asian, and (5) Latinx represents &gt;80% of the US population with the studied condition]. Fair inclusion scores averaged transparency and representation, overall and by subgroup. Results were reported at the trial, product, and sponsor levels and compared across 2012–2017 vs 2018–2023 approvals. Data sources included Drugs@FDA, ClinicalTrials.gov, publications, US Cancer Statistics, and the American Cancer Society. Results: Between January 1, 2018 and December 31, 2023, the FDA approved 75 oncology therapeutics based on 80 pivotal trials from 52 sponsors. At the sponsor level, transparency improved for older adults (2012–2017: 78%, 2018–2023: 95%, p = 0.002) and racial and ethnic minorities (67% vs 91%, p = 0.003). Representation did not improve for women (94% vs 94%, p = 0.99), older adults (85% vs 81%, p = 0.29), or racial and ethnic minorities (75% vs 67%, p = 0.13). Fair inclusion scores improved modestly (81% vs 86%; p = 0.04). Conclusions: Sponsors have improved demographic reporting, particularly for older adults and racial and ethnic minorities. However, representation has not improved for any subgroup. Overall gains in fair inclusion were driven by transparency. Comparison of mean sponsor scores on transparency, representation, and fair inclusion for 2012-2017 vs 2018-2023 oncology FDA approvals, by sex, age, race and ethnicity. 2012-2017 Scores (n = 25) 2018-2023 Scores (n = 52) p-value Women  Transparency 96% 99% 0.32  Representation 94% 94% 0.99  Fair Inclusion 97% 95% 0.28 Older Adults  Transparency 78% 95% &lt; 0.01  Representation 85% 81% 0.29  Fair Inclusion 79% 86% 0.07 Race and Ethnicity  Transparency 67% 91% &lt; 0.01  Representation 75% 67% 0.13  Fair Inclusion 66% 78% 0.06 Overall  Transparency 82% 95% &lt; 0.001  Representation 85% 80% 0.06  Fair Inclusion 81% 86% 0.04

Genetic characteristics of combined hepatocellular-cholangiocarcinoma tumors in a tertiary care center: A case series.

e16215 Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare malignancy (1) with a 5-year OS as low as 10% (2-4). While cHCC-CC tumors demonstrate a spectrum of HCC or CC features (1,5-8), due to the rarity of this malignancy, pathological and clinical characterization has been challenging, compounded by the heterogeneity of the disease (5,8-10). In this case series, we review clinicopathologic factors from cases within our hospital system related to survival outcomes and review the genomic landscape to inform potential future therapeutic decision making. Methods: 1,392 cases from the Banner Health MDA system were reviewed. Of these, fifteen cases were confirmed as cHCC-CC. Six patients have evaluable records of their complete treatment course. NGS data was available for seven patients. Results: Of the six patients that had evaluable records, the average time from diagnosis to transition to hospice or last visit was 11.5 months (range of 2-44 months, median 6 months). Four of these patients were initially diagnosed with stage IV disease, and two were initially diagnosed with stage II disease. Two patients did undergo disease recurrence during their treatment course. Five patients transitioned to hospice less than one year after diagnosis, with an average of 4.6 months to this transition (range 2-8 months). One patient experienced prolonged survival of 44 months and is still alive at the time of analysis. All six patients had cHCC-CC that more closely resembled CC as opposed to HCC. Of the seven patients who underwent NGS sequencing of their tumors, 24 unique mutations of interest were detected, including 8 that have not been previously described in cHCC-CC. The most common alterations were in TP53 (present in five patients) and the TERT promoter region (present in four patients), which was consistent with previous studies. Multiple recurrent signaling pathway alterations were identified in the MAPK/RAS/ERK pathway (MAP2K2 (MEK2), non-V600 BRAF Class II, PTPN11), MHC Class 1 antigen presentation (B2M), glutathione metabolism/detoxification pathway (GSTP1), and TGF-B/BMP (BMPR1A). Copy number gain of Myc and Met are also described. This analysis demonstrates that cHCC-CC harbors alterations targetable by novel therapeutics in development including RAS inhibitors and BET inhibitors. In addition, approved drugs such as capmatinib that target MET amplification and tovorafenib that can inhibit Class II BRAF alterations are promising avenues of investigation. Conclusions: We describe a series of cHCC-CC that pathologically mostly resembles a cholangiocarcinoma phenotype, but harbor alterations not seen in either type of cancer that have strong potential for future therapeutic targeting.