Browse Articles
Discover research articles across all indexed journals
Prospective, non-interventional, multisite evaluations of TRAQinform Immuno algorithmic quantitative treatment response analysis on treatment intent decisions in metastatic melanoma.
9529 Background: Molecular imaging plays a critical role in assessing immunotherapy response in metastatic melanoma, but current assessment methods may not fully leverage imaging data to inform clinical decision-making. This study prospectively evaluated whether integrating TRAQinform Immuno quantitative analysis into clinical assessment would alter oncologists' treatment intent in metastatic melanoma patients receiving checkpoint inhibitor combinations. Methods: In this prospective, multisite, non-interventional study (NCT05819255), patients with metastatic melanoma receiving dual-agent immunotherapy were enrolled at the University of Wisconsin Carbone Cancer Center and Massachusetts General Hospital Cancer Center. FDG PET/CT scans were acquired at baseline, 3-4 weeks and 12 weeks. All scans were analyzed using a research version of the TRAQinform IQ (TRAQinform) algorithmic quantitative software. At each timepoint, treating oncology and nuclear medicine teams recorded treatment intent before and after review of the TRAQinform analysis report. A cross-site, blinded review was conducted to assess potential status quo bias. Results: Twenty-six patients were enrolled (12F, 14M, mean age 65 years), 25 of whom completed all study scans. At week 3-4, 27% of cases (7/26) showed an intent to change treatment after oncologists reviewed the TRAQinform report, (p=1.0). At the 12-week assessment, 56% of cases (14/25) demonstrated intent to change treatment (p=0.0008). Considering either timepoint, 65% of cases (17/26) exhibited a change in treatment intent compared to baseline (p=0.000006). Cross-site analysis indicated minimal influence of status quo bias on intent decisions. Conclusions: In this prospective study assessing intent to treat, TRAQinform analysis of standard-of-care FDG PET/CT images influenced oncologists treatment decision in the majority of metastatic melanoma patients, suggesting it provides clinically actionable information. For oncologists managing patients on dual-agent immunotherapy - where treatment decisions often involve uncertainty and clinical judgment, this study demonstrates that TRAQinform offers an additional data-driven tool to support optimal therapeutic decision-making. Research reported in this abstract was supported by the National Cancer Institute of the National Institutes of Health and under Award Number R44CA257253. The content is solely the responsibility of the authors and does not necessarily represent the official news of the National Institutes of Health. Clinical trial information: NCT05819255 .
Molecular residual disease (MRD) detection using an ultra-sensitive assay in a prospective colorectal cancer cohort: The VICTORI study.
3629 Background: Circulating tumor DNA (ctDNA) detection of molecular residual disease (MRD) is prognostic in colorectal cancer (CRC) but missed recurrences highlight constraints in assay performance. VICTORI is a prospective observational study investigating an ultrasensitive MRD assay (NeXT Personal) in CRC patients undergoing curative treatment. Methods: Whole-genome informed panels of ~1,800 variants interrogated plasma collected pre-curative loco-regional treatment, q2 weeks post-surgery (weeks 2–8, landmark window), and subsequently every 3 months (3-36 months, surveillance window). Results: 795 plasma samples from 109 patients were analyzed, with median follow-up of 21.1 months and 31 recurrences observed. Cohort characteristics: 61 (56.0%) rectal cancer, 48 (44.0%) colon cancer; 81 (74.3%) stage I-III; 56 (50.5%) had neoadjuvant treatment; 106 (97.2%) had surgery as curative procedure. Pre-surgical sensitivity (treatment-naïve) was 96.0% (n=48/50) and specificity was 100% (no detection in pathologic complete responders; 0/10). Landmark window overall sensitivity for recurrence was 83.9% (n=26/31) with 69.2% (18/26) of detections being <100 ppm. Sensitivity was similar weeks 4–8 (81.5% week 4 [n=22/27]; 82.1% week 6 [23/28]; 85.7% week 8 [24/28]), and lower at week 2 (52.4% [11/21]) when post-surgical cell-free DNA peaked (median 2.80 ng/mL pre-surgery to 9.40 at week 2; p=8.7×10⁻¹²). Sampling between weeks 4-8 yielded a sensitivity of 80.0% (n=24/30) at the first available timepoint and 89.7% (26/29) with incorporation of an additional subsequent sample. Detection of ctDNA at any landmark window timepoint was associated with inferior outcomes (adjusted HR [aHR]: 10.28 [95% CI: 4.03-26.23], p =1.06x10 -06 ). Week-4 detection <100 ppm was prognostic and conferred a 6.5 month longer lead time than detections ≥100ppm (HR 4.09, p=0.018). All patients who recurred with surveillance samples had ctDNA detected prior to recurrence (sensitivity: 100% (n=28/28). ctDNA identified 100% of lung- and liver-only metastases; most initial detections were <100 ppm (75% and 71.4%, respectively). In evaluable patients, lead time from ctDNA detection to recurrence was 176 days (including patients with expedited imaging upon receipt of a ctDNA detection result). If a higher threshold for ctDNA was used (≥100 ppm) in the same population, the lead time would be >two months shorter (105 days, p<0.001). All patients without ctDNA detected on surveillance remain disease free (NPV 100% [n=63/63]). Conclusions: NeXT Personal demonstrated high accuracy, prognostic value, and early detection at ultrasensitive levels with no loss in specificity. The ideal postoperative landmark time point for MRD testing is at 4-8 weeks. Our results show strong clinical potential for an ultrasensitive MRD assay for landmark MRD and longitudinal surveillance in CRC.
