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miR-29a-3p regulates SPARC to inhibit ferroptosis and promote cell proliferation in gastric cancer

Dynamic mechanism for subtype selectivity of endocannabinoids

Cancer risk and screening-preventable malignancies in transgender populations: A systematic review and meta-analysis.

e22522 Background: Transgender people experience health vulnerabilities shaped by structural barriers to care and differential exposure to cancer risk factors. However, epidemiologic evidence on cancer risk and screening-relevant malignancies in TGD populations remains scarce and fragmented. Methods: We conducted a PRISMA-guided systematic review and meta-analysis to synthesize relative risks of malignancies amenable to screening in TGD populations compared with cisgender reference groups. We searched MEDLINE/PubMed, Embase, and LILACS through December 2025 (last search January 2026), with no language restrictions. Observational studies reporting standardized risk measures (SIR, PIR, HR, or equivalent) were included. Random-effects meta-analyses were performed when clinically and statistically appropriate, and study quality was assessed using the Newcastle–Ottawa Scale. Results: Twelve studies met inclusion criteria. Among transgender women, prostate cancer risk was significantly reduced compared with cisgender men (pooled RR 0.35; 95% CI 0.28–0.42). Anal canal cancer risk was markedly increased in transgender populations compared with cisgender men (RR 13.6; 95% CI 7.6–24.4), with consistent findings across sensitivity analyses. Breast cancer risk in transgender women was substantially higher than in cisgender men (RR 32.3; 95% CI 17.7–58.8) but lower than in cisgender women (RR 0.28; 95% CI 0.21–0.38). Transgender men showed increased breast cancer risk compared with cisgender men, while comparisons with cisgender women were inconclusive. For lung cancer, transgender populations had higher risk compared with cisgender women (RR 1.55; 95% CI 1.31–1.84) and no significant difference compared with cisgender men. Evidence for colorectal and cervical cancers was insufficient for meta-analysis. Conclusions: Cancer risk in TGD populations varies by tumor site and likely reflects biological, behavioral, and structural factors, including differential screening and data limitations. These findings support organ-based, gender-affirming approaches to prevention and early detection and highlight the need for improved gender identity data capture in health systems.

Clinical utility of MRI in breast cancer diagnosed over age 70.

e12689 Background: Previous observational studies evaluating the role of MRI in the management of breast cancer patients have shown alterations in management in 14-18% of cases due to detection of more extensive disease, and higher yield in younger women with dense breasts. However, a randomized controlled trial evaluating the clinical efficacy of MRI in women with primary breast cancer showed that the addition of MRI has no benefit on reduction of reoperation rate. We aim to assess the utilization and impact on management of MRI in breast cancer patients age 70 and older. Methods: A retrospective chart review was conducted of 1200 patients age 70 and older diagnosed with breast cancer between 2018-2023 who either received preoperative MRI or did not. Data was analyzed for correlation between MRI use, additional biopsy after MRI, result of additional biopsy, and type of surgery performed. Results: Of 1200 patients, 473 (39%) underwent MRI whereas 727 (61%) did not. Patients in the 70-79 age group were more likely to undergo MRI compared to those 80+; 396/924 (43%) vs. 77/276 (28%) (OR 0.52, 95% CI 0.38-0.69; p< 0.001). Patients with high breast density (C/D) were more likely to receive an MRI compared to those with low breast density (A/B); 168/349 (48%) vs. 171/501 (34%) (OR 1.79, 95% CI 1.35-2.37; p< 0.001). Of 345 patients who had MRI, 88 (26%) had an additional biopsy recommended. See Table for biopsy results. The likelihood of having an additional biopsy was similar in patients across both age brackets, as was the overall yield of cancer, both ipsilateral and contralateral. Conclusions: Breast cancer patients aged 80 and above are less likely to undergo preoperative MRI. However, when they do have an MRI, they are just as likely to undergo an additional biopsy with a similar ipsilateral and contralateral breast cancer yield compared to patients aged 70-79. Therefore, MRI remains clinically useful in a select subset of older patients, particularly those with higher breast density. Utilization and diagnostic yield of MRI. Outcome All Patientsn/N (%) Age 70-79n/N (%) Age ≥ 80n/N (%) Odds Ratio [95% CI] p-value MRI utilization 473/1200 (39.4) 396/924 (42.9) 77/276 (27.9) 0.52 [0.38–0.69] <0.001 Additional biopsy recommended 88/345 (25.5) 74/293 (25.3) 14/52 (26.9) 1.09 [0.56–2.12] 0.799 Biopsy yield for cancer 49/88 (55.7) 41/74 (55.4) 8/14 (57.1) 1.07 [0.34–3.40] 0.904 Biopsy yield for contralateral cancer 19/88 (21.6) 17/74 (23.0) 2/14 (14.3) 0.56 [0.11–2.75] 0.474 Odds Ratio compares the odds of the outcome in Age ≥ 80 to the odds in Age 70-79. OR < 1 indicates lower odds in ≥ 80; OR > 1 indicates higher odds.

Interpretable machine learning to identify health system levers for survival outcomes of patients with breast cancer.

