An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.

Prognostic value of tumor-infiltrating immune cells and immune checkpoints in elderly head-and-neck squamous cell carcinoma patients undergoing definitive (chemo)radiotherapy.

BACKGROUND AND PURPOSE: Tumor-infiltrating lymphocytes (TILs) are associated with locoregional control (LRC) in head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. As immunosenescence results in reduced immune activity, the role of TILs in elderly HNSCC patients may differ compared to younger patients, providing a rationale to study the prognostic role of TILs and immune checkpoints (ICs) in this population. MATERIAL AND METHODS: Sixty-three HNSCC patients aged ≥ 65 years undergoing definitive (chemo)radiotherapy between 2010 and 2019 with sufficient material from pre-treatment biopsies were included in the analysis. Immunohistochemical stainings of CD3, CD4, CD8, PD-L1, TIM3, LAG3, TIGIT and CD96, and of osteopontin as an immunosenescence-associated protein were performed. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method, and Fine-Gray's models were used for locoregional failure (LRF) analyses. RESULTS: While there was no correlation between patient age and IC expression, osteopontin levels correlated with increasing age (r = 0.322, p < 0.05). Two-year OS, PFS, and LRC were 44%, 34%, and 71%, respectively. Increased LAG3 expression, both intraepithelial (SHR = 0.33, p < 0.05) and stromal (SHR = 0.38, p < 0.05), and elevated stromal TIM3 expression (SHR = 0.32, p < 0.05) corresponded with reduced LRFs. Absent tumoral PD-L1 expression (TPS = 0%) was associated with more LRFs (SHR = 0.28, p < 0.05). There was a trend towards improved LRF rates in elderly patients with increased intraepithelial CD3 + (SHR = 0.52, p = 0.07) and CD8 + (SHR = 0.52, p = 0.09) TIL levels. CONCLUSION: LAG3, TIM3 and TPS are promising biomarkers in elderly HNSCC patients receiving (chemo)radiotherapy. Considering the frequency of non-cancer related deaths in this population, the prognostic value of these biomarkers primarily relates to LRC.

Familial hypercholesterolemia: A systematic review of modeling studies on screening interventions.

BACKGROUND AND AIMS: FH is still underdiagnosed. Cost-effectiveness results of preventive screening strategies vary. We aimed at systematically assessing the benefits, harms and cost effectiveness of screening for familial hypercholesterolemia (FH) and at providing an overview of the main characteristics and methodological approaches of applied decision-analytic models. METHODS: A systematic literature search was conducted in MEDLINE, EconLit, CRD-databases and the CEA-registry for FH screening starting 2012. Earlier studies were included from a published systematic review. Results were reported in standardized semi-quantitative evidence tables. Costs were converted to current euros. Incremental cost-effectiveness ratios (ICERs) were recalculated according to economic guidelines. RESULTS: Out of our 211 retrieved studies, eight were included in the review in addition to six studies from an earlier review. Studies were conducted in Europe (UK, The Netherlands, Spain, Poland), USA and Australia evaluating cascade (CS), opportunistic (OS), universal screening (UniS), or combinations using genetic testing, clinical criteria or combinations. Studies evaluating only CS identified strategies with an ICER of up to 37,100 EUR/quality-adjusted life-year (QALY) but some strategies were dominated depending on test combinations. UniS of newborns in combination with CS had an ICER≤15,000 EUR/QALY for sequential cholesterol-genetic screening. In other studies, UniS was dominated by OS/CS. CONCLUSIONS: Our systematic review demonstrates the values of FH screening and provides an overview of potentially relevant screening strategies to be tested using a decision-analytic model for the respective country or region. Future research is needed on the transferability of results to other countries and modeling spillover effects to newborns.

Effectiveness, benefit harm and cost effectiveness of colorectal cancer screening in Austria.

BACKGROUND: Clear evidence on the benefit-harm balance and cost effectiveness of population-based screening for colorectal cancer (CRC) is missing. We aim to systematically evaluate the long-term effectiveness, harms and cost effectiveness of different organized CRC screening strategies in Austria. METHODS: A decision-analytic cohort simulation model for colorectal adenoma and cancer with a lifelong time horizon was developed, calibrated to the Austrian epidemiological setting and validated against observed data. We compared four strategies: 1) No Screening, 2) FIT: annual immunochemical fecal occult blood test age 40-75 years, 3) gFOBT: annual guaiac-based fecal occult blood test age 40-75 years, and 4) COL: 10-yearly colonoscopy age 50-70 years. Predicted outcomes included: benefits expressed as life-years gained [LYG], CRC-related deaths avoided and CRC cases avoided; harms as additional complications due to colonoscopy (physical harm) and positive test results (psychological harm); and lifetime costs. Tradeoffs were expressed as incremental harm-benefit ratios (IHBR, incremental positive test results per LYG) and incremental cost-effectiveness ratios [ICER]. The perspective of the Austrian public health care system was adopted. Comprehensive sensitivity analyses were performed to assess uncertainty. RESULTS: The most effective strategies were FIT and COL. gFOBT was less effective and more costly than FIT. Moving from COL to FIT results in an incremental unintended psychological harm of 16 additional positive test results to gain one life-year. COL was cost saving compared to No Screening. Moving from COL to FIT has an ICER of 15,000 EUR per LYG. CONCLUSIONS: Organized CRC-screening with annual FIT or 10-yearly colonoscopy is most effective. The choice between these two options depends on the individual preferences and benefit-harm tradeoffs of screening candidates.

Budget Impact Analysis of Cancer Screening: A Methodological Review.

BACKGROUND: Budget impact analyses (BIAs) describe changes in intervention- and disease-related costs of new technologies. Evidence on the quality of BIAs for cancer screening is lacking. OBJECTIVES: We systematically reviewed the literature and methods to assess how closely BIA guidelines are followed when BIAs are performed for cancer-screening programs. DATA SOURCES: Systematic searches were conducted in MEDLINE, EMBASE, EconLit, CRD (Centre for Reviews and Dissemination, University of York), and CEA registry of the Tufts Medical Center. STUDY ELIGIBILITY CRITERIA: Eligible studies were BIAs evaluating cancer-screening programs published in English, 2010-2018. SYNTHESIS METHODS: Standardized evidence tables were generated to extract and compare study characteristics outlined by the ISPOR BIA Task Force. RESULTS: Nineteen studies were identified evaluating screening for breast (5), colorectal (6), cervical (3), lung (1), prostate (3), and skin (1) cancers. Model designs included decision-analytic models (13) and simple cost calculators (6). From all studies, only 53% reported costs for a minimum of 3 years, 58% compared to a mix of screening options, 42% reported model validation, and 37% reported uncertainty analysis for participation rates. The quality of studies appeared to be independent of cancer site. LIMITATIONS: "Gray" literature was not searched, misinterpretation is possible due to limited information in publications, and focus was on international methodological guidelines rather than regional guidelines. CONCLUSIONS: Our review highlights considerable variability in the extent to which BIAs evaluating cancer-screening programs followed recommended guidelines. The annual budget impact at least over the next 3-5 years should be estimated. Validation and uncertainty analysis should always be conducted. Continued dissemination efforts of existing best-practice guidelines are necessary to ensure high-quality analyses.