Browse Articles

Obesity-associated genomic heterogeneity in breast tumors.

e12611 Background: Obesity is associated with increased breast cancer risk and worse outcomes; however, its molecular and ancestry-specific effects across breast cancer subtypes remain poorly defined. This is particularly relevant for aggressive subtypes that disproportionately affect women of African ancestry. We investigated the clinical, molecular, and survival associations of obesity across breast cancer subtypes, with a focus on basal-like disease. Methods: Breast cancer cohorts with available body mass index (BMI), molecular subtype, gene expression, clinical outcomes, and genetic ancestry data were analyzed. Patients were classified as normal weight, overweight, or obese. Associations between BMI and subtype distribution, disease-free survival (DFS), and vital status were assessed using chi-square and survival analyses. Genome-wide correlations between BMI and gene expression were performed, followed by pathway enrichment analyses. Subtype-specific analyses were conducted, including comparisons within Basal and Luminal-B tumors. Findings were examined across multiple cohorts, including Vanderbilt BEST and METABRIC. Results: Among 663 patients, 80.8% were overweight or obese, with obesity significantly enriched in basal-like and luminal B subtypes (p < 0.05). Basal-like and HER2-enriched tumors showed the highest obesity prevalence (70.3% and 62.5%, respectively). Overweight and obese tumors were associated with higher African ancestry, particularly West African ancestry, with the strongest enrichment observed in obese patients with basal-like disease. A total of 533 genes positively correlated with BMI were enriched in metabolic and DNA repair pathways, including glycine, serine, and threonine metabolism and homologous recombination. In contrast, 384 genes negatively correlated with BMI were enriched in ketone body and thiamine metabolism pathways. Among basal-like tumors, overweight and obese patients experienced significantly poorer DFS and exhibited distinct obesity-associated transcriptional profiles. These associations were not consistently observed across all subtypes or in the METABRIC cohort. Conclusions: Obesity and its association with poorer outcomes in hormone-receptor positive breast cancer is well known. However, here we show it is also associated with aggressive breast cancer subtypes which is associated with adverse outcomes in basal-like disease. This appears to be associated with distinct metabolic and DNA repair-related transcriptional programs, particularly among patients with higher African ancestry. These findings will be validated in independent cohorts using clinically annotated data from Caris Life Sciences Molecular Profiling to confirm robustness across diverse populations. Future analyses will also identify obesity-associated somatic mutations using whole-genome sequencing data and characterize genomic-wide alterations in obese breast cancers.

A feasibility study of tumor-infiltrating lymphocytes (TIL) in patients with cutaneous squamous cell carcinoma and Merkel cell carcinoma after anti–PD-1 therapy.

TPS9616 Background: Tumor infiltrating lymphocyte (TIL) therapy is an autologous cellular therapy isolated from a patient's tumor. Clinical data demonstrated that TIL therapy in heavily pretreated melanoma patients yielded an objective response rate (ORR) in 30% of patients with 5-year overall survival (OS) of approximately 20%. TILs were approved by the FDA in February 2024 for the treatment of metastatic or unresectable melanoma that have progressed on anti-PD-1 therapy and BRAF+MEK inhibitors (in patients with BRAFV600 mutation). Non-melanoma skin cancers, including cutaneous squamous cell cancer (CSCC) and Merkel cell cancer (MCC), share biologic features with melanoma, including an “inflamed” tumor microenvironment and high responsiveness to anti-PD-1 therapy. However, approximately, a third of patients will experience disease progression after anti-PD-1 therapy or will discontinue treatment due to toxicity and subsequently experience disease progression. Given the overlap between melanoma and CSCC/MCC, we hypothesize that TIL therapy may induce immune response against non-melanoma skin cancers. Because some of these tumors are superficial and are often ulcerated and can contain polymicrobial contamination, this trial will also assess the feasibility of TIL production in this unique patient population, alongside its safety and efficacy. Methods: Ten patients with CSCC (Cohort A) and 4 patients with MCC (Cohort B) adults will be eligible for TIL if they have disease progression after anti-PD-1 therapy. Eligible patients should have adequate organ function and be able to receive dose-reduced non-myeloablative lymphodepletion (NMA-LD) and interlukin-2 (IL-2). Following tumor harvest and TIL manufacturing, patients will receive NMA-LD including cyclophosphamide (30 mg/kg on days –5 and –4), and fludarabine (25 mg/m2 on days –5 to –1). Subsequently, patients will receive TIL on day 0 followed by IL-2 (600,000 IU/kg) for up to 6 doses. The primary objective is to evaluate feasibility and safety of TIL production and administration in cohorts A and B (defined by successful tumor harvest that leads to a TIL product that contains ≥ 1 x 10^9 cells, administration of NMA-LD, infusion of TIL therapy and complete at least 1 dose administered of IL-2). Secondary objectives include ORR, progression-free survival, duration of response, OS and correlative studies. Within Cohort A, efforts will be made to achieve an approximately equal distribution of ulcerated and non-ulcerated lesions. To maintain this balance, ulceration status will be monitored throughout the enrollment process, and eligibility criteria may be modified as necessary to ensure proportional representation of each subtype. Clinical trial information: NCT07288073 .

