PURPOSE:Although KRAS mutations represent the primary oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), the association between codon-specific alterations and patient outcomes remains poorly elucidated, largely because of a lack of data sets coupling genomic profiling with rich clinical annotations across disease stages. MATERIALS AND METHODS:We used American Association for Cancer Research's GENIE Biopharma Consortium Pancreas v1.2 data set to test the association of codon-specific KRAS mutations with clinicogenomic features and patient outcomes in patients with PDAC diagnosed with localized (stages I to III) and advanced disease (stage IV). Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS:Among 1,032 eligible patients, 949 (92%) exhibited mutant KRAS. These mutations were predominantly observed at G12D (n = 390, 41%), G12V (n = 305, 32%), and G12R (n = 149, 16%). In the group of patients who presented with localized disease, those with G12V mutation had notably longer survival compared with G12D mutation (P = .03). By contrast, patients with G12V mutation who presented with metastatic disease experienced shorter OS compared with those with G12R (P = .04) and G12D mutations (P = .04). Furthermore, no significant differences were observed in the frequencies of coaltered driver genes, including TP53, CDKN2A, and SMAD4, across the different KRAS mutations. CONCLUSION:These findings demonstrated that codon-specific KRAS mutations affect PDAC outcomes differently based on disease stage at diagnosis. As studies testing KRAS inhibitors continue to emerge and mature, the prognostic variability of individual KRAS mutations must be carefully considered to avoid confounding and ensure accurate evaluation of therapeutic efficacy in early-phase studies.

INTRODUCTION:The College of American Pathologists (CAP) Biorepository Accreditation Program (BAP) was established in 2012 with the goal of providing standardized requirements that ensure high quality for procuring, processing, storing, distributing, and computerizing information of biospecimens for scientific investigations. CAP BAP was the first biorepository accreditation program, and, since the program started in 2012, the world's second biorepository accreditation standard was issued by the International Organization for Standardization (ISO) as ISO 20387 in 2018. CAP BAP serves as an interface between several programs and draws best practices from renowned organizations. This elective program is based on a peer-inspection model to ensure that the inspectors have proper expertise and to promote educational efforts through information sharing. On-site inspections occur every 2 years, like other CAP Accreditation Programs, with an interim self-inspection in the off year. The program compliance is assessed based on CAP Accreditation Checklists, which are regularly revised. OBJECTIVE:This article reviews the accomplishments of the first 10 years of the CAP Biorepository Accreditation Program. RESULTS:As of December 2024, 104 biorepositories are CAP BAP accredited, which increased from 53 accredited biorepositories in 2018. Accreditation of 10 additional biorepositories is underway. A total of 88 inspections were completed between January 2017 and December 2022; 16 were initial inspections and 72 were reinspections. Deficiencies, defined as insufficient or lack of evidence of compliance with a checklist item, were mainly related to equipment/instrumentation (24%), quality management (15%), safety (14%), information technology (13%), personnel (13%), specimen handling and quality control (9%), facilities (6%), and regulatory (6%) issues. The proportion of deficiencies between categories was like the first 5 years. CONCLUSION:The increased number of accredited biorepositories, in both academic and commercial settings, highlights the continued success of the program and its applicability to maintaining high standards for biorepositories.

Black men suffer disproportionately from prostate cancer (PCa) compared to men of other races and ethnicities. Comparing the molecular landscape of PCa among Black and White patients has the potential to identify targets for development of new precision medicine interventions. Herein, we conducted transcriptomic analysis of prostate tumors and paired tumor-adjacent normals from self-reported Black and White PCa patients and estimated patient genetic ancestry. Clinical follow-up revealed increased biochemical recurrence (BCR) among Black patients compared to White patients with high-grade PCa. Transcriptomic analysis identified differential alternative RNA splicing events (ARSs) between Black and White PCa patients. Genes undergoing genetic ancestry-concordant ARSs in high-grade or low-grade tumors involved cancer promoting genes. Most genes undergoing genetic ancestry-concordant ARSs did not exhibit differential aggregate gene expression or alternative polyadenylation. A number of the genetic ancestry-concordant ARSs associated with BCR; thus, genetic ancestry-concordant RNA splice variants may represent unique targets for PCa precision oncology.

