Citations

Abstract Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. Significance: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

Abstract The minichromosome maintenance 2-7 (MCM2-7) proteins form a hexameric protein complex that is the structural core of replicative helicase, which is essential for accurate DNA replication. While their role in replication is well-established, the biological functions of excess chromatin-bound MCM2-7 proteins remain unclear. Here, we identify a transcriptional regulatory function of MCM2-7 through its interaction with nuclear factor κB (NF-κB) p65. We demonstrate that MCM2-7 proteins and NF-κB p65 reciprocally recruit each other to target gene promoters. Consequently, MCM2-7 proteins facilitate the localization of RNA Pol II to NF-κB target gene promoters and along the gene body, thereby promoting transcription of NF-κB target genes. These findings reveal MCM2-7 proteins promote NF-κB target gene transcription by facilitating p65 and RNA Pol II recruitment, offering a potential avenue for fine-tuning NF-κB target gene transcription.

Cutaneous metastases occur in up to 20% of patients with advanced melanoma and can be difficult to manage with systemic therapy alone. Pembrolizumab is a standard therapy with limited local treatment options for cutaneous manifestations. Imiquimod has shown activity in other skin cancers but is less well studied in melanoma. We conducted a pilot trial to evaluate the feasibility, safety, and preliminary efficacy of combining topical imiquimod with intravenous pembrolizumab in patients with unresectable melanoma with cutaneous metastases. This was a single-center, open-label, non-randomized interventional study (NCT03276832). Eligible patients received pembrolizumab IV every 21 days plus topical imiquimod 5% applied Monday–Friday each cycle. The primary endpoint was objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, and safety. In this study, seven patients were enrolled, five were male and two females; one was Hispanic and six were non-Hispanic White. Median treatment exposure was 8 cycles. ORR was 57.1%, with 3 patients (42.9%) achieving complete response, 1 partial response, and 2 stable disease. The 7-month PFS rate was 57.1%. At study closure, 4 patients remained alive without progression, 2 were alive following progression, and 1 had died of disease. Toxicities were mostly grade 1, with fatigue and anemia most common with minimal grade 2 events. The combination of topical imiquimod and pembrolizumab was feasible, safe, and demonstrated promising antitumor activity in unresectable cutaneous melanoma. A 42.9% CR rate in this small elderly cohort supports further evaluation of local immune modulation with systemic PD-1 blockade for cutaneous melanoma.

Tumor-associated antigens (TAAs) are non-mutated antigenic peptides expressed in cancer tissue at abnormally high levels but in normal tissue either at negligible levels, during only particular developmental stages, or in a tissue-restricted manner. The shared nature of TAAs across patients makes them attractive targets for off-the-shelf immunotherapies. However, no studies have comprehensively surveyed the TAA potential of all possible wild-type peptides originating from cancer-associated genes. In this study of 16 cancer tissue types and 39 normal tissue types, we analyzed the expression profiles of protein-coding genes to identify those with aberrantly high RNA levels across multiple solid tumor types and low RNA levels across all normal tissue types examined. We then developed a score to quantify tumor specificity of gene expression. Compared to previously reported TAA genes, those we identified exhibited substantially greater tumor specificity. Seven of these genes demonstrated consistently elevated expression in at least five tumor types and minimal expression across all non-immune-privileged normal tissues. To assess Human Leukocyte Antigen (HLA) class I presentation potential of the multi-cancer-associated genes, we computationally predicted the binding affinities between the most common class I HLA alleles and all possible wild-type TAA epitopes of 8–11 amino acids arising from those genes. We then applied rigorous filtering criteria to prioritize the most promising multi-cancer TAA peptide candidates and evaluated their HLA binding and cell-surface presentation using T2 and immunopeptidome analysis. Our results highlight new potential targets for multi-cancer immunotherapies.

Background Tumor-infiltrating lymphocytes (TILs) are established determinants of clinical outcomes in breast cancer. 1–6 While stromal TILs (sTILs) are commonly evaluated due to easier scoring and higher interobserver reproducibility, intraepithelial TILs may provide additional insights into anti-tumor immunity. 7 We aimed to comprehensively characterize immunotype-associated cellular landscapes in triple-negative breast cancer (TNBC) and identify features associated with clinical outcomes. Methods 212 TNBC tumors were classified into three immunotypes based on immune infiltrate location and density: immune desert (ID), immune excluded (IE), and immune inflamed (IN). 8 Single-cell spatial transcriptomics was performed on 75 tumors to define the cellular composition and functional states of the tumor microenvironment across immunotypes. Findings were validated and integrated with bulk RNA sequencing data and clinical outcome datasets from FinXX, CALGB-40603, I-SPY 2, and Real-World Clinico-Genomic Data (RWCGD) cohorts. Results Patients with IN tumors had significantly improved outcomes compared with ID tumors. Despite high sTILs, IE tumors showed poor outcomes similar to ID tumors. Single-cell spatial analysis revealed that ID and IE tumors exhibited reduced major histocompatibility complex I/II expression and fewer tumor-resident plasmacytoid dendritic cells (pDCs) compared with IN tumors, which were enriched for interferon-alpha (IFNα) and interferon-gamma (IFNγ) responses. High IFN response scores were associated with favorable outcomes across multiple therapy types in independent datasets. Deconvolution of RWCGD bulk RNA-seq data confirmed that pDC abundance correlated with improved outcomes specifically in hormone receptor–negative subtypes. Conclusions Our study highlights pDCs and IFN signaling as hallmarks of effective anti-tumor immunity in TNBC. Immunotype-based profiling underscores the limited prognostic value of sTILs alone in immune-excluded tumors and supports pDCs and IFN pathways as potential biomarkers for prognosis and therapeutic development in TNBC.

