Foster, Nathan R.

Abstract Globally, gastric adenocarcinoma is the fourth leading cause of cancer mortality and a major cancer disparity in the United States. Chemoprevention strategies are lacking for high-risk individuals with gastric premalignant conditions (GPMC). Curcumin, the principal curcuminoid in turmeric, exerts immunomodulatory effects in the epithelium and against Helicobacter pylori, and studies suggest chemoprevention potential. We conducted a double-blind, phase IIa randomized controlled trial in high-risk populations in Puerto Rico and Honduras. We investigated the utility of a bioavailable formulation of curcumin (Meriva) among individuals with H. pylori–negative GPMC, specifically, multifocal atrophic gastritis (MAG) or gastric intestinal metaplasia (GIM). Patients were 1:1 randomized to 1,000 mg Meriva daily or placebo for a 6-month intervention with endoscopy at baseline and 6 months. Outcomes included assessment of epithelial cytokine and chemokine levels, histology, and DNA damage as assessed by γ-H2AX phosphorylation IHC. Of the 110 subjects screened, 50 participants were randomized, and 48 completed the trial. A significant reduction in gastric mucosal IL1β levels from baseline in the gastric body, the primary endpoint, was observed in the Meriva group (P = 0.032). Changes in epithelial IL8, TNFα, and inducible protein 10 levels and gastric mucosal histology and DNA damage (secondary endpoints) were similar between arms. Curcumin (Meriva) was safe, well-tolerated, and showed potential as a curcuminoid chemoprevention agent in H. pylori–negative patients with GPMC. A potential reduction in gastric inflammation as measured by gastric mucosal IL1β levels was observed. Further studies are warranted, including studies in H. pylori–positive individuals, based upon the curcuminoid direct effects on H. pylori. Prevention Relevance: Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Chemoprevention candidates for GPMCs are limited. This randomized phase IIa trial evaluated a bioavailable curcumin formulation in high-risk individuals with MAG and GIM. The results support further study of curcuminoids for gastric cancer risk reduction. See related Spotlight, p. 387 See related article by Morgan et al., p. 391

Management of locoregionally advanced human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV(+) OPSCC) can include induction chemotherapy followed by definitive chemoradiation. The standard induction regimen of cisplatin, docetaxel, and 5-fluorouracil (TPF) is associated with high toxicity. Given the chemosensitivity of HPV(+) OPSCC, platinum doublets are frequently used as induction therapy with potentially less toxicity. This retrospective study aimed to compare outcomes between treatment-naive HPV(+) OPSCC patients receiving induction TPF and those receiving an induction platinum doublet. Data collected included tumor characteristics, response after chemoradiation, hospitalization rates, and overall survival (OS). Fifty-five patients (18 TPF and 37 platinum doublet) were included. There was no significant difference in response after completion of definitive chemoradiation (TPF: CR 83.3%, PR 5.6%, progression or metastasis 11.1% vs. platinum doublet: CR 75.7%, PR 16.2%, progression or metastasis 8.1%; p = 0.5241). There were also no differences in hospitalizations for adverse events (38.9% in TPF vs. 40.5% in platinum doublet, p = 0.907) or recurrence (11.1% in TPF vs. 2.7% in platinum doublet, p = 0.198). The 5-year OS was 84.6% in the TPF group and 81.5% in the platinum doublet group (p = 0.581). Induction platinum doublet regimens offer comparable OS, response, and hospitalization rates to TPF in locally advanced HPV(+) OPSCC. Induction with a platinum doublet may be a viable de-escalation strategy for patients who are not candidates for TPF.

