Citations

Background Cardiovascular biomarkers such as NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) are used for heart failure risk stratification in patients with acquired heart disease, but there are limited data about its role in patients with congenitally corrected transposition of the great arteries. The current study aims to assess the role of serial NT‐proBNP measurements for risk stratification in adults with congenitally corrected transposition of the great arteries. Methods We studied adults with congenitally corrected transposition of the great arteries with ≥2 NT‐proBNP measurements (2003–2024). Temporal change in NT‐proBNP was calculated as relative change from baseline levels. Results Of 152 patients (age 47±13 years, 45% men), baseline NT‐proBNP was 539 (interquartile range, 193–1549) pg/mL, and relative change from baseline levels of NT‐proBNP was 34% (interquartile range, −11 to 67). Of 152 patients, 45 (30%) had cardiovascular events (heart failure hospitalization [n=29], ventricular assist device [n=5], heart transplantation [n=11], and death [n=10]), yielding a 10‐year incidence of 26%. Higher baseline NT‐proBNP and relative change from baseline levels were associated with cardiovascular events. Serial NT‐proBNP measurements had incremental prognostic value compared with baseline measurement. The correlates of higher NT‐proBNP levels were atrial fibrillation, hypertension, right ventricular dilation and dysfunction, and atrioventricular valve regurgitation. Renin–angiotensin–aldosterone system antagonist was associated with lower NT‐proBNP levels and lower risk of cardiovascular events. Conclusions NT‐proBNP testing is inexpensive, widely available, and noninvasive, making it well suited for longitudinal surveillance in adults with congenital heart disease. Most of the correlates for elevated NT‐proBNP levels were modifiable, providing target for therapeutic interventions.

Abstract Purpose: In RET-rearranged non–small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear. This study evaluates outcomes of SRI retreatment. Experimental Design: This multicenter retrospective study included patients with advanced RET-rearranged NSCLC who received ≥2 SRI-based therapy lines. Of 411 SRI-treated patients, 41 (10%) underwent SRI retreatment. Outcomes included objective response rate (ORR), progression-free survival (PFS), 6-month PFS, time to treatment failure, adverse events (AE). Results: Among 41 patients, 14 (34%) discontinued the initial SRI because of toxicity and 27 (66%) because of progression. After discontinuation for toxicity, all switched to an alternate SRI, achieving an ORR of 67%, median PFS of 9.9 months, and 6-month PFS of 80.3%. AEs reoccurred in nine patients (64%), with grade ≥3 AEs in 3 (21%) who switched at full dose. Among patients who discontinued because of progression, SRI monotherapy (n = 13) achieved an ORR of 23%, median PFS of 7 months, and 6-month PFS of 61.5%. Benefit was observed in patients with brain-only or oligoprogressive disease or dose reduction on first SRI. Combination therapy (n = 14; targeted agents, n = 11; chemotherapy, n = 3) achieved an ORR of 39%, median PFS of 4 months, and 6-month PFS of 27.3%. Conclusions: Same-class SRI switch after toxicity is feasible and clinically active but warrants cautious, dose-adjusted switching to mitigate toxicities. The efficacy of SRI rechallenge after progression seems limited overall. However, selected patients, such as those with brain-only or oligoprogressive disease, may derive benefit.