Knowledge, attitude, and practice of cardio-oncology amongst oncologists and cardiologists of south-east Asia: An Asian Cardio-Oncology Society (ACOS) survey.
e24019 Background: Asian Cardio Oncology Society (ACOS) was started in 2020 to promote awareness regarding cardio-oncology in south-eastern Asia. This study describes our baseline survey on knowledge, attitude and practice (KAP) of cardio-oncology amongst cardiologists & oncologists of India and south-east Asia. Methods: A 38-question survey was administered online via google forms using email and watsapp to contact members of ACOS and other cardiologists/oncologists in south-east Asia from December 2020 to January 2021. Results: Total 215 responses were collected. Maximum respondents were from India (90%) followed by Bangladesh (4%). Majority were medical oncologists (41%) followed by cardiologists (23%) & radiation oncologists (20%). Female participation was 18%. Cardiologists encountered cancer diagnosis in 5% of their patients while oncologists encountered average 30% patients with cardiac disease. Risk of cancer therapy related cardiac dysfunction (CTRCD) was estimated < 10% by 39%, 10-20% by 25% and > 20% by 35%. Regarding knowledge of cardio-oncology and familiarity with guidelines, 29% rated themselves poor, 48% average and 23% good. 85% did not have dedicated cardiologist at their centre. Echocardiography was not performed by trained cardiologists at 33% centres. 68% believed in baseline cardiac evaluation for all oncology patients. Cardiology referral was opined for all patients before starting anticancer therapy by 24%, while 10% believed in referral only for cardiac symptoms/toxicity and 66% believed in referral only before starting cardio-toxic therapy. Only 21% were confident of using potentially cardio-toxic treatment in patients with high risk of cardiotoxicity or suboptimal cardiac function. 67% expressed need for separate guidelines for CTRCD in lower-middle-income countries (LMIC) and 70% strongly agreed for separate cardio-oncology clinic to improve patient outcomes. Conclusions: Despite significant growth in field of cardio-oncology in West, there are significant gaps in KAP among health care providers in south-east Asia. Collaboration between cardiologists and oncologists and separate cardio-oncology guidelines will improve KAP of cardio-oncology and consequentially the patient outcomes, for south-east Asian region and LMIC.
Patterns and incidence of brain metastases in high-grade neuroendocrine carcinomas.
e14025 Background: High-grade neuroendocrine carcinomas (HGNEC) are aggressive malignancies with early dissemination. While small cell lung cancer (SCLC) is highly neurotropic, the incidence of brain metastases (BM) in large cell neuroendocrine carcinoma (LCNEC) and extrapulmonary NEC (EP-NEC) remains poorly characterized. We evaluated baseline and cumulative BM incidence and overall survival (OS) across HGNEC subtypes. Methods: Patients with HGNEC (SCLC, LCNEC, EP-NEC) treated at Roswell Park Comprehensive Cancer Center (2000–2024) were retrospectively reviewed. Baseline BM were intracranial lesions on imaging within 90 days of diagnosis; subsequent BM were new lesions >90 days post-diagnosis. Cumulative BM incidence was estimated using competing-risks methodology with death as the competing event. Multivariable Fine–Gray and Cox models assessed BM risk and OS. Results: Of 1665 patients (SCLC n=1215; EP-NEC n=366; LCNEC n=84), 270 (16.2%) had baseline BM. Baseline BM prevalence differed by histology (SCLC 19.5%, LCNEC 17.9%, EP-NEC 4.9%; p<0.001). Among 1394 patients without baseline BM, 24-month cumulative BM incidence was highest in SCLC (26.5%) versus LCNEC (10.1%) and EP-NEC (6.3%; p<0.001). SCLC had significantly higher subsequent BM risk versus EP-NEC (sHR 3.77, 95% CI 2.40–5.93; p<0.001). Median OS in BM-free patients was 15.8 months (SCLC), 20.2 months (LCNEC), and 13.9 months (EP-NEC; p=0.07); among patients with BM, median OS was 14.7, 14.1, and 10.3 months, respectively (p=0.054). Post-2018 diagnosis was associated with higher BM incidence (sHR 1.37, p=0.022) but improved OS (HR 0.79, p<0.001). Conclusions: In the largest single-institution HGNEC cohort reported to date, BM risk varies markedly by histology. SCLC demonstrates the highest baseline and cumulative BM incidence, followed by LCNEC, while EP-NEC shows the lowest CNS tropism. These findings support routine CNS surveillance for pulmonary HGNEC and a symptom-directed approach for EP-NEC. Histology SCLC (n=1215) EP-NEC (n=366) LCNEC (n=84) Baseline BM (%) 19.5 4.9 17.9 BM CI (%) 6/12/18/24 mo 3.6/17.7/23.7/26.5 2.0/4.6/6.0/6.3 1.4/7.2/10.1/10.1 OS, mo (BM-/BM+) 15.8/14.7 13.9/10.3 20.2/14.1 CI=cumulative incidence; OS=overall survival (months).
Isatuximab plus pomalidomide-dexamethasone in relapsed/refractory multiple myeloma: Subgroup analysis by prior anti-CD38 exposure from the phase 3 IRAKLIA trial.
7516 Background: With the growing use of anti-CD38 therapies in early multiple myeloma (MM) management, there is a need for data in patients previously exposed to anti-CD38 therapy to guide decision making. In the Phase 3 IRAKLIA trial (NCT05405166), patients with relapsed/refractory MM (RRMM) received the anti-CD38 monoclonal antibody isatuximab (Isa) subcutaneously (SC) delivered via an innovative on-body injector (OBI) or intravenously (IV), with pomalidomide and dexamethasone (Pd). In this post hoc analysis, we examined outcomes in IRAKLIA patients with vs without prior anti-CD38 exposure. Methods: RRMM patients ≥18 years with ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor were randomized to receive Isa SC (n=263) or IV (n=268) weekly in Cycle 1, then every 2 weeks, with Pd. Patients with prior anti-CD38 exposure <9 months (mos) before randomization or intolerance to anti-CD38 were excluded. Refractory patients were defined as those who failed to achieve minimal response on treatment or had progression within 60 days after last dose. Patients receiving Isa SC or IV were pooled. Results: Overall, 67 patients (12.6%) had prior anti-CD38 exposure with a median washout period of 20.2 mos, of which 26 (38.8%) were anti-CD38 refractory. Baseline characteristics were largely consistent between patients with or without prior anti-CD38 exposure; the median follow-up for the overall population was 12 mos. Patients with prior anti-CD38 exposure had an overall response rate (ORR) of 52.2%, 12-mo progression-free survival (PFS) rate of 40.6%, and median PFS of 8.5 mos. In patients without prior exposure, an ORR of 73.5%, 12-mo PFS of 68.8%, and non-estimable (NE) median PFS were reported. Anti-CD38 non-refractory vs refractory patients had an ORR of 48.8% vs 57.7%, 12-mo PFS of 38.9% vs 42.2%, and median PFS of 9.0 vs 7.5 mos. Patients with a longer washout period (>median of 20.2 mos) had an ORR of 63.6%, 12-mo PFS of 61.8% and NE median PFS, whereas patients whose prior anti-CD38 therapy ended more recently (≤median of 20.2 mos) had an ORR of 41.2%, 12-mo PFS of 19.2%, and median PFS of 6.7 mos. The safety profile of Isa + Pd was similar in patients with vs without prior anti-CD38 exposure. Conclusions: Isa + Pd demonstrated clinical benefit across anti-CD38–naïve, anti-CD38–exposed, and anti-CD38–refractory patients. A washout period >median of 20.2 mos resulted in outcomes comparable to those in anti-CD38–naïve patients, and outcomes were consistent between anti-CD38–exposed and anti-CD38–refractory patients after a >9-mo washout period. Efficacy of Isa + Pd in patients with prior anti-CD38 exposure from the IRAKLIA trial presents an opportunity to address an unmet need in a difficult-to-treat patient population. Clinical trial information: NCT05405166 .