1594 Background: Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer death among women worldwide. Despite advances in screening and treatment, global disparities in breast cancer outcomes remain stark. The mortality-to-incidence ratio (MIR) is an ecological measure of cancer control performance. We applied interpretable machine learning to quantify country-level determinants of the breast cancer MIR within the health system, facilitating examination of interrelated factors for each individual country. Methods: We developed a CatBoost gradient-boosting model with SHAP (SHapley Additive exPlanations) analysis to predict female breast cancer MIR across 185 countries using GLOBOCAN 2022 data. Health system indicators were compiled from WHO, World Bank, and DIRAC databases, including GDP per capita, UHC index, radiotherapy centers per 1000 population, health spending metrics, workforce densities (physicians, nurses, surgical workforce per 1000), pathology services, gender inequality index, and breast screening program status. The model was trained with repeated leave-one-country-out cross-validation (10 repeats; 1850 total predictions) and nested hyperparameter optimization. SHAP values quantified country-specific feature attributions. Results: The model demonstrated robust predictive performance, with R² = 0.793 (95% CI: 0.726-0.844), RMSE = 0.068 (95% CI: 0.060-0.076), and correlation r = 0.891 (p<0.001). Global SHAP analysis identified GDP per capita as the most influential predictor (mean |SHAP| = 0.0245), followed by the UHC index (0.0217), physicians per 1000 population (0.0196), the gender inequality index (0.0151), radiotherapy centers per 1M population (0.0150), and nurses/midwives per 1000 (0.0143). The binary breast screening program indicator showed low importance (0.0066), reflecting collinearity with other health system measures. Country-specific SHAP decompositions revealed substantial heterogeneity in dominant drivers, with workforce density and deficits in radiotherapy infrastructure emerging as major barriers in lower-resource settings. Conclusions: Strategic investments in healthcare workforce development, radiotherapy infrastructure, and UHC expansion are associated with improved national breast cancer survival, alongside complex health system strengthening factors. These findings enable evidence-based, context-specific prioritization of health system strengthening interventions for global breast cancer control, though prospective validation is needed.

Neuroprotective potential of BOLD-100 when utilized in combination with FOLFOX for the treatment of advanced gastrointestinal cancers.

e15029 Background: BOLD-100 is a ruthenium-based anticancer agent in Phase 2 development for gastrointestinal (GI) cancers (NCT04421820). Previous data showed BOLD-100 plus FOLFOX improved overall survival (OS) and progression-free survival (PFS) in patients (pts) with advanced colorectal (mCRC), gastric (GC), and biliary tract cancer (BTC). Pts treated with the BOLD-100 combination had a lower incidence of oxaliplatin-induced peripheral neuropathy (OIPN). Many pts treated with FOLFOX experience OIPN leading to dose reductions and treatment discontinuations. A retrospective analysis of adverse events (AEs) from this study was conducted to investigate the impact of BOLD-100 on OIPN. Methods: BOLD-100-001 is a prospective, open-label, phase 2 study in pts with mCRC, GC, BTC & pancreatic cancer with measurable disease (RECIST v1.1) and BRAF wildtype tumor status. Pts received FOLFOX plus BOLD-100 every 2 weeks via IV infusion. OIPN-related AEs were analyzed and compared to historical benchmarks. Analyses included OIPN incidence by BOLD-100 dose level, demographics, and oxaliplatin treatment delays or discontinuations. Univariate and multivariate analyses were performed. Results: Study enrolled 109 participants. Median age was 62 years (range 48-84). Female pts made up 45%, all pts had an ECOG PS ≤1. All pts had a primary diagnosis of adenocarcinoma, 42 (39%) colorectal, 22 (20%) bile duct, 24 (22%) pancreatic, and 21 (19%) gastric cancer. 106 pts (97%) were stage IV at study entry and all but one had prior chemotherapy in the advanced setting. The median number of prior systemic therapies was 3 (range 0-8) with 95% treated with oxaliplatin (65%) or cisplatin (30%). 45 pts (41%) had prior neuropathy. On study, 24 pts (22%) had at least one OIPN-associated AE. Lower PN incidence was observed across all cohorts relative to benchmarks: mCRC (14% vs 53%), BTC (36% vs 68%), GC (19% vs 63%), and pancreatic cancer (29% vs 38%). Only 9 pts (8.2%) discontinued oxaliplatin, with only 2 attributed to OIPN. Of 69 dose reductions, 16 (23%) were due to OIPN. Pts at the highest BOLD-100 dose level (625 mg/m 2 ) had the lowest OIPN incidence. Multivariate analysis suggests Asian descent (OR = 0.09; p = 0.04) and medical history of prior neuropathy (OR = 0.18; p = 0.02) were significantly associated with the absence of OIPN. Univariate analysis suggested longer OS (OR = 1.1; p = 0.006), PFS (OR = 1.13; p = 0.002), and a higher number of cycles (OR = 1.17; p = 0.0003) were associated with an increased likelihood of OIPN. Conclusions: Analysis of safety and dosing data from BOLD-100-001 suggests a potential neuroprotective effect of BOLD-100 against FOLFOX-induced PN. Further investigations are ongoing to characterize this effect in a randomized arm of the BOLD-100-001 clinical trial which is exploring changes in health-related and neuropathy-related quality of life per EORTC-QLQ-30 and EORTC-QLQ-CIPN20 scores. Clinical trial information: NCT04421820 .

Safety and efficacy of puxitatug samrotecan (Puxi-Sam, AZD8205) in patients with biliary tract cancer (BTC): A first-in-human phase 1/2a study (BLUESTAR).