Overcoming resistance to prior CAR-T therapy: Efficacy and safety of a sequential, multi-antigen targeted CAR T-cell strategy in B-cell NHL.

7021 Background: Relapse following CAR T-cell therapy is a significant unmet need for patients with B-cell non-Hodgkin lymphoma (B-NHL). Strategies to effectively salvage these patients are urgently required. We report the results of a prospective study evaluating a novel approach of sequential CAR T-cell administration, often with alternative antigen targeting, in this heavily pre-treated population. Methods: In this single-center, Phase I/II investigator-initiated trial, we enrolled patients with R/R B-NHL who had progressed after at least one prior CAR T-cell infusion. Patients received a second autologous CAR T-cell product targeting a different (e.g., CD20, CD22, CD79b) or re-challenging the same antigen with a different construct. The primary endpoints were safety and overall response rate (ORR). The cohort included high-risk subtypes such as primary central nervous system lymphoma (PCNSL). Results: As of the data cut-off, 26 patients with R/R B-NHL (DLBCL, n=18; PCNSL, n=6; Burkitt, n=2) were infused. The median number of prior therapies was 5 (range 3-8). All patients had failed a prior CAR-T therapy. With a median follow-up of 10.2 months, the ORR was 88.5% (23/26), with an outstanding CR rate of 73.1% (19/26). Efficacy was profound even in the most challenging histologies; in the cohort of 6 patients with R/R PCNSL, the CR rate was an unprecedented 83.3% (5/6). The safety profile was highly encouraging. Cytokine release syndrome (CRS) occurred in 92.3% (24/26) of patients, with the majority being Grade 1 (61.5%) or Grade 2 (30.8%). No Grade ≥3 CRS was observed. Immune effector cell-associated neurotoxicity syndrome (ICANS) was rare and mild, with only Grade 1 events reported in 19.2% (5/26) of patients; no Grade ≥2 ICANS occurred. Hematologic toxicities were manageable and reversible. Conclusions: Sequential CAR T-cell therapy is a highly effective and safe strategy that can induce high rates of durable complete responses in B-NHL patients who have relapsed after initial CAR-T treatment. The exceptional activity observed in PCNSL suggests this approach can overcome the blood-brain barrier and address a critical unmet need. These results support the integration of sequential CAR T-cell therapy as a new standard of care for this patient population. Clinical trial information: ChiCTR1900025419.

DNA methylation–based liquid biopsy for longitudinal monitoring of treatment response in metastatic breast cancer.

e15051 Background: Treatment response in metastatic breast cancer patients is currently monitored with CT-scans every 3-6 months leaving many patients on ineffective therapies while their disease progresses. The methylation DETEction of Circulating Tumour DNA (mDETECT) assay is a targeted DNA methylation-based Next Generation Sequencing liquid biopsy designed to detect cancer specific DNA methylation patterns. The mDETECT breast cancer assay targets 58 hypermethylated regions across the genome, assessing over 400 CpG sites. The assay has been designed to detect all subtypes of breast cancer, and is quantitative for molecules of methylated DNA. As a tumour and treatment agnostic assay with compact sequencing requirements (2 million sequencing reads per sample), mDETECT is ideal for frequent disease monitoring. The mDETECT breast cancer assay has shown 93% sensitivity at 100% specificity for TNBC and has a limit of detection of 0.025%. Methods: We are conducting a prospective multi-centre observational cohort study to monitor metastatic breast cancer patients using the mDETECT liquid biopsy as they undergo treatment. Metastatic breast cancer patients are eligible regardless of subtype or treatment and are followed through treatment changes. 20mL of blood was collected at each standard of care blood draw for up to 3 years. Plasma was extracted from patient blood draws and assessed using the mDETECT assay. To date, 128 participants have been enrolled, generating over 700 longitudinal blood sample timepoints (1-22 timepoints per patient). Patient’s longitudinal samples were assessed for their response to treatment and monitored over time for disease progression. Results: This initial analysis focuses on fifteen patients who were followed with standard of care blood draws throughout their treatments until death. Results show decreasing mDETECT levels during initial treatment response indicating response or partial response to treatment. In multiple patients, increasing mDETECT levels were observed prior to treatment change, radiological disease progression, and death. In some patients, the final timepoints before death showed a dramatic increase in both plasma cell free DNA levels and mDETECT determined circulating tumour DNA levels, consistent with advancing disease. Conclusions: These findings demonstrate the potential of methylation-based longitudinal monitoring of treatment response for metastatic breast cancer patients, a key clinical need given the large number of available therapies and complex treatment sequence decisions to be made. Longitudinal DNA methylation trajectories measured by mDETECT reflect treatment response and rising disease burden in metastatic breast cancer, suggesting a potential role for earlier identification of ineffective therapies and more timely treatment decision-making.