Abstract Specialized immune niches located in the stroma-tumor junction promote interactions between tumor-resident antigen-presenting cells and effector lymphocytes that are required for immunotherapy efficacy. We have hypothesized that this stromal-based immune crosstalk may be regulated by provisional extracellular matrix signals, analogous to the early-stages of wound healing where provisional matrix hosts robust immune activity. A cardinal provisional matrix remodeling event, the regulated proteolysis of the large proteoglycan versican (VCAN) generates an immunomodulatory fragment (matrikine), versikine, that engages adaptive immunity. We have previously shown that VCAN proteolysis correlates with T-cell infiltration across multiple solid and liquid cancers with the most immune-evasive cancers showing low to negligible rates of VCAN proteolysis (e.g., 0% in pancreatic adenocarcinoma). A recent clinical trial generated informative prospective data linking VCAN proteolysis with immunotherapy outcomes: patients whose metastatic colorectal tumors categorized as VCAN proteolysis-weak (VPW, 60% of cases) demonstrated inferior responses to checkpoint inhibition (CPI, pembrolizumab) and worse outcomes compared to VCAN proteolysis-predominant (VPP, 40%) cases. Leveraging these prospective trial data, we hypothesized that versikine therapy may rationally reverse the immunosuppression associated with the prevalent VPW phenotype. To tailor versikine therapy to specific human biomarker-stratified tumor phenotypes, we studied experimental models replicating partially T-permissive VPW-VCANlo human cancers and poor-prognosis, immune-exclusionary VPW-VCANhi cancers. Across VPW-like tumors, versikine promoted the stromal accumulation of CD40lghiIcoshiFoxp3neg Tfh-like CD4+ T cells that engaged dendritic cells (DC) and CD8+ T cells in “immune triads” even at baseline (prior to CPI), concurrently with the intratumoral expansion of activated CD8+ T cells expressing cytolytic molecules (granzymes, perforin). In VPW-VCANlo tumors, versikine delivered as LNP-mRNA or recombinant protein demonstrated monotherapy activity, dependent on Batf3-lineage DC and CD8+ T cells. When combined with single-agent CPI, versikine cured most VPW-VCANlo tumors with memory to tumor re-challenge. In VPW-VCANhi tumors, versikine synergized with combination immunotherapy modulating “mature DCs enriched in immunoregulatory molecules” (mregDC). Our data provide mechanistic rationale for the biomarker-stratified, therapeutic restoration of a provisional matrix-regulated immune signaling network to reverse resistance to CPI. Moreover, the data highlight the need to reevaluate prior approaches to globally disrupt tumor stroma in favor of biomarker-driven, pathway-focused harnessing of stromal signals that modulate anti-tumor immunity. Citation Format: Daniel J. Lagal, Duncan Hong, Athanasios Papadas, Emma Geatches, George Yacu, Surabhi Naik, Alicia Gibbons, Alexander Cicala, Kersi Pestonjamasp, Peter Toth, Kristina Matkowskyj, Dustin A. Deming, Fotis Asimakopoulos. Biomarker-driven restoration of tumor provisional matrix signaling network reverses resistance to checkpoint inhibition immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6746.

Abstract Background: Prostate cancer (CaP) is among the most common cancers in U.S. men, with Black men experiencing a 1.7-fold higher incidence and nearly twice the mortality rate compared with non-Hispanic White men. While early detection has improved survival, differences remain in recovery and quality of life (QoL). Sexual dysfunction after treatment affects identity, relationships, and well-being, yet stigma, cultural norms, and limited access to patient-centered care prevent open discussion. Few initiatives address the intersection of identity, stigma, and survivorship in this population. Community town halls provide a trusted, culturally responsive space for shared learning, peer connection, and open dialogue on survivorship and sexual health. Methods: Two community-engaged CaP town halls were convened by the Multidisciplinary Health Outcomes Research and Economics (MORE) Lab at the University of Oklahoma Health Campus (OUHC) to explore survivorship issues among Black CaP survivors. The first, held virtually in June 2024, included watch parties in Georgia and Texas. The second, in November 2024, was hybrid, hosted at OUHC and via Teams with a watch party at the Willa D. Johnson Recreation Center, a community center in Oklahoma City. Panelists included oncologists, psychologists, survivors, partners, and Community Advisory Board members. Both town halls featured survivor storytelling, provider Q&A, and interactive discussion. Post-event surveys captured demographics, satisfaction, and impact. Open-discussion transcripts were analyzed using Braun and Clarke’s reflexive thematic analysis, guided by a constructivist framework. Results: A total of 124 participants attended both town halls. Survey respondents (n=17; 13.7%) provided demographic and satisfaction data; remaining insights came from all participants who engaged in open dialogue. Respondents ranged in age from 19-76 years (mean=48.7 ± 21.8). Of the 17 respondents, 93% rated the events as very good or excellent; 23.5% were CaP survivors, all identifying as Black. Five themes emerged: (1) Masculinity, stigma, and silence limit help-seeking; (2) Sexual dysfunction and identity loss cause major emotional burdens; (3) Navigation challenges highlight systemic barriers; (4) Spousal and psychological support aid coping; and (5) Survivorship empowerment. Participants valued hearing “real stories from real men,” validating their experiences. Conclusions: Community town halls are a feasible and culturally relevant strategy to engage Black CaP survivors in survivorship and sexual health discussions. By centering lived experiences and facilitating two-way communication between survivors, clinicians, and researchers, these events build trust and reduce stigma. Future work will assess changes in knowledge, engagement, and confidence in care navigation and explore scaling this community-academic model to improve survivorship QoL. Citation Format: Parisa Ghasemi, Gaurav Kumar, Ernest T. Kaninjing, Adanma Ayanambakkam, Yaw A. Nyame, Amy Siston, Jordan M. Neil, Adam C. Alexander, Andrew G. McIntosh, Yan Zhao, Zsolt Nagykaldi, Kathleen A. Dwyer, Mary Ellen Young, Sabrina Dickey, Daniel Morton, Opeyemi Bolajoko, Darla E. Kendzor, Motolani E. Ogunsanya. Survivorship and sexual health: What we learned from Black men in community town halls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2483.

