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4145 Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death. Outcomes remain poor, due to irresectability at diagnosis for many and sub-optimal responses to systemic therapy. Cytotoxic chemotherapy remains the standard of care. High microsatellite instability (MSI-H) predicts response to immune checkpoint inhibition (ICI) in many cancers. Detecting high MSI is rare in PDAC (incidence <2%), but case reports demonstrate potential therapeutic benefit with ICI. Here, we present multi-institutional data to characterize the clinical behavior of MSI-H PDAC, with special attention to response to ICI. Methods: Cases of MSI-H PDAC were obtained by reviewing data of all PDAC patients from our tertiary cancer center who had undergone genomic sequencing by one commercially available platform. The resulting cohort was supplemented with MSI-H PDAC cases identified by GI oncology specialists at multiple institutions. De-identified patient data were compiled and analyzed. Results: 15 MSI-H PDAC patients were identified. 20% had stage II disease at diagnosis, 27% stage III, and 53% stage IV. 73% of patients received ICI (n=11); 40% as 1st line and 33% as 2nd line. These patients demonstrated 100% overall response rate; 45% complete response (1 pathologic CR, 4 radiographic CR) and 55% partial response. No patient that received ICI had lost response or died after a median follow-up of 18 months (range 6-89 mos). 1 patient had oligoprogression of a single hepatic lesion after 7 mos that was then irradiated; this patient retained radiographic CR for 17 subsequent mos (ongoing). In this cohort, we observe poor responses to cytotoxic chemotherapy. In total, 12 regimens were trialed among 9 patients. Overall response rate was 0%. 42% achieved disease stability, with median duration of response of 2 mos; only 2 cases maintained disease stability for >5 mos. 4 patients did not receive ICI; all patients died, with a median survival of 7.5 mos. Conclusions: MSI-H PDAC represents a rare but important subtype of PDAC with unique clinical behavior. Given its rarity, large-scale analyses and trials are unlikely to be performed, making case series such as ours crucial. In our cohort, we observe impressive, durable responses to ICI, along with very poor responses to cytotoxic chemotherapy. Our data argues for consideration of ICI in any patient presenting with MSI-H PDAC, including in the first-line and neoadjuvant settings.

3601 Background: Two cfDNA assays are FDA-approved for use in advanced cancer pts across solid tumors. While several NCCN guidelines recommend cfDNA as a valid and useful method for molecular testing, the utility varies by cancer type. Despite the growing number of molecular alterations pertinent to first-line treatment in mCRC, current guidelines offer little guidance on the use of cfDNA in mCRC. Here we assess the ability of cfDNA to detect guideline-relevant actionable biomarkers informative for first-line therapy selection and beyond in patients with mCRC. Methods: We queried consecutive samples from advanced cancer pts with a diagnosis of CRC who underwent testing via a commercially available cfDNA assay (Guardant360) from September 2018 to January 2022. Validation and content of this assay has been previously described. To enrich for less heavily treated pts, we limited analysis to those whose first cfDNA test was done during the study period and only included the pt’s first test. The maximum variant allele fraction (maxVAF) for each test was used as a proxy for tumor shed and was compared between cancers with a Mann-Whitney test. The frequency of suspected germline alterations was assessed only in pts who received testing via a panel version with expanded mismatch repair (MMR) gene coverage. Tissue frequencies for select biomarkers were obtained from the MSK-IMPACT Clinical Sequencing Cohort in cBioPortal. Results: In total, 14,345 pts with mCRC received their first cfDNA test during the study period, with 92% of pts (13,190) having >1 cfDNA alteration detected. Median age was 62 and 44% of pts were female. The frequencies of key biomarkers are listed in Table 1. The median maxVAF was 5.6%, compared to 2.5% and 1.8% for pts with advanced gastric and NSCLC, respectively (p = < 0.0001 for both). The average turnaround time (TAT) for tests was 7 calendar days. Conclusions: cfDNA results from pts with mCRC demonstrated detection of biomarkers essential to first-line treatment decisions at a frequency comparable to what has been reported via tissue genotyping. mCRC pts had significantly higher tumor shed compared to other cancer types with guidelines that recommend cfDNA as an option for molecular testing, suggesting a potential gap in coverage. Tissue availability in mCRC does not guarantee comprehensive testing is completed quickly (compared to the 7-day TAT seen for cfDNA here), making it an attractive alternative strategy for first-line therapy selection in mCRC. [Table: see text]

