The International Association for the Study of Lung Cancer Molecular Database Project: Objectives, Challenges, and Opportunities

Abstract

With an estimated 2.2 million worldwide cases and 1.9 million deaths in 2017, lung cancer is the leading cause of cancer mortality in most countries.1Fitzmaurice C. Abate D. et al.Global Burden of Disease Cancer CollaborationGlobal, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study [published correction appears in JAMA Oncol. 2020;6:789].JAMA Oncol. 2019; 5: 1749-1768Crossref PubMed Scopus (929) Google Scholar In the aggregate, 5-year survival of patients with lung cancer, as low as 4% in low or middle-income countries, was estimated at 21% in the United States in 2020.1Fitzmaurice C. Abate D. et al.Global Burden of Disease Cancer CollaborationGlobal, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study [published correction appears in JAMA Oncol. 2020;6:789].JAMA Oncol. 2019; 5: 1749-1768Crossref PubMed Scopus (929) Google Scholar,2Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2020.CA Cancer J Clin. 2020; 70: 7-30Crossref PubMed Scopus (10040) Google Scholar There is a great opportunity, with the emergence of molecular biomarkers of disease behavior, to improve treatment and survival. Biomarker testing, the portal to personalized treatment of lung cancer, has splintered a once seemingly monolithic disease into fragments of genomic and proteomic disease subsets with widely different, but generally improving, treatment, and survival expectations.3Pao W. Hutchinson K.E. Chipping away at the lung cancer genome.Nat Med. 2012; 18: 349-351Crossref PubMed Scopus (161) Google Scholar, 4Howlader N. Forjaz G. Mooradian M.J. et al.The effect of advances in lung-cancer treatment on population mortality.N Engl J Med. 2020; 383: 640-649Crossref PubMed Scopus (299) Google Scholar, 5Adjei A.A. Controversies in thoracic oncology.J Thorac Oncol. 2021; 16: 366-367Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Rapid evolution in the knowledge of lung molecular carcinogenesis and biomarkers promises to enhance our strictly anatomy-based structural classification of the likely severity of disease (stage). Staging serves three main purposes: communication, prognostication, and direction of treatment.6Detterbeck F.C. Tanoue L.T. Boffa D.J. Anatomy, biology and concepts, pertaining to lung cancer stage classification.J Thorac Oncol. 2009; 4: 437-443Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar The TNM system is a strictly anatomy-based communication of the extent of cancer and, by inference, its likely impact on quality of life and death (prognosis), which then informs the choice of treatment modalities. Since its introduction between 1966 and 1968, the TNM staging system has facilitated communication about lung cancer across time and space, bridging geographic, linguistic, healthcare infrastructural, socioeconomic, and cultural differences. The system has gone through seven revisions, each designed to improve its use in identifying anatomical clusters of patients with similar prognoses, and, indirectly, improve its practical use in guiding treatment. The International Association for the Study of Lung Cancer (IASLC) provided evidence that informed the seventh and eighth editions of the lung cancer staging system. Under the guidance of the Staging and Prognostic Factors Committee, a team of analysts at Cancer Research And Biostatistics (CRAB) rigorously analyzed granular patient-level data provided by multiple worldwide partners.7Rami-Porta R. Bolejack V. Giroux D.J. et al.The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer.J Thorac Oncol. 2014; 9: 1618-1624Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar For the ninth edition of the TNM staging system, CRAB is collecting data on lung cancers diagnosed from January 1, 2011 to December 31, 2019, with follow-up through December 31, 2021. The current plans are to publish the newly proposed staging criteria in 2024, which is for international adoption in 2025.8Giroux D.J. Van Schil P. Asamura H. et al.The IASLC lung cancer staging project: a renewed call to participation.J Thorac Oncol. 2018; 13: 801-809Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Because prognosis varies with molecular features as widely as with anatomical features, and staging details and therapies may differ for different molecular subsets of tumors, the Staging and Prognostic Factors Committee has made a parallel call for molecular data with which to supplement the analysis of TNM-associated survival differences. Although the present manuscript describes the efforts directed toward lung cancer, similar efforts will be carried out for other thoracic malignancies—esophageal cancer, mesothelioma, and thymoma. Biological heterogeneity and highly effective targeted therapies are blurring the lines of demarcation among patients with NSCLC of different TNM stages. For example, whereas the aggregate 5-year survival of patients with stage IV lung cancer in the United States was estimated at approximately 5% in 2020,3Pao W. Hutchinson K.E. Chipping away at the lung cancer genome.Nat Med. 2012; 18: 349-351Crossref PubMed Scopus (161) Google Scholar patients with activating mutations of the EGFR treated with the first generation of tyrosine kinase inhibitors at a single U.S. institution between 2002 and 2009 had an aggregate 5-year survival of 15%, similar to the aggregate 5-year survival of patients with the monolithic NSCLC with clinical stage IIIA.9Lin J.J. Cardarella S. Lydon C.A. et al.Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs.J Thorac Oncol. 2016; 11: 556-565Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Very long survival time has also been reported with first-generation EGFR tyrosine kinase inhibitors in some patients with stage IV NSCLC, with a median survival extending beyond 11 years10Hirsch F.R. Sequist L.V. Gore I. et al.Long-term safety and survival with gefitinib in select patients with advanced non-small cell lung cancer: results from the US IRESSA Clinical Access Program (ICAP).Cancer. 2018; 124: 2407-2414Crossref PubMed Scopus (10) Google Scholar; patients with stage IV ALK-mutated NSCLC treated with alectinib had a 5-year overall survival rate of 62.5%, similar to the expected survival rate of recipients of curative-intent surgery for stage I NSCLC.11Mok T. Camidge D.R. Gadgeel S.M. et al.Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.Ann Oncol. 2020; 31: 1056-1064Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar In the ADAURA trial, adjuvant osimertinib therapy for Union for International Cancer Control/American Joint Committee on Cancer eighth edition pathologic stage IIA to IIIB NSCLC with L858R or deletion of exon 19 mutations of EGFR was associated with a hazard ratio for disease recurrence or death at 24 months of 0.2 (95% confidence interval: 0.14–0.3).12Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (371) Google Scholar Biomarker-delineated subsets of lung cancer may not only be predictive of sensitivity to specific types of treatment, but they may also possess intrinsic biological differences that impact prognosis even in early-stage patients who undergo curative-intent surgical resection without adjuvant therapies.13Kneuertz P.J. Carbone D.P. D’Souza D.M. et al.Prognostic value and therapeutic implications of expanded molecular testing for resected early stage lung adenocarcinoma.Lung Cancer. 2020; 143: 60-66Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,14Suda K. Mitsudomi T. Shintani Y. et al.Clinical impacts of EGFR mutation status: analysis of 5780 surgically resected lung cancer cases.Ann Thorac Surg. 2021; 111: 269-276Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar The prognostic and predictive value of targetable gene mutations and comutations across the spectrum of the NSCLC stage needs to be clarified in large, global datasets with sufficient statistical power. Existing lung cancer molecular databases include the following: (1) the Lung Cancer Mutation Consortium, a group of 14 National Cancer Institute–designated comprehensive cancer centers which tested 1007 patients with stage IV adenocarcinoma for one to 10 oncogenic driver mutations15Kris M.G. Johnson B.E. Berry L.D. et al.Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.JAMA. 2014; 311: 1998-2006Crossref PubMed Scopus (1115) Google Scholar; (2) The Cancer Genome Atlas, which includes multiomics data on slightly more than 1000, mostly resected early-stage NSCLC with limited treatment and follow-up data16Campbell J.D. Alexandrov A. Kim J. et al.Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.Nat Genet. 2016; 48: 607-616Crossref PubMed Scopus (600) Google Scholar; (3) the Catalog Of Somatic Mutations In Cancer, which includes published cancer cases with mutation and gene copy number alterations17Sanger InstituteCosmic: Catalogue Of Somatic Mutations In Cancer.https://cancer.sanger.ac.uk/cosmicDate accessed: March 3, 2021Google Scholar; and (4) the American Association for Cancer Research’s Genomics Evidence Neoplasia Information Exchange project, which has more than 200,000 profiled samples (from 18 major cancer centers including 13 from the United States and approximately 14,000, patients with, mostly, advanced lung adenocarcinoma), focuses on cataloging mutations, and has limited clinical and pathologic information.18AACR Project GENIE ConsortiumAACR project GENIE: powering precision medicine through an international consortium.Cancer Discov. 2017; 7: 818-831Crossref PubMed Scopus (587) Google Scholar Indeed, these data sets all have limited clinical and pathologic information. Given the diversity in the prevalence of genomic aberrations such as EGFR mutations and the relative rarity of others, there is a great opportunity to: (1) leverage IASLC’s global reach to construct a robust, detailed, and rigorously curated database with which to study the molecular diversity of lung cancer across geographic, cultural, racial and ethnic boundaries; and (2) to better understand how the molecular profile of lung cancer intersects with patterns of care delivery and outcomes.19Smeltzer M.P. Wynes M.W. Lantuejoul S. et al.The International Association for the Study of Lung Cancer global survey on molecular testing in lung cancer.J Thorac Oncol. 