4106 Background: B7-H4 is a transmembrane glycoprotein that negatively regulates T-cell function and is highly expressed in many cancers, including BTC, making it an attractive target for an antibody–drug conjugate (ADC). Puxi-Sam (also known as AZD8205), a novel B7-H4–directed topoisomerase I inhibitor (TOP1i) ADC, demonstrated favorable toxicity and promising antitumor activity during the dose escalation phase of the first-in-human Phase 1/2a BLUESTAR (NCT05123482) trial. Here, we report the pooled analyses for patients with BTC in the dose-escalation and dose-expansion phase of BLUESTAR. Methods: Eligible patients were ≥18 years old with nonresectable, recurrent, or metastatic B7-H4-positive BTC, with measurable disease per RECIST v1.1, and an ECOG performance status of 0 or 1. B7-H4 positivity was defined as ≥25% tumor cell staining by central immunohistochemistry in archival tumor samples. Patients must have received prior adequate standard-of-care therapy; prior treatment with a TOP1i was not allowed for patients in the dose-expansion phase. Patients received Puxi-Sam 2.4 mg/kg IV Q3W until disease progression, unacceptable drug-related toxicity, or consent withdrawal. The primary objective was assessment of safety; secondary objectives included assessment of antitumor activity. Results: As of 30 October, 2025, 20 patients received 2.4 mg/kg Puxi-Sam. The median (min–max) age was 61.5 years (44–88) and patients had received a median (min–max) of 2 (1–4) prior lines of treatment. Sixteen (80.0%) patients had treatment-related adverse events (TRAE), most commonly nausea (55.0%), and anemia (50.0%). Eleven (55.0%) patients had Grade ≥3 TRAEs, most commonly anemia (50.0%) and neutropenia (30.0%). Dose interruptions, reductions, and discontinuations due to TRAEs were required in six, two, and one patient, respectively. Two patients achieved a partial response (PR), corresponding to a confirmed objective response rate (ORR) of 10.0%. Disease stabilization was observed in a meaningful proportion of patients; 10 patients (50%) had stable disease (SD), and 12-week disease control rate (DCR) was 25.0% (5/20). Median progression-free survival (PFS) was 2.2 months, with a median follow-up of 2.2 months, supporting early signals of disease control (Table). Conclusions: Puxi-Sam demonstrated a favorable safety profile and showed modest clinical activity with prolonged disease stabilization observed in a subset of heavily pretreated patients with nonresectable, recurrent, or metastatic BTC. Clinical trial information: NCT05123482 . Efficacy summary (interim response evaluable patients). Puxi-Sam2.4 mg/kgN=20 ORR, % (95% CI) 10.0 (1.2–31.7) PR, n (%) 2 (10.0) SD, n (%) 10 (50.0) PD, n (%) 7 (35.0) NE, n (%) 1 (5.0) DCR at 12 weeks, %(95% CI) 25.0(8.7–49.1) Median PFS, months(95% CI)* 2.2(1.4–4.6) * Full analysis set. NE, not evaluable; PD, progressive disease.

Home-based palliative care delivery by a freelancing palliative care specialist to terminally ill cancer patients in Kolkata, India: An audit of the service model.

e24045 Background: Home-based palliative care (HBPC) can provide continuity of care, symptom-management and end-of-life-care (EOLC) support to terminally-ill cancer patients who often have high care-giving needs. In a resource-constrained setting like India, access to community-based palliative care and EOLC is limited. We developed a model of palliative care delivery by training one of our departmental medical officers to provide HBPC as a freelancing palliative care specialist physician. This is an audit to evaluate the service utilization, patient clinical characteristics ,outcomes, and caregiver satisfaction amongst the patients receiving HBPC over three years in this model. Methods: This is a retrospective study including consecutive oncology patients enrolled between January 2022 and December 2024 in our HBPC model. De-identified patient data was extracted from our database and electronic medical health records, including demographics, diagnosis, symptom burden by Edmonton symptom scale with score of ≥4 considered significant, palliative interventions, requirement to shift at hospital, time from referral to death and caregiver feedback via Likert scale. Descriptive statistics were applied. Results: A total of 160 patients were included (median age 59 years; 56% male).The most common cancers were head-and-neck (22%), gastrointestinal (18%), and breast (16%). Mean survival of the patients from referral to death was 17.5 ± 8.5 days. Pain management was the leading reason for referral (78%).The other common reasons were wound-care and dressing including bedsores (24%), breathlessness (18%), terminal delirium (8%), nutritional management (15%), lymphedema & DVT management (6%). 82% received exclusive home care till death while 18% required hospital admission for intractable symptoms at end of life. Most common reasons for transfer to hospital were: requiring BIPAP support, unavailability of IV morphine at community level (terminal sedation), USG guided pleural or ascitic tapping & accessibility to health-insurance schemes. Common procedures performed at home included IV cannulation, Ryles tube insertion, wound management, stoma care including tracheostomy, acupuncture for pain relief, chemoport and indwelling vascular access care and ascitic tapping. Procedure-related complications were minimal (3%). Mean caregiver satisfaction score was 4.4 ± 0.6 on a 5-point scale. Conclusions: This study demonstrates that our HBPC model is safe, feasible, well-utilized and valued by families, with low complication rates and reduced hospital utilization. Structured expansion of such programs can enhance end-of-life care access and reduce health-system burden in India.

Can a simple pre-mobilization complete blood count predict stem cell yield? Low-cost predictors of CD34⁺ mobilization in multiple myeloma.

e19513 Background: Autologous hematopoietic stem cell transplantation (ASCT) remains a critical component of consolidation therapy in multiple myeloma. Adequate CD34⁺ stem cell yield is essential for transplant success; however, mobilization failure occurs in a substantial proportion of patients, leading to increased costs and resource utilization. While peripheral blood CD34 and mononuclear cell (MNC) monitoring guide leukapheresis, these assays are costly and not universally available. We evaluated whether routinely available pre-mobilization complete blood count (CBC) parameters could serve as affordable predictors of stem cell collection success. Methods: We performed a retrospective analysis of 94 newly diagnosed multiple myeloma patients undergoing stem cell mobilization and collection between 2018 and October 2025 at a tertiary cancer centre. All patients received G-CSF–based mobilization, with pre-emptive plerixafor administered when clinically indicated. Pre-mobilization CBC indices—including hemoglobin, total leukocyte count (TLC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), platelet count, and platelet-to-WBC ratio—were correlated with CD34⁺ yield. Statistical analyses included chi-square testing, univariate and multivariable logistic regression, and receiver operating characteristic (ROC) curve analysis. Results: Among 94 multiple myeloma patients (median age 59 years; 57% male), most had ISS stage I–II disease (82%) and IgG myeloma (89%). Median baseline hemoglobin was 12.3 g/dL, and the majority received lenalidomide-based induction, achieving a median CD34⁺ yield of 6.6 × 10⁶/kg. Excellent CD34⁺ yield was significantly associated with MNC count (p = 0.017), total leukocyte count (p = 0.037), absolute monocyte count (AMC; p = 0.018), and plerixafor use (p = 0.003). On multivariable analysis, pre-mobilization platelet count ≥164 × 10⁹/L independently predicted excellent mobilization. ROC analysis showed modest discrimination for platelet count (AUC ≈ 0.61) with high sensitivity (~97%). In patients mobilized without plerixafor, ANC ≥2.775 × 10⁹/L and AMC ≥0.475 × 10⁹/L demonstrated the best overall discriminatory performance. Conclusions: A simple pre-mobilization platelet count is a low-cost, widely available, and independent predictor of excellent CD34⁺ stem cell yield in multiple myeloma. Integration of CBC-based markers may enable earlier risk stratification, optimize apheresis timing, guide selective plerixafor use, and reduce unnecessary costs in resource-constrained settings. Prospective validation and composite CBC-based predictive models are warranted.