Correction: Unpacking the dual psychological paths of employee-AI collaboration on creativity: The role of proactive behavior

Enantioselective Synthesis of Inherently Chiral Tetraphenylene Analogues Enabled by NHC‐Catalyzed Benzoin Condensation

ABSTRACT Herein, we report an enantioselective N‐heterocyclic carbene (NHC)‐catalyzed intramolecular benzoin reaction of bisaldehydes featuring a 1,1′:2′,1′′‐terphenyl linkage to afford eight‐membered α‐hydroxy ketones in which six of the eight ring atoms are benzene carbons. The benzene‐rich framework is conformationally inflexible and thus inherently chiral, adopting a saddle‐shaped conformation. A variety of heteroaromatic‐ and naphthalene‐embedded tetraphenylene analogues were prepared enantioselectively by routine transformations of the α‐hydroxy ketone moiety. Density functional theory (DFT) calculations elucidate the reaction mechanism and provide insights into the origin of the stereoselectivity.

Green synthesis of CuO nanoparticles using Ixora chinesis leaf extract for photocatalytic decolourisation of Rhodamine B and antibacterial performance

Neural crest gene regulatory networks as drivers of development, diversification and disease

3D‐Printable, Honeycomb‐Inspired Tissue‐Like Bioelectrodes for Patient‐Specific Neural Interface (Adv. Mater. 31/2026)

Stable Antisymmetric Magnetoresistance in Fe ₃ GaTe ₂ /InSe/Fe ₃ GaTe ₂ van der Waals Heterostructures With Multi‐State Functionality

ABSTRACT Ferromagnetic van der Waals (vdW) heterostructures are pivotal for next‐generation spintronics, especially in realizing novel functionalities like antisymmetric magnetoresistance (ASMR). While ASMR holds immense potential for multi‐state memory and logic operations, achieving stable performance across a broad range of conditions and realizing diverse multi‐state functionalities remain key challenges. Here, we report the demonstration of multi‐state ASMR signals in a Fe 3 GaTe 2 /InSe/Fe 3 GaTe 2 vdW heterostructure, effectively operating up to 320 K. Intriguingly, the conventional three‐state ASMR undergoes a unique temperature‐induced shape reversal, which is precisely correlated with the temperature‐dependent crossover of the coercive fields of the two Fe 3 GaTe 2 layers. Through adapted measurement configurations, an unconventional four‐state ASMR, featuring distinct high, intermediate‐1, intermediate‐2, and low resistance states, has been obtained, holding significant promise for enhancing multi‐state memory density. Crucially, the device exhibits superior signal stability across wide variations in bias current (0.01–100 µA ) and magnetic field angle (0 ° –360 ° ). Programmable prototype devices demonstrating highly distinguishable states are also presented. The junction resistance of our devices is only a few kiloohms owing to the perfect Fermi level alignment between Fe 3 GaTe 2 and InSe, making them highly compatible with complementary metal–oxide–semiconductor circuits. This work lays a solid foundation for future stable multi‐state memory applications.

Molecular dynamics of deuterium plasma on TiB₂ sputtering in tokamak wall surfaces for Shannon entropy of computation

Profiling of fatty acids and lipids in animal and human tissues yields new leads for disease progression biomarkers of X-linked adrenoleukodystrophy

Use of a patient-facing digital tool for glioblastoma outside scheduled clinic visits.