Abstract Background: Hepatocellular carcinoma (HCC) is largely refractory to immune checkpoint blockade due to immune exclusion, stromal barriers, and aberrant vasculature. We evaluated whether multimodal therapy - external beam radiotherapy (EBRT) for antigen release, intratumoral dendritic cell (DC) vaccination for antigen presentation, PD-L1 blockade for immune activation, and VEGF inhibition for vascular normalization - could convert “cold” HCC tumors into sustained immune-inflamed states. Methods: Serial biopsies (baseline, post-EBRT, end-of-treatment [EOT], and progression [PD] when available) from three patients enrolled in an ongoing phase II trial (NCT03942328) underwent multiplex immunofluorescence, spatial neighborhood analysis, and transcriptomic profiling. Longitudinal changes in cellular composition, immune-stromal architecture, spatial contact networks, and pathway activity were compared. Results: Baseline tumor microenvironments (TMEs) were strongly immune-excluded, dominated by tumor (PanCK+60-70%) and stroma (SMA+/Vimentin+25-30%) with sparse immune infiltration (<10-15%). Post-therapy, immune complexity and spatial connectivity increased 2-3-fold in all patients. Patient 1 showed robust cold-to-hot conversion with CD8+(3x), CD4+(2.2x), and DC (2.3x) expansion, increased CD8-DC interactions (2.5x), and reduced tumor fraction (-40%). Transcriptomics showed marked upregulation of IFN-γ (↑3.4x), HLA-DRA (↑2.7x), and reductions in VEGFR2 (↓50%) and HIF1A (↓40%), consistent with vascular normalization. Patient 2 exhibited stromal/vascular remodeling and improved T-cell infiltration but restricted immune diversity, with CD4+/CD8+ dyads (↑2.2x) and B/NK cells(↓ 60%). Neighborhood diversity rose (3→7 communities) and immune-tumor proximity improved (distance ↓ 35%). Patient 3 showed transient inflaming with CD8+(↑3x), DC(↑2x), and new CD4-CD20/CD4-CD56 interactions, followed by relapse marked by stromal/myeloid re-expansion (SMA+↑1.8x, CD14+↑2.5x), angiogenic resurgence (VEGFR2/CD34+↑2.2x), contraction of immune networks, and genomic shift from activating CTNNB1 mutation loss to ATM gain. DCs accumulated but localized mainly to DC-DC or DC-myeloid niches, indicating non-productive antigen presentation. Conclusions: Multimodal EBRT+DC+PD-L1/VEGF blockade induces four-sided synergistic TME reprogramming - antigen release, immune priming, checkpoint release, and vascular normalization - promoting cold-to-hot conversion in HCC. Durable inflaming correlates with sustained T-cell/DC expansion and vascular remodeling, whereas relapse reflects stromal/myeloid reinforcement and genomic adaptation. These findings define mechanistic trajectories of TME remodeling and highlight actionable barriers to sustained immunotherapy response in HCC. Citation Format: Lionel Aurelien Kankeu Fonkoua, Christopher L. Hallemeier, Basim Salem, Arina Tkachuk, Kaitlynn McCay, Panwen Wang, Ying Li, Thomas D. Atwell, Krishan R. Jethwa, Caitlin Conboy, Nguyen H. Tran, Leslie A. Washburn, Melody Wu, Chen Wu, Andre De Menezes Silva Corraes, Rondell P. Graham, Jose Caetano Villasboas, Kevin Regan, Zuoyi Shao, Rayaan Kamal, Nathan R. Foster, Haidong Dong, Sean Park, Yi Lin, Lewis R. Roberts. Multimodal immunotherapy remodels the tumor microenvironment in hepatocellular carcinoma: Integrative spatial and transcriptomic profiling from a Phase II trial [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 7935.

Objectives: This trial served as a proof-of-concept for whether inhibition of protein kinase C iota (PKCι) with auranofin and sirolimus provide antineoplastic effects in patients with recurrent high-grade serous ovarian cancer. Methods: This drug combination was administered to patients with recurrent high-grade serous ovarian cancer. Dosing was based on unpublished phase 1 data and consisted of auranofin 6 mg and sirolimus 5 mg both orally per day of a 28-day cycle. The primary endpoint was tumor response. Available tumor tissue was assessed for PKCι protein expression by immunohistochemistry (IHC) and PRKCI copy number by fluorescence in-situ hybridization (FISH) after the start of cancer therapy. Results: Twenty-two patients were enrolled, and 21 were evaluable for all clinical trial endpoints. One patient was unevaluable because she did not receive a full chemotherapy cycle. No tumor responses were seen in the first 21 patients, resulting in early trial termination per a priori trial design. The median progression-free survival was 2.1 months (95% CI: 1.8-3.7). The median overall survival was 4.4 months (95% CI: 2.6-12.5). Fourteen (67%) patients had at least one grade 3 or worse adverse event. Nineteen of 21 evaluable patients had available tumor tissue, which showed the median PKCι copy number averaged per cell of 3 (range: 2 to 7), and PKCι expression (at least 1+) in all. Conclusions: As prescribed here, auranofin and sirolimus manifested no antineoplastic activity in patients with recurrent high-grade serous ovarian cancer that expressed PKCι.