Temporal trends in oncology clinical trial complexity and duration: A retrospective analysis of 5,261 industry-sponsored trials.

11018 Background: Clinical trial complexity has been cited as a contributor to rising drug development costs and increasing trial duration. We aimed to quantify multidimensional oncology trial complexity and describe temporal trends. Methods: We conducted a retrospective analysis of industry-sponsored interventional drug and biological oncology trials from the Aggregate Analysis of ClinicalTrials.gov (AACT) database, restricted to concluded trials initiated 2007-2017 for post-FDAAA reporting consistency and adequate follow-up. Five complexity dimensions were derived using principal component analysis: protocol (eligibility criteria, arms, outcomes), operational (sites, countries, planned enrollment), disease (MeSH breadth), intervention (modality count), and governance (team structure). Temporal trends were analyzed across completed trials only; Pearson correlations between dimensions and duration/early termination were calculated across all concluded trials. Trends were estimated using linear regression on yearly medians stratified by phase. Results: Among 6,752 concluded oncology trials (78% completion rate), temporal trends were analyzed in the 5,261 completed trials. Protocol complexity significantly increased (+0.083 SD/year), driven by total eligibility criteria (+0.56/year), secondary outcomes (+0.35/year), and exclusion criteria (+0.35/year). Operational complexity showed a significant increasing trend (+0.014 SD/year), with facilities increasing +0.51/year. Overall trial duration significantly increased (+16.7 days/year), with Phase 1 trials increasing +18.2 days/year and Phase 2 trials +18.4 days/year, while Phase 3 trials showed a non-significant trend (+20.7 days/year). Across all trials, protocol complexity was weakly correlated with early termination (r=0.03) and duration (r=0.14). Operational complexity showed the strongest correlation with duration (r=0.36). Conclusions: Among concluded oncology trials, protocol and operational complexity are significantly increasing, particularly eligibility criteria burden, endpoint multiplicity, and study scale. Trial duration is significantly increasing for early-phase trials, driven primarily by operational complexity. Operational and protocol trends in oncology trials. Metric (median) 2007 Value 2017 Value Slope/Year P-value Total I/E Criteria 15 22 +0.56 <0.001 Secondary Outcomes 4 7 +0.35 <0.001 Exclusion Criteria 8 12 +0.35 <0.001 Inclusion Criteria 6 9 +0.22 <0.001 Total Outcomes 8 11 +0.30 <0.001 Number of Sites 6 12 +0.51 <0.001 Phase 1 Duration (days) 1080.5 1220 +18.2 0.010 Phase 2 Duration (days) 1249 1347 +18.4 0.028 Phase 3 Duration (days) 1583 1673 +20.7 0.214 Overall Duration (days) 1247 1378 +16.7 0.006 Observed medians are reported for 2007 and 2017. Slopes and p-values were derived from linear regression on yearly medians.

Adherence to lower endoscopic surveillance in high-risk colorectal cancer populations: A meta-analysis of U.S. studies.

e22536 Background: High-risk individuals, including those with a history of colorectal cancer (CRC), advanced adenomas, or hereditary syndromes, require routine lower endoscopic surveillance to reduce recurrence and mortality. However, real-world adherence in U.S. healthcare systems remains poorly characterized. This meta-analysis quantified adherence and examined variability by surveillance interval ( < 2 vs. ≥2 years). Methods: We conducted a systematic review and random-effects meta-analysis of studies reporting surveillance adherence among high-risk CRC populations in U.S. healthcare settings. Eligibility was restricted to peer-reviewed studies published in English that reported quantifiable adherence rates to lower endoscopic surveillance (e.g., colonoscopy, CT colonography). Subgroup analyses stratified studies by surveillance interval ( < 2 years vs. ≥2 years post-index). Pooled estimates were calculated using a logit transformation. Between-study heterogeneity was assessed using I² and τ², and prediction intervals were reported to estimate expected adherence in future settings. Results: The primary meta-analysis (4 studies; N = 11,071) demonstrated a pooled adherence rate of 44% (95% CI: 19–72%; prediction interval: 5–92%; I² = 99.7%). Subgroup analyses, which included additional eligible studies contributing interval-specific data, showed higher adherence in the < 2 years surveillance interval (3 studies; N = 16,884; 56%; 95% CI: 3–98%; I² = 99.9%). In the ≥2 years subgroup (5 studies; N = 12,305), pooled adherence was 45% (95% CI: 19–74%; I² = 98.8%). Considerable between-study heterogeneity was observed across analyses. Conclusions: Adherence to lower endoscopic surveillance among high-risk CRC populations in the U.S. remains suboptimal and variable. Shorter surveillance intervals were associated with modestly higher adherence, though estimates varied substantially across studies. These findings highlight the need for improved surveillance tracking systems and targeted interventions. An ongoing thematic synthesis will further characterize multilevel barriers to inform future quality improvement efforts.

