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A universal nomenclature of the anatomic extent of lung cancer has been critical for individual patient care as well as research advances. As progress occurs, new details emerge that need to be included in a refined system that aligns with contemporary clinical management issues. The ninth edition TNM classification of lung cancer, which is scheduled to take effect in January 2025, addresses this need. It is based on a large international database, multidisciplinary input, and extensive statistical analyses. Key features of the ninth edition include validation of the significant changes in the T component introduced in the eighth edition, subdivision of N2 after exploration of fundamentally different ways of categorizing the N component, and further subdivision of the M component. This has led to reordering of the TNM combinations included in stage groups, primarily involving stage groups IIA, IIB, IIIA, and IIIB. This article summarizes the analyses and revisions for the TNM classification of lung cancer to familiarize the broader medical community and facilitate implementation of the ninth edition system., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: M. J. G. reports honoraria from AstraZeneca, Daiichi Sanyo, and Regeneron (all unrelated to the topic). H. S. P. reports institutional grants from RefleXion and Merck; and consulting fees from RefleXion and AstraZeneca. S. D. reports honoraria from AstraZeneca and Medscape; and is the chair of the IASLC pathology committee. G. A. W. reports grants from the American Cancer Society and the International Lung Cancer Foundation; a career enhancement grant from the Yale SPORE in lung cancer; and consulting fees from AstraZeneca. None declared: (F. C. D., A. S. B., L. T. T.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: A clinically-certified gene expression profile improved survival in a cohort of stage I-IIA NSCLC patients by identifying those likely to benefit from adjuvant intervention. EGFR mutation status has not provided this type of predictive risk discrimination in stage IA NSCLC, and overtreatment of low-risk stage IB patients may have limited the overall benefit seen recently in the adjuvant application of a third-generation TKI. We compared EGFR mutation data to molecular risk stratification in a prospective, early-stage cohort., Materials and Methods: Two hundred fifty eligible stage I-IIA non-squamous NSCLC patients underwent prospective molecular risk stratification by the 14-gene prognostic assay. Platinum doublet adjuvant chemotherapy (AC) was recommended for molecular high-risk (MHR). Differences in freedom from recurrence (FFR) and disease-free survival (DFS) were evaluated., Results: At 29 months, prospective molecular testing yielded an estimated FFR of 94.6% and 72.4% in low-risk and untreated MHR patients, respectively, and 97.0% among MHR patients receiving AC (P < .001). In contrast, there was no association between EGFR status and recurrence, while molecular risk predicted survival and response to AC within both the EGFR mutation(+) and mutation(-) populations. Sixty-seven percent of EGFR(+) and 49% of EGFR(-) patients were molecular low-risk., Conclusion: This prospective study demonstrates the utility of the 14-gene assay independent of EGFR mutation. Basing adjuvant intervention in early-stage NSCLC on EGFR status alone may undertreat up to 51% of EGFR(-) patients likely to benefit from adjuvant intervention, and overtreat as many as 67% of EGFR(+) patients more likely to be free of residual disease., Competing Interests: Declaration of competing interest Dr. Woodard, Dr. Haro, Dr. Gubens and Dr. Jones have no disclosures related to this study. Dr. Blakely and Dr. Kratz are consultants for Oncocyte Corporation. Dr. Kratz, Dr. Mann and Dr. Jablons have an equity interest in OncoCyte Corporation and receive royalties related to the prognostic assay., (Copyright © 2021. Published by Elsevier Inc.)

Importance: Improved staging for non-small cell lung cancer (NSCLC) represents a critical unmet need. External validations of the eighth edition of the TNM staging system have yielded disappointing results, with persistently high mortality observed in early-stage disease., Objective: To determine whether incorporation of a molecular prognostic classifier into conventional TNM staging for NSCLC improves estimation of disease-free survival., Design, Setting, and Participants: This cohort study was conducted at an academic, quaternary care medical center from 2012 to 2018. A consecutive series of 238 patients underwent surgical resection of stage I to IIIC nonsquamous NSCLC and had molecular prognostic classifier testing performed. Data analysis was conducted in May 2019., Exposures: Patients were restaged according to the seventh and eighth editions of the TNM staging system and the novel TMMB staging system, which maintains the order and structure of the eighth edition of the TNM but downstages or upstages according to low or high molecular risk, respectively., Main Outcomes and Measures: The primary outcome was disease-free survival 3 years from the time of surgical resection. Reclassification statistics were then used to evaluate performance and improvement measures of the TNM seventh and eighth editions and the TNMB staging system., Results: Two hundred thirty-eight patients (144 [60.5%] female; median [interquartile range] age, 70 [63-75] years) were analyzed. The median (interquartile range) follow-up was 25 (14-40) months, and the disease-free survival rate was estimated to be 58.3% (95% CI, 45.7% to 69.0%). One hundred fifty-nine patients (66.8%) were reclassified by the TNMB staging system. Overall model fit remained the same for the seventh and eighth editions of the TNM staging system, whereas the R2 statistic (change from 0.22 to 0.31), concordance index (change from 0.68 to 0.73), and log-rank χ2 (change from 38 to 108) were all associated with improvements after TNMB adoption. The TNMB system, compared with the TNM eighth edition, was associated with enhanced identification of high-risk patients and better differentiation of those without recurrence from those who had recurrence (net reclassification improvement, 0.28; 95% CI, 0.08 to 0.46; P < .001), whereas the eighth edition compared with the seventh edition was not associated with improvement of this measure (net reclassification improvement, 0.02; 95% CI, -0.18 to 0.21; P = .87)., Conclusions and Relevance: The TNMB staging system was associated with improved estimation of disease-free survival compared with conventional TNM staging. Incorporation of a molecular prognostic classifier into staging for NSCLC may lead to better identification of high-risk patients.

The seventh edition of the non-small cell lung cancer (NSCLC) TNM staging system was developed by the International Association for the Staging of Lung Cancer (IASLC) Lung Cancer Staging Project by a coordinated international effort to develop data-derived TNM classifications with significant survival differences. Based on these TNM groupings, current 5-year survival estimates in NSLCC range from 73 % in stage IA disease to 13 % in stage IV disease. TNM stage remains the most important prognostic factor in predicting recurrence rates and survival times, followed by tumor histologic grade, and patient sex, age, and performance status. Molecular prognostication in lung cancer is an exploding area of research where interest has moved beyond TNM stage and into individualized genetic tumor analysis with immunohistochemistry, microarray, and mutation profiles. However, despite intense research efforts and countless publications, no molecular prognostic marker has been adopted into clinical use since most fail in subsequent cross-validation with few exceptions. The recent interest in immunotherapy for NSCLC has identified new biomarkers with early evidence that suggests that PD-L1 is a predictive marker of a good response to new immunotherapy drugs but a poor prognostic indicator of overall survival. Future prognostication of outcomes in NSCLC will likely be based on a combination of TNM stage and molecular tumor profiling and yield more precise, individualized survival estimates and treatment algorithms.