Standard Of Care Therapy Research Articles

BIOM-43. SOMATICTP53, PIK3R1, NF1 ORTERT MUTATIONS ARE ASSOCIATED WITH INFERIOR CLINICAL OUTCOME IN H3K27M-ALTERED DIFFUSE MIDLINE GLIOMA: AN INTERNATIONAL, MULTI-INSTITUTIONAL STUDY

Abstract BACKGROUND H3K27-altered diffuse midline gliomas (DMGs) have poor prognosis with no standard of care therapy beyond radiation (RT). While RT prolongs survival, not all patients respond. Molecular biomarkers can be a strategy to predict RT response and thus patient outcomes. METHODS We performed a retrospective analysis of patients with biopsy-proven H3K27M-altered DMG between 2013-2023 from six US medical centers and the DMG Center in Zurich. Patients with tumor genomic sequencing and completion of RT were eligible. Genomic alterations were evaluated for somatic mutations, fusions, and chromosomal instability. Cox proportional hazard models were used to evaluate associations between genomic alterations and survival. Multivariate analysis included all significant variables at P <0.1 in initial analysis, including age at diagnosis, tumor location, TP53 and PIK3R1 alterations. RESULTS 297 patients (135 female; median age 8.3 years; range 0.2-71.4 years) were included. Median progression-free survival (PFS) and overall survival (OS) was 7.6 months (95%CI: 6.9-8.6) and 14.0 months (95%CI: 12.9-15.7). In univariate analysis, TP53 or PIK3R1 status correlated with shorter OS (TP53-mutant 12.5 vs. TP53-wildtype 17.5 months; HR=1.5; 95%CI: (1.1-2.0), P= 0.005); (PIK3R1-mutant 12.6 vs. 14.5 months; HR=1.9, 95%CI: (1.1-3.4), P = 0.03). Multivariate analysis corroborated TP53-mutant status with poorer OS (HR=1.5; 95%CI: (1.2-2.0), P= 0.003). Subgroup univariate analysis of pontine DMG patients showed poorer OS with TP53, NF1, or TERT mutations (TP53-mutant 11.9 vs. 15.2 months; HR= 1.6; 95%CI: (1.1-2.3), P= 0.02); (NF1-mutant 8.4 vs. 13.6 months; HR= 2.3; 95%CI: (1.1-5.0), P=0.03); (TERT 8.5 vs. 13.6 months; HR= 2.5; 95%CI: (1.1-5.7), P= 0.03). Subsequent multivariate analysis corroborated the association of TERT mutations with poorer OS in pontine DMG (HR=2.5; 95%CI:1.05, 5.9, P= 0.03). CONCLUSIONS This is the largest cohort of H3K27M-altered DMG patients with volumetric imaging analysis ongoing. Taken together, our data suggests these genetic alterations can risk-stratify patients for RT and future investigations of radiosensitizers targeting these alterations may improve survival.

CTNI-41. LONG-TERM SURVIVAL AND PATTERNS OF PROGRESSION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH OR WITHOUT TUMOR TREATING FIELDS (TTFIELDS) IN A REAL-WORLD SETTING

Abstract BACKGROUND Tumor Treating Fields therapy (TTFields) is an FDA-approved locoregional treatment for patients with newly diagnosed glioblastoma (ndGBM). Previous trial data showed the addition of TTFields to standard TMZ-based therapy to significantly improve overall survival (OS), but real-world data is lacking, particularly with long follow-up duration. Here, we report real-world survival and patterns of progression for patients with ndGBM treated with or without TTFields. METHODS Patients diagnosed with GBM and treated with standard of care therapy at the Medical College of Wisconsin between March 2015–March 2023 were included. Progression-free survival (PFS) and OS outcomes were assessed, and compared across groups who received or did not receive TTFields therapy during maintenance treatment. Patterns of disease progression were analyzed via anatomic assessment. Patients were followed through March 1, 2024. RESULTS A total of 210 patients (TTFields: n=110/52.4%; No-TTFields: n=100/47.6%) were included for analysis. Median age was 60 and 63 years for the TTFields and No-TTFields groups, respectively, with each group 43% female. Other baseline characteristics were consistent across groups. Median TTFields duration was 6.8 months (range: 1–94). OS was significantly improved for the TTFields group vs No-TTFields group (median OS: 21.6 months [18.4–24.8] vs 17.7 months [15.0–20.8]; HR 0.73 [95% CI: 0.54–0.99, P=0.042]). Median PFS was 12.1 months (10.3–14.4) vs 9.6 months (8.5–12.8) with HR 0.77 (95% CI: 0.58–1.02; P=0.071). 5-year OS was 17% (10–28) for the TTFields group, and 11% (5–22) for No-TTFields group. Patients treated with TTFields exhibited a higher rate of non-local progression compared with the No-TTFields group (28% vs 15%, [P=0.044]). CONCLUSIONS Analysis of patients from a large institutional dataset reveals an association between TTFields use and long-term survival benefit. Higher incidence of non-local patterns of progression among TTFields users is consistent with pivotal trial findings.