1514 Background: Care for patients with glioblastoma is largely organized around scheduled clinic encounters, yet symptom management, decision-making, and caregiver responsibility extend beyond office visits. While patient portals, phone triage, and after-hours call coverage exist, these pathways are often resource-intensive, variably available, and insufficient to meet ongoing informational and emotional needs. Scalable, low-cost tools that extend access to vetted support outside clinic hours without increasing clinician workload may help address gaps in care delivery. We evaluated real-world use of a freely accessible, patient- and caregiver-facing digital support tool in glioblastoma. Methods: A freely accessible AI chatbot supporting informational, emotional, and care-navigation needs was deployed online without registration or recruitment. The tool excluded medical decision-making and clinical recommendations. De-identified conversation logs generated during routine use were retrospectively analyzed over a 4-month period (Sep 15, 2025 – Jan 14, 2026). Analyses included descriptive characterization of conversation volume, geographic distribution, timing of use, engagement depth, user-reported feedback, and primary topics addressed. All analyses used aggregate, de-identified data with no interaction or intervention involving human subjects. The protocol is IRB exempt per 45 CFR 46.104(d)(4) (WCG IRB 20260304). Results: During the study period, the chatbot supported 1,661 conversation threads comprising 15,197 messages across 54 countries. Most conversations originated from the United States (59.9%), followed by the United Kingdom (7.3%), Australia (5.2%), Canada (4.1%), and Greece (3.8%). Conversations were predominantly multi-turn and included use outside clinic hours. The tool was used primarily in English; however, ~12% of messages occurred in other languages, most commonly Spanish and French with additional use of Arabic, German, Italian, Portuguese, Hebrew, Hindi, and several Central and Eastern European languages. Conversations most frequently addressed imaging interpretation and scan-related uncertainty, treatment decision-making, symptom management and treatment-related side effects, and caregiver concerns. Additional topics included clinical trial exploration and prognosis clarification. When clinical trial–related questions arose, users were directed to a brain tumor trial finder. Across the study period, 374 users engaged in trial searches across 22 countries; among respondents to a trial-interest query (n = 251), 92% expressed interest. Voluntary user feedback (n = 97) demonstrated high perceived usefulness and trust (net promoter score, 80). Conclusions: A freely accessible AI chatbot demonstrated feasibility as a scalable approach to extending access to care for patients with glioblastoma and their caregivers outside office hours.

Phase III CR-SEQUENCE trial of FOLFOX+panitumumab followed by FOLFIRI+bevacizumab (SEQ1) versus FOLFOX + bevacizumab followed by FOLFIRI + panitumumab (SEQ2) in previously untreated RAS wild-type, left-sided, unresectable metastatic colorectal cancer.

3512 Background: The optimal sequencing of systemic therapy for patients with RAS wild-type, left-sided metastatic colorectal cancer (mCRC) remains under debate. This study evaluates whether starting with SEQ1 improves the 36-months progression-free survival rate (PFSR) versus SEQ2. Methods: Adult patients were randomized (1:1) to SEQ1 or SEQ2 and treated until second-line progression or unacceptable toxicity. Key inclusion criteria were untreated left-sided and wild type RAS (per local test) primary mCRC, ECOG-PS<2, measurable disease (RECIST 1.1), and adequate organ function. Primary endpoint was 36-month PFSR in ITT. Secondary endpoints included overall survival (OS), total PFS, objective response rate (ORR), PFS1, PFS2, and safety. Results: A total of 418 patients were analyzed (SEQ1=210; SEQ2=208); 54.76% and 70.19% of randomized patients received 2L treatment in SEQ1 and SEQ2 arms, respectively. The median follow-up was 62.2 months (95%CI 55.2 – 65.5). SEQ1 yielded a higher 1st-line ORR (80.95% vs 64.25%, p <0.01) and significantly improved median PFS1 (14.09 vs 12.39 months, p=0.03). In second line, SEQ2 (FOLFIRI + panitumumab) resulted in a higher ORR (40.43% vs 27.27%, p=0.03). There was no significant difference in 36-months PFS rate (28.57% vs. 22.36%; p=0.224). Median total PFS and OS were 22.93 vs 21.39 months (p=0.2241) and 36.57 vs 31.74 months (p=0.2949), respectively. Longer follow-up for PFS and OS is ongoing. Curative intent procedures were performed in 22.86% (SEQ1) and 19.23% (SEQ2) of patients, respectively. Rescue surgery improved PFS and OS across both sequences. Common related G3-4 adverse events included neutropenia (42%), rash (15.7%), diarrhea (13%), peripheral neuropathy (12%), and fatigue (12.3%). Conclusions: SEQ1 did not improve the 36-month PFSR versus SEQ2. However, starting with SEQ1 yielded superior early efficacy (higher ORR and longer PFS1), which may be clinically relevant in a subset of patients. Molecular profiling and genomic correlation analyses are ongoing to identify biologically defined clusters that may improve selection of sequential treatment strategies. Longer follow-up for clinically relevant secondary endpoints (total PFS and OS) is ongoing. Clinical trial information: 2024-510967-41-00. Baseline characteristic by treatment arm. Characteristic SEQ 1 (n=210) SEQ 2 (n=208) Age, median (IQR*), years 63 (57-71) 63 (57-71) Sex, n (%) FemaleMale 53 (25.2)157(74.8) 58(27.9)150 (72.1) ECOG-PS, n (%) 01 112 (53.3)98 (46.7) 118 (56.7)90 (43.3) Metastasis per organ, median (range) 2 (1-6) 2(1-7) Baseline CEA, median (IQR), ng/mL 40.7 (11.6 – 364.3) 74.5 (11.8 – 643.9) Prior therapies Adjuvant chemoRadiationPrimary tumor resection 27 (12.9)23 (10.9)56 (26.7) 24 (11.5)18 (8.6)72 (34.6) *IQR: interquartile range.