Genomic characterization and clinical associations of rare co-mutations in <i>RAS</i> and <i>RAF</i> genes in colorectal cancer.

e15581 Background: In colorectal cancer (CRC), mutations in RAS family genes and BRAF are typically mutually exclusive. However, with the widespread application of next-generation sequencing (NGS), case reports of such co-mutations are accumulating, warranting a systematic investigation of their genomic features, cooperative mechanisms, and clinical significance. Methods: A retrospective analysis was performed on a CRC patient cohort who underwent DNA-based NGS using a 733-gene panel (full-length coverage) between 2023 and 2025. Samples were primarily formalin-fixed, paraffin-embedded (FFPE) tissues, mostly from primary sites. Results: Among 1379 CRC patients, 834 harbored RAS and/or RAF mutations. Seventeen patients (1.23%, 17/1379) exhibited concurrent RAS and RAF mutations. The co-mutation patterns were: KRAS+BRAF in 13 patients (76.47%), NRAS+BRAF in 3 (17.65%), and KRAS+ARAF in 1 (5.88%). The cohort included 11 males (64.71%) with a median age of 61 years (range: 49-88), and 15 cases (88.24%) originated in the colon. KRAS variant sites included G12C/D/V (n = 6), A146T/V (n = 4), G13C/A59S/Q61H/K147E (each n = 1). NRAS variants included G12C/D (n = 2) and Q61L (n = 1). These RAS mutations clustered in critical functional domains (exons 2-4), disrupting the P-loop, Switch II region, and G-domain, thereby abrogating guanosine triphosphatase (GTPase) activity and causing constitutive activation. BRAF mutations comprised: Class I V600E (n = 5); Class II G469A/R (n = 2) and K601N (n = 3); Class III D594E/N (n = 3) and G466E (n = 1); and unclassified variants F247L and F468S (each n = 1). These mutations predominantly localized to the kinase domain (exons 11/15), affecting key functional regions including the P-loop, A-loop. The co-occurrence of RAS and BRAF may lead to additive MAPK pathway activation, with cooperative mechanisms varying by BRAF mutation class: (1) RAS + Class III BRAF (low kinase activity): RAS activation provides sustained upstream signaling, potentially maintaining moderate but persistent pathway output. (2) RAS + Class II BRAF (moderate kinase activity, RAS-independent): Co-mutation may amplify signaling via positive feedback or enhanced dimerization. (3) RAS + Class I BRAF V600E (high kinase activity): Both are strong activators; this rare combination might lead to excessive signaling, possibly subject to negative selection during tumor evolution. Conclusions: Co-mutations in RAS and RAF represent a rare but noteworthy genomic event in CRC. They likely confer resistance to single-agent targeted therapies, such as EGFR monoclonal antibodies and BRAF inhibitors. Future therapeutic strategies should consider multi-level MAPK pathway inhibition (combining MEK inhibitors or RAF dimer inhibitors). The precise biological functions and clinical prognosis associated with these co-mutations require further validation with treatment response and survival data.

Feasibility and implementation of remote geriatric assessment–guided supportive care (GAIN-S) in public oncology settings.

1582 Background: The ASCO Global Guideline recommends routine geriatric assessment (GA) for adults aged ≥65 years with cancer to identify vulnerabilities beyond standard oncology evaluation and guide tailored management. However, real-world implementation of GA-guided interventions in low-resource settings remains limited. Building on prior feasibility work in private (PRI) oncology settings, we evaluated the feasibility and implementation of a remote, multidisciplinary GA-guided intervention in public (PUB) oncology settings in Brazil. Methods: We conducted a prospective feasibility and implementation study in PUB settings, with contextual reference to prior PRI experience. Patients aged ≥65 years initiating chemotherapy underwent baseline GA assessing functional status, depressive symptoms (GDS), cognitive screening (Mini-Cog), chemotherapy toxicity risk (CARG), nutritional status, and quality of life (FACT-G), with repeat assessment at 12 weeks. Identified impairments prompted referral to telehealth interventions (geriatrics, nutrition, psychology/psychiatry, exercise). Feasibility outcomes included recruitment, GA completion, referral recommendations, and follow-up retention. Implementation barriers in PUB settings were prospectively documented. Results: A total of 109 patients were included (PRI n=61; PUB n=48). The PUB cohort was younger (mean age 72 vs 76), included a higher proportion of Black participants (58% vs 44%), had lower education (no/limited 19% and elementary school 50% vs college degree 47%), and more advanced disease (92% stage III-IV vs 54% stage IV). Baseline geriatric vulnerability was similar (median CARG 6 vs 7, GDS 2); weight loss was more frequent in PUB (54% vs 36%). Quality of life was lower in PUB (FACT-G -5 points). GA identified actionable vulnerabilities, with 21% referred to ≥1 specialist (vs 33% in PRI) and 44% to ≥2 specialists (vs 28% in PRI). Key challenges included delayed recruitment, limited digital literacy (63%), restricted videoconferencing (73%), delays in nutritional supplements (38%), and exercise adaptation (50%), prompting ongoing, context-specific adaptations. Conclusions: Remote GA delivery and identification of actionable vulnerabilities were feasible in PUB settings in Brazil. Similar geriatric vulnerability profiles and characterization of implementation barriers support the scalability of GA-guided care in low-resource settings. Clinical trial information: NCT07084454 .

Dual BRAF/MEK inhibition in <i>BRAF</i> ^V600E –mutated biliary tract cancer with exploratory histology-dependent response: A systematic review and meta-analysis.