Objectives: To analyze the association between primary infertility and infertility type with the age of natural menopause. Methods: This is a retrospective cohort study reviewing a subset of women from the Mayo Primary Infertility Cohort (MPIC). The MPIC is a cohort of 1,001 women diagnosed with primary infertility and 1,001 age-matched referent women. In this study, we included all women at risk for natural menopause and further evaluated those who had reported natural menopause in the medical record. We compared the risk of natural menopause using Cox proportional hazard models with infertility status and infertility type as covariates. In those with documented menopause during the study period, the association between primary infertility and early and premature menopause was analyzed with χ 2 testing. We evaluated the association between age at natural menopause, primary infertility status, and infertility type in this group using linear regression. Results: In all, 461 women with primary infertility, with 530 referent individuals, were at risk of natural menopause, and of these, 340 women with infertility and 346 referent women underwent documented natural menopause on review of medical records. Women with primary infertility had an increased risk of natural menopause (hazard ratio: 1.25, 95% CI: 1.06-1.46) and underwent menopause 1 year earlier than referent individuals (β=−1.17, 95% CI: −1.82 to −0.52) after adjustment for body mass index, tobacco use, race, menstrual cycle regularity, and previous contraception use. Women with primary infertility were more likely to undergo early menopause (age 40-45) than referent women (7.6% vs. 3.0%, P =0.01). Compared with referent women, women with endometriosis underwent menopause 2.75 years earlier (95% CI: −4.38 to −1.13, P =0.0009), and women with unexplained infertility underwent menopause 1.45 years earlier (95% CI: −2.26 to −0.64, P =0.0005). Conclusions: Women with primary infertility had an increased risk of early menopause and collectively underwent menopause 1 year earlier than women without a history of primary infertility.

Background: Colorectal cancer (CRC) remains one of the common causes of cancer-related morbidity and mortality in the United States. Emerging increases in early-onset CRC and persistent disparities remain major public health concerns. Objective: To characterize long-term CRC incidence and mortality trends in the United States, with particular emphasis on identifying demographic groups experiencing rising or plateauing disease burden. Methods: We conducted a population-based ecological study using CRC incidence data from the United States Cancer Statistics database (1999–2022) and mortality data from CDC WONDER (1999–2023). Temporal trends were evaluated using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC), stratified by age, sex, race/ethnicity, and urbanization level. Results: Overall CRC incidence and mortality declined during the study period (both AAPC approximately −2.08%). However, incidence increased significantly among adults younger than 55 years, particularly those aged 20–24 years. Mortality also increased among younger adults aged 25–44 years and remained elevated among individuals aged 45–54 years. Non-Hispanic Black individuals consistently experienced the highest incidence and mortality rates. Mortality declines plateaued in several older age groups after 2018–2020. Conclusions: Despite overall improvements in CRC burden, increasing incidence and mortality among younger adults and persistent disparities highlight the need for risk-stratified prevention, earlier detection strategies, and tailored therapeutic approaches.

