ES23.01 Pro-Con: Non-Anatomic Parameters Should Be Included Into Current TNM Classification (Genetic, Molecular, Histology, etc)

Abstract

Since the Tumor Node Metastasis (TNM) staging system for lung cancer was introduced between 1966 and 1968, it has gone through sequential iterations in the never-ending quest to improve its clinical utility in communicating the likely severity of disease (prognostication) and, indirectly, approaches to treatment. The N-category was initially stratified as Nx,N0,N1; the N2 category was introduced in 1973; and the N3 category was introduced by the Union for International Cancer Control in 1987. With the 7th edition of the staging system, the International Association for the Study of Lung Cancer (IASLC) has taken over responsibility for revising the staging system, using an international database managed by Cancer Research and Biostatistics (CRAB).1 There is an ongoing worldwide request for contribution of data to help develop the 9th edition of the lung cancer staging system, due in 2025.2 For the first time, the IASLC also empaneled a Molecular Database Sub-committee within the Staging and Prognostic Factors Committee, tasked with examining how best to use rapidly emerging knowledge about lung cancer biology to improve our understanding of lung cancer care and outcomes. All staging systems exist to facilitate communication between people across time and space. The anatomy-based TNM staging system is our venerable lingua franca that serves this purpose. It standardizes our communication of the prevailing best understanding of the severity of disease, thereby directly telling us what is likely to come (prognosis), indirectly, what to do about it (treatment).3 In general, the more severe or dangerous the cancer, the more desperate the treatment (up to a point). Ultimately, the purpose of staging is to help us learn how to overcome cancer. In the past decade or so, there has been an explosion of our understanding of the molecular drivers of disease which affect prognosis, predict likelihood of treatment success, potentially predict patterns of spread and the biologic behavior of lung cancer. As recently as 2012, almost 50% of lung adenocarcinomas had no identifiable driver gene mutation,5 in 2015 this was down to 36%;6 in 2020, a ‘back-of-the-envelope’ calculation would suggest that only 11% of stage IV lung adenocarcinomas do not have a US Food and Drug Administration-approved targeted treatment. Targeted therapies are rapidly blurring the lines between anatomically-distinct TNM-based survival statistics. For example, 5-year survival rates of appropriately-treated patients with EGFR and ALK-mutated lung cancer is probably by now in excess of 20%, compared to less than 4% in patients who do not undergo biomarker-driven therapy, and similar to biomarker agnostic patients who undergo curative-intent resection of stage pN2 (IIIA) adenocarcinoma. Which begs the question: are they even the same disease anymore? This question will only grow in importance: the US Food and Drug Administration, as of December 8, 2020, has essentially approved target-specific therapy for ten different subsets of lung cancer (Table 1); the ADAURA trial showed that patients whose completely resected (IASLC 8th edition stage IIA to IIIB) lung cancer expressing either of the two most common activating mutations of EGFR was treated with the tyrosine kinase inhibitor Osimertinib, had recurrence-free survival that was drastically better than those who did not receive the drug.7 Considering that EGFR-mutation-positive lung cancer already has significantly better prognosis than adenocarcinoma without that mutation, the question ‘are they even the same disease anymore?’ becomes more insistent. Imposing identical, strictly anatomy-based language to communicate our current understanding of what is to come for these clearly different populations of lung cancer patients, and worse, potentially mis-communicating what the optimal treatment ought to be, as the ADAURA trial principle is proven for other biomarker-targetable subsets of lung cancer patients, and (further down the line) such targeted therapy moves from the postoperative to the preoperative setting, will only raise clamor for us to augment our lung cancer staging system with the full armamentarium of knowledge available to us. The Staging and Prognostic Factors Committees lung cancer biomarker project is therefore a vitally important pathway to the future. It is likely to take us to a world in which lung cancer becomes a disease of inconvenience, rather than mortality. Our lingua franca will be challenged to grapple with this opportunity.