Social determinants of health, diagnostic delay, and treatment abandonment in advanced lung cancer care.
e13521 Background: Social determinants of health (SDOH) significantly influence cancer outcomes, particularly in low- and middle-income countries. Evidence on how SDOH affect diagnostic timelines and treatment adherence in advanced lung cancer remains limited. This study evaluated the association between SDOH, time to diagnosis and treatment, and treatment abandonment in patients with recurrent or metastatic lung cancer. Methods: We conducted a cross-sectional study including patients with recurrent or metastatic lung cancer treated at a Instituto Nacional de Enfermedades Neoplasicas, Lima-Peru. SDOH were assessed using the Social Determinants of Health Questionnaire (STBH-Q), generating a global continuous score (range 0–128), where lower scores indicate higher social risk. Time to diagnosis, time to molecular diagnosis, time to treatment initiation, and time to target or immunotherapy initiation were analyzed as continuous non-normally distributed variables using Spearman correlation. Treatment abandonment (yes/no) was analyzed using Mann–Whitney U test and binary logistic regression. A two-sided p-value < 0.05 was considered statistically significant. Results: A total of 54 patients were included in the analysis. Higher social risk (lower STBH-Q global score) was significantly associated with longer time to initial diagnosis (Spearman ρ = −0.276, p = 0.043). No significant correlations were observed between the global STBH-Q score and time to molecular diagnosis (Sρ = 0.119, p = 0.404), time to treatment initiation (Sρ = 0.150, p = 0.295), or time to initiation of specific therapy (Sρ = 0.061, p = 0.684). Treatment abandonment occurred in 13 patients. The global STBH-Q score differed significantly between patients who abandoned treatment and those who did not (Mann–Whitney U test, p = 0.002). In binary logistic regression, higher STBH-Q scores were independently associated with a lower probability of treatment abandonment (B = −0.049; OR 0.95; 95% CI 0.92–0.98; p = 0.004), indicating that each unit increase in the global STBH-Q score reduced the odds of abandonment by approximately 5%. Conclusions: Social determinants of health are significantly associated with diagnostic delays and higher risk of treatment abandonment in patients with advanced lung cancer. These findings highlight the need to integrate systematic SDOH assessment into oncology care pathways to identify vulnerable patients and implement targeted interventions aimed at improving timely diagnosis and treatment adherence in resource-limited settings.
A review of representation in clinical trials for metastatic prostate carcinoma.
e23329 Background: Metastatic prostate carcinoma is a leading cause of cancer related deaths among men in the United States (U.S.). Incidence and mortality are highest among Black men in the U.S. and globally (Lillard Jr et al., 2022). Significant advances in treatment for metastatic disease have been accomplished in the past decade, with multiple publications and data showing increased survival rates for men (Kyriakopoulos et al., 2018). Despite these advances, mortality disparities persist, raising concerns for the generalizability of the clinical trial evidence supporting these therapies. Methods: To understand the impact of this disparity, publications associated with disease treatment approval by the U.S. Food and Drug Administration (FDA) from the last 10 years were reviewed. FDA.gov was utilized to identify that 19 drug approvals were indicated as evidentiary for the FDA’s approval. These studies were reviewed for their racial and ethnic representation relative to disease epidemiology. Trial representativeness was assessed using the DRIVE score, a validated framework measuring demographic alignment between clinical trial populations and affected patient populations in order to determine if they have transportability and generalizability for all patients in the U.S. with metastatic prostatic carcinoma. A DRIVE Score of ≥ 3 is the threshold for clinical excellence (Birhiray & Birhiray, 2023). Results: Of the 19 clinical trials of the approved drugs reviewed, 3 met the minimum DRIVE criteria for clinical excellence, 9 received 1, 2 received 0, 4 received 0*, and one approval was ineligible to be scored due to not taking place in the U.S.. Black men were consistently underrepresented relative to disease prevalence across the majority of trials. Conclusions: The majority of the clinical trials reviewed were not generalizable or transportable to minority populations. Current guidelines published by the American Society of Clinical Oncology do not acknowledge the existing disparities in clinical trials, potentially contributing to therapeutic misappropriation. Regulatory agencies, sponsors and professional societies share responsibility for ensuring that trial data reflects the populations affected by the disease. Using the DRIVE score informs clinicians of existing disparities, and empowers them to choose agents based on their clinical relevance to the populations they serve. Therapeutic misappropriations are common in the treatment of metastatic prostatic carcinoma, as advances in treatment do not apply to minority populations, and a lack of transparency with clinicians about this information leads to further disparities in its treatment.
Targeting cfDNA and NETs with DNAse I to augment CAR T-cell function and antitumor efficacy.