Effect of statin use on survival in patients with endometrial cancer.

e17641 Background: Statin use has been found to reduce cancer related mortality in multiple cancer types. Prior studies have not specifically studied endometrial cancer independently from other tumors. This study investigates concurrent statin use on cancer related mortality in patients diagnosed with endometrial cancer. Methods: This is a single institution retrospective cohort study of patients diagnosed with endometrial cancer between 2014-2017. Statin use was defined as patients with initiation of therapy prior to the initial date of surgery or within 30 days postoperatively. Demographic, clinicopathologic, and treatment data were collected from the medical record. Proportional variables were compared using Chi-square and Fisher’s exact tests, while continuous variables were compared using t-tests and Mann-Whitney U-tests. Disease-specific survival (DSS, time from diagnosis to death due to cancer) was estimated using Kaplan-Meier plots, with log-rank and Cox proportional hazards analysis used to compare groups. Results: 765 patients were diagnosed with endometrial cancer and met inclusions criteria. 273 patients were taking a statin at the time of their diagnosis. Most patients were white race (n=704, 92.0%), diagnosed with FIGO grade 1 endometrial cancer (n=523, 68.3%), endometrioid histology (n=667, 87.2%), stage I disease (n=612, 80.0%), MMR proficient status (n=571, 74.6%). Overall, 86.1% (n=659) patients did not have disease recurrence and 67.6% (n=517) did not require adjuvant therapy following surgery. When compared with those who did not use statins, the statin group was older with an average age of 65.0 (SD +/- 9.3, p=<0.0001). BMI, race, FIGO grade, histology, stage, MMR status, recurrence, and adjuvant therapy were not statistically significant between the two groups. Most patients who took statins had a duration of use of >5 years surrounding the study period (70.7%). On multivariate analysis, there was no effect on DSS (HR 0.71 [0.35-1.35], p=0.3025) after adjusting for the above factors. Conclusions: Treatment with statins at the time of endometrial cancer diagnosis did not impact DSS in our cohort. Further studies are needed to elucidate the mechanism of cancer risk reduction of statin therapy and its effect on different cancer types, including endometrial cancer.

Comparative efficacy of immune checkpoint inhibitor backbones in <i>STK11/KEAP1</i> -mutant advanced non–small cell lung cancer: A systematic review and meta-analysis.