CTIM-21. FIRST-IN-HUMAN PHASE I CLINICAL TRIAL USING 8R-70CAR T CELLS FOR NEWLY DIAGNOSED ADULT GLIOBLASTOMA

Abstract BACKGROUND To address the challenges of chimeric antigen receptor (CAR) T cell therapy in GBM, we utilized IL-8 release from tumor cells as a ‘GPS homing signal’ to enhance T-cell trafficking with a novel CD70-specific CAR design (8R-70CAR) that targets GBM. The 8R-70CAR offers several advantages: 1) Improved CAR T-cell trafficking, enhancing antitumor efficacy; 2) Reduced CD70, reshaping the tumor microenvironment (TME) and boosting endogenous immunity; 3) Utilized CD27 as the CAR, a co-stimulatory molecule that enhances T-cell functions; 4) Enabled CAR T cells to act as a sink to neutralize or remove IL-8, a pro-cancer chemokine, from the TME; and 5) Required only 120 ml of whole blood (not leukapheresis) for CAR T cell production. Preclinically, 8R-70CAR significantly enhanced CAR-T cell tumor migration and persistence, leading to complete tumor regression and sustained immune memory in a chemo/radiation/PD-1-blockade-resistant GBM model. These findings led to a phase-I trial (IMPACT trial: FDA-IND#23881, NCT05353530) using 8R-70CAR T cells for CD70 -positive newly diagnosed adult GBM. METHODS We aim to recruit 18 adult patients (3 + 3 dose-escalation design) with CD70-positive (>20%) tumors. The CAR T cells will be given intravenously after completing standard-of-care (SOC) therapy. Primary endpoints: Evaluate safety, tolerability, and dose-limiting toxicities (DLTs) to determine the maximum tolerated dose. Secondary endpoints: Assess preliminary efficacy. Immune monitoring and correlative studies will also be conducted. RESULTS To date, four patients have been enrolled in the IMPACT trial, with 2 eligible patients participating in treatment at dose level 1 (1x10^6/kg). One patient has completed treatment with 8R-70CAR T cells, experienced no DLTs, and is currently in follow-up. The remaining patient is under SOC therapy before receiving CAR T cell treatment. CONCLUSIONS This study aims to address current therapeutic gaps and offers options for implementing a novel CAR design for the development of a more effective therapeutic modality for GBM.

CTNI-81. PROPOSAL FOR A PHASE IB PILOT CLINICAL TRIAL TO STUDY SAFETY AND IMPROVING ANTI-NEOPLASTIC ADVERSE EFFECTS BY ADDITION OF NATURAL MARINE PRODUCT FUCOIDAN TO THE STANDARD THERAPY FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

Abstract INTRODUCTION GBM is the most aggressive primary brain tumor. Despite standard of care (SOC) with the Stupp protocol and tumor treating fields (TTFs), survival remains poor. In addition, SOC treatment is associated with 96% any adverse effects (AE) and 25% severe AEs (Chinot et al, NEJM 2014), which affects quality of life (QOL) and can lead to early treatment termination. Therefore, novel therapies are needed and minimization of chemoradiation-related AEs is crucial. Marine natural product, fucoidan, may have an important role in oncological management as tumor-directed therapy and as a protectant against chemoradiation-related AEs. Fucoidan is a seaweed-derived sulfated polysaccharide. Mounting evidence garnered from randomized clinical trials for colon, head and neck, and lung cancer patients suggests that fucoidan can improve certain AEs associated with chemoradiation. Furthermore, data gleaned from multiple studies have shown that fucoidan is tolerable with a good safety profile. HYPOTHESIS Fucoidan is safe in combination with chemoradiation and chemotherapy and improves treatment related AE profile. Fucoidan may improve survival outcome in GBM patients by augmenting cytotoxic effects, inhibiting angiogenesis, and improving the tolerability of SOC therapy. METHOD 12 newly diagnosed GBM patients will be enrolled. A Fucoidan-based product will be administered orally at the established dose for cancer patients daily with concurrent chemoradiation therapy and adjuvant chemotherapy over 6 months. Patients will be evaluated weekly to monthly for AEs and QOL scoring; laboratory and brain MRI monitoring will be performed per SOC guidelines. NK cell activity, proinflammatory cytokines, including interleukin (IL)-1β, will be measured. POTENTIAL OUTCOME This pilot study may establish a foundation for future larger randomized clinical trials to treat brain cancer more effectively by adding nature products.

TMIC-55. CHARACTERIZATION OF THERAPEUTICS EFFECTS IN GLIOBLASTOMA THROUGH INTEGRATED SPATIAL SINGLE-CELL MULTIOME PROFILING OF LONGITUDINAL SAMPLES: UNVEILING CLINICALLY RELEVANT SUBTYPES OF PATHOLOGICAL CHANGES

Abstract Glioblastoma (GBM) remains a highly malignant, intrinsically resistant and inevitably recurring brain tumor with dismal prognosis. The aggressiveness and lack of effective GBM treatments can be attributed to the highly heterogeneous and plastic nature of GBM tumor cells, which easily confer resistance to standard-of-care (SOC) therapy. While tumor progression has also been attributed to interactions with the tumor microenvironment, quantitative data describing these interactions are still largely missing. Here, we used an multiome approach combining high-dimensional, multiplexed immunohistochemistry and spatial transcriptomics to map evolutions in the spatial, single-cell tissue architecture of 357 paired adult GBM tumor samples derived from 52 patients at diagnosis (ND) and upon recurrence (REC) following SOC treatment. We mapped the spatial distribution of a multitude of GBM tumoral subtypes across this multicentric cohort, through which we identified a high level of heterogeneity defined by specific tumoral niches within and across patients and which evolved when subjected to SOC therapy. In addition, we describe the relationship of the various tumoral niches with their local immune-infiltrates, highlighting an even more immunosuppressive environment following SOC resistance. Finally, by aligning these findings to the observed genomic aberrations and the clinical data of the patients, we are now able to more precisely describe the heterogeneous landscape of glioblastoma and how it evolves under SOC treatment at spatial, single-cell resolution.