7531 Background: Chimeric antigen receptor (CAR) T-cell therapy induces high initial response rates in B-cell malignancies; however, limited persistence and early relapse remain major clinical challenges. Accumulation of cell-free DNA (cfDNA) and neutrophil extracellular traps (NETs) within the tumor microenvironment represents a potential mechanism of CAR T-cell dysfunction through induction of exhaustion, immunosuppression and impaired expansion. We hypothesized that enzymatic degradation of extracellular DNA using DNase I could enhance CAR T-cell persistence and antitumor efficacy. Methods: The effects of cfDNA and NETs on human CD19 CAR T-cell function were evaluated using sequential killing assays, proliferation assays, and flow cytometry–based phenotyping. DNase I was assessed for its ability to reverse cfDNA/NET-mediated suppression and prevent exhaustion. In vivo efficacy, expansion, and persistence of CAR T cells were studied in xenogeneic B-cell acute lymphoblastic leukemia (Nalm-6) and Burkitt lymphoma (Raji) mouse models. Longitudinal in vivo tracking of CAR T-cell expansion was performed using bioluminescence imaging and serial peripheral blood analysis. Translational relevance was further explored through compassionate-use administration of DNase I in combination with CAR T-cell therapy in a pediatric patient with relapsed/refractory Burkitt lymphoma. Results: cfDNA and NETs suppressed CAR T-cell proliferation and cytotoxicity while promoting upregulation of exhaustion markers, including PD-1, LAG-3, and TIM-3. DNase I efficiently degraded extracellular DNA, preserved CAR T-cell effector function, improved CD8:CD4 ratios, and reduced exhaustion across multiple rounds of tumor rechallenge in vitro. In vivo, DNase I significantly enhanced CAR T-cell expansion and persistence following infusion, as demonstrated by longitudinal tracking studies. Combination therapy resulted in improved tumor control, delayed relapse upon rechallenge, and prolonged survival in both NALM-6 and Raji xenograft models. In a single pediatric patient with highly refractory Burkitt lymphoma, DNase I co-administration was associated with marked CAR T-cell expansion and progressive reduction in tumor burden after prior CAR T-cell failure. Conclusions: Extracellular DNA and NETs constitute a critical barrier to durable CAR T-cell efficacy. DNase I enhances CAR T-cell persistence and antitumor activity by eliminating cfDNA/NET-driven immunosuppression, supporting further clinical evaluation of DNase I as a combinatorial strategy to improve CAR T-cell therapy outcomes.
Signatures of biological heterogeneity associated with treatment outcome in diffuse large B-cell lymphoma.
7063 Background: Genetic subtypes of diffuse large B-cell lymphoma (DLBCL) capture biological differences between tumors that influence the response to immunochemotherapy (Schmitz et al., NEJM 2018). However, nearly 40% of DLBCL cases remain unclassified. The addition of gene expression signatures can accelerate classification and inform therapeutic intervention. Methods: We generated single-cell RNA sequencing of 103 DLBCL patient biopsies from Weill Cornell Medicine, New York Presbyterian Hospital, and the National Institutes of Health. We also utilized bulk genomic data from a discovery cohort (n=311, Ennishi et al., J Clin Oncol 2019) and a validation cohort (n=574, Schmitz et al., NEJM 2018). Results: Single cell sequencing allowed us to isolate the malignant B cells and develop genetic subtype signatures. The MCD signature was associated with poor overall survival (p<10 -6 ), as was the BN2 signature within ABC tumors (p<10 -3 ). When applied to unclassified tumors, the subtype signatures identified characteristic genetic alterations including SLC1A5 mutations in MCD (p<10 -5 ), UBE2A mutations in BN2 (p<10 -13 ), C10orf12 truncations and copy number loss in EZB (p<10 -6 ), and SGK1 mutations in ST2 (p<10 -7 ). Moreover, we discovered that most DLBCL tumors (80%) contained two or more genetic subclones (median 2, range 1-5) based on DNA copy number differences. The genetic subclones had distinct phenotypes based on expression of six recurrent gene expression meta-signatures, herein termed themes. The germinal center (GC) B cell, memory B cell, plasma cell, and pan-B cell themes reflect B cell differentiation whereas two other themes – cell cycle and cell growth – reflect proliferative and metabolic states that are independent of the differentiation states. Surprisingly, 23% of DLBCL (24/103) harbored genetic subclones expressing B cell differentiation themes that distinguished them from other malignant cells in the same tumor. The GC B cell theme was associated with a favorable response to R-CHOP chemotherapy (p<0.02), as expected, while the cell growth theme (but not the cell cycle theme) was associated with adverse survival (p<0.02). Conclusions: Our study revealed that genetic subtypes have distinct gene expression signatures. We further demonstrated a role for tumor subclones in generating intra-tumoral biological diversity. We developed signatures of inter and intra-tumoral heterogeneity that are associated with overall survival.
Subtype-specific representation of thyroid cancers in contemporary basket clinical trials (2018–2024): A pooled analysis.
e18021 Background: Basket clinical trials (BCTs) are designed to overcome histology-based drug development by enrolling patients according to shared molecular alterations. A pooled analysis by Hazim and Prasad (2018) focused on biomarker (BM)-driven BCTs and reported an under-representation of thyroid cancers (TCs) as a single entity. Since then, BCT methodology has evolved and multiple actionable alterations have been identified in TCs. We assessed the representation of TC subtypes in contemporary BCTs, contextualizing enrollment patterns against population-level cancer incidence. Methods: We conducted a systematic review of BCTs published between April 2018 and December 2024. BCTs were categorized according to prior BM selection (none BM, single BM, multiple BM). Cancer-specific crude incidence rates per 100,000 persons in 2022 were derived from the Global Cancer Observatory across the EU and US for both sexes aged >20 years. Association between incidence and BCT enrollment was assessed using semi-log and log-log linear models. Incidence estimates for TC subtypes were literature-derived. An observed-to-expected (O/E) enrollment ratio (ER) was calculated for anaplastic, differentiated, and medullary TCs (ATC/DTC/MTC), comparing observed BCT accrual with expected numbers based on subtype-specific incidence-weighted counts. Results: Among 137 screened publications, 26 BCTs enrolling 2,448 patients in 372 centers (58.6% US, 27.3% EU) met inclusion criteria. Across 25 cancer types, incidence was associated with BCT enrollment in both semi-log (β ≈ 69.7, 95%CI 26.8–112.5, p=0.003, R² ≈ 0.34) and log–log models (β ≈ 0.39, 95%CI 0.08–0.69, p=0.015, R² ≈ 0.24). Overall, 83 patients with TC (3.4%) were included: 57 ATC, 12 DTC, 3 MTC, 11 unspecified. TC inclusion was concentrated in 7 BCTs (26.9%): 97.2% of ATC patients were enrolled in 2 BCTs with BRAF inhibitors or immune checkpoint inhibitors. MTC patients were mainly enrolled in a RET-targeted BCT, and DTC patients in a PD-L1 inhibitor trial. TC macro-category was well represented, lying above the regression line in both models. However, O/E analyses revealed marked subtype-specific heterogeneity, with over-representation of ATC (ER 133.7), and under-representation of MTC (ER 9.6) and DTC (ER 0.15), indicating a strong deviation from incidence-driven representation. Conclusions: Overall TCs inclusion in BCTs has increased since 2018, driven by few trials on a restricted number of targets or ICI. TC’s apparent adequate representation in contemporary BCTs reflects aggregation effects that mask clinically relevant subtype-specific disparities. These findings highlight structural barriers in translating molecular actionability into equitable access to novel therapies for the majority of patients with advanced TCs, and support the need for integrated precision oncology pathways and centralized referral strategies.