e20640 Background: Immunotherapy is a cornerstone of treatment for advanced non–small cell lung cancer (NSCLC), though efficacy varies by genomic context. Mutations in STK11 and KEAP1 are associated with immune resistance and poor outcomes, while co-occurring KRAS G12C mutations or higher tumor mutational burden (TMB) may influence response. Multiple immune checkpoint inhibitor (ICI) backbones are used, but their comparative efficacy in STK11/KEAP1-mutant NSCLC remains unclear. We performed a systematic review and meta-analysis to compare outcomes across ICI strategies and molecular subgroups. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science for randomized trials and comparative observational studies evaluating ICI-based regimens in advanced NSCLC with STK11 and/or KEAP1 mutations. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included response rates and toxicity. Random-effects meta-analyses pooled log-transformed hazard ratios (HRs) using an inverse-variance DerSimonian-Laird model, with heterogeneity assessed by I². Prespecified subgroup analyses examined the treatment backbone, mutation profile, and TMB (as available). Analyses were performed in R. Results: Twenty-five studies encompassing 13,065 patients were identified; seven studies (n = 7,467) contributed to the meta-analysis. Most studies showed male predominance. Patients predominantly had non-squamous NSCLC (largely adenocarcinoma), were treated primarily in the first-line setting, and had reported genomic alterations, with primary emphasis on STK11 and KEAP1 mutations. Compared to chemotherapy alone, chemoimmunotherapy improved OS (pooled HR 0.79; 95% CI, 0.70–0.89; I² = 9.8%) and PFS (HR 0.71; 95% CI, 0.63–0.80; I² = 0%). Dual ICI plus chemotherapy yielded similar benefits (OS HR 0.75; 95% CI, 0.67–0.84; PFS HR 0.71; 95% CI, 0.63–0.80). Mutation-specific analyses revealed inferior outcomes in STK11-mutant versus wild-type tumors (pooled PFS HR 1.46; OS HR 1.57). Median OS and PFS varied substantially across regimens. PD-L1 expression and TMB were inconsistently reported and could not be pooled. Toxicities were primarily hematologic and constitutional; serious immune-mediated events and treatment-related mortality remained uncommon. Conclusions: In advanced NSCLC harboring STK11 and/or KEAP1 mutations, intensified ICI backbones, particularly chemoimmunotherapy and dual ICI plus chemotherapy, provide survival benefits over chemotherapy alone, mitigating the adverse prognostic impact of STK11 mutations. These results support prioritizing combination ICI strategies in this high-risk subgroup and highlight the need for prospective, genomically stratified trials with standardized TMB assessment to refine treatment selection.

Sociodemographic variation in live birth incidence and access to assisted reproductive services among female cancer patients in the United States.

1640 Background: Sociodemographic variation in fertility outcomes after cancer is not well described. We constructed a novel longitudinal dataset to capture sociodemographic variation in 1) live births and 2) use of assisted reproductive technology (ART) among female cancer patients across the US from 2004-2022. Methods: We linked population-based cancer registry data (2004–2018 in 12 states; 2004–2011 in California) with live birth certificates (2004–2022) and the Society for Assisted Reproductive Technology (2004-2022) database, which captures ~90% of ART cycles nationally, to create a dataset integrating oncologic characteristics, obstetric outcomes, and ART use. Patients aged 15-45 at diagnosis of cancer were included. The primary outcome was 5-year cumulative live birth incidence (CLBI) using the Fine and Gray method to account for all-cause death as a competing event and log-rank tests to compare by age, race/ethnicity, insurance, cancer site, cancer stage, and receipt of systemic therapy. Secondary outcome was use of ART after cancer diagnosis, defined as &gt;1 autologous oocyte/embryo cryopreservation or embryo transfer cycles. Patients were categorized by expected fertility detriment, defined as pelvic malignancy and/or receipt of chemotherapy, hormone therapy, or abdominal or pelvic radiation, and covariates compared descriptively. Person-years were accrued from diagnosis date to first post-diagnosis birth/use of ART, death, age 51 (oldest age a post-cancer birth was observed), or December 31, 2022, whichever occurred first. The study was approved by the institutional review board. Results: 286,198 female cancer patients were included with 15 live births per 1,000 person-years. 5-year CLBI was 6.14% [6.05, 6.24]. Lower CLBI was observed in Hispanic (4.5% [4.31, 4.76]) and non-Hispanic Black (NHB) (5.23% [4.98, 5.50]) populations compared to non-Hispanic white (NHW) populations (6.75% [6.62, 6.88]) (p&lt;0.001). Patients with public insurance also had significantly decreased CLBI (4.68% [4.47, 4.90]) than those with private insurance (6.08% [5.95, 6.20], p&lt;0.001). NHB, Hispanic, and patients with public insurance comprise higher proportions of patients with expected fertility detriment versus those without detriment (12.6 vs 8.6%, 18.2 vs 13.1%, and 18.7 vs 13.3%, p&lt;0.001) but lower proportion of patients that use ART versus those that do not (5.9 vs 11.4%, 7.6 vs 16.6%, and 4.1 vs 17.1%, p&lt;0.001). Conclusions: National vital statistics data demonstrates high fertility rates among Hispanic and NHB populations; among cancer patients, however, these trends are flipped, with lower cumulative incidence of live births in these groups. Despite a higher burden of anticipated fertility detriment, NHB, Hispanic, and publicly insured patients were less likely to access fertility care, revealing stark inequities in survivorship care.