8524 Background: Teliso-V is a c-Met–directed antibody-drug conjugate comprising telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E (MMAE) payload. In the Ph2 LUMINOSITY study (NCT03539536), Teliso-V showed durable responses and manageable safety (Camidge et al, JCO 2024;42:3000-11) resulting in its accelerated approval in locally advanced/metastatic NSQ NSCLC with high c-Met protein OE (3+, ≥50%), as determined by an FDA-approved test. MET amp is a negative prognostic risk factor in advanced NSCLC, frequently associated with recurrent disease. High levels of MET amp and c-Met OE are hallmarks of MET -addicted tumors. Here, we analyzed the effects of MET amp on clinical responses to Teliso-V in LUMINOSITY. Methods: MET amp was evaluated by FISH and ctDNA in baseline samples from 108 NSQ EGFR WT NSCLC pts with c-Met OE (3+, ≥25%). MET amp by FISH was defined as having focal MET amp (MET/CEP7 ≥2.0) with MET gene copy number (GCN) ≥4. MET amp (focal) by ctDNA was defined as having plasma MET GCN ≥4 with no co-amplification in CDK6 and EGFR. c-Met OE by Immunohistochemistry (IHC; SP44) was defined as 3+ tissue staining intensity in ≥25% tumor cells (high c-Met OE: 3+, ≥50%; intermediate [int] c-Met OE: 3+, 25% to 49%). Exploratory analysis of tumor response was assessed in 76 efficacy evaluable pts with c-Met OE and MET amp assay results. Results: MET amp was detected in 34% (37/108) of pts with c-Met OE (3+, ≥25%) and was enriched by c-Met levels: 22% (11/50) in pts with Int c-Met OE (3+, 25% to 49%) and 45% (26/58) in pts with high c-Met OE (3+, ≥50%). The effects of MET amp on tumor response in LUMINOSITY are shown in Table 1. The majority of c-Met OE pts (79%) with PFS ≥10 mo (n=14) had GCN ≥10 and/or c-Met IHC 3+ ≥50%. No new safety signals were reported in pts with c-Met OE and MET amp. Conclusions: MET amp is more common in pts with high c-Met OE in this retrospective subgroup analysis. Tumor activity with Teliso-V was observed regardless of MET amp status. The impact of MET amp in pts with c-Met OE will be further evaluated in ongoing Phase 3 study (NCT04928846). Teliso-V efficacy in NSQ EGFR -WT NSCLC pts with c-Met OE with or without MET amp in LUMINOSITY. Total c-Met OE(3+, ≥25%) Total c-Met OE(3+, ≥25%) Intermediate c-Met OE(3+, ≥25%-49%) Intermediate c-Met OE(3+, ≥25%-49%) High c-Met OE(3+, ≥50%) High c-Met OE(3+, ≥50%) MET amp(N) No (N=53) Yes (N=23) No (N=30) Yes (N=7) No (N=23) Yes (N=16) ORR %(95% CI) 28 (18.0, 41.6) 39 (22.2, 59.2) 23 (11.8, 40.9) 57 (25, 84.2) 35 (18.8, 55.1) 31 (14.2, 55.6) PFS,median, mo(95% CI) 5.26 (3.71, 8.11) 8.02 (4.47, 14.65) 5.32 (2.69, 8.11) 7.52 (4.47, NA) 4.17 (3.25, 8.87) 8.02 (3.06, 25.92) OS,median, mo(95% CI) 14.5 (8.18, 17.38) 13.86 (6.54, 22.24) 14.03 (3.65, 17.02) 9.79 (6.54, NA) 16.26 (5.59, 36.44) 13.86 (3.06, 30.29)

4213 Background: Elraglusib (9-ING-41), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has multimodal antitumor activity. In the international, open-label, randomized phase 2 1801 Part 3B study, elraglusib plus gemcitabine/nab-paclitaxel (GnP) was evaluated in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC), with patients randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (mOS) and 1-year survival. The GnP control arm demonstrated shorter mOS than contemporary randomized trials (7.2 months vs 9.2 months in NAPOLI-3 and 9.7 months in PASS-01), driven by higher early mortality (0–2 months: 23.1% vs 10.1% in NAPOLI-3). Given balanced randomization, similar early mortality was inferred in the elraglusib/GnP arm, prompting post-hoc analyses to contextualize efficacy and identify factors associated with early death. Methods: Efficacy and safety were summarized descriptively. Time-to-event endpoints were analyzed using Kaplan–Meier estimates, log-rank testing, and Cox proportional hazards models. Response rates were compared using the Cochran–Mantel–Haenszel test. Post-hoc subgroup, sensitivity, and machine-learning–based multivariate analyses explored clinical, demographic, and biomarker correlates of survival and early mortality. Results: In the full randomized population (elraglusib/GnP n=155; GnP n=78), elraglusib/GnP improved mOS by 2.9 months versus GnP (10.1 vs 7.2 months; HR 0.62; 95% CI 0.46–0.84; p=0.01), with 1-year survival rates of 44.1% versus 22.3%. Among patients receiving ≥1 full treatment cycle, mOS was 12.5 months with elraglusib/GnP and 8.5 months with GnP, comparable to contemporary registrational trials. Across multiple post-hoc sensitivity analyses—including evaluable patients, those matched to NAPOLI-3 baseline tumor burden, patients treated in the EU (early mortality 4%), and those achieving ≥20% CA19-9 decline within the first 1–2 cycles—elraglusib/GnP consistently demonstrated a ≥4-month OS advantage. Early death was associated with low baseline albumin (<3 g/dL), high CA19-9 (>800 U/mL), high tumor burden, and KRAS, TP53, and CDKN2A co-mutations. Conclusions: The elevated early mortality in the GnP control arm reflects enrollment of a heterogeneous, real-world mPDAC population with less restrictive eligibility than recent registrational trials. Post-hoc analyses identify key clinical and molecular drivers of early death and confirm a consistent survival benefit with elraglusib/GnP. These hypothesis-generating findings directly inform eligibility criteria, stratification, and endpoint assumptions for the planned phase 3 trial. Clinical trial information: NCT03678883 .