Mortality trends and persistent disparities among U.S. adults with lung cancer and hypertensive diseases (1999–2023): A nationwide retrospective analysis.
e20668 Background: Hypertension is a prevalent comorbidity in patients with lung cancer and may exacerbate cardiovascular vulnerability, treatment-related toxicity, and mortality. However, long-term national mortality trends among individuals with concomitant lung cancer and hypertensive diseases remain poorly characterized. We evaluated temporal trends and sociodemographic disparities in mortality among U.S. adults with lung cancer and hypertensive diseases listed as contributing causes of death. Methods: We conducted a population-based retrospective MCOD analysis using the CDC WONDER database from 1999 to 2023. Adults aged ≥45 years with lung cancer and hypertensive diseases recorded as contributing causes of death were included. Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated using the 2000 U.S. standard population. Temporal trends were assessed using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC). Stratified analyses were performed by sex, race/ethnicity, census region, urbanization, age group, state, and place of death. Results: From 1999 to 2023, AAMRs increased nearly threefold, from 22.23 to 61.79 (AAPC 2.57%; 95% CI, 1.98–3.15; p < 0.05). Mortality increased among both males and females, with a notable decline between 2007–2018 followed by a sharp resurgence after 2018. The South experienced the steepest long-term increase, with marked post-2017 acceleration. Nonmetropolitan areas demonstrated faster mortality growth than metropolitan areas. Racial disparities were evident, with the highest increases among American Indian/Alaska Native and White individuals. Older adults exhibited the highest absolute mortality, while middle-aged adults showed the fastest rising trends. During 2018–2023, the highest state-level AAMRs were observed in Mississippi, Oklahoma, and Nebraska. Home deaths increased over time, accounting for 45.3% of deaths in the most recent period. Conclusions: Mortality among U.S. adults with lung cancer and hypertensive diseases has increased substantially over the past two decades, with widening regional, racial, and rural disparities and a concerning post-2018 resurgence. These findings underscore the need for integrated cardio-oncology strategies to mitigate hypertension-related risks in lung cancer care.
A phase I/IIa study to evaluate the safety and tolerability, activity, and PK of a potential novel CNTN4-targeted checkpoint inhibitor, EP0089, in patients with advanced solid tumors.
TPS2688 Background: Contactin 4 (CNTN4) has recently been identified as a novel cancer target which is overexpressed across a range of tumor types, including gastrointestinal, genitourinary, melanoma, breast and lung. Preclinical data shows that CNTN4 functions as an immune checkpoint through its binding to the T-cell transmembrane protein APP (Amyloid Precursor Protein). The interaction between CNTN4 on the surface of tumor cells and APP diminishes T cell receptor signaling cascades, inhibiting the activation and proliferation of CD4+ and CD8+ T cells. Tumor upregulation of CNTN4 may facilitate tumor immune evasion. Elevated CNTN4 levels have been associated with poorer outcomes for patients treated with anti-PD-1 checkpoint inhibitors. Therapeutic agents that block the interaction of CNTN4 with APP therefore have the potential to address significant unmet medical needs across a range of tumor types. EP0089 is a humanized IgG4 monoclonal antibody which specifically binds CNTN4 and inhibits the interaction between CNTN4 and APP, thereby enabling an immune response within the tumor microenvironment. In vitro and i n vivo studies demonstrated that EP0089 neutralized CNTN4-mediated suppression of T cell activation and promoted killing of CNTN4 over-expressing tumors. Methods: This is a first-in-human, open-label, phase I/IIa study (NCT07030478). Eligible patients will have a confirmed diagnosis of an advanced solid tumor with no available standard therapy or for whom standard therapy has failed, ECOG performance status of 0-1, life expectancy greater than 3 months, and measurable disease per RECIST v1.1 (or specified disease-specific guidelines). The population will be enriched for tumor types known to express CNTN4, including gastric, gastro-esophageal, esophageal adenocarcinoma, hepatocellular, bladder, gallbladder, endometrial, melanoma, and prostate. The primary objective is to determine the maximum tolerated dose and recommended phase II dose of EP0089. The secondary objectives are to characterize the PK and immunogenicity profile of EP0089 and assess preliminary antitumor activity. Exploratory objectives are to evaluate biomarkers of response, including the impact of CNTN4 expression and other PD biomarkers. Part A consists of dose-escalation, utilizing a 3+3 design, and dose expansion to further evaluate dose levels/regimens of interest. Part B will be determined based on review of Part A data and may include further dose optimization, and/or evaluation of specific populations of interest. Patients will initially receive EP0089 by IV infusion once every 2 weeks, subject to ongoing Safety Monitoring Committee review throughout dose escalation. The study is being conducted in the Republic of Korea, Australia and United States and later in Europe. Target recruitment is approximately 250 patients. Clinical trial information: NCT07030478 .