Abstract Background: Multiple myeloma is the second most common adult blood cancer and remains incurable, despite recent advances. The IMWG/IMS recently published updated risk criteria, Consensus Genomic Staging (CGS), combining genomic events with clinical measures to identify high-risk patients (Avet-Loiseau, et al. JCO 2025). We applied CGS risk criteria to baseline samples from the Multiple Myeloma Research Foundation CoMMpass Study (NCT01454297), a prospective, longitudinal observational study that enrolled more than1100 participants between 2011-2017. Methods: We assessed patient risk following CGS criteria. Criteria 1: del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation. Criteria 2: an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32). Criteria 3: monoallelic del(1p32) along with 1q+ or biallelic del(1p32). Criteria 4: beta-2 microglobulin >= 5.5 mg/L with normal creatinine. Patients meeting one or more criteria were classified as High Risk. To test if risk showed association with genetic ancestry, we grouped patients into those with high African genetic ancestry and those with low African genetic ancestry. Genetic ancestry was measured using ADMIXTURE in comparison to 1000 Genomes. Results: We evaluated the CGS risk status of 877 CoMMpass patients, finding 69.2% (573/828) to be Standard Risk (SR) and 30.8% (255/828) to be High Risk (HR). HR patients showed worse progression-free survival (median PFS 26.3 months vs. 42.5 months; log rank test, p < 0.0001) and overall survival (median OS 63.9 months vs. median not reached; p < 0.0001). 10.6% (91/858) of patients met Criteria 1, 10.7% (93/873) met Criteria 2, 5.6% (49/877) met Criteria 3, and 8.7% (73/835) met Criteria 4. We found 14.2% (123/867) of patients to have high African-like genetic ancestry (AFR-high) and 85.8% (744/867) to have low African-like genetic ancestry (AFR-low). We observed significantly fewer HR patients within the AFR-high group (20%, 23/115) than in the AFR-low group (32.4%, 231/712) (Fisher’s exact test, p = 0.0065). The AFR-high group met HR criteria at a lower rate across all criteria, but only with Criteria 3 was the difference significant (p-value = 0.03). Higher levels of creatinine in AFR-high patients may have impacted meeting the normal creatinine requirement of Criteria 4. Conclusions: HR patients comprise 30.8% of CoMMpass subjects and show significantly worse PFS and OS than SR patients. AFR-high patients met HR criteria at a lower rate than AFR-low patients according to the CGS criteria. Clinical trials that utilize CGS criteria to determine patient eligibility may be challenged to enroll a representative patient population, including AFR-high patients. Screening and eligibility criteria should be carefully considered to mitigate potential enrollment disparities. Citation Format: Steven M. Foltz, Chaitanya R. Acharya, Alexander Gout, Yuxin Jin, David E. Avigan, Ravi Vij, Shaji Kunnathu Kumar, Sagar Lonial, Hearn Cho, Katie Wozniak, Jonathan J. Keats, Craig Cole, John D. Carpten, George J. Mulligan. Multiple myeloma risk classification of CoMMpass using Consensus Genomic Staging identifies differences between patients with high and low African genetic ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3887.