Fatigue and Sleep-related Impairment as Predictors of the Effect of Nonpharmacological Therapies for Active duty Service Members With Chronic Pain: A Secondary Analysis of a Pragmatic Randomized Clinical Trial.

First-line treatments for chronic pain include selected complementary and integrative health therapies, including spinal manipulation, acupuncture, yoga, and massage; and standard rehabilitative care, including physical and occupational therapies. This study aimed to uncover critical factors that contribute to pain impact and the effectiveness of complementary and integrative health therapies and standard rehabilitative care among people with chronic pain, with a focus on the role of sleep-related impairment. We conducted a secondary analysis of data from a pragmatic randomized clinical trial of 280 U.S. active duty service members with chronic pain. Our study's multiple mediation analysis examined the indirect effect of complementary and integrative health therapies on pain impact through fatigue (β = - 0.43; 95% CI, -0.99 to -0.07). When stratified by sleep-related impairment, participants with T scores above the median of 62 demonstrated a significant negative indirect effect of complementary and integrative health therapies through fatigue (β = - 0.80; 95% CI, -2.31 to -0.14). This negative indirect effect was not significant for participants with sleep-related impairment T scores below the median (β = - 0.64; 95% CI, -1.48 to 0.07). These findings suggest that complementary and integrative health therapies are particularly effective in reducing pain impact for individuals with higher levels of sleep-related impairment, and that the effect of complementary and integrative health therapies is supported primarily by reducing fatigue.

Feasibility and Acceptability of a Palliative Care Intervention Among Older or Adults with Advanced CKD and their Caregivers.

In non-nephrology settings, specialty Palliative Care (PC) improves decision-making, patient's quality of life (QoL), advance care planning (ACP), and certain indicators of the quality of end-of-life (EoL) care. This pilot RCT explored the feasibility and acceptability of a PC intervention, CKD-EDU, for older adults ≥75 years with eGFR ≤25 ml/min and their caregivers. Participants randomized to the control group received standard nephrology care and routine kidney therapy (KT) education, while those randomized to CKD-EDU received a decision aid and met with a PC clinician up to three times to discuss KT decisions and EoL planning. Patients were assessed at baseline, 4-6, 12-14, and 24-26 weeks. Main outcomes included intervention feasibility and acceptability, decision-conflict, and patient QoL. The mediating effects of reduced decision conflict on improved QOL were explored, as were the effects of CKD-EDU on ACP, EoL treatment intensity and 6-month-hospitalization. Statistical analyses encompassed descriptive analyses, adjusted repeated-measure-models, mediation analyses and logistic-regression models. Among the 127 eligible patients screened, 58 (44%) consented: 30 were randomized to CKD-EUD and 28 to the control arm. All patients completed baseline assessments, and 89% completed at least one intervention session (n=26/29), underscoring intervention adherence and feasibility. Similarly, assessments completion rates at 4 (83%, n=45/54) ), 12 (93%, n=42/45), and 24 (95%, n=40/42) weeks were high. The intervention received over 85% acceptability ratings for all questions. Patients exposed to CKD-EDU exhibited significant improvement in decisional conflict scale scores (P = 0.003) at 4-6 weeks and improvements in QoL at 24-26 weeks (P=0.02). Exploratory analyses were not statistically significant in this pilot, but all effect sizes were in the predicted direction. This study demonstrates the feasibility and acceptability of CKD-EDU. A larger scale trial is warranted to assess its effectiveness in improving key outcomes important to patients and families.

Estimation of Plasma Concentration of L-Carnosine and its Correlation with Core Symptoms of Autism Spectrum Disorder Children: A Pilot Clinical Trial.

Literature indicates that L-carnosine may be deficient in autism spectrum disorder (ASD) children. The aim of the present study was to estimate the level of L-carnosine in plasma and correlate it with the Autism Treatment Evaluation Checklist (ATEC) and Childhood Autism Rating Scale 2nd Edition, Standard Version (CARS2-ST) scores. To measure L-carnosine level, a bio-analytical method was developed using reverse phase high- liquid chromatography and validated as per International Conference on Harmonization guidelines. Children were supplemented with L-carnosine (10-15 mg/kg) along with standard care therapies for 2 months. Before and after supplementation, scores on the ATEC, CARS2-ST, BEARS sleep screening tool, 6-item Gastrointestinal Severity Index, and Parental Stress Scale were evaluated, and L-carnosine was measured at the end of the trial. The calibration curve was linear in the range of 100-600 ng/mL (R2 = 0.998). The level of L-carnosine quantified was 33.7 ± 0.2 ng/mL. There was no significant difference found in any of the outcome measures (p > 0.05). Despite the fact that L-carnosine is detectable in the blood, it was found to be ineffective in the management of ASD in children. The study was registered in the Clinical Trial Registry-India, registration number: CTRI/2019/07/020102.