Divergent age-specific trends in colorectal cancer mortality: A 22-year analysis of the emerging early-onset crisis.
e15722 Background: Despite overall improvements in colorectal cancer (CRC) outcomes, concerning trends have emerged in younger populations. We examined two decades of US mortality data to characterize age-specific trajectory differences and identify inflection points in the epidemiologic landscape of CRC. Methods: Using CDC WONDER data (1999–2020), we analyzed age-adjusted CRC mortality rates (ICD-10: C18–C20) stratified by age: early-onset (≤44 years) versus late-onset (≥45 years). Joinpoint regression analysis (Version 5.4.0.0) with permutation testing identified significant trend changes. Annual Percent Change (APC) estimates with 95% confidence intervals assessed temporal patterns, with statistical significance set at α = 0.05. Results: Late-onset CRC (≥45 years): Mortality rates declined substantially from 69.26 to 40.49 per 100,000, representing a 41.6% reduction. A critical inflection point occurred in 2014 (95% CI: 2011–2015), marking a deceleration in the rate of improvement. The pre-2014 period showed robust decline (APC: −3.06%; 95% CI: −3.18 to −2.93; p < 0.000001), which slowed significantly post-2014 (APC: −1.61%; 95% CI: −2.12 to −1.09; p = 0.000006)—a 47% reduction in the pace of mortality improvement.Early-onset CRC (≤44 years): In stark contrast, mortality rates increased from 0.92 to 1.13 per 100,000, representing a 22.8% rise. No inflection points were identified; instead, a persistent upward trajectory characterized the entire 22-year period (APC: +0.78%; 95% CI: +0.54 to +1.02; p = 0.000001). This yielded a continuous, unabated increase in deaths among young adults. Conclusions: This analysis reveals a troubling paradox in US colorectal cancer mortality: while older adults experienced substantial but decelerating improvements, young adults faced steadily worsening outcomes throughout the study period. The 2014 inflection point in older adults, coinciding with slowed screening expansion and potential changes in risk factor prevalence, coupled with the relentless rise in early-onset mortality, signals an urgent need to reassess prevention strategies, lower screening age thresholds, and investigate biological and environmental drivers of early-onset disease. The nearly 23% increase in mortality among those ≤44 years represents a growing public health crisis demanding immediate action.
Impact of cell-type–specific circadian disruption in pediatric B-ALL on clock-based biomarkers with implications for chronotherapy.
6541 Background: B-cell acute lymphoblastic leukaemia (B-ALL) is the most common paediatric malignancy. While cure rates exceed 90%, treatment remains intensive and is frequently associated with relapse, toxicity, and long-term adverse effects. The circadian clock regulates DNA repair, metabolism, immune function, and drug pharmacokinetics—processes central to cancer therapy. Although treatment timing has been shown to influence outcomes in childhood ALL, the molecular circadian landscape of malignant versus healthy hematopoietic cells in paediatric patients remains unexplored. Methods: We performed an integrated molecular and clinical circadian profiling study in paediatric ALL patients (N=7) and age-matched healthy controls (N=10). Peripheral blood, bone marrow, and saliva samples were collected at diagnosis. CD19⁺ (leukemic B cells) and paired CD19⁻ (non-B cells) populations were isolated and used to establish an internal, patient-specific circadian baseline. Expression of ~800 cancer-, immune-, and clock-related genes was quantified using NanoString SPRINT technology. Rhythmicity parameters (acrophase, amplitude, MESOR), differential expression, and machine-learning–based classification were integrated with longitudinal clinical and physiological data. Results: Malignant CD19⁺ cells exhibited marked circadian dysregulation compared with paired CD19⁻ cells from the same patients. Core clock architecture was altered specifically in leukemic cells, including disrupted BMAL1–PER2 phase relationships and reduced rhythmic amplitude. CD19 expression itself displayed cell-type–specific circadian modulation, with higher amplitude and phase variability in CD19⁺ cells. In contrast, CD19⁻ cells retained more coherent circadian organization, supporting their use as an internal normalization reference. Preliminary analyses suggest that the degree of circadian misalignment between CD19⁺ and CD19⁻ compartments correlates with treatment dynamics, including early response and therapy duration. Conclusions: Our findings reveal profound, cell-intrinsic circadian disruption in paediatric B-ALL and demonstrate that comparing malignant CD19⁺ cells against paired non-malignant CD19⁻ cells enables robust detection of clock dysregulation. These results provide a molecular framework for developing circadian biomarkers and support the rational design of chronotherapy strategies aimed at optimising efficacy while minimising toxicity in paediatric leukaemia.
A small extracellular vesicle protein-based model for ovarian cancer relapse detection and monitoring.
5564 Background: Recurrence surveillance of epithelial ovarian cancer (EOC) is a major clinical challenge, given the suboptimal performance of serum CA125 levels and limitations of radiological assessments. Serum small extracellular vesicle (sEV)-based liquid biopsy provides tumor-enriched and stable biomarkers, with potential to improve the precision of recurrence monitoring and support post-treatment surveillance. This study aimed to develop and preliminarily validate a serum sEV protein-based model to enhance recurrence monitoring in ovarian cancer. Methods: The study was designed with two stages (model development and validation) and plans to prospectively enroll 200 patients with EOC (NCT06925126). This analysis reports preliminary stage I data, and patients were categorized into relapse and non-relapse groups based on imaging-confirmed recurrence status. All relapsed patients were platinum-sensitive with low tumor burden. Quantitative assessment was performed on biomarkers derived from sEVs (specifically, E-CA125, E-HE4, and E-C5a) as well as corresponding serum markers measured in routine clinical practice (namely, H-CA125 and H-HE4), utilizing peripheral blood samples. Biomarker distributions were compared between groups, and predictive performance for recurrence detection was evaluated using receiver operating characteristic (ROC) analysis, including area under the curve (AUC), accuracy, sensitivity, and specificity. Results: A total of 113 patients were analyzed (42 non-relapsed, 71 relapsed), with a median age of 57 years. The majority (95/113) of patients had high-grade serous ovarian cancer, while other histological types were also included. Levels of E-CA125, E-HE4, H-CA125, and H-HE4 were significantly higher in relapsed patients compared with non-relapsed patients (all p < 0.01), while E-C5a showed no discriminative value between the two groups. Among individual sEV biomarkers evaluated, E-CA125 demonstrated the highest performance for recurrence detection (AUC = 0.877), followed by E-HE4 (AUC = 0.689) and E-C5a (AUC = 0.528). Moreover, the sEV protein-based model achieved an accuracy of 77.9% with a sensitivity of 71.8% and a specificity of 90.9%. This performance surpassed that of the conventional serum CA125, which exhibited an accuracy of 50.0%, a sensitivity of 26.8%, and a specificity of 100.0%. These results indicate that the sEV protein-based model may provide added clinical value when serum CA125 monitoring is unreliable after prior therapy. Conclusions: The sEV-derived CA125 and the sEV model demonstrate promising performance for recurrence detection in EOC. These findings support the feasibility of a serum sEV-based surveillance strategy that may improve the reliability of post-treatment monitoring. Prospective validation is ongoing to determine its potential role in guiding clinical surveillance and intervention. Clinical trial information: NCT06925126 .
