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Social vulnerability index as an independent poor prognostic factor in patients with chronic hematological malignancies in Arkansas.
e13526 Background: Recent therapeutic advances have significantly improved outcomes in many chronic hematological malignancies (CHMs). However, these novel therapies are expensive and are primarily concentrated in large academic centers, leading to inequities in access to healthcare. Community-level socioeconomic factors, including poverty level, access to healthcare, and transportation, directly influence access to these therapies. Arkansas has a predominantly rural population ( > 43%), providing a good setting to examine the impact of these factors on survival. Methods: We obtained de-identified patient data of all patients diagnosed with common CHMs, including multiple myeloma (MM), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), and follicular lymphoma (FL), in Arkansas between 2000 and 2023 from the Arkansas Department of Health. The social vulnerability index (SVI), obtained from the CDC SVI interactive map based on the patients' residential zip codes and tract-level poverty data published by the American Community Survey were used as indicators of community-level socio-economic vulnerability to assess their impact on survival. Results: A total of 10,241 patients were diagnosed with MM (4,766), CLL (4,011), FL (921), and CML (543) between 2000 and 2023 in Arkansas. 58% were males. 81% identified as White, 16% as Black, 1% as Hispanic, and 1% as other. MM was relatively more common among Black patients (33%). Median age at diagnosis was 69 years (MM: 69 years, CLL: 71 years, FL: 69 years, and CML: 62 years). The mean SVI for the overall cohort was 0.698 ± 0.203. Mean SVI values were 0.710 ± 0.201 for MM, 0.685 ± 0.205 for CLL, 0.691 ± 0.202 for FL, and 0.699 ± 0.208 for CML. The median overall survival (OS) was 71.8 months (95% CI: 69.4-74.2 months). Disease-specific OS was 47.4 months for MM, 91.8 months for CLL, 104.0 months for FL, and 96.6 months for CML. Higher SVI was significantly associated with shorter survival (Spearman’s ρ = -.021, p = .03). Similarly, higher community poverty level was associated with inferior survival (Spearman’s ρ = -.054, p < .01). Notably, the inverse association between SVI and survival was stronger among Black patients (Spearman’s ρ = -.093, p < .01) than among White patients (Spearman’s ρ = .005, p = .68). In contrast, poverty level showed a stronger inverse association with survival among White patients (Spearman’s ρ = -.047, p < .01) than among Black patients (Spearman’s ρ = -.029, p = .24). Conclusions: Community-level socioeconomic vulnerability, as reflected by the SVI and the neighborhood poverty level, is independently associated with inferior survival in patients with CHMs. Given that a substantial proportion of the U.S. population resides in rural areas, SVI may serve as a useful tool to guide resource allocation and develop targeted strategies to reduce disparities and improve cancer outcomes at a population level.
Impact of adalimumab on mortality and cancer risk in patients with inflammatory diseases.
e24131 Background: Adalimumab is a commonly used medication for diverse inflammatory conditions. More information is required regarding the potential survival benefits of this medication and its impact on the development of common solid organ malignancies. This retrospective observational study aimed to investigate the potential impact of Adalimumab use in patients with inflammatory pathologies on mortality and the development of common malignancies over a 5-year period. Methods: The TriNetX Global collaborative network was queried from January 2005 to December 2020 for patients 18 years or older diagnosed with rheumatoid arthritis (RA), inflammatory bowel disease, psoriasis, ankylosing spondylitis, hidradenitis suppurativa (HS), and uveitis based on ICD-10-CM codes. Patients were stratified into 2 cohorts based on Adalimumab use after exclusion of genetic susceptibility to malignancies. Propensity score matching was performed for sociodemographics, obesity, cigarette use, alcohol use, and medications, which resulted in 125,097 patients in each cohort. The primary outcome was all-cause mortality. Secondary outcomes were common thoracoabdominal solid malignancies and Merkel cell cancer (CA). Cox proportional Hazard ratios (HRs) were used to compare outcomes over a 5-year follow-up period. Cox Proportional Hazards Model analysis was performed to investigate the effect of various covariates on mortality between both cohorts. Results: Adalimumab use correlated with significantly lower rates of the primary outcome (HR 0.49; 95% CI: 0.47-0.51, p < 0.0001). The Adalimumab cohort also had lower rates of some solid malignancies, including lung cancer (HR 0.67; 95% CI 0.61-0.74, p < 0.0001), Hepatocellular cancer (HR 0.74; 95% CI 0.62-0.88, p = 0.001), prostate cancer (HR 0.71; 95% CI 0.62-0.80, p < 0.0001), and breast cancer (HR 0.81; 95% CI 0.73-0.90, p < 0.0001), No significant difference was seen between Adalimumab users and the control cohort for Merkel cell CA (HR 0.57; 95% CI: 0.27-1.19, p = 0.130), colorectal CA (HR 0.95; 95% CI: 0.84-1.09, p = 0.471), pancreatic CA (HR 0.89; 95% CI: 0.72-1.10, p = 0.261), Renal and renal pelvis CA (HR 0.87; 95% CI: 0.73-1.03, p = 0.097), or with nephrolithiasis, which was used as a falsification endpoint. Aalen-Johansen Cumulative Incidence curve was plotted to evaluate the cumulative incidence of competing risks for various malignancies in the Adalimumab cohort, with the highest being breast cancer (3.43%), prostate cancer (2.52%) and urinary tract cancers (2.21%). Cox regression revealed diverse covariates with higher hazards of mortality, notably male sex, Crohn’s disease, RA, HS, and various CAs. Conclusions: Among patients with certain inflammatory disorders, Adalimumab use was associated with a significant survival benefit and significantly lower rates of lung, hepatocellular, prostate and breast cancers but no higher rates of Merckel Cell CA over a 5-year period.
UTOPIA: A phase 3 trial of UGN-103, an intravesical mitomycin reverse thermal hydrogel, in recurrent low-grade intermediate-risk non-muscle invasive bladder cancer.