4108 Background: The BRAF V600E mutation defines an actionable subset of rare cancers. Metastatic BTC carries a poor prognosis, with median survival under one year on standard chemotherapy. Given the rarity of BRAF V600E-mutated BTC and the absence of RCTs, rigorous evidence synthesis is needed; existing data for dabrafenib plus trametinib come only from single arm basket trials such as ROAR and NCI-MATCH. The low prevalence of this mutation limits the feasibility of large randomized studies. This SRMA aimed to quantify the efficacy of dual BRAF/MEK inhibition in BTC and explore potential histology dependent differences in response. Methods: We performed a systematic review and meta-analysis (SRMA) pooling single arm Phase II basket trial cohorts (N = 53 BTC; N = 17 CNS). Seven case reports were summarized qualitatively and excluded from pooled analyses. The primary endpoint was pooled overall response rate (ORR). A random effects model was used. Subgroup and heterogeneity analyses were performed given the tissue-specific behavior of V600E-driven tumors. Histology was evaluated as an exploratory moderator and heterogeneity was quantified. Results: In the pooled cohort of 70 patients (53 BTC and 17 CNS), the overall ORR was 45.3% (95% CI: 24.5-66.9%). Heterogeneity for the BTC subgroup was moderate (I 2 = 62.6%), while overall pooled heterogeneity across all studies was low (I 2 = 14%). ORR in BTC was numerically higher than in Central nervous system (CNS) cohorts (34.9%) but subgroup differences did not reach statistical significance (P = 0.3386). The observed median OS of 13.5 months in the ROAR BTC cohort compares favourably with historical outcomes commonly reported in the 6-12 month range for advanced BTC. The consistency of pooled estimates, despite non-randomized designs, suggests a stable treatment signal while acknowledging that causality cannot be inferred from uncontrolled data. Median progression-free survival was 9.0 months in BTC and 5.5-8.0 months in CNS cohorts. Median OS in the ROAR BTC cohort was 13.5 months (95% CI: 10.4-17.6), exceeding historical expectations. The pooled rate of Grade ≥3 AEs was 59.2%, consistent with the known safety profile of dabrafenib plus trametinib; no treatment-related deaths were reported. Qualitative data from case reports confirmed regression of CNS metastases and feasibility in patients with severe hepatic dysfunction. Conclusions: Dual BRAF/MEK inhibition shows clinically meaningful activity in BRAF V600E-mutated BTC, with survival exceeding historical expectations. Exploratory analyses indicate histology-dependent differences, supporting tumor-specific therapeutic stratification. These findings align with growing tissue-agnostic evidence for MAPK inhibition and reinforce the value of routine molecular profiling, though conclusions are limited by small cohorts and single arm studies.

Determinants of pathologic complete response in early-stage triple-negative breast cancer at a single institution.

e12664 Background: Triple-negative breast cancer (TNBC) has been widely reported as having worse outcomes among Black women. However, Black women remain markedly underrepresented in clinical trials, limiting the generalizability of these conclusions and raising concern that observed disparities may reflect inequities in access to high-quality care rather than tumor biology alone. Pathologic complete response (pCR) following neoadjuvant therapy is a validated surrogate for long-term outcomes. Using real-world data from a racially and socioeconomically diverse population, we evaluated whether race and care-related factors were associated with achieving pCR in stage II–III TNBC. Methods: We conducted a single-institution retrospective cohort study using real-world data to evaluate factors associated with pCR following neoadjuvant therapy in stage II–III TNBC. Analyses followed a prespecified, internally reviewed plan developed prior to data extraction and statistical evaluation. Data was extracted from electronic health records in the REDCap electronic database. Eligible patients received neoadjuvant systemic therapy with curative intent and had evaluable surgical pathology. The primary endpoint was pCR. Multivariable logistic regression was used to evaluate associations between pCR and race, zipcode income, clinical stage, treatment regimen, and time-to-care metrics. Results: Among 72 patients with stage II–III TNBC (75% Black), the overall pCR rate was 44%. Race was not associated with pCR on unadjusted analysis (Fisher's exact p = 1.00) and remained non-significant after adjustment. Neoadjuvant chemoimmunotherapy (CIO) was associated with higher pCR compared with chemotherapy alone in the overall cohort (58.3% vs 35.4%; Fisher's exact one-sided p = 0.055). Among Black patients (n = 55), pCR rates were similarly higher with CIO compared to chemotherapy (62.5% vs 33.3%; one-sided p = 0.046). Beyond pCR, residual cancer burden analysis showed 44% achieved RCB-0, 44% RCB-1, and 13% RCB-2/3. Conclusions: In this predominantly Black, socioeconomically diverse TNBC cohort, race was not independently associated with pCR when contemporary neoadjuvant therapy was delivered. CIO was associated with a large, clinically meaningful absolute increase in pCR rates across both the overall cohort and Black patients, with consistent effect sizes despite borderline statistical significance, likely reflecting limited sample size. These findings support the hypothesis that treatment regimen and access to high-quality care, rather than race, drive early response outcomes in TNBC. The high proportion of patients achieving minimal residual disease further highlights favorable outcomes in this diverse urban population and underscores the need for larger studies to better define the impact of healthcare delivery on disparities in TNBC outcomes.

Real-world efficacy and safety of darolutamide-based triplet therapy in Chinese patients with metastatic hormone-sensitive prostate cancer (mHSPC): A multicenter analysis from Zhejiang province (YHCG-006 study).

e17090 Background: The ARASENS trial established that androgen deprivation therapy (ADT) combined with Darolutamide and Docetaxel improves survival in mHSPC. Given the lower chemotherapy tolerance reported in Asian populations and the paucity of Chinese real-world data, The Yi-Huan Genitourinary Cancer Group conducted a multicenter analysis (YHCG-006) to validate the efficacy and safety of this triplet regimen in a Chinese cohort in Zhejiang Province. Methods: We retrospectively analyzed 100 consecutive mHSPC patients (pts) treated with ADT, Darolutamide, and Docetaxel across 18 centers in Zhejiang Province, China (Aug 2022–Jan 2026). Evaluations included baseline characteristics, Docetaxel utilization, PSA dynamics, and treatment-related adverse events (AEs). Results: 100 mHSPC pts were included. The median age was 70 years (range, 43–87). All pts had metastatic disease at baseline, distributed as non-regional lymph nodes (M1a) 12%, bone (M1b) 70% with a median of 8 lesions, and visceral metastasis (M1c) 18%. High-grade histology was common (Gleason score ≥8 in 83%), and performance status was favorable in most (ECOG PS 0–1 in 86%; ECOG PS 2 in 12%). A high-risk classification was present in 80%, and high-volume disease was prevalent (69%). The median baseline PSA was 121.76 ng/ml (IQR, 33.60–375.07). With a median follow-up of 9.2 months (range, 0.8–37.3), ≥6 cycles of Docetaxel were administered in 62% of pts. Dose modifications included Docetaxel reduction in 18 pts (typically to 60 mg/m²) and Darolutamide reduction in 1 patient (to 600 mg/day due to rash). Supportive care included bone-protective agents in 41% and granulocyte colony-stimulating factor (G-CSF) in 32% (prophylactic in 5 pts). At 3 and 6 months, PSA 90 rates were 95.5% (84/88) and 97.8% (90/92), respectively. The proportions achieving PSA &lt; 0.2 ng/ml were 44.3% (39/88) at 3 months and 59.1% (55/93) at 6 months. During follow-up, 67% of pts achieved a nadir PSA &lt; 0.2 ng/ml, and 44% reached an ultra-low nadir PSA &lt; 0.02 ng/ml. The median time to PSA &lt; 0.2 ng/ml was 4.7 months. 9 pts experienced disease progression; median radiographic progression-free survival (rPFS) and overall survival (OS) were not reached at the time of analysis. 38 of 100 pts experienced ≥grade 3 AEs. Neutropenia was the most frequent grade 3 or 4 AE (30 cases), with febrile neutropenia in 13.3% (4/30) of these neutropenia cases. Conclusions: In this real-world Chinese cohort characterized by predominantly high-volume and high-risk disease, Darolutamide-based triplet therapy yielded rapid and deep PSA responses with acceptable toxicity. These findings support the feasibility and clinical utility of this regimen in Chinese mHSPC pts, while underscoring the importance of vigilant monitoring for chemotherapy-related AEs, particularly neutropenia.