e15722 Background: Cell proliferation is a hallmark of cancer growth, and regulation of transcription and translation is key to controlling proliferative capacity. A crucial connection between transcriptional regulation and the cell cycle occurs via transcriptional cyclin-dependent kinases (CDKs), CDK12 and its paralog, CDK13, which regulate transcription by phosphorylating the c-terminal domain of RNA polymerase II. Both CDK12 and CDK13 are often upregulated in solid tumors, rendering them compelling targets for therapeutic intervention. Methods: A total of eight CDK12 or CDK12/13 inhibitors with different mechanisms of action (covalent, non-covalent, proteolysis-targeting chimera, and molecular glue) were screened against a panel of cancer cell lines spanning five solid tumor types (breast, colorectal, lung, ovarian, and prostate). Colorectal cancer patient-derived organoids (PDO) were used to validate the most efficacious agents, covalent binders (THZ531 and CDK12-IN-E9). In order to determine whether CDK13 plays a compensatory role for loss of CDK12 function, knockdown of CDK13 by siRNAs was employed, followed by CDK12-specific inhibition using a proteolysis-targeting chimera (BSJ-4-116). Finally, synergy was conducted to determine whether CDK12/13 inhibition increases sensitivity to poly-ADP ribose polymerase (PARP) inhibition. qPCR quantified the presence of short and long isoforms of BRCA1 following CDK12/13 inhibition to confirm whether transcription elongation in DNA damage repair genes was prevented. Results: Covalent inhibition of CDK12/13 was the most efficacious across pan-cancer cell lines. Validation in colorectal cancer PDO showed greater inhibition by covalent inhibitors than standard of care chemotherapies for colorectal cancer (oxaliplatin, SN38, and 5-FU). CDK13 siRNA-mediated knockdown sensitized colorectal cell lines to the CDK12-specific inhibitor, BSJ-4-116, suggesting CDK13 may compensate for CDK12 loss of function. CDK12/13 inhibition led to downregulation of long isoforms of BRCA1, rendering cells susceptible to dual CDK12 and PARP inhibitors. These compelling data prompted evaluation of CT7439, a CDK12/13 inhibitor and cyclin K glue-degrader, which showed efficacy in the low nanomolar range for a panel of colorectal PDO. Conclusions: Here we highlight CDK12/13 inhibition as a compelling target for colorectal cancers and other solid tumors and show the importance of CDK13 compensation during CDK12 inhibition. These findings support further evaluation of the novel CDK12/13 inhibitor, CT7439, for the treatment of solid tumors with CDK12/13 upregulation.

Rationale: Primary ciliary dyskinesia (PCD) is a heterogeneous, rare genetic disorder characterized by dysfunctional motile cilia. PCD pulmonary manifestations include impaired airway mucociliary clearance, mucus obstruction, recurrent infection, and bronchiectasis (BE). Notably, thoracic imaging studies indicate that alveolar atelectasis is more prevalent in children with PCD than in age-matched children with cystic fibrosis (CF). However, morphologic and molecular analyses of the site of initiation and progression of PCD airway disease and relationships to PCD alveolar disease have not been reported. In this study, we analyzed region-specific morphologic and molecular characterizations of airway epithelia and alveolar regions in PCD lungs excised at transplantation to address these questions. Methods: Nine PCD lungs and seven non-diseased control lungs were included in the morphometric studies. Bronchi and proximal and distal bronchioles were defined using unique morphologic structures, and distal airway secretory cell (DASC) markers were used to differentiate between proximal and distal bronchioles. Morphologic characteristics of airway epithelia and luminal mucus were quantitated by histology, immunohistochemistry, and RNA in situ hybridization. Spatial transcriptomic technologies (GeoMx) characterized region-specific transcript expression in three airway epithelial regions (bronchi, proximal bronchioles, and distal bronchioles), intraluminal mucus plugs, and alveolar regions of PCD compared to control lungs. Finally, pulmonary function data from a cohort of PCD subjects were analyzed to investigate correlations between alveolar morphologic findings and alveolar gas exchange function, i.e. diffusing capacity for carbon monoxide (DLCO). Results: PCD bronchi and proximal bronchioles exhibited ectasia, characterized by increased MUC5AC and MUC5B-producing cells, mucus plugs containing MUC5AC and MUC5B mucins infiltrated by neutrophils, and epithelial gene signatures associated with ectasia. In contrast, PCD distal bronchioles were not ectatic and exhibited MUC5B-dominant DASCs, mucus plugs containing selectively MUC5B mucin infiltrated by mixture of neutrophils and macrophages, and gene signatures suggestive of impaired ciliogenesis. Molecular analysis revealed upregulation of pathways associated with muco-inflammation, antimicrobial defense, and the innate immune system routinely in PCD airway epithelia. IL-1β gene signatures were observed in both PCD airway and alveolar epithelia, whereas interferon-stimulated gene signatures were restricted to airway epithelia. Transcriptomic and morphologic analyses suggested that PCD alveolar disease was initiated by distal bronchiolar obstruction, associated with chronic microatelectasis, progressive loss of alveolar epithelial type 2 (AT2) cells, and eventual non-resolving fibrosis. A significant percentage (28%) of people with PCD exhibited reduced DLCO. Conclusions: PCD airway disease is manifest by distinct profiles of proximal vs distal bronchiolar disease associated with microatelectatic and fibrotic alveolar disease.