Cost-effectiveness analysis of denosumab versus alendronate for improving bone mineral density in renal transplant recipients: a comparative study

BackgroundDenosumab and alendronate had a positive impact on bone mineral density (BMD) preservation after kidney transplantation. However, the cost-effectiveness of these agents in the context of kidney transplantation remains largely unexplored. We have conducted a cost-effectiveness analysis to compare the cost and the clinical outcomes of adding subcutaneous (SC) 60 mg denosumab every 6 months vs. oral weekly 70 mg Alendronate, to the standard care therapy (vitamin D and calcium) in renal transplant recipients (RTRs). The impact of both drugs on BMD t-score improvement and fracture prevention was investigated. A decision-analysis model from a health care payer perspective was applied.ResultsThe cost-effectiveness analysis has shown that alendronate add-on to the standard therapy was the most cost-effective regimen, in terms of BMD improvement and fracture prevention with an incremental cost-effectiveness ratio (ICER) of $154/patient/year. The one-way sensitivity analyses have delineated the change in cost-effectiveness when alendronate retail unit price was increased by 25% and 50%, or when denosumab retail unit price was decreased by 25% and 50%. The model was sensitive to the uncertainties (95% confidence interval) in the probabilities of fracture prevention and the probabilities of attaining the desired outcome.ConclusionThe model suggests that oral once weekly alendronate add-on regimen to standard therapy seems to be substantially more cost effective than twice yearly SC denosumab in terms of BMD improvement and fracture prevention in RTRs. Longer time horizon models with longer follow-up periods for fracture risks and adverse events are warranted to validate these data.

Lactobacillus rhamnosus Helps to Reduce the Duration of Bleeding in Breastfed Infants with Allergic Proctocolitis.

Background: Cow's milk protein allergy (CMPA) is the most common food allergy in infants. The current standard of care (SOC) involves eliminating the allergen from both the infant's and mother's diet for 2-4 weeks. The purpose of this study is to assess the effectiveness of Lactobacillus rhamnosus (Ramnoflor) in reducing the duration of bleeding in these infants. Methods: This randomized clinical trial was conducted at Bahrami Children's Hospital on breastfed infants who were diagnosed with CMPA and had a positive occult blood (OB) test. Patients were randomly assigned to either the control or case groups. All patients received SOC therapy, with the case group receiving Ramnoflor and the control group receiving a placebo. Data were recorded on the checklist, and the children were followed and visited three times during the study, with an OB assessment at each visit. Results: The study enrolled 48 infants. Among the infants in the case group, the OB test was positive in four cases (8.3%) on the fifth day. However, there were no positive cases on the 14th and 30th days. The prevalence of this test was significantly lower in patients who received probiotics compared to the control group on the fifth day (p < 0.001). There were no positive OB tests on the 14th and 30th days in any of the groups, and no significant difference was observed between the groups. Conclusion: The addition of L. rhamnosus to SOC therapy led to a decrease in the duration of rectal bleeding in infants with CMPA compared to the control group.

Patient feasibility as a novel approach for integrating IRT and LCA statistical models into patient-centric qualitative data-a pilot study.

Clinical research increasingly recognizes the role and value of patient-centric data incorporation in trial design, aiming for more relevant, feasible, and engaging studies for participating patients. Despite recognition, research on analytical models regarding qualitative patient data analysis has been insufficient. This pilot study aims to explore and demonstrate the analytical framework of the "patient feasibility" concept-a novel approach for integrating patient-centric data into clinical trial design using psychometric latent class analysis (LCA) and interval response theory (IRT) models. A qualitative survey was designed to capture the diverse experiences and attitudes of patients in an oncological indication. Results were subjected to content analysis and categorization as a preparatory phase of the study. The analytical phase further employed LCA and hybrid IRT models to discern distinct patient subgroups and characteristics related to patient feasibility. LCA identified three latent classes each with distinct characteristics pertaining to a latent trait defined as patient feasibility. Covariate analyses further highlighted subgroup behaviors. In addition, IRT analyses using the two-parameter logistic model, generalized partial credit model, and nominal response model highlighted further distinct characteristics of the studied group. The results provided insights into perceived treatment challenges, logistic challenges, and limiting factors regarding the standard of care therapy and clinical trial attitudes.

Real-world clinical outcomes among patients with non-squamous advanced non-small cell lung cancer (aNSCLC) treated with docetaxel-based regimens post initial standard of care (SOC) in the United States.