The long-term influence of adverse social determinants of health on clinical outcomes in breast cancer survivors: Insights from a propensity score–matched cohort study using federated electronic health records.

e12745 Background: Social determinants of health (SDOH), including housing instability, food insecurity, and socioeconomic challenges, are increasingly recognized as modulators of cancer outcomes. However, their long-term effects on breast cancer survivors remain underexplored. This study examines associations between adverse SDOH and clinical outcomes in breast cancer patients using real-world data. Methods: Utilizing the TriNetX federated network, we conducted a retrospective analysis to compare outcomes on adult breast cancer patients (ICD-10-CM: C50) from 88 healthcare organizations. Cohort A (Breast_SDOH; n = 21,947) comprised patients with documented adverse SDOH (e.g., homelessness [Z59.0], food insecurity [Z59.41]), while Cohort B (Breast_nonSDOH; n = 1,031,237) excluded such factors. Propensity score matching (1:1) balanced cohorts (n = 21,184 each) on demographics, comorbidities, and BMI. Outcomes assessed starting 1-day post-index event (first breast cancer or SDOH diagnosis), included mortality, severe sepsis, lymphedema, pain, malaise/fatigue, memory loss, and angiosarcoma. Analyses included measures of association, Kaplan-Meier survival, and instance counts, with statistical significance at p &lt; 0.05. Results: Adverse SDOH were associated with significantly higher risks and hazards for several outcomes. Mortality risk was elevated (15.9% vs. 13.4%; risk ratio [RR] 1.186, 95% CI 1.132-1.243; p &lt; 0.001), with a hazard ratio (HR) of 1.849 (95% CI 1.755-1.948; p &lt; 0.001). Severe sepsis showed increased risk (4.5% vs. 3.6%; RR 1.248, 95% CI 1.134-1.373; p &lt; 0.001; HR 1.872, 95% CI 1.695-2.068; p &lt; 0.001). Malaise and fatigue (23.1% vs. 22.0%; RR 1.048, 95% CI 1.001-1.097; p = 0.047; HR 1.520, 95% CI 1.441-1.603; p &lt; 0.001) and memory loss (13.5% vs. 11.7%; RR 1.161, 95% CI 1.099-1.228; p &lt; 0.001; HR 1.895, 95% CI 1.783-2.014; p &lt; 0.001) were also more prevalent. Conversely, lymphedema (5.9% vs. 8.3%; RR 0.713, 95% CI 0.663-0.768; p &lt; 0.001) and angiosarcoma (19.1% vs. 38.4%; RR 0.497, 95% CI 0.475-0.521; p &lt; 0.001; HR 0.505, 95% CI 0.479-0.532; p &lt; 0.001) risks were lower, potentially reflecting differential healthcare access or documentation biases. Pain exhibited mixed findings, with marginally lower risk (19.3% vs. 20.4%; RR 0.944, 95% CI 0.899-0.991; p = 0.021) but higher hazard (HR 1.508, 95% CI 1.426-1.594; p &lt; 0.001), suggesting accelerated onset in the SDOH group. Conclusions: Adverse SDOH exacerbate long-term risks of mortality, sepsis, and neurocognitive symptoms in breast cancer survivors, underscoring the need for integrated social support interventions. Lower risks for certain treatment-related outcomes may indicate barriers to care or underreporting. These findings call for SDOH screening and mitigation strategies in oncology to improve equitable outcomes.

Rad2Nivo: Phase IB study of radium-223 (Rad) with nivolumab (Nivo) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