3590 Background: Co-occurring alterations (COAs) in the HER2 and MAPK pathway are rare in mCRC. RAS, HER2 and BRAF alterations have been associated with resistance to EGFR inhibitor therapy (EGFR-mab). Typical co-occurring mutually exclusive gene mutations such as in KRAS and BRAF have been reported. This study aims to evaluate the prevalence of co-occurring alterations in the MAPK pathway or across MAPK/ HER2 and correlate to outcomes in patients with mCRC treated with EGFR-mab. Methods: This is a retrospective study of patients with mCRC within the Mayo Clinic database who have available blood-based NGS Guardant 360 data (September 2017-November 2021) and contained co-alterations in the MAPK pathway or across MAPK/ HER2. MSI-high cases were excluded. Typical-RAS was defined as alterations in codons 12, 13, 59, 61, 117, and 146 of KRAS, HRAS, and NRAS. Atypical-RAS alterations were considered mutations at other codons of these genes. Patient characteristics, specific mutations, and outcome data were assessed. Results: 692 patients (pts) with mCRC were identified and 66 (9.5%) of those had COAs detected. 59/66 pts had clinical data available. Median age was 52 years, 55.9% were male, and 61.0% had left-sided tumors. The frequency of detected alterations was: BRAF-V600E (7.3%), BRAF-non-V600E (7%), BRAF-amplification (3.04%), RAS-typical (39.5%), RAS-atypical (2.1%), HER2 amp (0.5%), HER2-mutation (1.2%) and PIK3CA (13%). COAs are described in the table. Twenty-three pts received EGFR-mab; COAs developed in 19 of them after progression on EGFR-mab. Four pts received EGFR-mab with documented COAs at baseline with none of them responding to treatment. Conclusions: COAs in MAPK and MAPK/ HER2 pathway are not uncommon in pts with mCRC emphasizing on the importance and feasibility of blood based NGS vs. selected gene testing. In pts with prior EGFR-mab treatment, COAs were detected after progression on treatment in the majority of pts, suggesting a mechanism of secondary treatment resistance. Further data including prospective validation is warranted. [Table: see text]

2583 Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.

PURPOSE This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. MATERIALS AND METHODS We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). RESULTS The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. CONCLUSION DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.

110 Background: Sarcopenia or a loss of muscle mass increases with aging and is associated with increased overall mortality in patients with cancer. Recent advances in machine learning–based CNN algorithms have allowed for the rapid processing of digital images to produce image classifications of body composition. Since incidence of MM is highly associated with aging, we sought to determine if the presence of sarcopenia, as determined by utilizing this machine learning–based CNN algorithm on CT images, had prognostic value in patients with NDMM. Methods: We identified all patients with NDMM from January 2003 to July 2019 who had a standard-dose CT scan that included the L3 vertebral level performed within 6 months of diagnosis. Using a machine learning–based CNN-algorithm, abdominal CT images were analyzed to measure muscle area. These measurements were normalized by dividing the area values by the height of the patient squared (m2) to obtain skeletal muscle index (SMI) values. Patients were categorized as sarcopenic according to international gender-specific consensus cutoffs for SMI (male: < 55 cm2/m2 and female: < 39 cm2/m2). Patients with the following FISH cytogenetics were considered high risk (HR): t(4;14), t(14;16), t(14;20), and deletion 17p/monosomy 17 whereas the remainder were standard risk (SR). Survival analysis was performed using the Kaplan-Meier method and compared via the log-rank method. Results: The study cohort consisted of 344 patients. 68 (20%) were categorized as HR based on FISH cytogenetics.187 (54%) patients were sarcopenic based on their peri-diagnosis standard-dose CT scan. Sarcopenic patients were more likely to have ISS-3 disease (45% vs. 30%; p =.023), be male (73% vs. 48%; p <.001), and be ≥ age 75 (27% vs. 14%; p =.002) compared to non-sarcopenic patients. The median OS for patients with HR FISH and ISS 2 / 3 disease was 40 months and 57 months respectively compared to 90 months and 119 months for those with SR FISH and ISS-1 disease respectively (FISH: p <.004; ISS: p <.001). The median OS for sarcopenic patients was 44 months compared to 90 months for those not sarcopenic (p <.001). The time to next therapy (TTNT) for sarcopenic patients was 39 months compared to 45 months for those not sarcopenic (p =.05). In a multivariable model, the presence of sarcopenia (HR 1.64, 95% CI, 1.05–2.56; p =.03) retained significance in the presence of HR FISH, ISS 2 / 3 disease, and age ≥ 75. Conclusions: Gender-specific sarcopenia identified by a machine learning–based CNN algorithm significantly affects OS in patients with NDMM and is independent of age, ISS stage, and cytogenetic status. Future studies utilizing this machine learning–based methodology of assessing sarcopenia in larger prospective clinical trials are required to validate these findings.

