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Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor–node–metastasis (TNM) classification in colorectal cancer. In non–small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8+ tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8+ TIL density as an immunoscore in NSCLC.Experimental Design: The prognostic impact of stromal CD8+ TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I–IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts.Results: Stromal CD8+ TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8+ TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8+ TIL density and pStage were independent prognostic variables.Conclusions: Stromal CD8+ TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore. Clin Cancer Res; 21(11); 2635–43. ©2015 AACR.

Purpose: Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. Kidney injury molecule-1 (KIM-1) has been shown to be elevated in the plasma of RCC patients. We aimed to test whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis.Experimental Design: KIM-1 concentrations were measured in prediagnostic plasma from 190 RCC cases and 190 controls nested within a population-based prospective cohort study. Cases had entered the cohort up to 5 years before diagnosis, and controls were matched on cases for date of birth, date at blood donation, sex, and country. We applied conditional logistic regression and flexible parametric survival models to evaluate the association between plasma KIM-1 concentrations and RCC risk and survival.Results: The incidence rate ratio (IRR) of RCC for a doubling in KIM-1 concentration was 1.71 [95% confidence interval (CI), 1.44–2.03, P = 4.1 × 10−23], corresponding to an IRR of 63.3 (95% CI, 16.2–246.9) comparing the 80th to the 20th percentiles of the KIM-1 distribution in this sample. Compared with a risk model including known risk factors of RCC (age, sex, country, body mass index, and tobacco smoking status), a risk model additionally including KIM-1 substantially improved discrimination between cases and controls (area under the receiver-operating characteristic curve of 0.8 compared with 0.7). High plasma KIM-1 concentrations were also associated with poorer survival (P = 0.0053).Conclusions: Plasma KIM-1 concentrations could predict RCC incidence up to 5 years prior to diagnosis and were associated with poorer survival. Clin Cancer Res; 24(22); 5594–601. ©2018 AACR.

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer–related dysregulation of CDCP1 expression years before diagnosis.Significance:Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms.See related commentary by Itzstein et al., p. 3441.

Supplemental Table II. Prognostic clinicopathologic variables as predictors for DFS in 797 NSCLS (univariate analysis,log-rank test)

Supplemental Table III. Prognostic clinicopathologic variables as predictors for Overall Survival in 797 NSCLS (univariate analyses,log-rank test)

Supplementary Methods, Figures and Tables.

Supplemental Figure 1. Disease-specific survival curves according to low, intermediate and high stromal CD8+ T-cell density in the Danish cohort (Odense University Hospital, n = 178). (A) Score from the invasive margin tumor area, (B) score from the central parts of the tumor. The maximum score for each patient was used.

Supplemental Table I. Prognostic clinicopathologic variables as predictors for DSS in 797 NSCLS (univariate analyses,log-rank test)

Supplementary Table 1, Supplementary Figures 1 and 2

Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. The identification of biomarkers of habitual alcohol intake may enhance evidence on the role of alcohol in cancer onset. Methods: Untargeted metabolomics was used to identify metabolites correlated with habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n=454). Significant correlations were replicated in independent datasets of controls from case-control studies nested within EPIC (n=281) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n=438) study. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results: Two metabolites displayed a dose-response association with alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound (m/z(+):231.0839). A 1-SD increase in log2-transformed levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR=2.14; 95% CI=1.39-3.31) and pancreatic cancer (OR=1.65; 95% CI=1.17-2.32) in EPIC and liver cancer (OR=2.00; 95% CI=1.44-2.77) and liver disease mortality (OR=2.16; 95% CI=1.63-2.86) in ATBC. Conversely, a 1-SD increase in log2-transformed questionnaire-derived alcohol intake was not associated with risk of HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with risk of liver disease mortality (OR=2.19; 95% CI=1.60-2.98) in ATBC. Conclusions: 2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies. Citation Format: Erikka Loftfield, Magdalena Stepien, Vivian Viallon, Laura Trijsburg, Joseph Rothwell, Nivonirina Robinot, Carine Biessy, Ingvar A. Bergdahl, Stina Bodén, Matthias B. Schulze, Manuela Bergmann, Elisabete Weiderpass, Julie A. Schmidt, Rual Zamora-Ros, Therese H. Nøst, Torkjel M. Sandanger, Emily Sonestedt, Bodil Ohlsson, Verena Katzke, Rudolf Kaaks, Fulvio Ricceri, Anne Tjønneland, Christina C. Dahm, Maria-Jose Sánchez, Antonia Trichopoulou, Rosario Tumino, María-Dolores Chirlaque, Giovanna Masala, Eva Ardanaz, Roel Vermeulen, Paul Brennan, Demetrius Albanes, Stephanie J. Weinstein, Augustin Scalbert, Augustin Scalbert, Neal D. Freedman, Marc J. Gunter, Mazda Jenab, Rashmi Sinha, Pekka Keski-Rahkonen, Pietro Ferrari. Novel biomarkers of habitual alcohol intake and associations with risk of pancreatic and liver cancers and liver disease mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 747.

Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor–node–metastasis (TNM) classification in colorectal cancer. In non–small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8+ tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8+ TIL density as an immunoscore in NSCLC. Experimental Design: The prognostic impact of stromal CD8+ TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I–IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts. Results: Stromal CD8+ TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8+ TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8+ TIL density and pStage were independent prognostic variables. Conclusions: Stromal CD8+ TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore. Clin Cancer Res; 21(11); 2635–43. ©2015 AACR.

There is an urgent need to improve lung cancer risk assessment as current screening criteria miss a large proportion of cases and result in a high rate of false positives on low-dose CT screening. A fixed effect meta-analyses of 4 epigenome-wide association studies of lung cancer revealed differential DNA methylation at 16 CpG sites (FDR Citation Format: Florence Guida, Therese H. Nøst, Caroline Relton, Paul Brennan, Torkjel M. Sandanger, Marc Chadeau-Hyam, Mattias Johansson. Lung cancer risk prediction using DNA methylation markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2209.