PURPOSE The development of colorectal liver metastases (CRLMs) is associated with poor prognosis, and recent data suggest that metastasis to the liver is associated with resistance to immunotherapy. We characterized the microenvironment of primary colorectal carcinomas (CRCs) relative to their synchronous CRLMs using a validated segmentation algorithm (QuantCRC) that quantifies 15 distinct morphologic tumor features. MATERIALS AND METHODS Adult patients with CRC with synchronous CRLM (N = 57) at Mayo Clinic were identified from the electronic health record. Routine tumor hematoxylin and eosin sections were digitized and reviewed for quality control. QuantCRC (Aiforia, Inc) was applied to digitized images to extract 15 GI pathologist predefined morphological features. Tumor features were compared between paired primary tumors and their synchronous CRLMs using the Wilcoxon signed-rank test overall and within subgroups. Linear regression models were used to find predictors of the paired differences in the distinct tumor morphological features. RESULTS The study included 57 patients (median age 59 years [IQR, 50-73], 51% female) with CRC primary and synchronous CRLM, and among primaries, 37 (65%) were left-sided. QuantCRC identified six of 15 morphological features that differed significantly between primaries and their CRLMs. Compared with the primary, CRLM showed reduced stroma, more high-grade tumor and necrosis, higher tumor–stromal ratio (TSR; all P < .05), and a trend toward increased tumor-infiltrating lymphocyte (TIL) density ( P = .052). Synchronous CRLM from patients with left-sided primary tumors had significantly higher TSR, percent high-grade, percent necrosis, and TIL density compared with the primary (all P values ≤0.04). Among right-sided primaries, CRLM had a significantly reduced percent mature stroma ( P = .0296) and a higher percent necrosis ( P = .0027). CONCLUSION Compared with the primary, synchronous CRLMs showed a higher TSR and increased high-grade tumor and necrosis, which are features of tumor aggressiveness and a metastatic phenotype.