Abstract Prostate-specific membrane antigen (PSMA) is highly expressed in tumor-associated neovasculature in hepatocellular carcinoma (HCC), highlighting its promise as a theranostic target. This prospective study aimed to evaluate the utility of novel biomarkers derived from PSMA positron emission tomography computed tomography (PET/CT) to assess treatment response in advanced HCC patients (pts) receiving first line immune checkpoint inhibitors (ICI). Methods: This study (NCT05176223) enrolled unresectable, advanced HCC pts eligible for first-line ICI (atezolizumab/bevacizumab [A/B] or durvalumab/tremelimumab [D/T]) with measurable disease according to RECIST criteria. Primary endpoints: progression-free survival (PFS) per RECIST 1.1 and mRECIST; overall survival (OS); and best overall response. The survival distribution was estimated using the Kaplan-Meier method. Observed agreement is defined as the proportion of pts whose responses, as classified by PET/CT or CT, were concordant. Weighted kappa and Cohen’s kappa were used to quantify the strength of agreement between PET/CT and CT. Pts completed up to five 68Ga-PSMA PET/CT scans and blood collections. Results: Twenty-six pts were enrolled (25 evaluable) between Oct 2022 and Nov 2024. Median follow up was 22.1 months (m) (Q1, Q3: 14.5-23.7). Median age 68 yrs, 72% male, 88% White, 68% Child-Pugh [CP] A, 32% CP B, 32% Barcelona Clinic Liver Cancer [BCLC] stage B, 68% BCLC stage C, 36% with microvascular invasion; 56% received A/B and 40% received D/T treatment. PSMA was positive in 96% of pts at baseline with median SUVmax 14.3 (range 5.1-40.5) and median background liver SUVmax 3.9 (range 2.1-6.8). Median (95%CI) PFS was 5.6 m (4.6-12.5) by both RECIST and mRECIST. Median (95%CI) OS was 18.6 m (7.2-not estimable), with 56% deceased. The observed agreement between PET/CT adapted PERCIST criteria compared to RECIST and mRECIST in determining the best response was 46% and 50% and weighted kappa of 0.63 (95% CI: 0.37-0.90) and 0.66 (0.41-0.92), respectively. Observed agreement between PERCIST compared to RECIST and mRECIST for responders’ assessment was 67% and 71% with Cohen’s kappa of 0.36 (0.03-0.68) and 0.43 (0.11-0.76), respectively. Conclusion: In this cohort, PSMA PET/CT avidity was observed in all but one pt with advanced HCC, each demonstrating moderate to high SUVmax values. Median OS and PFS were consistent with outcomes reported in clinical trials. Response assessment using 68Ga-PSMA PET/CT according to PERCIST criteria showed good concordance with both RECIST and mRECIST standards. Analysis of immune biomarkers is ongoing. Citation Format: Nguyen H. Tran, Jacob Hirdler, Ajith Antony, Jacob Teske, Sudhakar K. Venkatesh, Amit Mahipal, Michael S. Torbenson, Scott M. Thompson, Thor R. Halfdanarson, Zhaohui Jin, Lionel Aurelien Kankeu Fonkoua, Leslie A. Washburn, Alexander Revzin, Haidong Dong, Robert R. Mcwilliams, Aminah Jatoi, Hani M. Babiker, Mitesh J. Borad, Tanios Bekaii-Saab, Gregory J. Gores, Lewis R. Roberts, Geoffrey B. Johnson, Ajit H. Goenka. Prospective evaluation of 68Ga-PSMA PET imaging in advanced hepatocellular carcinoma patients undergoing first line immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2611.

Abstract Purpose: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor, with a median survival of only 15 months. Effective therapeutic advances remain limited, with few clinical trial patients exhibiting robust responses to experimental therapies. This has led to efforts to identify molecular biomarker signatures capable of stratifying patient responses either prognostically (pre-treatment) or diagnostically (post-treatment). This study aims to assess the robustness and reproducibility of published transcriptional GBM biomarker signatures for predicting clinical outcomes in GBM trials. Methods: We analyzed published RNA-seq data from 4 clinical trials involving oncolytic virotherapy and immune checkpoint inhibitors, as well as multiple cohorts of patients treated via the Stupp protocol. The performance of reported immune gene signatures was evaluated across all datasets using both grouped and continuous survival modeling. Intra-patient signature variation between different biopsy sites and timepoints was assessed using longitudinal, multi-site sampling collected by the Break Through Cancer Accelerating GBM Therapies TeamLab. LASSO, multivariate Cox regression, and risk scoring with FDR adjustment were used to identify novel signatures with cross-cohort utility. Key Findings: No single published signature consistently predicted survival across all analyzed trials. A post-treatment ssGSEA antitumor cytokine signature that was associated with survival in the CAN-3110 OV trial (R = 0.74, p < 0.01) was also significantly associated with improved survival in an adjuvant anti-PD1 trial (R = 0.75, p = 0.03) and neoadjuvant anti-PD1 trial (R = 0.30, p = 0.05), but not in standard-of-care controls. PAM clustering of MCP immune signatures, as reported for the DNX-2401 OV+Anti-PD1 trial, also stratified post-treatment survival in the CAN-3110 OV trial (p < 0.01), with the coldest TME subtype consistently predicting worse survival. However, the prognostic value of the most immune enriched TME subtype was inconsistent and did not extend to the Anti-PD1 trials. Furthermore, multi-site, longitudinal biopsy samples revealed marked heterogeneity in biomarker signatures between biopsies from individual patients, even when assessed at the same timepoint. We’ve identified several candidate transcriptomic signatures that show promise for generalizable prognostic value in GBM patient cohorts and are characterizing their spatiotemporal variability. Conclusions: While no individual immune signature is universally predictive in GBM immunotherapy, certain post-treatment cytokine signatures and TME stratifications are significant in multiple immunotherapy contexts, though not in standard-of-care patient cohorts. Marked spatiotemporal heterogeneity in these signatures underscores the need for composite prognostic markers resilient to sampling variance. Citation Format: Christopher M. Jannotta, C Zoe Linke, Charles A. Whittaker, Vikas Patil, Accelerating GBM Therapies TeamLab, Farshad Nassiri, Gelareh Zadeh, E Antonio Chiocca, Alexander L. Ling. Assessing biomarker reproducibility for glioblastoma patient response stratification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1055.