Burden, mortality patterns, and treatment disparities of prostate cancer across G20 countries: Insights from the Global Burden of Disease 2023 study.
5032 Background: Prostate cancer is the leading male malignancy in G20 nations, yet cross-national disparities in detection, treatment, and outcomes remain insufficiently characterized. This study examines incidence, mortality, and treatment patterns across G20 countries, with attention to socioeconomic and health system factors. Methods: We analyzed prostate cancer incidence, mortality, and disability-adjusted life years (DALYs) in all 20 G20 member states from 1990 to 2023 using GBD 2023 data. Analysis focused on men aged ≥50 years. Age-standardized rates were calculated, and incidence-to-mortality ratios were used as a proxy for early detection and treatment access. Radical treatment rates (surgery, radiotherapy) and PSA screening availability were correlated with survival patterns. Country-level economic estimates included diagnostic, therapeutic, and end-of-life expenditures. Results: In 2023, G20 countries reported 3.24 million new prostate cancer cases and 512,000 deaths, resulting in 11.8 million DALYs. Age-standardized incidence rates ranged from 23.4 to 112.6 per 100,000 men—a 4.8-fold variation—strongly associated with national healthcare development index (r = 0.78, p < 0.001). High-income G20 nations reported incidence-to-mortality ratios between 4.2:1 and 5.8:1, while middle-income countries such as India, Indonesia, and Mexico ranged from 1.3:1 to 1.8:1. India and Indonesia together accounted for 24% of G20 prostate cancer deaths despite contributing only 18% of total incident cases. Radical treatment rates spanned from 8% in India to 68% in the USA, correlating with long-term survival trends. Average healthcare expenditure per prostate cancer death ranged from $2,100 in low-resource settings to $89,400 in high-income countries. Within high-income nations, men in the lowest socioeconomic quintile experienced 2.1 times higher mortality than those in the highest quintile. Conclusions: Marked disparities in prostate cancer burden and treatment access persist across G20 nations, shaped by income level and healthcare system capacity. Strategic expansion of PSA-based screening and curative treatment in middle-income settings could substantially reduce preventable deaths and narrow the outcome gap.
Breast cancer patient navigation to identify individual needs and offer medical and supportive care referrals.
1547 Background: Despite evidence that patient navigation (PN) improves access to comprehensive care for patients with breast cancer (BC), its adoption in Mexico remains limited, likely due to multifactorial barriers. To address this gap, our center implemented one of the country’s first PN programs to systematically identify and document patients’ medical and support needs and provide referrals to appropriate services. This study describes patient needs and referral attendance up to 6 months (m) post-diagnosis. Methods: Patients newly diagnosed with BC are identified after their first medical oncology consultation at Hospital Zambrano Hellion TecSalud and are consecutively invited to the PN program, which consists of assessments at baseline, 3m, and 6m. At each timepoint, patients answer validated surveys and target questions to explore their needs. The navigator then shares the results with each patient and refers them to the required specialty or support services. Attendance to baseline and 3m referrals is assessed at 3m and 6m, respectively. This analysis includes patients navigated from 2020-2025. Results: 421 patients had reached 6m of follow-up: 357 (85%) and 261 (62%) completed their 3m and 6m navigation, respectively. Median age at diagnosis was 48 years (IQR 41-58). Most were married (76%), and had ≥1 child (84%), higher education (75%), and private healthcare (76%). The most common baseline referrals were to nutrition (86%), psychology (68%), support groups (47%), and wig providers (42%). At follow-up, patients mainly required referral to sexology counseling (3m: 82%, 6m: 79%), nutrition (3m: 78%, 6m: 77%), psychology (3m: 51%, 6m: 39%), and lymphedema counseling/therapy (3m: 40%, 6m: 66%). Attendance was highest to support groups (90-95%), wig providers (64-87%), and geriatric assessment (67-80%). Despite high need, attendance was notably lower for nutrition (47-52%), psychology (58%), and sexology counseling (0%). Main reasons for nonattendance were lack of interest (48%), time constraints (38%), and financial issues (10%). Conclusions: In this PN program, referrals were mostly needed for nutrition, sexology, and psychology. While attendance was high for some services, rates were suboptimal for the most common referrals, especially sexology counseling. Efforts to better convey referral rationale and importance may increase uptake and access to comprehensive quality-of-life focused care. Patient needs and attendance to referrals. BaselinereferralsN=421 (%) Baseline - 3mattendance% 3mreferralsN=357 (%) 3m - 6mattendance% 6mN=261 (%) Nutrition 361 (86) 47 278 (78) 52 202 (77) Sexology - - 291 (82) 0 206 (79) Psychology 287 (68) 58 181 (51) 58 102 (39) Support group 197 (47) 90 90 (25) 95 47 (18) Wigs 175 (42) 87 22 (6) 64 8 (3) Lymphedema 134 (32) 28 144 (40) 23 171 (66) Geneticist 126 (30) 69 42 (12) 43 25 (10) Fertility preservation 78 (19) 52 19 (5) 100 3 (1) Geriatrics 7 (2) 67 5 (1) 80 5 (2)
Characteristics of tumor microenvironment in <i>STK11</i> <sup> <i>m</i> </sup> <i> TP53 <sup>m</sup> KRAS <sup>m</sup> </i> non-small cell lung cancers and survival outcomes.