Stromal remodeling and neoantigen clonality as used to evaluate benefit from SIRT–nivolumab in HCC.

e16285 Background: The combination of selective internal radiation therapy (SIRT) and nivolumab has shown encouraging clinical activity against hepatocellular carcinoma (HCC). However, the molecular determinants of clinical benefit (CB) and the mechanisms underlying therapeutic resistance remain poorly defined. This study aimed to characterize the genomic, transcriptomic, and spatial features that govern response to this combination. Methods: In the NASIR-HCC phase II trial, patients with unresectable HCC received SIRT followed by nivolumab. Baseline tumor biopsies were analyzed using whole-exome sequencing, bulk RNA sequencing, multiplex immunofluorescence, and spatial proteomics. T-cell receptor (TCR) dynamics were monitored in both tumor tissue and peripheral blood. Results: Unlike monotherapy with immune checkpoint inhibitors, pre-existing immune infiltrates and inflammatory signatures did not predict CB. Instead, non-responders exhibited a significant enrichment in fibroblast-related programs, including epithelial-to-mesenchymal transition (EMT) and extracellular matrix remodeling. Spatial proteomics revealed that activated lymphocytes in non-responders were confined within fibrotic stromal regions, suggesting a physical barrier to effective anti-tumor immunity. Transcriptomic integration identified oncofetal cancer-associated fibroblasts (CAFs) and macrophage signatures as hallmarks of resistance. Conversely, patients experiencing CB showed enrichment in oxidative phosphorylation pathways and specific neoantigen (NeoAg) profiles. While total tumor mutational burden (TMB) was uninformative, CB correlated with a higher load of expressed, high-affinity Class II NeoAgs and a more dominant clonal architecture (higher Gini and Clonality indices). Furthermore, SIRT induced diversification of the peripheral TCR repertoire and the maintenance of this effect after nivolumab associated with CB and longer progression-free and overall survival. Conclusions: The efficacy of SIRT plus nivolumab in HCC does not appear to be primarily determined by baseline T cell infiltration and may instead be influenced by fibroblast-driven stromal features and oncofetal CAF-associated immunosuppression. Better outcomes are expected in the presence of high-affinity Class II clonal NeoAgs and with sustained systemic T cell diversification. These findings indicate that stromal remodeling and fibroblast reprogramming could represent promising avenues to enhance responses to SIRT–immunotherapy combinations, although further validation is required.

AI-driven RNA-based homologous recombination deficiency algorithm to predict first-line platinum response in metastatic pancreatic cancer.

4210 Background: Developing predictive diagnostics for metastatic pancreatic cancer remains an unmet clinical need. Here, we present the Tempus HRD-RNA algorithm: an AI-driven, 1,660-gene logistic regression model trained on RNA-seq (Tempus xR) from pan-cancer solid tumor tissue samples. This dynamic RNA-based signature can identify clinically relevant patient populations likely to benefit from platinum-based regimens and PARP inhibitors, including patients without BRCA1/2 or PALB2 mutations. Methods: This is a prospectively designed retrospective RWD analysis in an independent validation cohort of 1,083 patients (pts) with treatment-naive metastatic pancreatic cancer diagnosed between 2017 and 2025. Treatment arms included first-line platinum-containing regimens (Arm A; n = 779; 97.0% FOLFIRINOX, 1.4% NALFIRINOX, 1.5% Gemcitabine/Cisplatin) or a non-platinum regimen (Arm B; n = 304; 86.6% Gemcitabine/Nab-paclitaxel, 13.4% Gemcitabine/Paclitaxel). BRCA1/2 and PALB2 mutations were determined via paired Tempus xT DNA sequencing. Key prognostic criteria included age, sex, ECOG score (0 or 1), surgery status and biopsy site. Unknown ECOG was imputed using the Laboratory Imputation Framework for EHRs (LIFE; PMID: 40595435). Overall survival (OS) differences between treatment arms were evaluated as independent Cox models for HRD+ vs. HRD- pts, including covariate adjustment. Results: Overall, 9.5% of pts were classified as HRD+: 78 pts (10.0%) in the platinum arm (Arm A) and 25 pts (8.2%) in the non-platinum arm (Arm B). OS was significantly higher in platinum-treated HRD+ pts than non-platinum. Median OS (mOS) was 12.8 months (95% CI: 8.5–16.6) in HRD+ platinum pts (Arm A) vs. 8.5 months (95% CI: 5.4–12.9) in HRD+ non-platinum-treated pts (Arm B; HR: 0.57; 90% CI: 0.33–0.99; p = 0.048). In contrast, in the HRD- group, there was no statistically significant difference in OS between platinum (Arm A; mOS 8.1 months; 95% CI: 7.1–9.1) and non-platinum (mOS 7.6 months; 95% CI: 6.6–8.8) arms (Arm B; HR: 0.91; 90% CI: 0.76–1.09; p = 0.190). Additional analyses were performed within the platinum-treated arm (Arm A) to assess if the survival benefit held independent of BRCA1/2 or PALB2 mutations. HRD+ and BRCA/PALB2mut pts (4.8%; n = 37) had a mOS of 13.3 months compared to 11.5 months in HRD+ and BRCA/PALB2wt (5.3%; n = 41) pts (HR: 0.7; 90% CI: 0.4–1.1). Comparatively, HRD- and BRCA/PALB2mut pts (2.1%; n = 16) had a mOS of 10.5 months compared to 8.3 months in HRD- and BRCA/PALB2wt (80.9%; n = 623) pts (HR: 0.7; 90% CI: 0.4–1.3). Conclusions: Tempus HRD-RNA is a novel predictive clinical biomarker that identifies a higher percentage of pts who may benefit from targeted treatment than current guidelines. The HRD-RNA algorithm offers a remarkable precision oncology tool to improve outcomes in pancreatic cancer, and has important clinical value in the era of novel HRD drug development.

