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Background: Current risk stratification for patients with malignant pleural mesothelioma based on disease stage and histology is inadequate. For some individuals with early-stage epithelioid tumours, a good prognosis by current guidelines can progress rapidly; for others with advanced sarcomatoid cancers, a poor prognosis can progress slowly. Therefore, we aimed to develop and validate a machine-learning tool-known as OncoCast-MPM-that could create a model for patient prognosis., Methods: We did a retrospective study looking at malignant pleural mesothelioma tumours using next-generation sequencing from the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). We collected clinical, pathological, and routine next-generation sequencing data from consecutive patients with malignant pleural mesothelioma treated at the Memorial Sloan Kettering Cancer Center (New York, NY, USA), as well as the MSK-IMPACT data. Together, these data comprised the MSK-IMPACT cohort. Using OncoCast-MPM, an open-source, web-accessible, machine-learning risk-prediction model, we integrated available data to create risk scores that stratified patients into low-risk and high-risk groups. Risk stratification of the MSK-IMPACT cohort was then validated using publicly available malignant pleural mesothelioma data from The Cancer Genome Atlas (ie, the TCGA cohort)., Findings: Between Feb 15, 2014, and Jan 28, 2019, we collected MSK-IMPACT data from the tumour tissue of 194 patients in the MSK-IMPACT cohort. The median overall survival was higher in the low-risk group than in the high-risk group as determined by OncoCast-MPM (30·8 months [95% CI 22·7-36·2] vs 13·9 months [10·7-18·0]; hazard ratio [HR] 3·0 [95% CI 2·0-4·5]; p<0·0001). No single factor or gene alteration drove risk differentiation. OncoCast-MPM was validated against the TCGA cohort, which consisted of 74 patients. The median overall survival was higher in the low-risk group than in the high-risk group (23·6 months [95% CI 15·1-28·4] vs 13·6 months [9·8-17·9]; HR 2·3 [95% CI 1·3-3·8]; p=0·0019). Although stage-based risk stratification was unable to differentiate survival among risk groups at 3 years in the MSK-IMPACT cohort (31% for early-stage disease vs 30% for advanced-stage disease; p=0·90), the OncoCast-MPM-derived 3-year survival was significantly higher in the low-risk group than in the high-risk group (40% vs 7%; p=0·0052)., Interpretation: OncoCast-MPM generated accurate, individual patient-level risk assessment scores. After prospective validation with the TCGA cohort, OncoCast-MPM might offer new opportunities for enhanced risk stratification of patients with malignant pleural mesothelioma in clinical trials and drug development., Funding: US National Institutes of Health/National Cancer Institute., Competing Interests: Declaration of interests MGZ has received consulting fees from Takeda, GlaxoSmithKline, Epizyme, Aldeyra Therapeutics, Novocure, and Atara; honoraria from Research to Practice, Medical Learning Institute, and OncLive; and grants from the National Institutes of Health/National Cancer Institute. MGZ serves as chair of the Board of Directors of the Mesothelioma Applied Research Foundation and is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering receives research funding from the US Department of Defense, the National Institutes of Health, GlaxoSmithKline, Epizyme, Polaris, Sellas Life Sciences, Bristol Myers Squibb, Millenium, Curis, and Roche for research done by MGZ. Memorial Sloan Kettering had an institutional agreement with IBM for Watson for Oncology and receives royalties from IBM. MO reports honoraria from PharmaMar, Novartis, and Targeted Oncology outside the submitted work. AR reports grants from Varian Medical Systems, Boehringer Ingelheim, and Pfizer; grants and personal fees from AstraZeneca and Merck; personal fees from Research to Practice, Cybrexa, and More Health; and non-financial support from Philips/Elekta, outside the submitted work. PSA's laboratory work is supported by grants from the National Institutes of Health (P30 CA008748, R01 CA236615-01, R01 CA235667, R21 CA213139, and T32 CA009501), the US Department of Defense (CA170630 and CA180889), the Memorial Sloan Kettering Technology Development Fund, the Miner Fund for Mesothelioma Research, Mr William H Goodwin and Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. PSA reports research funding from ATARA Biotherapeutics; scientific advisory board or consultant roles with ATARA Biotherapeutics, Carisma Therapeutics, Imugene, and Takeda Therapeutics; patents, royalties, and intellectual property on mesothelin-targeted CAR; and pending patent applications on other T-cell therapies. VWR receives grant support for institutional clinical trials from Genelux and Genentech, and receives travel reimbursement for robotic mentoring from Intuitive Surgical. VWR is also co-chair for the Thoracic Malignancy Steering Committee and National Cancer Institute; and a member of the Data Safety Monitoring Committee, MARS2 Trial (UK). MGK receives personal fees from AstraZeneca, Pfizer, Regeneron, and Daiichi-Sankyo; received honoraria for participation in educational programmes from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, AstraZeneca, and Research to Practice; and received travel support from AstraZeneca, Pfizer, Regeneron, and Genentech. MGK is an employee of Memorial Sloan Kettering. Memorial Sloan Kettering has received research funding from the National Cancer Institute, The Lung Cancer Research Foundation, Genentech Roche, and PUMA Biotechnology for research done by MGK. Memorial Sloan Kettering has licensed testing for EGFR T790M to MolecularMD. JLS reports stock ownership in the following companies: Allergan, Chemed, Johnson & Johnson, Merck, Pfizer, and Thermo Fischer Scientific. ML reports honoraria for ad-hoc advisory board participation from Merck, AstraZeneca, Bristol Myers Squibb, Takeda, Bayer, and Lilly Oncology; and research support from LOXO Oncology, Merus, and Helsinn Therapeutics. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

A new lung adenocarcinoma classification is being proposed by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS). This proposal has not yet been tested in clinical datasets to determine whether it defines prognostically significant subgroups of lung adenocarcinoma. In all, 514 patients who had pathological stage I adenocarcinoma of the lung classified according to the Union for International Cancer Control/American Joint Committee on Cancer 7th Edition, and who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS adenocarcinoma classification. Statistical analyses were made including Kaplan-Meier and Cox regression analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33-89 years) and 298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade: adenocarcinoma in situ (n=1) and minimally invasive adenocarcinoma (n=8) had 100% 5-year disease-free survival; intermediate grade: non-mucinous lepidic predominant (n=29), papillary predominant (n=143) and acinar predominant (n=232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade: invasive mucinous adenocarcinoma (n=13), colloid predominant (n=9), solid predominant (n=67) and micropapillary predominant (n=12), with 75, 7170 and 67%, 5-year disease-free survival, respectively (P<0.001). Among the clinicopathological factors, stage 1B versus 1A (P<0.001), male sex (P<0.008), high histological grade (P<0.001), vascular invasion (P=0.002) and necrosis (P<0.001) were poorer prognostic factors on univariate analysis. Both gross tumor size (P=0.04) and invasive tumor size adjusted by the percentage of lepidic growth (P<0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS histological classification (P=0.038), male gender (P=0.007), tumor invasive size (P=0.026) and necrosis (P=0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in identifying candidates for adjunctive therapy. The slightly stronger association with survival for invasive size versus gross size raises the need for further studies to determine whether this adjustment in measuring tumor size could impact TNM staging for small adenocarcinomas.