4604 Background: Management of recurrent low-grade (LG), intermediate-risk (IR) non-muscle invasive bladder cancer (NMIBC) remains challenging due to frequent recurrence following standard surgical management with transurethral resection of bladder tumor (TURBT). UGN-102 is an intravesical mitomycin reverse thermal hydrogel, approved by the Food and Drug Administration for treatment of adults with recurrent LG-IR-NMIBC based on the Phase 3 ENVISION trial demonstrating a complete response (CR) rate of 80% (95% confidence interval [CI]: 74, 85) at 3 months, with an 82% (95% CI: 76, 87) probability of remaining in response 12 months from initial CR. UGN-103 is a novel formulation of UGN-102 developed to simplify drug preparation and shorten manufacturing time. Methods: UTOPIA (NCT06331299) is an ongoing, multicenter, single-arm, Phase 3 study evaluating UGN-103 as primary treatment for adults with recurrent LG-IR-NMIBC. Eligible patients provided written informed consent and received six once-weekly intravesical instillations of UGN-103 (mitomycin 75 mg in 56 mL admixture). Disease assessment was performed 3 months after start of treatment. Patients with no detectable disease entered a follow-up period, with evaluations every 3 months until recurrence, progression, death, or completion of follow-up (12 months after the 3-month visit). The primary endpoint was CR rate (defined as the proportion of patients assessed as having no evidence of disease at the 3-month visit) based on cystoscopy, for-cause biopsy, and urine cytology. Secondary endpoints include durability of response, safety and tolerability, and pharmacokinetics. Data cut off: September 3, 2025. Results: A total of 99 patients received ≥1 instillation of UGN-103; of these, 97% (n=96) received all 6 instillations. At baseline, median patient age was 71 years (range 46, 93), with 78% (n=77) being ≥65 years old. Most patients were male (72%; n=71) and 99% (n=98) were White. Most patients had multiple tumors (90%; n=87), with the longest tumor diameter being ≤3 cm in 96% (n=93). At 3 months, 77 of 99 patients in the intent-to-treat population achieved CR (CR rate: 78% [95% CI: 68, 86]). Non-CR outcomes included residual disease in 16% (n=16) and progression to high-grade disease in 4% (n=4). Two (2%) patients had missing/indeterminate responses. Treatment-emergent adverse events (TEAEs) were reported in 60% of patients (n=59), with the most common TEAE (≥10%) being dysuria (19%; n=19). Two (2%) patients had a total of 3 serious TEAEs, including atrial fibrillation, osteoarthritis, and respiratory failure; none were treatment related. No TEAE led to death. Conclusions: UGN-103 demonstrated a safety and efficacy profile similar to that observed with UGN-102 in patients with recurrent LG-IR-NMIBC, supporting continued evaluation of UGN-103 as an intravesical treatment option. Clinical trial information: NCT06331299 .
Long-term hair loss associated with brentuximab vedotin–containing chemotherapy and its psychosocial impact: A retrospective observational study conducted at the Royal Marsden Hospital.
e19036 Background: Alopecia is a recognised toxicity of Brentuximab Vedotin (BV), but data on the duration and long-term psychosocial consequences are limited. This study aimed to characterise the patterns of BV-associated alopecia and its impact on patient wellbeing. Methods: Patients diagnosed with Hodgkin’s Lymphoma, aged 16 years or above who received Brentuximab Vedotin along with AVD (Adriamycin, Vinblastine, Dacarbazine) were included. All patients had a minimum follow-up of 12 months post completion of chemotherapy. A structured, patient-completed questionnaire captured responses about patterns of hair loss, and various domains of patient wellbeing. Alopecia was graded using CTCAE criteria. Results: Thirteen patients were included, median age 45(range 16-60); female: male (9:4). Twelve (92%) patients completed six cycles of BV+AVD. All patients (100%) experienced generalised alopecia after starting treatment, with a median onset of 4 weeks. One patient had pre-existing androgenic alopecia. Hair regrowth after stopping chemotherapy was reported as normal in 8/13 (61.5%), while 5/13 (38.5%) had persistent abnormal regrowth at a median follow-up of 27 months (range 12-62 months) after treatment. Among these, one reported grade 2 and four reported grade 1 alopecia. Four patients attempted dermatologic treatments with minimal benefit. Qualitative comments highlighted substantial heterogeneity: some patients embraced hair loss or viewed it as an expected treatment effect, while others reported profound self-consciousness, changes in identity, avoidance of social situations, and persistent difficulty moving beyond the “cancer patient” identity. Eyebrow and eyelash loss were described as particularly distressing. Conclusions: Despite brentuximab vedotin’s wide use and favourable therapeutic profile, this evaluation highlights a crucial and under-recognised toxicity. Nearly 40% of patients reported persistent alopecia more than two years after treatment, with significant psychosocial consequences. The prolonged nature of hair loss underscores the need for further research into the mechanisms underlying BV-associated alopecia, to better guide prevention, counselling, and supportive interventions as this valuable therapy continues to be widely used. Patient-Reported QoL Outcome Percentage Reduced self confidence 29 Reduced willingness for social activities 29 Emotional distress related to alopecia 36 Difficulty accepting changes in appearance 36 Felt adequately supported (family/friends/healthcare staff) 64 Reported insufficient support 21 Financial burden from hair-loss treatments 14
Parent willingness to enroll children with acute lymphoblastic leukemia in escalation and de-escalation clinical trials.
12098 Background: Patient and parent willingness to participate in clinical trials has and will continue to be essential to improve care for children with acute lymphoblastic leukemia (ALL). Clinical trials for ALL can involve escalation of therapy (i.e., addition or intensification of chemotherapy or immunotherapy) or in subgroups with excellent prognosis, de-escalation of therapy (i.e., removal of agents or blocks of therapy with aim of minimizing toxicity). Understanding parents’ decision making for trial participation is particularly important in de-escalation trials. We aimed to characterize parent willingness to enroll children with ALL in escalation and de-escalation clinical trials, identify sociodemographic and clinical determinants of willingness, and delineate decision making information needs. Methods: Parents of children currently or previously treated for ALL who are members of the Momcology support and advocacy organization completed an investigator-developed, parent-piloted online survey. Parents were presented with theoretical escalation and de-escalation trial scenarios and completed items about willingness to enroll their child and associated informational needs. Quantitative data were summarized descriptively and Spearman correlations examined associations with sociodemographic and clinical determinants. Qualitative data were analyzed using content analysis. Results: A total of 456 parents responded. Mean child age at diagnosis was 5.5 years [SD = 0.2, range 0-19]; 79% (369) had B-ALL and 17% (78) had T-ALL; and 65% (297) had completed therapy and were alive at the time of survey. Results showed that 22% (99) of parents would consider enrolling their child in a de-escalation clinical trial, 47% (216) would not, and 31% (141) were unsure. Responses for escalation trials (N = 423) were similar, with 21% (90) yes, 42% (179) no, and 36% (154) unsure. There was a significant negative correlation between both parent education level (rho = -0.12, p = 0.013) and annual household income (rho = -0.10, p = 0.047) with willingness to consider de-escalation, but not escalation, trial enrollment. Child age at diagnosis, current treatment status and distance from treatment center were not correlated with willingness. Parent decision making information needs clustered into three overarching domains:1) impact on likelihood of relapse, survival outcome, and late effects, 2) evidence credibility, and 3) applicability to their child’s individual risk profile. Conclusions: Across a large parent sample, substantial hesitation to enroll children with ALL in both escalation and de-escalation trials exists. Sociodemographic factors were associated with de-escalation decision making. Further research is needed to incorporate evidence-based parent decision making support in future ALL trials and to evaluate decision making and correlates in real world scenarios.