Standardized mean differences of primary outcomes found in randomized controlled trials of wellness interventions among medical trainees: A systematic review and meta-analysis.

9011 Background: In the era of physician shortages, wellness interventions among medical trainees is an area of ongoing research interest in hopes of promoting clinician wellness and preventing burnout as a means of reducing clinician attrition. To our knowledge, there has not been a systematic review and meta-analysis of randomized controlled trials among medical trainees (medical students, residents, and fellows) to characterize the overall efficacy of wellness interventions in this population. Methods: A medical librarian searched Embase, MEDLINE, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), APA PsycINFO, and Clinicaltrials.gov from the earliest timepoint to March 2022 for randomized controlled trials of wellness interventions among medical trainees. Measures of wellness included but were not limited to depression, stress, and anxiety. Outcomes were analyzed using Standardized Mean Differences (SMD) calculated as Hedges’ g to correct for small sample bias. To ensure consistent interpretation, effect sizes were adjusted for directionality such that a positive SMD indicates a beneficial outcome for the intervention group regardless of the original scale (e.g., higher happiness or lower stress). Results: Our search strategy resulted in 3,806 unique articles. 161 articles passed initial screening of titles and abstracts, and 46 studies were included for data extraction with dates ranging from 1980 to 2022. 23 studies with means and standard deviations reported for the primary outcome were included for meta-analysis purposes. The pooled effect size was 0.017 with a 95% confidence interval of -0.501 to 0.536 with an I^2 heterogeneity of 0.904. Conclusions: Our systematic review and meta-analysis of randomized controlled trials of wellness interventions among medical trainees suggest that interventions to promote wellness and prevent burnout in medical trainees, as an aggregate, have been heterogenous in design and with little-to-no overall effect. An updated search of the literature with sub-group analyses by intervention type and/or outcome measure may yield more promising results, inform future research, and better assist training programs in weighing the opportunity cost of wellness interventions, particularly in resource-constrained settings or in fields with significant rates of burnout such as hematology and oncology.

Clinical outcomes for patients (pts) with synchronous versus metachronous metastatic urothelial cancer (mUC) treated with enfortumab vedotin and pembrolizumab (EV-P).

4587 Background: Synchronous versus metachronous metastases in mUC has prognostic significance, and EV-P has emerged as standard first-line therapy for pts with mUC. How primary disease in synchronous mUC should be best treated remains unclear. This study evaluated clinical outcomes of pts with synchronous vs metachronous mUC treated with EV-P. Methods: A retrospective analysis of all consecutive pts with mUC treated EV–P at UTSW was performed. Patients were grouped by synchronous mUC or metachronous mUC. Baseline characteristics were compared using Wilcoxon rank-sum and Chi-squared tests. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox proportional hazards models. Results: For 159 pts with mUC treated with EV-P between 9/2020 and 12/2025, 40 had synchronous mUC and 119 had metachronous mUC. Baseline characteristics were similar with median age 71.5 years vs 73.0 years (p=0.90), male 75% vs 94%(p=0.76), and visceral metastases (20% vs 26%, p=0.58). In metachronous mUC, 76 (63.9%) had prior cystectomy and 42 (35.3%) had prior radiation as definitive treatment. Patients with metachronous mUC demonstrated a median PFS of 16.0 months vs not reached (NR) for patients with synchronous mUC (HR 1.95, 95% CI 1.05–3.62; p = 0.035). Similarly, the median OS was 21.9 months for metachronous mUC vs not reached in the synchronous mUC (HR 2.61, 95% CI 1.24–5.49; p = 0.011). Median cycles of EV-P was 13.5 for synchronous mUC vs 10 for metachronous mUC. For synchronous mUC, 22 (55.0%) underwent cystectomy and 8 (20.0%) underwent radiation as consolidative treatment. Conclusions: Synchronous and metachronous mUC treated with EV-P have significantly different disease courses on EV-P. Metachronous mUC has earlier progression on EV-P, needing more treatment options in refractory disease. Consolidation treatment for synchronous mUC needs further prospective trials for optimal outcomes. Comprehensive baseline characteristics and clinical outcomes. Characteristic Synchronous met Metachronous met P value Number of patients 40 119 Age at treatment initiation, median (IQR) 71.5 (64.5–76.0) 73.0 (64.0–78.0) 0.904 Male sex, n (%) 30 (75.0%) 94 (79.0%) 0.759 Prior local therapy Prior radical cystectomy N/A 76 (63.9%) Prior radiation therapy N/A 42 (35.3%) Metastatic burden Any visceral metastasis 8 (20.0%) 31 (26.1%) 0.578 Liver metastasis 6 (15.0%) 17 (14.3%) 1.000 Treatment and outcomes EV-P cycles, median (range) 13.5 (1–39) 10.0 (1–57) 0.281