6106 Background: Treatment options for pts with R/M SGC are limited. Responses to chemotherapy (CT) are low with high toxicity and responses to immune checkpoint inhibition (ICI) are <10%. Pemetrexed (PTX) is safe and tolerable with responses reported in pts with R/M SGC. 1 Given enhanced responses with PTX and pembrolizumab (PMB) for lung cancer, we hypothesized that PTX and PMB will have activity for SGC. Herein we present the efficacy results in pts with non-adenoid cystic carcinoma (ACC). Methods: MC200708 is a single arm phase II study of PTX and PMB in pts with R/M SGC (NCT04895735). Pts were treated in 2 cohorts: ACC (cohort A) and non-ACC (cohort B). Key eligibility criteria: ≥18 years, ECOG 0-1, measurable disease. Prior ICI and/or PTX was allowed. Key exclusion criteria: serious comorbidities, autoimmune disease, and brain metastases. Simon’s 2-stage design was used for each cohort. Primary endpoint was overall response rate (ORR). Secondary endpoints: progression free survival (PFS), overall survival (OS), and toxicity. All pts received PTX 500 mg/m2 IV + PMB 200 mg IV q3 weeks until progression or treatment intolerance. Imaging was q3 cycles. Results: 25 pts were enrolled Aug 2021-Feb 2024; 1 cancelled prior to treatment. Of 24 eligible and treated pts, median age was 59.5 years (46-77), 66.7% male, performance status 0 (62.5%) or 1 (37.5%). Histologies were salivary duct carcinoma (SDC, 11), acinic cell carcinoma (8), mucoepidermoid carcinoma (MEC, 3), myoepithelial carcinoma (1), and carcinoma NOS (1). 7 pts had no prior therapies (29.2%). The remaining pts had 1 (33.3%), 2 (29.2%), or ≥ 3 lines of therapy (8.3%). 83.3% of pts had no prior ICI. Median cycles of treatment was 8 (2-34), and duration of response was 12.5 months (4.1-20.6). 9 of 24 pts had a confirmed partial response (PR) for ORR of 37.5% (CI: 18.8-59.4). PRs were seen in 7 pts with SDC (7 of 11, 63.6% PR), 1 with MEC, and 1 with acinic cell. Stable disease (SD) was seen in 5 (20.8%), progressive disease in 8 (33.3%), and 2 didn’t have post-baseline imaging, but were considered non-responders per protocol. Clinical benefit rate was 58.3% (CI: 36.6-77.9). With median follow-up of 12.0 months (2-34.7), median OS is 20.7 months (CI: 17.3-not reached) and median PFS is 6.2 months (CI: 2.1-17.3). 1-year OS and PFS rate is 76.3% (95% CI: 59.9-97.2) and 36.1% (CI: 21.01-62.2), respectively. Common toxicities were grade 1 fatigue and nausea. 6 pts (25.0%) had ≥1 grade 3-4 toxicity possibly related to treatment, mostly hematologic. The 4 pts with grade 3-4 non-heme toxicity had grade 3 fatigue, rash, and heart failure, and 1 grade 4 hypokalemia. Correlative studies investigating biomarkers of response are underway. Conclusions: PTX and PMB has activity in pts with R/M SGC, with promising responses in pts with SDC and median response duration of 1 year. 1 Viscuse et al. Head Neck 2019;41(6):E99-103. Clinical trial information: NCT04895735 .

6061 Background: PDS0101 is a T cell stimulating immunotherapy (therapeutic vaccine) targeting HPV16. The combination of PDS0101 + pembrolizumab (5 cycles) has shown durable clinical responses in HPV-positive recurrent/metastatic HNSCC. MC200710 is a window of opportunity study in patients with HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC). This prospective phase II trial utilized 2 cycles of neoadjuvant PDS0101 aloneor in combination with pembrolizumab prior to surgical resection or chemoradiotherapy (CRT). Herein, we report the initial results, including primary endpoint of ctDNA response. Methods: Between June 2022 and September 2024, 20 patients (10 per Arm) with locally advanced HPV+ OPSCC were enrolled in a sequential alternating design. Arm A received 2 cycles of PDS0101 and Arm B received 2 cycles of PDS0101 and pembrolizumab with all patients undergoing subsequent surgery or CRT. Assessments were done at baseline, post cycle 1, and post cycle 2 (prior to surgery or CRT). The coprimary endpoint of ctDNA response was defined as a ≥50% decline in ctDNA post cycle 2 compared to baseline as quantified using NavDx (TTMV fragments/mL). Radiologic objective response rate (ORR) was assessed as per RECIST 1.1. Toxicity through the neoadjuvant period was assessed using CTCAE criteria and recurrence rates following surgery or CRT are reported. Results: Patients were similar between arms: male 90%, median age 61 years, cT1/T2 70%, cN1 65%, and no smoking history 65%. All patients completed both cycles of therapy with 13 (65%) undergoing primary operative management and 7 CRT (35%). The most common toxicity was injection site reaction 85% grade 1, 15% grade 2, 0% grade 3, consistent with prior studies. One patient experienced grade 2 pneumonitis during the neoadjuvant window (Arm B). There was one grade 3 toxicity (5%) possibly attributable to study intervention with one patient experiencing transient hepatitis requiring hospitalization (Arm A). Zero of 10 patients in Arm A had a ≥50% decline in ctDNA from baseline while 5 of 10 patients (50%) met this primary endpoint in ARM B (p=0.03). After Cycle 2, based on RECIST 1.1, no Arm A patients had a partial response (PR), with 7 having stable disease (SD); Arm B had 2 patients with PR and 8 with SD. With median follow up of 6 months, 2 patients in Arm A recurred and 0 patients in Arm B. Conclusions: The combination of PDS0101 and pembrolizumab met the trial’s primary endpoint of ctDNA response and shows promise for further evaluation. ctDNA can be used to assess early response and future studies could use ctDNA to adapt neoadjuvant therapy. Based on these findings, a neoadjuvant dose optimization study in HPV16+ oropharyngeal carcinoma is warranted and evaluation of PDS0101 and pembrolizumab in comparison to pembrolizumab alone. Clinical trial information: NCT05232851 .