e20559 Background: KRAS mutations define a molecular subgroup of non-small cell lung cancer (NSCLC). KRAS G12C inhibitors have been approved in clinic and targeting other KRAS mutation subtypes is under development. Further investigation of cellular and molecular components of KRAS -mutant ( KRAS m ) NSCLC is warranted to understand the disease mechanisms and guide precise treatment. Methods: Comprehensive genomic and transcriptomic profiling of KRAS m NSCLC was performed using the Illumina TruSight Oncology 500 kit and TruSeq RNA Exome kit. Tumor mutation burden (TMB) differences among groups were assessed by the Kruskal–Wallis test. Survival curves were estimated using the Kaplan–Meier method and compared by the log-rank test. For RNA-based supervised clustering, we applied an ANOVA F-test to rank genes by their between-group variance relative to within-group variance, and selected the top 200 most discriminatory features. Immune infiltration was inferred using the ESTIMATE algorithm. Results: Among 162 cases of KRAS m NSCLC, TP53 was the most commonly co-mutated gene followed by STK 11 . Based on the co-mutation status of TP53 and STK11 , patients were classified into four groups: KO ( KRAS m -only, n = 31), KP ( TP53 m KRAS m , n = 79), KL ( STK11 m KRAS m , n = 32), and KPL ( STK11 m TP53 m KRAS m , n = 15). KPL patients had the worst overall survival (OS, p = 0.034) of 217 days, and lower tumor mutation burden (TMB, p = 1.54×10 -6 ), lower immune score by ESTIMATE (p = 0.0264), lowest expression of STK11 ( p < 0.001). Compared to KP or KL subgroup, KPL tumors were systematically inhibited regarding the functions of calcium, sodium, potassium and other ion transport channels, and T cell related pathways and the activation of NK-T cells and mast cells were also inhibited. In KPL tumors, NF-κB, TGF-β, mTOR, Wnt signaling pathways were highly enhanced, showing special characteristics of high proliferation, high oxidative phosphorylation and high lipid metabolism in this subgroup. The poor prognosis of KPL patients significantly associated with the high expression of SMOX, SLC7A5, RHOV, MAFK, LBP and NR4A2 genes and the low expression of TRPV2, PIK3CG, P2RX7. Conclusions: KRAS m NSLCLs are highly heterogeneous, and TP53 and STK11 co-alterations could stratify patients into four groups (KO, KP, KL, KPL) with distinct immune landscape and prognosis. STK11 m TP53 m KRAS m (KPL) tumors were specifically highly immune cold, with high proliferation, oxidative phosphorylation, and lipid metabolism and associated with a worst survival. This data may inform further investigation for targeted vulnerabilities of this KPL subgroup.
The psychosocial status of children who have a parent with cancer.
12083 Background: While numerous studies have investigated the psychosocial status of children affected by childhood cancer, the number of studies investigating this situation in children whose parents have cancer is extremely limited. The purpose of this study is to determine the prevalence and causes of emotional and behavioral problems in children whose parents have cancer. Methods: We conducted the study in the medical oncology outpatient clinics between February and April in 2025. We included 73 children who have a parent diagnosed with cancer (case group) and an age- and gender-matched control group from healthy 59 children between the ages of 8-16. We subjected all the participants to the Revised Child Anxiety and Depression Scale (RCADS), recording their age, gender, parent gender and age, educational status, duration and severity of disease, number of siblings. Results: No statistically significant difference was found between the groups in terms of age, gender, education level, parent's age, gender, education level, and number of siblings (p>0.001). The case group exhibited significantly elevated anxiety (p<0.001) and depression scores (p=0.002), along with higher total scale scores (p<0.001), in comparison to the control group . Correlation analyses revealed weak but statistically significant positive correlations between age and total anxiety, depression, and total score in the case group (p= 0.010). Further examination of anxiety subdimensions showed similarly weak yet significant correlations with PaD, SAD, and OCD (p<0.001). The females within the case group exhibited significantly higher anxiety (p=0.030) and depression (p=0.035) scores, and higher total scale score (p=0.025) compared to males. Significant differences were observed in anxiety scores (p=0.018) and total scale scores (p=0.047) according to parental education level, with the highest scores consistently found among children whose parents held a master’s degree. No significant differences were observed in anxiety, depression, or total scale scores according to the child’s educational level, parent age, whether the patient was the father or the mother, disease duration and severity, and sibling status. Conclusions: Children of cancer patients are affected by their parents' health problems. These children should be considered in light of the “comprehensive approach to cancer”. It should be noted that these children may need psychological rehabilitation at least as much as their parents with cancer.
Antibody-drug conjugate (ADC) after ADC: Predicting survival in patients with HER2-low metastatic breast cancer with lung metastasis using artificial intelligence (AI) and radiomics.
1027 Background: With the approval of multiple antibody drug conjugates (ADCs) for HER2-low metastatic breast cancer (MBC), defining which patients (pts) will benefit from an ADC after ADC approach is essential. No reliable biomarker exists to predict overall survival (OS) in the ADC after ADC setting. This study investigates whether AI informed radiomic texture features derived from CT scans prior to ADC therapy in pts with lung metastases who received both trastruzumab deruxtecan (T-DXd) and sacituzmab govitecan (SG) are associated with OS in HER2-low MBC. Methods: A single-institution retrospective study was conducted including pts with HER2-low MBC treated with both T-DXd and SG at Winship Cancer Institute of Emory University between 2020 and 2024. Among 44 pts reviewed (median age, 55 years), 21 pts with evaluable lung lesions were included. Radiomic texture features characterizing tumor heterogeneity were extracted from baseline pre-treatment CT scans of lung metastases before ADC initiation. A least absolute shrinkage and selection operator Cox regression model was applied within a 50-fold cross-validation framework to identify prognostic features associated with OS. OS was defined as the interval from initiation of first ADC therapy to death from any cause and was censored at the date of last follow-up for patients who were alive. A radiomic risk score (RRS) was calculated as a linear combination of the selected features weighted by their corresponding coefficients. Pts were stratified into high- and low-risk groups based on the median RRS. Cox proportional hazards regression was used to evaluate associations with OS. Results: Among the total 44 pts, the median duration of response was 6.1 months for the first ADC and 2.7 months for the subsequent ADC. 59.1% received SG as ADC1. For the 21 pts with lung metastasis, mOS was 20.8 months (95% CI: 14.33–30.8). In univariable analysis, the RRS was significantly associated with OS (HR = 2.5, 95% CI: 1.3–4.8; P = 0.006). In multivariable analysis adjusting for clinicopathologic factors including race, ER status, number of prior lines of therapy before ADC treatment, and relapsed vs de novo metastatic disease, RRS remained the only variable independently associated with OS (HR = 2.6, 95% CI: 1.2–5.5; P = 0.01). Conclusions: These preliminary findings suggest that CT-derived radiomic features may serve as a non-invasive biomarker to identify pts at higher risk of poor OS in the ADC after ADC setting for HER2-low MBC, for whom we need better, novel therapeutics after resistance develops to initial ADC therapy. This radiomics approach has the potential to inform treatment sequencing and risk stratification. Future work will include prospective validation in a larger cohort which includes other sites of metastatic disease.