Subgroup analysis of participants (pts) with HER2 IHC0 in the ASCENT-07 study of sacituzumab govitecan (SG) vs chemotherapy in HR+/ HER2− metastatic breast cancer (mBC).
1065 Background: SG was evaluated in the phase 3 ASCENT-07 study (NCT05840211) of pts with HR+/HER2−, locally advanced unresectable or mBC who had received prior endocrine therapy (ET) and were eligible for first chemotherapy; the primary end point (PFS by blinded independent central review [BICR] vs chemotherapy treatment of physician’s choice [TPC]) was not met (HR 0.85; 95% CI, 0.69-1.05; P = .130). We report exploratory outcomes in pts with HER2 IHC0 expression status. Methods: Pts were randomized 2:1 to receive SG 10 mg/kg IV or TPC (capecitabine, nab-paclitaxel, or paclitaxel). Descriptive analyses of pts with HER2 IHC0 were performed for the primary end point of PFS by BICR, secondary end points of PFS by investigator (INV), overall survival (OS), objective response rate (ORR) and duration of response (DOR) by BICR, and safety. HER2 status was tested locally. Results: Of 690 pts enrolled, 292 (42%) had HER2 IHC0 (SG: 192; TPC: 100). Baseline demographics and pt characteristics were similar to the overall population. Median age was 58 yrs; 176 (92%) and 91 (91%) pts in SG and TPC groups, respectively, received prior ET + CDK4/6i in the metastatic setting; 88% and 86% had visceral disease. At 15.4-mo median f/u, SG showed numerical improvement in PFS vs TPC by BICR (HR 0.75; 95% CI 0.55-1.02; nominal P = .0601) and by INV (HR 0.66; 95% CI 0.50-0.86; nominal P = .0024). Although OS data were not mature (maturity rate for IHC0 subgroup, 28%), an early improvement trend favoring SG was observed. ORR by BICR was similar for SG and TPC, and median DOR by BICR was longer for SG vs TPC. Despite a higher proportion of pts experiencing grade ≥ 3 treatment-emergent adverse events (TEAEs) with SG vs TPC, the rate of treatment discontinuation was lower with SG (Table). The most common grade ≥ 3 TEAEs were neutropenia (SG: 54%; TPC: 21%), leukopenia (12%; 7%), and anemia (11%; 5%). Safety profile was consistent with overall population and prior reports. Conclusions: In this exploratory analysis from ASCENT-07, numerical trends of improved efficacy vs TPC and the overall population as well as a manageable safety profile support further investigation into the potential benefit of SG in patients with HR+/HER2− mBC and HER2 IHC0 status who are candidates for first chemotherapy. Clinical trial information: NCT05840211 . SG (n = 192) TPC (n = 100) Median PFS by BICR (95% CI), mo 9.2 (8.2-10.4) 8.1 (6.3-10.4) HR (95% CI) 0.75 (0.55-1.02); P = .0601 a Median PFS by INV (95% CI), mo 8.5 (8.2-10.4) 6.1 (4.5-8.1) HR (95% CI) 0.66 (0.50-0.86); P = .0024 a Median OS (95% CI), mo Not reached (NR-NR) 20.2 (19.5-NR) HR (95% CI) 0.68 (0.44-1.05); P = .0820 a ORR by BICR (95% CI), % 41 (34-48) 40 (30-50) Median DOR by BICR (95% CI), mo n = 78 10.8 (6.4-12.6) n = 40 8.3 (5.5-11.2) TEAEs, n (%)Any gradeGrade ≥ 3Led to dose reductionLed to treatment discontinuation n = 190 189 (99)139 (73)83 (44)4 (2) n = 100 97 (97)46 (46)35 (35)7 (7) a Nominal P value; unstratified log rank.
Initial phase 1 study results of NT-175 engineered T-cell therapy in <i>TP53</i> R175H–mutated unresectable advanced solid tumors.
2506 Background: TP53 is the most frequently mutated tumor suppressor gene across various tumor types, but no approved targeted therapies exist. NT-175 is an autologous engineered T-cell receptor (eTCR) T-cell therapy expressing an HLA-A*02:01-restricted TCR that targets the TP53 R175H tumor neoantigen. Methods: This open-label Phase 1 study (NCT05877599) enrolled HLA-A*02:01-positive adults with advanced/metastatic, TP53 R175H-mutated solid tumors. NT-175 was manufactured from autologous T cells modified by CRISPR/Cas9 gene-editing to delete endogenous TGFβR2 and replace the TCRα locus with the A*02:01-restricted R175H specific TCR. Patients (pts) received lymphodepletion with fludarabine and cyclophosphamide followed by a single NT-175 infusion along with subcutaneous recombinant IL-2. NT-175 was administered at 3 escalating dose levels (DLs) of eTCR+ T-cells. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus definitions. Response was determined by investigator assessment per RECIST v1.1. The primary objective was safety; secondary and exploratory objectives included preliminary antitumor activity and pharmacokinetics (PK), respectively. Results: As of Oct 31, 2025, 26 pts were enrolled and 21 were infused with NT-175 (median age 58 years, [range 43–77] across all DLs (DL1, n = 3; DL2, n = 4; DL3, n = 13; other, n = 1). Pts had a median of 3 prior lines of systemic therapy. Median time from apheresis to NT-175 infusion was 36 days and median follow-up was 6.0 (range: 0.9–9.5) months. Pts had colorectal adenocarcinoma (CRC, n = 10), pancreatic adenocarcinoma (PDAC, n = 6), breast cancer (BC, n = 2), and other solid tumors (n =3). There were no DLTs or Grade 5 events. CRS occurred in 11 (52.4%) pts (Grade ≥3 in 2 [9.5%]); ICANS occurred in 1 pt (Grade 3, 4.8%). Across all dose levels, objective response rate (ORR, including 7 confirmed and 3 unconfirmed responses) was 47.6% (95% CI, 25.7–70.2); in DL3, ORR was 53.8% (95% CI, 25.1–80.8). Partial responses (PR) were observed in 10 pts including 5/6 pts (83%) with PDAC and 5 pts across various tumor histologies (2/10 CRC, 2/2 BC, 1 other), and stable disease in 4 pts. Of 7 evaluable PR pts with ≥6 months of follow up, 5 remain in PR (2 PDAC, 1 leiomyosarcoma, and 2 CRC). Overall, disease control rate was 66.7% (95% CI, 43.0–85.4). Peripheral blood PK analyses (n =21) showed dose-dependent NT-175 expansion, peaking at Week 1 post-infusion, and persistence > 300 days. Conclusions: Manufacturing and treatment with autologous NT-175 eTCR T cells was safe and feasible in pts with heavily pre-treated metastatic TP53-mutated malignancies. Further, NT-175 demonstrated encouraging preliminary antitumor activity across multiple histologies, with most notable early signals in PDAC and may offer a prolonged treatment-free interval in pts with refractory solid tumors. Clinical trial information: NCT05877599 .