392 Background: Immunotherapy (IO) or targeted therapy used separately or in combination with platinum-based chemotherapy (PBC) are SOC among treatment naïve aNSCLC patients. After progression on SOC, patients have limited treatment options. Previous US-based real-world studies have shown docetaxel ± ramucirumab as the most used line of treatment (LOT) post-SOC. This study sought to assess clinical outcomes associated with docetaxel+ramucirumab (DTX-R) or docetaxel monotherapy (DTX) received post SOC among patients with non-squamous aNSCLC independent of genomic alteration status. Methods: This retrospective study, using electronic medical record data from the ConcertAI Patient360 NSCLC data product (01/2015–09/2022), included adult patients (≥18 years) with stage IIIB-IV non-squamous aNSCLC who received docetaxel-based regimens (DTX-R or DTX) as subsequent LOT (index LOT) after discontinuation of the prior qualifying SOC LOT (IO + PBC or targeted therapy + PBC). Kaplan-Meier analysis was used to estimate median time to discontinuation (TTD), time to next treatment (TTNT), real-world progression-free survival (rwPFS), and real-world overall survival (rwOS) on docetaxel-based index regimens. Results: Out of 656 non-squamous aNSCLC patients which discontinued prior SOC therapy, 165 (25.2%) received a docetaxel-based regimen (n = 96 [DTX-R]; 69 [DTX]) which was the most commonly received index regimen. Other patients received a variety of other treatments, most commonly, pembrolizumab monotherapy (11.4%), pemetrexed + pembrolizumab (8.4%), pemetrexed monotherapy (4.4%), carboplatin + pemetrexed (4.1%), and osimertinib (3.8%). Among patients with index DTX-R and DTX, median age was 66 and 65 years; 36.5% and 60.9% were female; 74.0% and 63.8% were White; 86.5% and 75.4% received care in community setting; 15.1% and 31.8% had brain metastasis; 63.6% and 65.2% had ECOG 0-1; 1 and 2 median prior LOT; and median follow-up from index was 10 and 11 months, respectively. Median TTD, TTNT, rwPFS, and rwOS for docetaxel-based regimens are reported in the table. Conclusions: Docetaxel ± ramucirumab is the most used regimen in a fragmented treatment landscape post SOC therapy among patients with non-squamous aNSCLC. Observed rwOS, rwPFS, and treatment durations on docetaxel-based regimens in this real-world setting suggested the limited clinical benefit associated with these therapies. Overall, there is a need for more effective treatment options post SOC therapies. Real-world outcomes for DTX-R and DTX treated patients post SOC. Outcome, months (median, 95% CI) Docetaxel+Ramucirumab Docetaxel Monotherapy rwOS 6.37 (4.4, 9.3) 4.73 (2.3, 7.8) rwPFS 3.88 (2.8, 6.0) 3.22 (2.0, 5.7) TTD 3.06 (2.4, 3.5) 1.71 (1.7, 2.4) TTNT 3.45 (2.9, 4.5) 3.02 (1.9, 4.6)

Randomised controlled trial of a psychotherapeutic intervention to improve quality of life and other outcomes in people who repeatedly self-harm: FReSH START study protocol

BackgroundSelf-harm is a major public health challenge, and repeated self-harm is common in those attending hospital following an episode. Evidence suggests psychological interventions could help people who self-harm, but few definitive studies have assessed their clinical and cost-effectiveness. Repeated self-harm is associated with poor quality of life, depression, suicide and increased health service costs which justify the development of psychotherapeutic interventions tailored for people with repeated self-harm.MethodsFReSH START is a multicentre individually 1:1 randomised controlled trial evaluating the clinical and cost-effectiveness of standard care plus psychological therapy or standard care alone for adults (≥ 18 years) presenting at an emergency department (ED) with repeated self-harm. Recruiting 630 participants, it includes an internal pilot, economic evaluation and process evaluation. The intervention will be delivered by mental health staff working in acute settings, with experience of assessing and managing risk in people presenting to emergency services with self-harm. Staff will be trained and supervised to deliver one of three specially adapted therapies: psychodynamic interpersonal therapy, cognitive behavioural therapy or acceptance and commitment therapy. Participants allocated to the intervention will receive one of the adapted therapies according to therapist allocation for up to 6 months via 12 weekly, one to one, 45–50-min sessions. The primary outcome is quality of life measured by the Clinical Outcomes in Routine Evaluation Outcome Measure at 12 months post-randomisation. Secondary outcomes include suicidal intent, depression and cost-effectiveness. Data are collected using hospital attendance records and online/postal/telephone questionnaires at 6 and 12 months post-randomisation, with resource use additionally collected at 3 and 9 months.DiscussionThis protocol outlines a randomised controlled trial to investigate whether modified therapies are cost-effective and improve quality of life for people who repeatedly self-harm. Few interventions are proven to be deliverable in the NHS for this population. This study is strengthened by the involvement of qualified mental health workers experienced in managing risk as therapists.Trial registrationRegistered on August 03, 2021.IRAS number: 297939.ISRCTN: https://doi.org/10.1186/ISRCTN73357210.REC reference: 21/EE/0145.Sponsor: University of Leeds.

Abstract Mo025: Noninvasive cardiac phenotyping in patients treated with chemo- and immunotherapy for breast cancer