Background and objectives:Control of cell division is tightly regulated in eukaryotic cells, and dysfunction in cell cycle checkpoints is a key hallmark of malignant transformation that promotes a fitness advantage over non-cancer cells. One of the most critical mechanisms of cell cycle regulation is via the cyclin-dependent kinases (CDKs), which connect resource availability sensing and growth signaling with cell division and transcription elongation processes. Novel combination therapy approaches to co-target cell cycle and transcriptional CDKs may improve cancer-specific targeting of CDK dysfunction. In the current study, we assessed the effectiveness of fadraciclib, a new CDK2/9 inhibitor, for the treatment of advanced colorectal cancer (CRC). Methodology:A panel of eighteen CRC patient-derived organoids (PDOs) was used to assess the efficacy of fadraciclib. Efficacy was further validated in patient-derived xenografts (PDXs). CDK2/9 target inhibition, cell cycle arrest, and cell killing mechanisms were investigated using western blotting, flow cytometry, and immunofluorescence staining, respectively. Results:CRC PDOs exhibited greater sensitivity to fadraciclib compared to chemotherapy and palbociclib. This efficacy was validated in vivo using three matched PDXs, showing significant tumor growth inhibition with fadraciclib compared to vehicle (P < .05) and no serious adverse effects. Fadraciclib induced G2/M cell cycle arrest, leading to multipolar mitosis and anaphase catastrophe. Conclusions and implications:Our results using patient-derived models suggest that fadraciclib is a promising therapy for advanced CRC by inhibiting CDKs 2 and 9, which affects critical pathways in cell cycle regulation and transcription.

Patients with 22q11.2 deletion syndrome or DiGeorge syndrome commonly report gastrointestinal symptoms in addition to more widely understood cardiac and immunodeficiency abnormalities. However, the morphologic features of gastrointestinal tract pathology in these patients are poorly understood. We previously reported that plasma cells are essentially absent from the luminal gastrointestinal tract of patients with "complete" DiGeorge syndrome. Herein, we add to the current understanding of the luminal gastrointestinal tract changes in patients with DiGeorge syndrome. Patients with cytogenetically confirmed DiGeorge syndrome were identified after approval from our institutional review board. Gastrointestinal tract biopsies from patients with DiGeorge syndrome that were severely immunosuppressed (complete DiGeorge syndrome, DGS-I), partially immunocompromised (partial DiGeorge syndrome, DGS), and from control patients were reviewed. Two panels of chromogenic multiplex immunohistochemistry (IHC) were performed to evaluate the immune cell infiltrate in the lamina propria of the duodenum and colon. "Panel #1" was composed of antibodies targeting CD3, CD20, and CD68. "Panel #2" was composed of antibodies targeting CD4, CD8, CD56, and TCRϒδ. Assessment of cell types identified by these antibody targets demonstrated a significant reduction of duodenal and colonic T-cells in patients with complete DiGeorge syndrome. In addition to establishing the morphologic phenotype of the luminal gastrointestinal tract of patients with DiGeorge syndrome, we also highlight our chosen technology of chromogenic multiplex IHC as a relatively accessible research and diagnostic tool with wide potential to be utilized across various disease processes.

CONTEXT.—:Biomedical research relies on available biomaterials and associated data, and the quality of this starting material can have a significant impact on the quality of the experimental results. In the 2000s, best-practice documents and guidelines for biorepositories were published, followed in the 2010s by standards documents used to support accreditation. The College of American Pathologists Biorepository Accreditation Program and the International Standards Organization's standard 20387 were launched in 2012 and 2018, respectively. OBJECTIVE.—:To identify quantitative and qualitative differences between the 2 aforementioned biorepository accreditation standards for use by the larger biomedical research community; the results will empower biorepositories to select an accreditation program that best fits their goals. DESIGN.—:Individual requirements of both accreditation standards were identified and a bidirectional crosswalk was performed to identify gaps. Requirements were assigned to one of several standardized categories to enable comparison of the relative emphasis of different categories between the standards. RESULTS.—:Quantitatively, the College of American Pathologists program is comprehensive and stands alone, with 523 requirements, whereas the International Standards Organization program contains 167 requirements and is comprehensive through its incorporation and reference to numerous related standards documents. Qualitatively, both programs rely heavily on the implementation of an overarching quality management system and both programs can accommodate different types of biobanks (eg, human and animal). CONCLUSIONS.—:The standards differ in number of requirements, distribution of requirements across categories, and amount of reliance on separate standard documents. This information may aid in selection of an appropriate accreditation standard.

209 Background: Colorectal cancer (CRC) is the third most common cancer in adults in the United States. Given the relative rapid cell division in cancer cells compared to most normal cells, drugs targeting mitosis and other cell cycle checkpoints are of interest in CRC treatment. One multi-tasking protein in cell division is polo-like kinase 1 (plk1). Plk1 is a serine threonine kinase that is highly expressed during mitosis and involved in a variety of functions, including spindle assembly, chromosome segregation, G2/M transition, and cytokinesis. Encouragingly, its expression is also significantly higher in CRC compared to normal mucosa, which makes it an attractive cancer-specific target in CRC. In this study, we sought to evaluate the efficacy of plogosertib (CYC149462), a novel plk1 inhibitor, in a series of preclinical models of advanced CRC. Methods: Fourteen CRC patient-derived organoids (PDOs) were generated from patients who underwent biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. Diagnosis of CRC is confirmed in PDOs using H&E and IHC. Subsequently, PDOs were treated with plogosertib in a range of concentrations from 256pM to 100µM. Drug screens were performed for standard of care agents 5FU, oxaliplatin, and SN38. Viability was assessed with Cell-Titer Glo (CTG) 72 hours after treatment. Using a matched PDX, mice were treated with vehicle or 40 mg/kg daily of plogosertib via oral gavage for 2 weeks, 5 days per week. Cell cycle analysis was performed by flow cytometry, and localization of DNA during mitosis was done by fluorescence staining. Results: CRC PDOs were more sensitive to plogosertib (CYC149462) than 5FU, and oxaliplatin, with significantly lower IC 50 values (518.86±377.47nM for plogosertib vs. 38.87±45.63µM for 5FU, and 37.78±39.61µM for oxaliplatin respectively (ANOVA, P < 0.05). Subsequently, we validated our findings in vivo using a matched PDX in which plogosertib treatment led to significant tumor growth inhibition compared to vehicle (t-test, p < 0.05) without serious adverse effects. Furthermore, we showed that plogosertib induces dysfunction in alignment of chromosomes and subsequent G2/M cell cycle arrest (p < 0.05). Conclusions: Together, our study shows that pharmacological inhibition of Plk1 using plogosertib represents a promising therapeutic approach for advanced CRC.

Targeting tumor-specific molecular alterations has shown significant clinical benefit. Molecular tumor boards (MTBs) connect cancer patients with personalized treatments and clinical trials. However, rural cancer centers often have limited access to MTB expertise. We established an academic–community partnership expanding our academic MTB to affiliated rural community cancer centers. We developed a centralized molecular registry of tumors (MRT) to aggregate the comprehensive genomic profiling (CGP) results and facilitate multidisciplinary MTB review. Of the 151 patients included, 87 (58%) had actionable genomic biomarkers, 42 (28%) were eligible for a targeted off-label therapy, and 27 (18%) were matched to a clinical trial. Of those with a clinical trial match, only 1 of 27 (3%) was enrolled in the identified trial. One year into implementation, community oncology providers were anonymously surveyed on persistent barriers to precision treatment utilization. The primary barriers to clinical trial enrollment were the distance to the trial center (70%), lack of transportation (55%), and lack of local trials (50%). This study offers a framework to improve access to molecular expertise, but significant barriers to the equitable use of CGP and trial enrollment persist.

While the FAIR (Findable, Accessible, Interoperable, and Reusable) principles are primarily concerned with data, samples can also be considered a distinct category of data. In light of these considerations, the FAIR principles represent a major challenge for biobanks, as discussed in detail in two recently published studies. We invited seven experts with diverse backgrounds to share their views on these studies and the FAIR principles in general. The contributions are written from different perspectives, including those from human biobanks operating globally, located in low- or middle-income countries or in high-income countries, as well as those from industrial or environmental biobanks. The last two contributions focused on technical feasibility and the necessary incentives. All authors agreed that while the FAIR principles present a challenge for biobanks, they also offer opportunities. Various useful instruments already exist, and more will follow. The key is to provide meaningful incentives.

In a surgical pathology setting, the clinical study of tissue specimens is often limited to evaluating an effectively 2D representation of an inherently 3D specimen and disease, most commonly by a several-micron thick hematoxylin and eosin (H&E) stained glass slide. X-ray transmission allows for the study of thicker tissue volumes but does not provide soft tissue contrast. Previous studies using X-ray diffraction (XRD) have shown that XRD can differentiate some soft tissue and disease types from one another. We focus here on simulation-based trade studies using a toy model to optimize and evaluate the imaging performance of a 3D structured illumination XRD imaging scheme. In particular, we quantify the lateral and axial spatial resolution and evaluate how these parameters depend on the angular extent and beamlet configuration of the primary structured illumination beam. We observe an optimal beamlet configuration and show that a transverse resolution of 100 um and an axial resolution of 500 um is achievable.

INTRODUCTION: We designed a race-conscious study to assess the presence of Helicobacter pylori virulence factor cagA in a retrospective cohort of patients with active H. pylori infection. METHODS: We compared cagA status by race in gastric tissue samples from 473 patients diagnosed with active H. pylori infection from 2015 to 2019. RESULTS: H. pylori + Black patients were 2 times more likely to be cagA + than H. pylori + White patients (82% vs 36%, P < .0001). DISCUSSION: Presence of cagA is common among endoscopy patients with active H. pylori infection; appropriate testing and treatment of H. pylori can both reduce gastric cancer risk and address health disparities.

BackgroundThere is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations.MethodsMedical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014.ResultsAmong 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7–47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy.ConclusionsTreatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.MicroAbstractThis study generated real-world evidence among patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) mutations. Treatment patterns were similar to mCRPC patients regardless of HRR-mutation status. Median OS was 3 years from initiation of first-line therapy and decreased for subsequent lines. Results highlight a need to identify optimal treatments and sequencing for patients with HRR-mutated mCRPC.

Specimen radiography is critical to cancer diagnostics, but conventional transmission X-ray imaging often lacks the contrast to conclusively differentiate healthy from cancerous tissue. X-ray diffraction (XRD), however, has been shown to be sensitive to structural changes in tissue that are correlated with cancer progression. We use a home-built XRD imaging system to study glioblastoma in brain tissue and ductal carcinoma in situ (DCIS) in breast tissue, and identify both commonalities and unique aspects of cancer structural changes in the brain and breast. These findings demonstrate the potential for XRD imaging as a new tool for use in both research and diagnostic medicine.

3596 Background: Colorectal cancer (CRC) is the third most common type of cancer among adults in the United States. Given the heterogeneous nature of the disease and the limited number of treatments available, there is an unmet need to identify new therapeutic vulnerabilities for advanced CRC. One promising approach is targeting of cyclin dependent kinases (CDKs). In our current study, we sought to understand the potential efficacy of fadraciclib (CYC065), a novel dual CDK 2/9 inhibitor, as a novel treatment for metastatic CRC. Methods: Eighteen CRC patient-derived organoids (PDOs) were generated from patients undergoing biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. IHC and H&E staining were first performed on the established PDOs to confirm the diagnosis of CRC. PDOs were treated with standard of care chemotherapy (oxaliplatin, irinotecan (SN38) and 5-Flurouracil), CDK4/6 inhibitor palbociclib, and fadraciclib (CYC065). All drugs were used in doses ranging from 6.4nM to 100µM, and drug sensitivities were determined using Cell-Titer Glo (CTG) 72 hours after treatment. Subsequently, three matching PDXs were generated for in vivo validation and treated with fadraciclib (CYC065) via oral gavage at a dose of 25 mg/kg BID five days a week for two weeks. Target validation for CDK2/9 inhibition was performed via western blotting, cell cycle arrest was determined via flow cytometry, and killing by anaphase catastrophe was determined by immunofluorescence staining. Results: CRC PDOs were more sensitive to fadraciclib (CYC065) than chemotherapy and palbociclib, with IC 50 values lower than chemotherapy or palbociclib (2.65±3.92µM for fadraciclib (CYC065) vs. 29.92±41.98µM for chemotherapy (P<0.05) or palbociclib (12.33±9.87µM)). Subsequently, we validated our findings in vivo using 3 matched PDX showing significant tumor growth inhibition (TGI) with fadraciclib (CYC065) compared to control (p<0.05) without serious adverse effects. We showed that fadraciclib (CYC065) induces G2/M cell cycle arrest, resulting in anaphase catastrophe as evident by the presence of multipolar mitosis in fadraciclib (CYC065)-treated cells. CDK2/9 inhibition leads to downregulation of c-Myc levels and upregulation of apoptosis induction as a second mechanism of action for this drug. Conclusions: Our data using both in vitro and in vivo patient-derived models support further exploration of fadraciclib (CYC065) has a potential therapy for advanced CRC. CDK2/9 inhibition impacts multiple critical pathways involved in transcription, mitosis and apoptosis. Further studies will be needed to reveal molecular biomarkers of sensitivity and resistance to this novel agent.

Spaghetti plots of CD4 and CD8 T cells by visits; stratified by overall response.

Signed-Rank Tests of V3-V2 Difference

2588 Background: Immunotherapies, including immune checkpoint inhibitors (ICI), have revolutionized the treatment of many cancers, producing significant improvements in survival in patients with many different cancers. However, the intended anti-tumor effects also result in a unique form of autoimmunity, known as immune-related adverse events (irAEs), which have emerged as a limiting factor for many immunotherapies. Cutaneous irAEs (cirAEs), the most frequently occurring ICI–related toxicities, have been associated with improved efficacy and survival but, in their severe forms, require systemic steroids and have in cases led to premature ICI discontinuation and fatality. There is a need for both robust biomarkers and adequate models that effectively predict which patients who develop irAEs may have improved outcomes. Methods: Using a microfluidic droplet technology that generates "mini" patient-derived organoids called MicroOrganoSpheres (MOS), we successfully generated skin MOS from skin biopsy samples in both healthy skin and tumor-involved skin that sustain the original patient skin immune microenvironment over three weeks. Using this model, we assessed skin cell toxicity and cytokine release in response to ICI and targeted therapies. Results: Clinical responses were largely consistent with the skin and tumor MOS assay readouts, indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Matched pairs of patient melanoma and skin MOS showed good concordance with patient outcome indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Enrichment of genes associated with atopic dermatitis, vitiligo, and psoriatic dermatitis were observed in MOS generated from skin of an ICI-sensitive patient compared to the MOS generated from skin of an ICI-resistant patient. These results indicated that the skin MOS platform can potentially predict the dermatological toxicity of ICI. As the MOS assay can be completed within 12 days after biopsy acquisition, this novel technology may enable personalized medicine approaches by prediction of cirAEs and efficacy for individual patients. Conclusions: This is the first study to date demonstrating the application of a patient-derived immune competent skin model deployable for assessing ICI efficacy and toxicity response. Matched tumor skin MOS from the same patients recapitulated the clinically observed association between ICI efficacy and toxicity and may provide key indicators for prospective irAE-predicting clinical trials.