ImportanceThe De-escalated Adjuvant Radiation Therapy (DART) phase 3 randomized clinical trial (RCT) showed that in patients with human papillomavirus (HPV)−associated oropharyngeal squamous cell carcinoma, postoperative minimal residual disease (MRD), detected through circulating tumor HPV DNA (ctHPVDNA), was associated with a higher risk of disease progression. When considered along with pathologic factors, postoperative ctHPVDNA assessment may improve patient selection for adjuvant treatment de-escalation; however, more data are needed to demonstrate how it may be used in personalizing treatment intensity.ObjectiveTo determine the association of postoperative MRD status with progression-free survival (PFS) after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Design, Setting, and ParticipantsThis was a secondary analysis of the DART RCT, which was conducted from October 2016 to August 2020 in multiple sites in the US. Participants from the de-escalated adjuvant radiation therapy group and the standard of care group with available blood specimen data were included. Reports from 3-month posttreatment surveillance visits were used to assess associations and outcomes. Data analyses were performed from March 2023 to March of 2025.InterventionsThe DART group received 30 to 36 Gy of radiation therapy in 1.5 to 1.8 Gy twice daily, plus docetaxel, 15 mg/m2, on days 1 and 8. The standard of care group received 60 Gy with or without weekly cisplatin, 40 mg/m2.Main Outcome and MeasurePFS.ResultsThe analysis included 140 patients (mean [SD] age, 59.1 [8.4] years; 12 [8.6%] females and 128 [91.4%] males; 97 [69.3%] with no smoking history); characteristics were similar to the overall DART RCT population. Of these, 17 patients (12.1%) had postoperative MRD (13 of 96 [13.5%] receiving DART and 4 of 44 [9.1%] receiving standard of care). For all patients, postoperative MRD positivity was strongly associated with worsened PFS at 24 months (MRD positivity, 69.5%; MRD negativity, 95.9%; hazard ratio [HR], 0.19; 95% CI, 0.06-0.59). MRD positivity was associated with PFS when evaluating only those patients in the DART group, where 24-month PFS was 68.4% compared to 92.6% for MRD-negative patients (HR, 0.28; 95% CI, 0.08-0.93). Three months after completion of all treatment, 8 of 117 patients (6.8%) had detectable ctHPVDNA, whereas 109 of 117 (93.2%) did not, and detection was highly associated with PFS (HR, 20.48; 95% CI, 6.91-60.67).Conclusions and RelevanceThis secondary analysis of the DART RCT found that patients with detectable ctHPVDNA after surgery had a higher risk of disease progression. When added to the pathologic factors considered, ctHPVDNA assessment may improve selection of patients for treatment de-escalation. In addition, the 3-month posttreatment time point, early in surveillance, may identify a sizable portion of patients with progression and may guide intervention and surveillance after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02908477

727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .

ABSTRACTAthletes are at high risk of iron deficiency even without anemia. In this systematic review and meta‐analysis that included 17,519 athletes in 122 references from 23 countries, participating in 62 unique sports over a 41‐year timeframe, approximately 53.9% of student‐athletes were found to be hypoferritinemic (ferritin concentration below 50 mcg/L) with 23.0% percent showing absolute iron deficiency based on current definitions (ferritin concentration below 20 mcg/L). These findings strongly suggest that changes in clinical practice guidelines are warranted to enable routine screening for iron deficiency among adolescent and collegiate athletes.