AbstractAchalasia is rare in the pediatric population and should prompt clinicians to consider genetic disorders associated with this condition. While AAA syndrome (also known as Allgrove or Triple A syndrome) is commonly considered, GMPPA‐congenital disorder of glycosylation (CDG) should also be in the differential diagnosis. We report a 9‐month‐old female born to nonconsanguineous parents with achalasia and alacrima found to have two novel compound heterozygous variants in the GMPPA gene associated with GMPPA‐CDG. This rare disorder is commonly associated with developmental delay and intellectual disability. We discuss management of this disorder including the importance of confirming a genetic diagnosis and summarize reported cases.

Abstract BACKGROUND: Central Nervous System- Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, treatment failures remain a poorly characterized disease with unfavorable outcomes. In this study, we sought to characterize the treatment failures in a large cohort of prospectively treated patients. METHODS: European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol-guidelines were included as an independent, non-overlapping cohort. RESULTS: A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy and additional eleven patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; p=0.026). In our analysis, focal or whole ventricular (WVI) radiation therapy was not associated with an increased risk of metastatic relapses. CONCLUSIONS: Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses, are associated with elevated tumor markers, and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.

Abstract PURPOSE: A subset of pediatric, adolescent and young adult (AYA) gliomas are located in the brainstem, eloquent locations, or present with diffuse/leptomeningeal disease, and are associated with high risk and low yield of biopsy. At the same time, accurate molecular diagnosis is necessary to direct optimal therapy. In such cases, analysis of cell free DNA (cfDNA) form cerebral spinal fluid (CSF) may represent a diagnostic alternative to biopsy. METHODS: We investigated the utility of CSF cfDNA sequencing through a stepwise approach, using clinically validated, targeted molecular assays. Testing was performed using a broad hybrid capture next generation sequencing assay (MSK-IMPACT) and subsequent targeted digital droplet PCR in a subset of cases. RESULTS: We analyzed 17 CSF samples from 17 pediatric (n=6) and AYA (n=11) glioma patients with primary or recurrent disease. Thirteen had tumors located within the brainstem, and four had leptomeningeal involvement. Somatic alterations were detected in 12/17 samples (71%). In 3/4 patients with leptomeningeal involvement, cfDNA testing revealed a BRAF fusion consistent with the diagnosis of diffuse leptomeningeal glioneuronal tumor (DLGNT). Among the 13 patients with brainstem involvement, four had somatic H3 K27M mutations, three had IDH mutations, and one had TP53 and ATRX mutations; five patients had no detectable mutations. CONCLUSION: In our analysis, we found that established glioma hotspot mutations were able to be detected within the CSF. We propose that in patients for whom tissue biopsy is high risk, not feasible, or tissue was nondiagnostic, CSF cfDNA sequencing has a substantial diagnostic yield and should be considered as a valuable novel diagnostic tool. Ongoing research is aiming to further increase the sensitivity of cfDNA testing, especially in patients with very low levels of CSF cfDNA.