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Introduction: Dual checkpoint inhibitor therapy with nivolumab and ipilimumab has been FDA-approved for a number of different cancers including melanoma, recurrent NSCLC, and hepatocellular carcinoma. However, their role in the treatment of ACC and other salivary gland carcinomas is not well established. Methods: We performed a Simon’s two-stage prospective single-institution phase II clinical trial of nivolumab (240 mg intravenously every 2 weeks for 16 weeks, then 480 mg every 4 weeks) with ipilimumab (1 mg/kg intravenously every 6 weeks), both of which were provided until intolerable toxicity or disease progression. Two cohorts were analyzed: patients with metastatic/recurrent ACC and patients with other salivary gland cancers. The primary endpoint was median progression-free survival (PFS) based on RECIST and immune-related RECIST (irRECIST) criteria; secondary endpoints were overall response rate (ORR), overall survival (OS), and toxicity. Results: Patients with ACC (n=19) and other salivary gland carcinomas (total n=5; parotid gland adenocarcinoma (n=3), salivary duct carcinoma (n=1), and myoepithelial carcinoma (n=1)) were enrolled between May 2017 and July 2019. Among the patients with ACC, the median OS was 30.0 months (95% confidence interval (CI) 15.3 months to not reached), the median PFS was 8.3 months (95% CI 5.5 - 30.0 months), and the disease control rate (DCR) was 53% (10/19). The ORR in the ACC group was 5% (CR 0%, n=0; confirmed PR 5%, n=1) using both RECIST and irRECIST criteria, with one patient having continued stable disease at the time of trial conclusion. In the salivary gland tumor cohort, the median OS was 10.4 months (95% CI 6.21 months to not reached), the median PFS time was 6.21 months (95% CI 2.83 months to not reached), and the DCR was 40% (2/5). The ORR in this cohort was 0% using both RECIST and irRECIST criteria. Across both cohorts, platelet counts above the joint cohort’s median were significantly associated with better OS (p=0.032) and PFS (p=0.046). Additionally, although not significant, there was a trend for improved OS and PFS among patients with neutrophil-to-lymphocyte ratios >5 (OS p=0.42, PFS p=0.25) and above median neutrophil counts (OS p=0.24, PFS p=0.18). Four patients with ACC underwent circulating tumor DNA sequencing, resulting in the identification of two MYB-NFIB translocations, one NOTCH1 Cys1383 frameshift mutation, one MTOR N1760K mutation, and one PDGFRA copy number gain. Common immune-related toxicities include fatigue (54%), lymphocytopenia (46%), and anemia (42%) with lymphocytopenia being the most common grade III/IV adverse event. Conclusion: In patients with recurrent or metastatic ACC and other salivary gland neoplasms, combination nivolumab with ipilimumab resulted in moderate disease control. Further studies are warranted to validate our findings. Citation Format: Young Kwang Chae, Richard Duan, Liam Il-Young Chung, Youjin Oh, Maria Matsangou, Mark Agulnik, Victoria Villaflor, Devalingam Mahalingam. Phase II study of nivolumab and ipilimumab for treatment of metastatic/recurrent adenoid cystic carcinoma (ACC) of all anatomic sites of origin and other malignant salivary gland tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT165.

Introduction: ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism as well as provides acetyl-CoA necessary for histone acetylation, linking cell nutrient status and epigenetic regulation. Several studies have shown that ACLY is upregulated in multiple cancer types. ACLY has two major splice isoforms: the full-length canonical “long” isoform and an uncharacterized “short” isoform where exon 14 is spliced out. RNAseq data from The Cancer Genome Atlas (TCGA) shows that the Percent Spliced In (PSI) of exon 14, i.e., the proportion of long isoform, is increased in several cancers compared to normal tissues. We therefore hypothesize that ACLY exon 14 inclusion can support tumor growth. Experimental Procedures: Extensive statistical analysis was performed on TCGA data to explore the connection between ACLY PSI and clinical parameters including tumor type, stage, and survival. We also noted a serine within exon 14 that is dynamically phosphorylated according to multiple phosphoproteomics studies. We used an in vitro activity assay and differential scanning fluorimetry to biochemically characterize purified ACLY isoforms and phosphomutants. We also expressed these isoforms and mutants in cells lacking endogenous ACLY to evaluated rescue of known ACLY functions including proliferation, de novo lipogenesis, and histone acetylation. Since exon 14 is located near a putative nuclear localization sequence, we also used confocal microscopy to study subcellular localization of these constructs. Ultimately, we developed a new C57BL6/J mouse model with ACLY exon 14 deleted by CRISPR to study the role of exon 14 in metabolic physiology and tumor growth in vivo. Results: In vitro assays showed no differences in activity and stability between ACLY isoforms and phosphomutants. Similarly, both isoforms and mutants were able to rescue known ACLY functions in cells, and deletion of exon 14 in mice does not impact normal metabolic physiology. Analysis of TCGA data offers compelling evidence that the long ACLY isoform is upregulated early in tumorigenesis and is associated with deadlier tumors and certain immune cell signatures, suggesting that exon 14 is particularly relevant in this disease context. Our mouse model was cross-bred to ApcMin/+ mice, a genetic model of colon cancer, and studies are underway to determine the impact of exon 14 on colon tumors and immune infiltration. Conclusions: ACLY exon 14 does not have obvious roles in enzymatic activity and known ACLY functions. However, alternative splicing could impact pathophysiological phenotypes such as cancer or other yet undescribed functions of ACLY. Citation Format: Julianna G. Supplee, Hayley C. Affronti, Richard Duan, Rebekah C. Brooks, Phuong Nguyen, Kollin Schultz, Ronen Marmorstein, Kathryn E. Wellen. Molecular and cancer-related roles of ATP-citrate lyase exon 14. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3711.