Current breast cancer diagnosis and treatment protocols achieve survival rates of&gt;80% at 10 years.However, long-term cancer survivors have&gt;4-fold higher incidence of cardiovascular complications, including heart failure.Early potentially reversible changes that may underlie downstream irreversible loss of mechanical function are unknown.Therefore, we aimed to test the feasibility of a noninvasive cardiac phenotyping protocol in patients undergoing treatment for breast cancer with doxorubicin, without or with immune checkpoint inhibitors, including multiparametric proton cardiac magnetic resonance(CMR) imaging and novel metabolic carbon13MR. A comprehensive set of studies included conventional 1HCMR,as well as metabolic 13CCMR using hyperpolarized(HP)[1-13C] pyruvate, following an oral glucose load. 13CCMR with HP[1-13C] pyruvate allows the detection of downstream metabolites of injected pyruvate within the myocardium: bicarbonate from mitochondrial oxidation and lactate from anaerobic cytosolic metabolism.HP[1-13C]pyruvate was prepared using dynamic nuclear polarization in a commercial polarizer.Imaging and spectroscopy(MRS) of hyperpolarized pyruvate was conducted using a 13C transmit/receive Helmholtz loop-pair coil on a 3Tscanner.13C data were acquired from a short-axis slice, ECG-triggered in end-systole. ProtonCMR images were analyzed using Circle, and 13CCMR images were analyzed using MATLAB. The left ventricular mid-myocardium and blood pool were segmented for metabolite quantitation. Baseline cardiac studies were performed in a consecutive series of 25 women treated for breast cancer. Of these 14(56%) were Caucasian, 3(12%) were Hispanic, 5(20%) Black, and 3(12%) Asian, with ages ranging 46±11 years.Patients received standard-of-care treatment plans based on the tumor type: 11 patients were treated with dose-dense anthracycline and cyclophosphamide, and 14 also received pembrolizumab. The comprehensive baseline phenotyping protocol is planned to be repeated after standard of care therapy in all patients. Baseline data are presented in Table1, with values reported as mean±standard deviation. Noninvasive cardiac phenotyping, including dynamic detection of metabolic substrate utilization is feasible,without showing significant adverse effects,and is well tolerated in a diverse group of patients.Completion of this protocol post-oncological therapy may allow to detect early changes in cardiac function due to chemo-and immunotherapy in susceptible patients.

Chronic endothelial dopamine receptor stimulation improves endothelial function and hemodynamics in autosomal dominant polycystic kidney disease

Altered polycystin-mediated endothelial flow mechanosensitivity contributes to the development of hypertension and cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD). Stimulation of endothelial type 5 dopamine receptors (DR5) can acutely compensate for the endothelial consequences of polycystin deficiency, but the chronic impact of this approach must be evaluated in ADPKD. Nineteen patients with ADPKD on standard of care therapy were randomized to receive a 2-month treatment with the DR agonist rotigotine using transdermal patches, nine at 2 mg/24hours and ten at 4 mg/24hours or while ten were untreated. Rotigotine at the dose of 4 mg/24hours significantly increased nitric oxide release (nitrite levels from 10±30 to 46±34 nmol/L) and radial artery endothelium-dependent flow-mediated dilatation (from 16.4±6.3 to 22.5±7.3%) in response to hand skin heating. Systemic hemodynamics were not significantly modified but aplanation tonometry showed that rotigotine at 4 mg/24hours reduced aortic augmentation index and pulse pressure without affecting carotid-to femoral pulse wave velocity. Plasma creatinine and urea, urinary cyclic AMP, which contributes to cyst growth in ADPKD and copeptin, a surrogate marker of vasopressin, were not affected by rotigotine. In mice with a specific deletion of polycystin-1 in endothelial cells, chronic infusion of the peripheral DR5 agonist fenoldopam also improved mesenteric artery flow-mediated dilatation and reduced blood pressure. Thus, our study demonstrates that in patients with ADPKD, chronic administration of rotigotine improves conduit artery endothelial function through the restoration of flow-induced nitric oxide release as well as hemodynamics suggesting that endothelial DR5 activation may represent a promising pharmacological approach to prevent cardiovascular complications of ADPKD.

The anti-aromatase and anti-estrogenic activity of plant products in the treatment of estrogen receptor-positive breast cancer

Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80 % of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERβ. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies.

DIPG-77. SOMATICTP53,PIK3R1, NF1 ORTERT MUTATIONS ARE ASSOCIATED WITH INFERIOR CLINICAL OUTCOME IN H3K27M-ALTERED DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND H3K27-altered diffuse midline gliomas (DMGs) have poor prognosis with no standard of care therapy beyond radiation (RT). While RT prologues survival, not all patients respond. Prior work has shown somatic TP53 mutations predict radiation resistance, and poorer outcomes. We report on a multi-center retrospective cohort study to identify molecular biomarkers of RT response in DMG patients. METHODS We performed retrospective chart reviews of patients with biopsy-proven H3K27M-altered DMG between 2013-2023 from six US medical centers and the DMG Center in Zurich. Patients with tumor genomic sequencing and completion of RT were eligible. Genomic alterations were evaluated for somatic mutations, fusions, and chromosomal instability. Cox proportional hazard models were used to evaluate associations between genomic alterations and survival. Multivariate analysis included all significant variables at P &amp;lt;0.1 in initial analysis, including age at diagnosis, tumor location, TP53 and PIK3R1 alterations. RESULTS 297 patients (135 female; median age 8.3years; range 0.2-71.4 years) were included. Median progression-free survival (PFS) and overall survival (OS) was 7.6months (95%-CI 6.9-8.6) and 14.0months (95%-CI 12.9-15.7). Univariate analysis identified TP53 or PIK3R1 status to be associated with shorter OS (TP53-mutant 12.5months vs. TP53-wildtype 17.5months; HR=1.5; 95%-CI (1.1-2.0), P=0.005); (PIK3R1-mutant 12.6months vs. PIK3R1-wildtype 14.5months; HR=1.9, 95%-CI (1.1-3.4), P=0.03). Multivariate analysis corroborated TP53 status association with shorter OS (HR=1.5; 95%-CI (1.2-2.0), P=0.003). Subgroup univariate analysis of pontine DMG patients showed reduced OS with TP53, NF1, or TERT mutations (TP53-mutant 11.9months vs. TP53-wildtype 15.2months; HR=1.6; 95%-CI (1.1-2.3), P=0.02); (NF1-mutant 8.4months vs. NF1-wildtype 13.6months; HR=2.3; 95%-CI (1.1-5.0), P=0.03); (TERT-mutant 8.5months vs. TERT-wildtype 13.6months; HR=2.5; 95%-CI (1.1-5.7), P=0.03). Subsequent multivariate analysis corroborated the association of TERT mutations with shorter OS in pontine DMG (HR=2.5; 95%-CI (1.05, 5.9), P=0.03). CONCLUSIONS This is one of the largest molecular characterized cohorts of H3K27M-altered DMG patients. DMGs with somatic TP53 or PIK3R1 mutations demonstrate inferior OS. Pontine DMG patients with somatic TP53, NF1 or TERT mutations demonstrate inferior OS.