AI-driven large language models for multimodal prediction of homologous recombination deficiency using clinical features and histopathological whole-slide images.
548 Background: Homologous recombination deficiency (HRD) implies the dysfunction of homologous recombination repair at the cellular level. The assessment of HRD status benefits making treatment plans and fertility counseling of breast cancer patients. Standard diagnostic tests for detecting HRD are expensive and not universally available. Methods: We trained a deep learning framework to predict HRD status by integrating routinely collected clinical records and histopathological imaging data, including hematoxylin and eosin (H&E)–stained whole-slide images, from primary breast cancer patients (n = 397) across three independent regional medical centers. The patient cohort was split into a training set (80%) and a validation set (20%). Clinical text as well as whole-slide images were encoded using large language model. This model integrated multimodal representation learning and was applied to generate robust HRD predictions. Results: Across breast cancer cohorts from three independent regional medical centers, the proposed approach demonstrated robust and consistent performance in predicting HRD. The reported AUC of 0.82 (95% CI, 0.79–0.84) represents the mean value over ten independent experiments with different random seeds. Notably, the model achieved a precision of 0.84 and a specificity of 0.92, indicating strong discriminatory power with a tendency towards cautious decision-making. Conclusions: Our model showed promising HRD predictive performance in breast cancers directly from routine multimodal data integrating clinical characteristics, imaging description with pathological slides. The HRD-positive predictions generated by this model show promise for clinical translation.
Characteristics of <i>SMAD4</i> alterations in an immune-cold genomic subtype of biliary tract cancers in the Indian population.
4151 Background: Biliary tract cancers (BTCs), comprising gallbladder cancer (GBC) and cholangiocarcinoma (CCA), are rare but highly aggressive malignancies with limited therapeutic options. While genomic profiling has identified actionable alterations in BTC, data from the Indian population remain underexplored. We characterized the mutational and pathway landscape of BTCs in Indian patients and identified subtype-specific and immune-relevant genomic features. Methods: We retrospectively analyzed 154 BTC tumors, including 69 CCA and 85 GBC cases, using data from targeted next-generation sequencing panels. Somatic single-nucleotide variants, copy-number variations (CNVs), and gene fusions in oncogenic and tumor suppressor genes were curated. Pathway enrichment analysis (Hallmark MSigDB database ( p < 0.05 )), and mutual exclusivity/co-occurrence testing (gene pairs selected based on Benjamini-Hochberg-corrected q-values < 0.05.) were performed to identify biologically relevant genomic signatures. Genomic alterations were correlated with PD-L1 status when available. Results: TP53 was the most frequently mutated gene (53%), followed by KRAS (18%), ARID1A (9%), IDH1 (7%), and PIK3CA (7%). Recurrent amplifications were observed in MYC (12%) and ERBB2 (9%). Pathway enrichment analysis revealed significant dysregulation in the PI3K-AKT-mTOR, Notch, and Wnt/β-catenin signaling pathways (p-value <0.05). IDH1 mutations were predominantly observed in CCA, supporting a clinically actionable subgroup amenable to IDH1-targeted therapy, whereas ERBB2 alterations were enriched in GBC, identifying HER2 as a key therapeutic target in this subtype. Importantly, PD-L1-negative tumors showed a higher frequency of SMAD4 mutations (Fisher’s exact test, p = 0.71), implicating disruption of TGF-β signaling in immune evasion and reduced tumor immune activation. Conclusions: This comprehensive genomic analysis of BTC from the Indian population delineates distinct molecular landscape between GBC and CCA. The subtype-specific actionable alterations, including IDH1 mutations in CCA and ERBB2 alterations in GBC, highlights clinically relevant opportunities for precision therapy. SMAD4 alterations are associated with an immune-cold, poorly immunogenic tumor subtype in BTCs and warrant further investigation as a predictive biomarker for patient stratification in immunotherapy-based treatment strategies. These findings support the utility of molecular stratification in BTC and provide a rationale for integrating targeted and immunotherapy-based approached in Indian patients.
Intratumoral spatial distribution of high-risk prostate cancer patterns: Evaluation on digital pathology.
e17123 Background: The most recent guidelines from the European Urology Association (EUA) have recommended implementation of perilesional sampling for prostate biopsies in addition to lesion center sampling during targeted biopsies (TBx). In this study we investigate the spatial distribution of high risk prostate cancer patterns on whole mount digital pathology slides. Methods: 1108 whole mount pathology slides from 316 men were included in this study. Digital slides were annotated by a GU pathologist to reflect intratumoral heterogeneity of morphology patterns. Annotated histology patterns were categorized into three different groups: low (Gleason Grade (GG)1), intermediate (GG2, GG3), and high risk (GG4, GG5, Cribriform). The spatial distribution of patterns within tumor foci was evaluated with respect to 1 and 3mm defined interior edges. The location of a pattern was defined as the ratio from 0 to 1 of the amount of a pattern found within the defined edge and size of the pattern, with higher values indicating pattern proximity to the edge. Tumor regions too small to define an edge sperate from a center and one-pattern regions were excluded. A linear mixed effects model summarized the effects of patient GG, tumor foci size, tumor pattern size, and pattern risk on the edge ratio for 1 and 3mm edges, calculated as pixel ratio with respect to low risk patterns. Results: Median edge ratio values for 1 and 3mm edges were 0.70 and 1.0 for low risk patterns, 0.30 and 0.72 for intermediate risk patterns, and 0.17 and 0.69 for high risk patterns, respectively. Intermediate (β=-0.17, p<0.001) and high risk patterns (β=-0.23, p<0.001) were less localized to both interior edges. Spatial distributions at both edges differed for all paired risk groups. The size of histology patterns (β=-0.06, p<0.001) and tumor foci (β=-0.10, p<0.001) were also associated with less localization towards both interior edges. At the 1mm edge, GG5 patients (n=27) had an increase (β=0.11, p<0.001) in incidence towards the edge, but was fewer than GG4 (n=37) and GG3 (n=53). Conclusions: Our results reveal that high risk patterns are more commonly located at the center of tumors compared to low risk patterns. These results highlight the importance of lesion center sampling approach during TBx to identify more aggressive GG patterns. The effects of patient GG, tumor foci size, pattern size, and pattern risk on the edge ratio for 1 and 3mm edges, calculated as pixel ratio ~ (1|MRN/tumor foci) + high risk pattern + scale (pixels pattern) + scale (pixels tumor foci) + patient GG are summarized. 1mm edge 3 mm edge Predictors β estimates p β estimates p intermediate risk pattern -0.17 <0.001 -0.03 0.102 high risk pattern -0.23 <0.001 -0.09 <0.001 pixels pattern -0.06 <0.001 -0.07 <0.001 pixels tumor foci -0.10 <0.001 -0.09 <0.001 patient GG3 0.01 0.806 -0.00 0.886 patient GG4 0.02 0.309 -0.04 0.109 patient GG5 0.11 <0.001 0.04 0.133
Development and external validation of a computational approach for accelerated read out of randomized clinical trials in metastatic prostate cancer.