2020; 15: 1434-1448Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,20Adjei A.A. A call to arms: reducing disparities in lung cancer care worldwide.J Thorac Oncol. 2020; 15: 1700-1702Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar The opportunity is especially great with rarer molecular subtypes, which cannot be sufficiently addressed through local or even national databases, and early-stage, potentially curable lung cancer, about which there is insufficient information.13Kneuertz P.J. Carbone D.P. D’Souza D.M. et al.Prognostic value and therapeutic implications of expanded molecular testing for resected early stage lung adenocarcinoma.Lung Cancer. 2020; 143: 60-66Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,14Suda K. Mitsudomi T. Shintani Y. et al.Clinical impacts of EGFR mutation status: analysis of 5780 surgically resected lung cancer cases.Ann Thorac Surg. 2021; 111: 269-276Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar The CRAB data management and analysis infrastructure create economies of scale that make this ambitious project feasible. Lung cancer is a disease of genomic aberration. As of December 2020, nine genomic or protein markers could be used to select U.S. Food and Drug Administration–approved treatment for stage IV lung cancer (EGFR, ALK, BRAFV600E, ROS1, NTRK, MET exon 14 skipping, and RET mutations; programmed death-ligand 1 tumor proportion score >50%; and microsatellite instability-high or mismatch repair-deficient tumors).5Adjei A.A. Controversies in thoracic oncology.J Thorac Oncol. 2021; 16: 366-367Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Two other biomarkers—mutations of ERBB2 and KRASG12C—received “breakthrough therapy designation” for fast-tracked clinical development. This trend will only increase with time along with the list of prognostic and predictive markers. The molecular profile project provides a timely opportunity to improve on the status quo in lung cancer. Although the initial effort has focused on lung cancer, in the future, we will expand the project to include mesothelioma and thymic tumors. Examples exist from other cancers, such as breast cancer and hematopoietic malignancies, in which the use of genomic and proteomic markers has long since been embedded in routine prognostication and pathways of treatment in ways that significantly augment the clinical utility of traditional classification systems, sometimes blurring the lines between hither-to anatomically distinct stage subsets. The first objective is to provide a global platform for a deeper, broader understanding of the value of molecular testing and targeted therapy for prognostication, prediction, and treatment selection across the full spectrum of the TNM stage. Second is to evaluate novel single or multiple prognostic markers that could add biological information regarding the outcome of patients in the different TNM stages. These novel prognostic factors would add to the current clinical definitive standard criteria and would be formally considered using the criteria developed by the Prognostic Factors Subcommittee and the Minimal Standards Working Group. Third, to create evidence in a set of highly characterized lung cancers with complete clinical, pathologic, and staging information to support the role of biomarkers in lung cancer diagnosis, prognosis, and treatment selection, across the stage spectrum. Fourth, to create evidence to support advocacy for routine genomic testing when appropriate.12Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (371) Google Scholar Fifth, to define important research questions that might be the focus of observational studies, pragmatic trials, and clinical trials of existing and emerging biomarkers and therapeutics. Finally, to invite applications for projects to analyze the molecular database. The primary challenge is to secure a sufficiently large, diverse, and globally representative data set across the full spectrum of TNM stage (not solely advanced-stage disease) to enable robust analysis and meaningful discovery. Differences in biomarker assays, testing platforms, test performance characteristics, variation in the clinical use of biomarker testing, selection biases in who gets tested and why, the complexity and rapid evolution of the tests, and interpretation of results, all represent significant challenges. These challenges are multiplied by national and regional differences in clinical practice and resources.19Smeltzer M.P. Wynes M.W. Lantuejoul S. et al.The International Association for the Study of Lung Cancer global survey on molecular testing in lung cancer.J Thorac Oncol. 