Assessing the impact of unmeasured confounding in external control arms via tipping point analyses.

e23065 Background: Estimates of the comparative efficacy of new therapies from single-arm settings can be obtained in advance of RCTs through use of external control arms (ECAs).[1] ECAs are collections of patients with the index disease who were treated outside of the single-arm trial, whose measured baseline attributes are matched to the single-arm trial patients and whose outcomes are compared to trial patients’ to estimate comparative efficacy. Without randomization, observed treatment-outcome associations may be confounded by unmeasured patient attributes. Applying established statistical methods, we estimate the magnitude and prevalence of unmeasured confounding required to move an apparently favorable hazard ratio (HR) to the “tipping point” where the new drug is no longer associated with a favorable survival statistically or clinically. Methods: Studying previously reported patients with multiple myeloma treated with an experimental therapy in a clinical trial (N = 290) and patients treated with standard of care therapy from a rigorously matched ECA (N = 290), we applied the method of Lin et al. to adjust the observed treatment effect (HR and 95% CIs) for overall survival to reflect the impact of a (set of) unmeasured confounder(s).[1,2] Lin’s formula incorporates both the unmeasured confounder’s theoretical association with mortality and its prevalence according to treatment group (i.e., single-arm trial vs. ECA). Results: The observed treatment effect for the single-arm trial treated vs. ECA patients was HR 0.76 (95% CI 0.63-0.91). We estimated the impact of an unmeasured confounder (where HR for overall survival of those patients with and without the confounder is set to 1.5) by its prevalence in each group. When the prevalence of the unmeasured confounder is balanced across groups there is no change in the observed treatment effect. When the presence of the confounder is 70% for ECA patients and absent in the trial patients, the clinical tipping point occurs with loss of the favorable HR (i.e., HR 1.02, 95% CI: 0.85-1.23). Conclusions: While novel analytic methods like ECAs have the potential to accelerate drug development, the lack of randomization raises concern for potential unmeasured confounding. Applying Lin’s method, we illustrate that the impact of unmeasured confounding on HR estimates from a single-arm trial vs.an ECA is a function of both the association with mortality and asymmetries in prevalence. Consistency in the efficacy conclusion for all clinically tenable assumptions indicates a qualitatively reliable conclusion. Friends of Cancer Research whitepaper (2019): available online at https://www.focr.org/sites/default/files/Panel-1_External_Control_Arms2019AM.pdf. Lin D, Psaty B, Kronmal R. Assessing the sensitivity of regression results to unmeasured confounders in observational studies. Biometrics.1998; 54:948–963.

A retrospective, descriptive analysis of a single-center experience with patients with metaplastic breast cancer.