1502 Background: While overall survival (OS) is the gold standard endpoint for clinical trials in metastatic prostate cancer (mPC), it requires years of follow-up. We sought to develop and externally validate a computational model for accelerated OS readout based on short term (4 months) PSA kinetic data. Methods: Longitudinal PSA data were obtained from 8 completed phase 3 mPC trials. Using data from the first 4 months on trial, 18 different PSA kinetic variables were developed, including 50% and 90% decline in PSA, PSA=0.1, and PSA=0.2 at 1, 2, 3, and 4 months, and slope and base of the exponential fit of PSA. TITAN, COU-AA-301, and ACIS comprised the training cohort. Data from those trials was used to model OS using a relaxed LASSO approach. The resulting model was applied to 5 validation trials (see Table 1) to simulate 1,000 potential outcomes for each trial (after Harden and Kropko). For the CHAARTED trial, a model using only PSA-kinetic data was used as most baseline variables were missing. The distribution of 1,000 simulated Hazard Ratios (HR) for each trial was compared against the reported HR. Results: Overall, > 100,000 PSA values were used with a total > 7,500 eligible study pts, with ~ 70,000 PSA values and ~5,000 patients comprised the validation cohort. The model identified baseline PSA at treatment, PSA50 at 4 months, and the PSA slope as the most informative PSA predictors of OS. Table 1 below compares the median predicted HR and 95%-interpercentile range from the 1,000 simulations with the reported HR for each validation trial. The model correctly predicted the OS point estimate and 95%-confidence interval using the first 4 months of PSA data in every validation trial. Conclusions: A computational simulation approach to predict the OS outcome of phase 3 mPC trials based on PSA kinetics from the first 4 months on trial was developed. This model correctly predicted OS outcomes in 5 completed validation phase 3 trials. This included phase 3 trials with both positive and negative outcomes for OS as well as in both hormone sensitive and resistant mPC, and involving AR signaling inhibitors, chemotherapy and a PARP inhibitor. This model is being further validated with additional completed phase 3 trials, and once prospectively validated, has the potential to significantly shorten the follow up required for OS readout from phase 3 trials in mPC. Predicted vs. reported HR of each trial. Validation Trial Predicted HR (median [95 th interpercentile range]) Actual HR [95%-CI] LATITUDE 0.64 [0.54 – 0.74] 0.66 [0.56 – 0.78] COU-AA-302 0.69 [0.60 – 0.80] 0.81 [0.70 – 0.93] MAGNITUDE 1.06 [0.88 – 1.26] 0.97 [0.79 –1.19]* CALGB 90401 0.89 [0.78 – 1.01] 0.91 [0.78 – 1.05] CHAARTED (Unselected) 0.79 [0.61 – 0.98] 0.72 [0.59 – 0.89] CHAARTED (High Volume) 0.72 [0.53 – 0.92] 0.63 [0.50 – 0.79] CHAARTED (Low Volume) 0.95 [0.61 – 1.52] 1.04 [0.70 – 1.55] *Observed HR used as overall OS HR not reported in manuscript.
Genetic susceptibility between psychiatric disorders and gynecologic cancers: A systematic review.
e22506 Background: Depression rates in women with cancer are notably increased, impacting quality of life and disease progression. This raises an important question on the genetic relationship between psychiatric disorders and gynecologic cancers as they encompass complex physiological mechanisms. The purpose of this review is to investigate the genetic influence on psychiatric disorders and gynecological cancer prevalence. Methods: A comprehensive systematic review was conducted utilizing research articles from PubMed and Scopus. The database search was coordinated through Boolean operations and key words. Rayyan software was used by three authors to screen studies that meet prespecified inclusion/exclusion criteria. A qualitative report of the included literature was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA 2020). Results: In total, 13 articles meet the inclusion criteria and were included in the systematic review within the years 2009 - 2025. Specific studies showed both ovarian and endometrial cancer had no causal relationship with depression bidirectionally. However, anxiety, mood disorders and depression were revealed to be genetically correlated with cervical cancer and only depression was found to have a significant causality. Other studies identified shared molecular genes, such as PTTG1, suggesting potential therapeutic targets. Conclusions: The findings in this study were mixed based on the type of gynecologic cancer and psychiatric disorder. This could be due to varying study designs or unaccounted external factors. This analysis provides a summary of the multiple genetic pathways that have been identified as potential links between two pathologies guiding future research. As gynecological cancers continue to be a leading cause of mortality amongst women, there's a strong need for identifying risk factors for the prevention of disease.