5060 Background: Rad is an α-emitting calcium-mimetic radiopharmaceutical that is FDA approved for pts with mCRPC with symptomatic bone metastasis (mets) and no visceral mets. Preclinical data suggest that radiation might enhance the anticancer effect from PD-1 therapy [PMID 25274032, 29137877]. Nivo is a PD-1 immune checkpoint antagonist. Few pts experience PSA reduction with Rad, and objective responses in bone mets cannot be assessed. We hypothesized that Rad+Nivo would be safe and result in decreased ctDNA variant allele frequency (VAF) as a marker of clinical efficacy. Methods: In this phase IB, prospective, open-label, single-center, single-arm study (NCT04109729), pts with symptomatic bone-metastatic mCRPC without visceral mets were eligible. Participants received intravenous Rad (55 kBq/kg IV) monotherapy for 6 cycles. Nivo (480mg IV) was introduced starting with cycle 3 and continued for up to 2 years. ctDNA collected at baseline, cycle 3 and 6 weeks after. Primary endpoints: (1) frequency of grade ≥3 non-hematologic treatment-emergent adverse events (TEAEs) and (2) change in ctDNA VAF from baseline compared to after 6 weeks of nivolumab therapy. Mean VAF was defined as average VAF of all somatic mutations present at baseline at a VAF 1%. Null hypothesis: proportion of pts with a non-zero ctDNA reduction is ≤ 20%. A one-sided exact binomial test was used to evaluate whether the proportion of pts demonstrating a decrease in mean VAF on-treatment exceeded 20%. With 36 pts, there will be 83% power at one-sided α = 0.05 to detect an alternative proportion of subjects with ctDNA reduction = 40%. Results: Overall, 39 pts were enrolled trial between 9/2020 and 1/2025, and 35 pts were treated with both Rad+Nivo. Median age was 71 years (54-84), median PSA at study entry was 13.9 ng/dL (0-3245). 22 pts (56.4%) had Gleason score ≥8 (unavailable for 3 pts). Median number of prior lines of therapy was 3 (1-7). 53.9% (n = 21) of pts had received prior chemotherapy. 61% (n = 24) of pts completed 6 doses of Rad (range 2-6). The median number of Nivo cycles was 4 (0-25). Dose holds or delays occurred in 26% (n = 10) and 31% (n = 12) of pts receiving Rad and Nivo, respectively. 38% (n = 15) of pts experienced at least one grade 3-5 TEAE regardless of attribution. Grade 3-4 TEAE related to Rad and Nivo occurred in 15% (n = 6) and 18% (n = 7) of pts, respectively. No dose-limiting toxicities were observed. Serious adverse events related to Rad and Nivo occurred in 5% (n = 2) and 2.6% (n = 1) of pts, respectively. Paired molecular data was available for 25 pts. VAF was measurable in all patients who had samples collected and reduction was observed in 15 of 25 pts (60%, one-sided 95% CI, 41.7%-100%; p &lt; 0.01). Conclusions: The study met its primary endpoints. Rad+Nivo appears to be safe and VAF was decreased in 60% of patients tested. Survival outcomes and clinical correlation data with VAF will be presented at the meeting. Clinical trial information: NCT04109729 .

A multicenter, randomized, double-blind, phase 2/3 study of ficerafusp alfa (BCA101) or placebo in combination with pembrolizumab for first-line treatment of HPV-negative, PD-L1–positive, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): FORTIFI-HN01.

TPS6129 Background: HPV-negative HNSCC is an aggressive disease characterized by high rates of recurrence, metastasis, and resistance to standard treatments. Most HPV-negative HNSCC tumors overexpress tumorigenic factors EGFR and TGF-β. In a phase 1/1b trial (NCT04429542), ficerafusp alfa demonstrated promising efficacy and a manageable safety profile in first-line R/M HNSCC. FORTIFI-HN01 (NCT06788990) is an ongoing randomized, double-blind, placebo-controlled, phase 2/3 trial designed to assess the efficacy and safety of ficerafusp alfa combined with pembrolizumab vs placebo plus pembrolizumab in patients with PD-L1-positive first-line R/M HPV-negative HNSCC. Methods: Eligible patients must have histologically confirmed R/M HNSCC with primary lesions in the oral cavity, larynx, or hypopharynx, or HPV-negative OPSCC confirmed by central laboratory testing. Additional eligibility criteria include no prior systemic therapy for R/M disease, PD-L1-positive tumor (CPS ≥1), measurable disease per RECIST v1.1, and ECOG performance status 0 or 1. The phase 2 objective was to determine the optimal biological dose (OBD) of ficerafusp alfa through an integrated analysis of safety, tolerability, PK, PD, and efficacy. Following OBD determination (1500 mg QW), the trial transitioned seamlessly into the phase 3 portion with 2:1 randomization (ficerafusp alfa:control). Randomization is stratified by PD-L1 CPS (1-19 vs ≥20) and disease extent (local/regional recurrence only, distant metastasis only, or both). Patients receive pembrolizumab (200 mg IV every 3 weeks for up to 35 cycles) and either ficerafusp alfa or placebo IV QW until disease progression or unacceptable toxicity. Tumor imaging occurs every 6 weeks during the first year and every 9 weeks thereafter. The primary endpoints are objective response rate (ORR) per RECIST v1.1 (blind independent committee review) and overall survival. An interim analysis evaluating ORR is planned. Secondary endpoints include safety, duration of response, progression free survival, clinical benefit rate, and patient-reported outcomes. The trial is actively recruiting, with planned enrollment of ~650 subjects. Clinical trial information: NCT06788990 .