Background: Globally, cancer results in 10.08 million deaths per year. A single blood-based screening tool that detects multiple cancer types could greatly reduce cancer burden. We aim to systematically review and statistically examine both the accuracy and applicability of blood-based MCED tests to strategize their utilization in improving cancer detection. Methods: Original articles were searched from Pubmed, Cochrane, and Embase for blood-based screening tests analyzing multiple cancer types and asymptomatic human subjects. We excluded studies with small sample size (n Findings: Of 1,074 records screened, 10 case-control and 6 cohort studies were analyzed, most of which utilized cfDNA-based diagnostic tests. Ten cfDNA studies selected for meta-analysis had a joint sensitivity of 0.66 (95%CI 0.54-0.75) and specificity of 0.98 (0.94-0.99) with an area under the curve of 0.883. For cohort studies, the joint positive and negative predictive values were 0.96 (0.29-1.00) and 0.81 (0.37-0.97) respectively. Sensitivity was higher for advanced staged cancers (III/IV 0.84 (0.84-0.86)) with breast cancer having the lowest sensitivity (0.42 (0.31-0.55)). Sensitivity and specificity were not affected by study type, gender, or assay type. Lastly, accuracy of tumor origin prediction was 0.792 (0.64-0.91) without significant differences across cancer types. Interpretation: Given high sensitivities and specificities, MCED tests show promise as additional screening tools. Although there exist multiple barriers to their application in clinic, MCED tests may improve patient outcomes for cancers with no conventional screening tools. Future prospective studies with large and diverse populations are warranted. Summarization of meta-analysis results on cfDNA based multi cancer early detection tests Sensitivity Specificity DOR PPV NPV No. of study included 10 10 10 4 4 Events/Total 5778/10033 14797/15020 Experimental group: 5778/6001 901/1373 10148/11216 Control group: 4202/19052 Proportion (95% CI) 0.652 [0.537; 0.751] 0.978 [0.936; 0.992] 69.290 [25.208; 190.457] 0.961 [0.293; 0.999] 0.812 [0.365; 0.970] Heterogeneity (p value) 98% ( Citation Format: Joo Hee Park, Youjin Oh, Liam Il-Young Chung, Richard Duan, Trie A. Djunadi, Sung Mi Yoon, Zunairah Shah, Chan Mi Jung, Ilene Hong, Leeseul Kim, Young Kwang Chae. Systematic review and meta-analysis of the accuracy and applicability of blood-based multi-cancer early detection (MCED) in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 783.

Background: Among the recently developed blood-based multi-cancer early detection (MCED) tests, determining the location of tumors is pivotal to guiding appropriate treatment. We aim to systematically review and statistically examine the accuracy of tumor of origin prediction among blood-based MCED tests. Methods: Original articles were searched from Pubmed, Cochrane, and Embase that featured blood-based screening tests, multiple cancer types, and asymptomatic human subjects. We excluded studies with small samples (n Findings: Of 1,074 records identified and screened, 4 cohort studies were analyzed using cfDNA-based diagnostic tests. The accuracy of tissue-of-origin (TOO) prediction for 3,762 cancer samples across cancer types was 0.79 (95% CI 0.64 - 0.91). Among six cancer types, colorectal cancers had the highest accuracy, and liver & bile duct cancers had the lowest, although the difference was statistically insignificant (0.89 (95% CI 0.79-0.97) vs. 0.68 (95% CI 0.40-0.90)). Additionally, cases were most frequently misclassified as colorectal cancer (Table 1). Lastly, two studies reported increased prediction accuracies when two sites of origin were assigned rather than a single site. The information for localizing TOO was derived from methylation patterns of cfDNA in two studies, fragmentation profiles of cfDNA in another study, and protein markers in the other research. Interpretation: Our results demonstrate that the primary site of cancers was accurately discerned in 79% of cases by MCED tests. However, the performance varies across cancer types. Further research on performance according to cancer stages and in combination with other molecular profiling is warranted. Table 1. Events/Total Accuracy of prediction (95% CI) misclassification type freqeuncy Total 3,129/3,762 0.79 (0.64 - 0.91) Colorectal 638/723 0.89 (0.79 - 0.97) stomach & esophagus 26/553 breast 8/553 Breast 443/538 0.86 (0.64 - 0.99) colorectal 20/349 pancreas & GB 4/349 lung 4/349 Ovarian Breast 132/159 0.85 (0.62 - 0.99) colorectal 39/261 uterus 13/147 Pancreatic & GB 289/338 0.82 (0.69 - 0.93) colorectal 12/300 stomach & esophagus 10/300 Stomach & Esophagus 225/311 0.75 (0.48 - 0.95) colorectal 39/261 lung 10/261 Lung 530/656 0.72 (0.45 - 0.92) colorectal 29/560 head and neck 8/560 Liver & Bile duct 95/144 0.68 (0.40 - 0.90) colorectal 13/220 pancreatic & GB 8/220 Abbreviations: CI = confidence interval; GB = gallbladder Citation Format: Youjin Oh, Joo Hee Park, Liam Il-Young Chung, Richard Duan, Trie Arni Djunadi, Sung Mi Yoon, Zunairah Shah, Chan Mi Jung, Ilene Hong, Leeseul Kim, Horyun Choi, Young Kwang Chae. Systematic review and meta-analysis of the accuracy of tumor origin detection in blood-based multi-cancer early detection (MCED) in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 784.