e13173 Background: Metaplastic breast cancer (MpBC) is a subtype of breast cancer (BC) that is commonly triple negative (TN) and chemotherapy (CT) resistant. Despite CT resistance, standard of care therapy is administered according to receptor status, regardless of metaplastic histology. Randomized data regarding optimal treatment of this rare histologic subtype are lacking. Methods: This was a retrospective analysis of MpBC patients (pts) treated at Miami Cancer Institute (MCI) between 2017 and 2021. Pts were identified using COTA real-world Analytics, an analytics platform enabling rapid investigation of longitudinal real-world data. Pt demographics, pathologic characteristics, staging, treatment, and survival outcomes were collected and analyzed. Results: 46 pts with MpBC were identified. Median age at diagnosis was 60.5 years, and 83.7% were post-menopausal. 84.8% were White, 10.9% were Black, and 54.3% were Hispanic (all White). 80.4% (n=37) had TNBC (ER &lt; 1% and HER2 negative by ASCO CAP guidelines). 13.0% of pts (n=6) had spindle cell morphology and these pts had numerically lower 5-yr overall survival (OS) compared to those with non-spindle cell morphology; (83.3%; 95% CI 53.5%-100% vs 91.7%; 95% CI 82.7%-100%). Of 21 pts (45.7%) who underwent germline genetic testing, a pathogenic variant was detected in 2 (9.5%); (BRCA2, PALBB2). At diagnosis, 93.5% (n=43) had early-stage disease, 2.2% (n=1) had de novo metastatic breast cancer (MBC), 2 were unknown. Of the early-stage pts, 12 (27.9%) had stage 1, 19 (44.1%) stage 2, and 6 (14.0%) stage 3 BC. Of 43 pts with treatment records available, 34 (79.1%) received CT and 20 (46.5%) received anthracycline-based CT in the early-stage setting. Of those who received CT, 50% (n=17) were treated in the neoadjuvant setting, and 2 pts (11.8%) achieved pathologic complete response (pCR). Median distant recurrence free survival (DRFS) and OS were not reached in the overall cohort. Two-year OS was 90.5% (95% CI 81.6%-99.4%) and two-year DRFS was 78.9% (95% CI 66.6%-91.2%). Of the 43 pts with early-stage MpBC at diagnosis, 11 (25.6%) developed MBC with lung as the most common site of metastasis. Only 15.2% (n=7) of tumors underwent somatic mutation analysis and 71.4% (5/7) were PIK3CA-mutated. Of the pts who developed MBC, median progression-free survival with cytotoxic chemotherapy was 9.0 months (95% CI 5.0-13.0). Conclusions: MpBC represents an aggressive phenotype of BC and optimal guidance regarding treatment is lacking. Consistent with published literature, a high proportion of MpBC in this study were TN (&gt;80%). Our dataset represents the largest cohort to date of Hispanic pts with MpBC. Despite the poor outcomes historically reported with MpBC, median DRFS and OS were not reached in this cohort, with short follow up. Further prospective randomized data on the optimal treatment of MpBC is warranted and a larger multi-institution review is planned.

Dual immune checkpoint inhibition with nivolumab and ipilimumab (N+I) in patients with advanced anaplastic thyroid carcinoma (ATC).

e18075 Background: There are no standard of care therapies in advanced incurable setting for BRAF wild type (WT) ATC, &amp; after dabrafenib and trametinib (D+T) for BRAF V600E mutant ATC. We previously showed promising clinical activity of dual inhibition with N+I in exploratory cohort of 10 patients (pts) with advanced ATC in a single arm phase II clinical trial, with objective response rate (ORR) of 30% (NCT03246958, Lorch ASCO 2020). Here, we present efficacy and safety outcomes from a real-world cohort of pts with advanced ATC treated with N+I regimen. Methods: We conducted a retrospective cohort study of pts with advanced ATC (unresectable or with distant metastases, DM) who were seen at the Dana-Farber Cancer Institute (DFCI) thyroid cancer center from July 2021 to Jan 2024, received at least one dose of N+I with palliative intent &amp; completed at least one response assessment (data cutoff, 1/31/24). Pts on the DFCI clinical trial were not included. Investigator-assessed ORR (for the first N+I based treatment regimen) and immune-related adverse events (irAEs, collected till cutoff regardless of ongoing treatment) were evaluated. Results: 19 pts with advanced ATC (5: unresectable disease, 14: DM) were included, BRAF WT 12/19 (63%). Median age was 70y (range, 34-81), 68% female. ECOG PS at start was 0-1 in 14/19 (74%), 2 in 4 (21%) &amp; 3 in 1 (5%) pts. 5/19 (26%) pts received N+I concurrently with D+T; 4/5 (80%) in 2nd line after either mixed response or progressive disease (PD) on D+T. Best overall response (BOR) in N+I+D+T group was partial response (PR, 1/5, 20%) &amp; stable disease (SD, 4/5, 80%); ORR 20%. 14/19 (74%) pts received N+I, 12/14 (86%) as 1st line palliative therapy. 5 pts in N+I group (all with DM) received local therapies concurrently (1: debulking thyroid surgery, 3: radiation therapy (RT) to thyroid, &amp; 1: palliative RT to bone DM). BOR in N+I group were: complete response, CR (4/14, 28.6%); PR (3, 21.4%); SD (4, 28.6%); &amp; PD (3, 21.4%); ORR 50%. Excluding 5 pts with concurrent local therapies, ORR was 33.3% (1/9 CR, 2/9 PR).PD-L1 TPS was available for 12/19 pts (4: N+I+D+T, 8: N+I) and ≥1 in all tumors (range, 1-100). In 8 pts in N+I group, ORR stratified by PD-L1 TPS: TPS &lt;50 (range, 1-30): 0% (0/2: 1 SD, 1 PD), &amp; TPS ≥50 (range, 80-100): 83.3% (5/6: 3 CR, 2 PR, 1 PD). Any grade irAEs were observed in 16/19 (84.2%) pts. ≥Grade 3 irAEs occurred in 11/19 (57.9%) pts, most frequent were colitis (5, 26.3%), dermatitis/pruritus (3, 15.8%), myocarditis (2, 10.5%), &amp; adrenal insufficiency (2, 10.5%). There were no treatment-related deaths. Conclusions: In this largest real-world cohort study of pts with advanced ATC, N+I therapy showed high ORR of 50% (congruent with DFCI trial), albeit with high rates of iRAEs. High ORR was seen with PD-L1 TPS ≥50. Survival outcomes and genomic biomarkers, currently under investigation, will be presented at the meeting. N+I merit further investigation in an ATC focused clinical trial.