2020; 15: 1434-1448Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,20Adjei A.A. A call to arms: reducing disparities in lung cancer care worldwide.J Thorac Oncol. 2020; 15: 1700-1702Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar However, these challenges are also a strength—the data will reflect real-world practices and varying implementation across the globe, and will not derive solely from elite academic institutions. As anatomical staging has had to evolve with improved surgical and staging technologies, so must this effort. Unrelated secular changes further confound outcomes analyses—not only are molecular tests changing over time, with new genetic and molecular metrics being developed, but general survivability is also improving. Most of this can be investigated with subgroup analyses or validation in an external data set. Both approaches require large, robust datasets. Genetic traits with smaller effect sizes will require a larger sample size for power to detect associated changes. Because a null finding could either be owing to a true lack of signal or lack of statistical power, analyses will have to prioritize genetic traits with adequate sample size for analysis. Finally, many genetic traits are relatively rare, so a large sample size is needed to capture enough mutation-positive patients for a meaningful analysis. This project will accelerate our understanding of lung cancer biology, clinical care, and care delivery on a global scale. It will improve our understanding of the prognosis and optimal treatment of lung cancer across time and space, a function currently served solely by the TNM staging system. The molecular subcommittee is actively soliciting high-quality data from the global community of researchers and clinicians. We seek patient demographic and clinical information, clinical and pathologic TNM details, and biomarker details from any validated assay or platform. Patients with newly diagnosed lung cancer of any histologic type, staged by the eighth edition TNM irrespective of stage or treatment, are eligible. Ideally, data should be submitted by means of CRAB’s Electronic Data Capture portal. Curators of large data sets can directly discuss alternative data submission approaches with CRAB. Contributors will be appropriately acknowledged in all publications arising from this data set. The IASLC will financially support large volume data contributors on a case-by-case basis depending on geographic priority, the size, and the quality of data contribution. Individuals and groups interested in contributing data to the IASLC staging project should visit the IASLC website, fill in their application, and send it online. Application forms are available at www.iaslc.org under “Research and Education, Research Committees and Projects, Staging and Prognostic Factors Committee, Submit Data” for the ninth edition. The “Protocol Document”, a Tool Kit, and an “Application for Funding” to defray the cost of data submission, template data use agreements, and frequently asked questions about the logistics of participation can also be found there. This study was supported by grants from the National Institute of Health (grant numbers 2UG1CA189873-06, 2R01CA172253, and 1UM1CA233080 through Dr. Osarogiagbon) and the ISCIII-Fondo de Investigación Sanitaria (grant number PI19/00098 through Dr. Montuenga). This work was funded by the IASLC, including with funds obtained through unrestricted grants from the pharmaceutical industry. The members of the Molecular Subcommittee (in alphabetical order) and their institutions are the following: Luiz H. Araujo, MD, PhD, Brazilian National Cancer Institute, Rio de Janeiro, Brazil; Frank Detterbeck, MD, FACS, FCCP, Department of Surgery, Yale University, New Haven, Connecticut; Oliver Gautschi, MD, University of Berne and Cantonal Hospital of Lucerne, Switzerland; Keith Kerr, MD, FRCPath, Department of Pathology, Aberdeen University School of Medicine, United Kingdom; Peter J. Kneuertz, MD, Division of Thoracic Surgery, Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; Philip Mack, PhD, Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai Health System, New York, New York; José María Matilla, MD, PhD, Department of Thoracic Surgery, Hospital Clínico Universitario Valladolid, University of Valladolid, Valladolid, Spain; Andrew G Nicholson, DM, Department of Histopathology, Royal Brompton and Harefield Hospitals, London and National Heart and Lung Institute, Imperial College, London, United Kingdom; Harvey Pass, MD, Department of Surgery, New York University, New York, New York; Carolyn J. Presley, MD, Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; Kenichi Suda, MD, PhD, Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan; Ignacio Wistuba, MD, Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, Texas; Dawei Yang, MD, Department of pulmonary medicine, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China; Yasushi Yatabe, MD, PhD, Department of Diagnostic Pathology, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan.