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BackgroundTreatment recommendations in early RA advocate a treat to target approach with the ideal goal of remission. But not all patients attain this goal. There is a need for outcome measures that are meaningful to patients and inform management of which alleviation of suffering is a key aim. PRISM1 is a novel, validated, brief method of measuring suffering consistent with Cassell's seminal conceptualisation2.ObjectivesTo understand the relationships between a patient's perception of the totality of the impact of RA and commonly used clinical assessments of disease activity, depression and illness intrusiveness.MethodsBasic sociodemographic and clinical data were collected from 182 RA patients from 3 international centres, assigned to one of four cohorts (two early RA and two established RA), at baseline, weeks 12 and 24. The two early RA cohorts (diagnosis <2 yr) comprised Group 1 on stable treatment (n=37) and Group 2 requiring csDMARD adjustment (n=34). Using the iPRISM App on a tablet, all patients were asked to complete the basic PRISM task to measure self-illness separation (SIS). The smaller the SIS, the greater the person's perceived suffering. In the PRISM+ task, patients were asked to identify two valued aspects of their life at the moment (X and Y) which bring pleasure, satisfaction, a sense of achievement, or a sense of purpose. The iPRISM App automatically records the distance between the centres of each of these disks and the Self disk to measure patients' perceptions of the intrusiveness of their illness on two personally valued aspects of their lives.For both groups, direction of change in SIS and the PRISM+ measures were compared with direction of change in disease activity measures and patient global disease activity (ptGbl), assessed at wks 12 and 24, using the sign test.ResultsPRISM was easy to use and most patients understood the simple instructions. Of 182 patients at baseline, SIS showed significant correlations with ptGbl (rs=-0.48, p<0.0001), pain VAS (rs=-0.45, p<0.0001), PHQ9 (rs=-0.45, p<0.0001) and illness intrusiveness scale (rs=-0.51, p<0.0001). Suffering was inversely correlated with the perceived controllability of the symptoms of RA; for Group 1, rs=0.41, p<0.0001, for Group 2, rs=0.32, p<0.0001.In Group 2, SIS and DAS28-ESR showed small trends to improvement by wk 12 (DAS28-ESR Δ=-0.11, p=0.557; SIS Δ=1.7, p=0.296) with significant improvement by wk 24 (DAS28-ESR Δ=-0.82, p=0.002; SIS Δ=3.85, p=0.029). However, there was no significant improvement in the intrusiveness of the illness on the valued aspects of life over this time period (Actual X, Δ=-0.25, p=0.557; Actual Y, Δ=1.89, p=0.169).ConclusionsPRISM is a novel PRO that quantifies factors salient to each individual with respect to the impact of RA and its treatment while allowing for incorporation of a wide range of such influences. It may have utility as an adjunct to disease activity measures in setting agreed personalised therapeutic targets.References T Sensky & S Buchi. PLoS ONE 11(5):e0156284, 2016.EJ Cassell. NEJM 3...

For patients with inoperable esophageal adenocarcinoma (EAC), prognosis on conventional chemotherapy (CTX) remains poor. In 2021, the FDA approved two αPD-1 immune checkpoint inhibitors (ICI) for addition to fluoropyrimidine/platinum-containing CTX in this first-line setting. As ICI+CTX enters the clinic, understanding ICI responses and predicting which patients will benefit from ICI addition are key challenges. To address these challenges, we assessed clinical and molecular profiles from the experimental LUD2015-005 trial (NCT02735239, EudraCT 2015-005298-19). Treatment consisted of an initial four-week ICI-only window with durvalumab (αPD-L1) with or without a single dose of tremelimumab (αCTLA-4), followed by 6 cycles of ICI+CTX (CapOx). 38 inoperable patients received treatment (35 EAC; 3 ESCC); median overall survival (OS) and progression-free survival (PFS) were 13.4 and 9.3 months, respectively. All patients reported at least one treatment emergent adverse event (TEAE), with 29 (76.3%) reporting grade 3 or higher TEAEs. EAC patients with available samples (n = 33) were taken forward for biomarker analysis, using tumor and adjacent normal biopsies collected at pre-treatment (PreTx), after four weeks of ICI-only (ICI-4W), and at the end of ICI+CTX (PostTx). Transcriptomic comparison of paired PreTx and ICI-4W EAC biopsies (n = 28) revealed ICI-induced upregulation of a novel T-cell inflammation signature (termed INCITE). Stronger INCITE upregulation correlated with greater tumor shrinkage during the ICI-only window, and tumors with minimal INCITE upregulation showed markers of ICI resistance, including Innate PD-1 Resistance (IPRES). Despite correlation with ICI-only responses, INCITE changes were not associated with overall ICI+CTX outcomes. To find predictive biomarkers of ICI+CTX outcomes, we conducted comprehensive genomic and transcriptomic profiling of PreTx EAC biopsies (n = 33). First, we generated a novel 65,000 cell scRNA-seq dataset and designed a deconvolution workflow to resolve tumor cell composition. Unexpectedly, monocyte composition was strongly linked with greater overall survival (OS) (HR: 0.40 [0.23-0.69]; p = 0.001; FDR = 0.047). Coding tumor mutational burden (TMB) was also associated with improved OS (HR: 0.50 [0.28-0.89]; p = 0.019). Multivariate modelling suggested monocyte composition and TMB were independent and complementary predictors of outcomes. Neither factor was associated with outcomes in a TCGA cohort of EAC patients not treated with ICI, suggesting these biomarkers may be specific to ICI or ICI+CTX. Our findings suggest monocyte composition and TMB may identify EAC patients likely to benefit from ICI+CTX. INCITE upregulation may also serve as a useful monitor of ICI efficacy. These timely findings further our understanding of ICI response and resistance and may help inform patient selection for ICI+CTX. Citation Format: Thomas M. Carroll, Joseph A. Chadwick, Richard P. Owen, Michael J. White, Joseph Kaplinsky, Iliana Peneva, Anna Frangou, Jaeho Chang, Phil F. Xie, Andrew Roth, Bob Amess, Hantao Lou, Katy J. McCann, Georgina Berridge, Roman Fischer, Chansavath Phetsouphanh, Ayo O. Omiyale, Brittany-Amber Jacobs, David Ahern, Simon R. Lord, Stewart Norris-Bulpitt, Sam T. Dobbie, Lucinda Griffiths, Kristen Aufiero Ramirez, Toni Ricciardi, Mary J. Macri, Aileen Ryan, Ralph R. Venhaus, Benoit J. Van den Eynde, Ioannis Karydis, Benedikt M. Kessler, Benjamin Schuster-Böckler, Mark R. Middleton, Xin Lu. Comprehensive molecular profiling to predict first-line immunochemotherapy outcomes in inoperable esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1247.