Effect of biennial mammography on stage at diagnosis and outcomes of breast cancer in the Brazilian public health system.
e23371 Background: Breast cancer is the leading cause of cancer-related death among women in Brazil. Biennial mammography is recommended for women aged 50–69 years, but adherence to this screening interval in the Brazilian Unified Health System (SUS) remains low. We evaluated whether adherence to biennial screening is associated with stage at diagnosis and breast cancer mortality. Methods: Using the Nodian platform, which integrates open-source data from DATASUS, we conducted a retrospective analysis of outpatient records. Women diagnosed with breast cancer who had at least one mammography record prior to diagnosis between January 2008 and June 2025 were included. Patients were classified into three groups: adherent (regular biennial screening), prevention (mammography performed > 24 months before treatment initiation), and diagnostic (mammography performed ≤24 months before treatment, consistent with diagnostic evaluation). Outcomes were stage at diagnosis and breast cancer–related mortality during treatment. Odds ratios (OR) were calculated for late-stage disease (stages III–IV). Results: Among 27 million women who underwent mammography within SUS, 94,342 were diagnosed with breast cancer and had a prior mammography record. Only 10.2% adhered to the biennial screening protocol. Late-stage disease occurred in 36.4% of adherent women, compared with 43.1% in the prevention group and 47.2% in the diagnostic group. Non-adherence was associated with higher odds of advanced-stage diagnosis (prevention vs adherent: OR 1.33, 95% CI 1.26–1.39; diagnostic vs adherent: OR 1.58, 95% CI 1.51–1.65). A total of 2,066 breast cancer–related deaths were recorded (2.2%). Most deaths occurred in the diagnostic group (75%), followed by the prevention group (18%), while only 7% occurred among women adherent to biennial screening. Conclusions: Adherence to biennial mammography screening, observed in only a small proportion of the Brazilian population, was associated with earlier stage at breast cancer diagnosis and a markedly lower proportion of deaths. These findings indicate that maintaining regular screening intervals is more effective than isolated or symptom-driven mammography and should be a priority for breast cancer control strategies within the SUS.
Real-world and randomized clinical trial comparison in patients with m <i>IDH1</i> CCA treated with ivosidenib: ProvIDHe vs ClarIDHy.
e16173 Background: Cholangiocarcinoma (CCA) is a rare disease, and most patients are diagnosed at an advanced stage. Ivosidenib is approved in many geographies for the treatment of IDH1 mutated CCA in second and later lines, based on ClarIDHy, a phase 3 randomized trial. More recently, ivosidenib has been investigated in the real-world phase 3b, open-label ProvIDHe study. This work aims to compare the effectiveness of ivosidenib in the RCT and real-world settings of these studies. Methods: Heterogeneity between the studies was assessed and characteristics likely to impact patient outcomes or treatment effect were validated by independent experts. Only patients with metastatic disease were included to homogenize patient populations across the two studies. To mitigate potential sources of bias in the comparison, a propensity score weighting model was implemented to align the ProvIDHe population with ClarIDHy with respect to the following characteristics: ECOG 0; one prior regimen of therapy; prior surgery; and prior cisplatin and gemcitabine. These were informed by clinician input and assessment of data availability. Using this adjusted data, overall survival (OS) and investigator-defined progression-free survival (PFS) were compared by estimating a hazard ratio (HR) using a weighted Cox proportional hazards (PH) model. Due to violations in the PH assumption for OS and PFS, Kaplan-Meier estimates of survival rates and restricted mean survival times (RMST) were compared. Results: After reweighting, 6- and 12-month PFS rates were 35.9% and 26.4% in the weighted ProvIDHe vs 29.8% and 10.0% in ivosidenib arm from ClarIDHy. The HR in PFS between ProvIDHe and ClarIDHy was 0.63 (95% confidence interval [CI]: 0.45, 0.90) indicating a marked improvement in PFS for those treated with ivosidenib in real-world. RMST estimates at 6 and 12 months for PFS were 3.90 and 5.69 months in the weighted ProvIDHe population, compared with 3.24 and 4.37 months in ClarIDHy. While no statistically significant difference in OS was identified (HR 0.75; 95% CI: 0.47, 1.21), OS was numerically superior in the weighted ProvIDHe population particularly at later timepoints, with 6-, 12- and 18-month OS rates of 74.0%, 57.9% and 42.8% compared to 67.5%, 42.9%, and 28.5% in ClarIDHy (RMST for OS after 18-months follow-up: 11.85 months vs 10.48 months). However, the lack of statistical significance surrounding this result may be due to the limited follow-up available for OS in the ongoing ProvIDHe study. Conclusions: Following alignment of the ProvIDHe and ClarIDHy populations, patients treated with ivosidenib in the real-world setting of ProvIDHe had significantly improved PFS and numerically improved OS compared to those who received ivosidenib in the RCT setting of ClarIDHy. This suggests that ivosidenib may provide greater benefit in the real-world than previously demonstrated in the RCT setting of the ClarIDHy study. Clinical trial information: NCT02989857 ; NCT05876754 .
AMPLIFY: A phase 3 study of <sup>64</sup> Cu-SAR-bisPSMA positron emission tomography in participants with biochemical recurrence of prostate cancer.
TPS5151 Background: Prostate cancer (PC) is the second most prevalent cancer in men globally. The need for improved PC imaging is reflected in a biochemical recurrence (BCR) rate of 20 to 40% after initial definitive therapy. Despite advances in technology, many patients will fail to have their recurrence accurately localized by imaging, especially at low PSA levels. Imaging modalities that are widely available and can accurately detect, monitor, and restage residual / recurrent loco-regional and metastatic disease are therefore highly desirable. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is strongly overexpressed in PC, making it an ideal target for imaging and therapy. 64 Cu-SAR-bisPSMA may offer several advantages over the currently approved PSMA positron emission tomography (PET) agents for PC due to the bivalent structure of SAR-bisPSMA and longer half-life of 64 Cu (t 1/2 = 12.7h), compared to the approved monovalent PSMA agents utilizing 18 F and 68 Ga (t 1/2 < 2h). Evidence has demonstrated prolonged tumor retention and 2-3x higher tumor uptake with detection of additional PC lesions using 64 Cu-SAR-bisPSMA compared to approved PSMA PET agents. Methods: AMPLIFY (NCT06970847) is a multi-center, single arm, open-label Phase 3 diagnostic performance study of 64 Cu-SAR-bisPSMA PET/CT in participants with a history of prostate adenocarcinoma and rising or detectable PSA after initial definitive treatment. The primary objective is to investigate the ability of 64 Cu-SAR-bisPSMA PET/CT to detect recurrence of PC, with co-primary endpoints of participant-level correct detection rate (CDR) and region-level positive predictive value (PPV) assessed independently for Day 1 and Day 2. Key secondary objectives include assessment of safety, participant-level PPV, and participant-level detection rate (DR). A total of 220 patients will be enrolled. All participants are required to have baseline conventional imaging. Eligible patients will receive a single administration of 64 Cu-SAR-bisPSMA (200 MBq) followed by a PET/CT scan on Day 1 (1-4h post-dose) and on Day 2 (24±6h post-dose). Participants will then continue into the follow-up period to verify the 64 Cu-SAR-bisPSMA PET/CT findings. The Day 1 and Day 2 scans will be interpreted individually by a qualified local reader and 3 independent, blinded, central readers for the presence of abnormal 64 Cu-SAR-bisPSMA uptake. 64 Cu-SAR-bisPSMA PET/CT results on Day 1 and Day 2 will then be assessed against a composite Reference Standard by a central expert panel. The study is open for recruitment in the United States and Australia. Clinical trial information: NCT06970847 .
Impact of neutrophil-to-lymphocyte ratio on pathological response in HER2-positive breast cancer patients: A retrospective analysis.
e12577 Background: Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) combined with HER2-targeted therapy is a strong surrogate for survival in HER2-positive breast cancer. However, treatment response remains heterogeneous. Identification of simple and cost-effective biomarkers capable of predicting pathological response is therefore of clinical importance. The neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation and immune status, has shown prognostic and predictive value in multiple malignancies, though its role in HER2-positive breast cancer remains incompletely defined. Methods: This retrospective study included 186 patients with non-metastatic HER2-positive breast cancer treated with NAC and trastuzumab with or without pertuzumab at a single tertiary care center. Baseline NLR was calculated from absolute neutrophil and lymphocyte counts obtained prior to initiation of NAC. Patients were categorized into high and low NLR groups using predefined cut-off values from published literature. Pathological complete response was defined as the absence of residual invasive disease in the breast and axillary lymph nodes (ypT0N0). Associations between NLR, pCR, and clinicopathological variables were analyzed using appropriate statistical methods. Results: The cohort was predominantly female, with most patients presenting with stage II–III disease and invasive ductal carcinoma. High-grade tumors and elevated Ki-67 indices were common. Patients received anthracycline- and/or taxane-based chemotherapy regimens with single-agent or dual HER2-targeted therapy. A higher frequency of pCR was observed among patients with low baseline NLR compared with those with elevated NLR. Elevated NLR was associated with lower pCR rates across treatment subgroups. No consistent association was observed between common comorbidities and pathological response. Conclusions: Baseline neutrophil-to-lymphocyte ratio appears to be a useful predictive biomarker for pathological response in HER2-positive breast cancer treated with neoadjuvant HER2-targeted therapy. Incorporation of NLR into routine pretreatment assessment may aid in risk stratification and individualized treatment planning.
Phase 1b study of a brain-penetrant MEK inhibitor, PF-07799544, plus next-generation BRAF dimer inhibitor, PF-07799933, in advanced <i>BRAF</i> -mutant melanoma.
9512 Background: Treatment of BRAF -mutant (mut) melanoma has been transformed by targeted inhibition of MEK and BRAF kinases. However, duration of clinical benefit has been limited by de novo and acquired resistance through RAF-kinases signaling as dimers, poor activity in brain metastases (BMs), and paradoxical activation adverse events (AEs) negatively impacting tolerability. PF-07799544 is an oral, brain-penetrant, reversible MEK inhibitor (MEKi). PF-07799933 is an oral, brain-penetrant, selective BRAF dimer inhibitor (BRAFi) with activity against BRAF V600 and non-V600 muts. We report initial results of this next-generation BRAFi/MEKi combination from ongoing phase 1 study. Methods: This platform study (NCT05538130) is evaluating PF-07799544 as monotherapy or combined with other targeted therapy for BRAF -mut melanoma and other solid tumors. Substudy B is an open-label, multicenter study assessing safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and clinical activity of PF-07799544 + PF-07799933. Dose escalation (DE) enrolled into 4 dose levels patients (pts) with BRAF -mut advanced melanoma who had progressed on standard therapy, including pts with BMs. Randomized dose optimization (DO) enrolled pts with BRAF V600 -mut advanced melanoma previously treated with 1-2 immunotherapy (IO) lines and ≤1 BRAFi ± MEKi line; pts with BMs were eligible if asymptomatic. We report pooled baseline characteristics and safety and separate efficacy. Results: As of Nov 12, 2025, 60 pts received ≥1 dose of study treatment. At baseline: median age, 54.5 years; female, 50%; White, 95%; ECOG PS of 0, 63%; adrenal insufficiency, 25%; BMs, 53%; and BRAF V600 mutation, 95%; 77% received ≥3 prior systemic anticancer therapies, 100% received prior IO, 100% of pts with BRAF V600 mutation received prior BRAFi ± MEKi, and 73% received BRAFi ± MEKi <6 months before beginning study treatment. Any-grade treatment-emergent AEs (TEAEs) occurred in 95%; most common (≥20%) were rash (40%), fatigue (37%), diarrhea (32%), and peripheral edema (22%). Grade ≥3 TEAEs occurred in 67%; most common (≥5%) were rash (7%), disease progression (7%), anemia (5%), and fall (5%). Dose modifications due to TEAEs (any-causality, treatment-related) included reductions (13%, 13%), interruptions (53%, 33%), and discontinuations (10%, 3%). Objective response rate (ORR; including unconfirmed) by investigator was 27% in 41 DE pts and 32% in 19 DO pts. In pts with baseline BMs, intracranial (IC) ORR was 30% in 23 DE pts and 22% in 9 DO pts. PK showed BRAFi/MEKi exposures consistent with preclinical exposures which showed antitumor activity supporting selected DO doses. Conclusions: PF-07799544 + PF-07799933 showed manageable safety and promising systemic and IC antitumor activity in heavily pretreated BRAF -mut advanced melanoma. Evaluation of dose expansion cohorts is ongoing. Clinical trial information: NCT05538130 .
Transdermal drug delivery to the normal and the radiated breast: Determinants of individual variation in skin permeation.
10570 Background: Primary prevention of breast cancer with oral drugs causes systemic effects which are unacceptable to 85% of high-risk women. Transdermal delivery through breast skin can minimize systemic exposure, but individual variation of permeation, the effects of breast radiation, or increased dose have not been studied. We report a prospective single-arm trial addressing these aspects, using 4-hydroxytamoxifen (4-OHT) an active metabolite of oral tamoxifen. Methods: Women with unilateral breast cancer treated with breast conservation and radiotherapy applied 4-OHT gel to both breasts for 4±1 weeks. In Cohort 1 (2 mg/breast/day) we evaluated inter-individual variation of 4-OHT skin permeation in the non-radiated breast based on demographic and skin characteristics. In Cohort 2 (4 mg/breast/day) we evaluated the effect of increased dose. All participants underwent bilateral post-intervention dermal punch and core needle breast biopsy. Drug concentration in tissue and plasma was measured using liquid chromatography-mass spectroscopy. Multivariable linear regression was used to examine the predictors of drug concentration in tissue and plasma. Stepwise model selection was conducted using AIC criteria, with multicollinearity assessed via variance inflation factor (VIF). Results: Of 156 consented women, 120 completed intervention and were evaluable for the primary endpoint (breast tissue drug concentration). On multivariable analysis, breast tissue 4-OHT concentration increased with age and White race. Drug concentration was equivalent in the radiated and the non-radiated breasts and was two-fold higher in Cohort 2 (4 mg/breast/day) compared to Cohort 1 (2 mg/breast/day), (p = 0.001). Plasma drug concentrations were low in both cohorts; 0.27ng/mL in Cohort 1 and 0.15ng/mL in Cohort 2, (p = < 0.001). Conclusions: Transdermal delivery of breast cancer prevention drugs is a viable strategy, with higher dose achieving proportional increase in tissue concentration, without increased leakage into the circulation. Further work should pursue formulations of highly active drug metabolites with excellent permeation. Clinical trial information: NCT04009044 .
Molecular imaging as a tool to predict patient outcomes in advanced HER2-low breast cancer on trastuzumab deruxtecan (T-DXd): The FHERAD trial.
1052 Background: The DESTINY-Breast04 trial demonstrated for the first time that trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate (ADC), benefits patients with HER2-low metastatic breast cancer (mBC). This efficacy in HER2-low disease (45–65% of cases) has spurred research into optimal methods for identifying eligible patients. We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DXd. Methods: HER2-low mBC patients with IHC1+ or IHC 2+/FISH ≤ 2.2 scheduled for T-DXd underwent paired HER2-targeted [ 18 F]AlF-HER2-BCH PET/CT (HER2–PET) and [ 18 F]FDG–PET/CT (FDG–PET) at baseline and 2 cycle follow-up. High-uptake was defined as having >50% of tumors with a baseline SUVmax >6.0 on HER2–PET; otherwise, it was low uptake. HER2-PET was defined as nonresponding showed no significant reduction of HER2 uptake (10%) at 2 cycle follow-up. Negative (NPV) and positive predictive values (PPV) of HER2–PET, FDG–PET, early HER2/FDG response, and their combination were assessed to predict morphological response (RECIST 1.1) after two T-DXd cycles and time-to-treatment failure (TTF). Results: In the 32 HER2-low mBC patients analyzed, 24 (75%) had high baseline HER2-PET uptake (SUVmax >6.0), while 8 (25%) had low uptake. Of 24 high-uptake patients, 14 (58.3%) achieved a complete response (CR), 7 (29.2%) initially reached a partial response (PR) after two T-DXd cycles but later developed progressive disease (PD) between cycles 5–10, and 3 (12.5%) experienced PD as early as cycle 2. In the low-uptake group (n=8), one patient (12.5%) with isolated pulmonary metastases maintained stable disease (SD) through 14 cycles, whereas 7 (87.5%) patients with multiple metastases developed rapid PD. Compared with RECIST1.1, respective NPV/PPV for baseline HER2–PET were 87.5%/87.5% for predicting treatment response at 2 cycles. When combining baseline HER2-PET uptake with early 2 cycles, patients with high baseline uptake and a ∆SUVmax >40% had a median TTF of 15.3 months [n = 14, 95% confidence interval (CI) 7.7––not calculable], those with high baseline uptake and a 10% < ∆SUVmax <40% a median TTF of 4.8 months [n = 7, 95% CI: 3.8–9.8]; and patients with a ∆SUVmax <10% a median TTF of only 1.3 months [n = 10, 95%CI: 1.3, 3.9]. Baseline FDG uptake was not associated with lesion response status, and while trends in ∆SUVmax aligned with those observed in HER2-PET, no clear cutoff value was established in this study. Conclusions: Baseline HER2-PET uptake, especially when combined with early on-treatment ∆SUVmax, not only improves the understanding of tumor heterogeneity but also offers an imaging-guided strategy to personalize management and select patients most likely to benefit from T-DXd in HER2-low mBC. Clinical trial information: NCT06909604 ; NCT04547309 .
Comprehensive genomic landscape of early-onset colorectal cancer: A comparative analysis with average-onset metastatic colorectal cancer in a next-generation sequencing cohort of 1,892 patients.
e15596 Background: The incidence of early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before the age of 50 years, has been rising globally, in contrast to declining rates in older populations. However, despite its distinct clinical features, the genomic characteristics of EOCRC and its biological relationship to average-onset colorectal cancer (AOCRC) remain incompletely defined, particularly in the metastatic setting. Methods: We conducted a genomic analysis of patients with metastatic colorectal cancer (CRC) who underwent next-generation sequencing (NGS) as part of routine clinical practice. Using targeted NGS panels (TruSight Oncology 500 and Oncomine Comprehensive Assay), we analyzed the genomic landscape of 1,892 patients, including 376 with EOCRC and 1,516 with AOCRC. Genomic alteration frequencies were compared between age groups, and age-stratified analyses were performed to evaluate associations between patient age and recurrent genomic alterations. Results: A total of 1,892 patients with metastatic colorectal cancer were analyzed, including 376 (19.9%) with early-onset CRC (EOCRC) and 1,516 with average-onset CRC (AOCRC). EOCRC patients had a median age of 44 years and were mainly aged 40–49 years. While the overall cohort was male predominant, EOCRC showed a higher proportion of female patients. Tumor mutational burden (TMB) was comparable between groups, though TMB-high tumors were more frequent in AOCRC. MSI-H tumors were rare but occurred more often in EOCRC, and all MSI-H tumors were TMB-high. PD-L1 positivity (CPS ≥1) was infrequent and showed no clear association with TMB or MSI. Genomic profiling of EOCRC revealed frequent alterations in TP53, APC, and KRAS, with common TP53–APC co-alterations. DNA damage repair–related genes, including BRCA2 and BARD1, were frequently altered. Comparative analysis demonstrated largely similar genomic landscapes between EOCRC and AOCRC; however, MYC alterations were significantly enriched in EOCRC. MSI-stratified analysis showed distinct genomic patterns, with MSS tumors dominated by chromosomal instability drivers, whereas MSI-H tumors exhibited a heterogeneous mutational landscape. Within EOCRC, several DDR-related genes showed higher alteration frequencies in younger patients, while major CRC drivers were not age-associated. Conclusions: In metastatic disease, EOCRC shares a conserved canonical genomic backbone with AOCRC, indicating that it is not a genomically distinct entity. Nevertheless, limited binary differences involving MYC and broader age-dependent enrichment of specific DNA damage response–related alterations suggest that colorectal cancer arising at younger ages may reflect distinct age-associated biological vulnerabilities.