Perspective Perspective on Mao et al., p. 984 The Dawn of a Revolution in Personalized Lung Cancer Prevention Fadlo R. Khuri Abstract Lung cancer prevention and early detection, which have fallen on hard times for more than the past 20 years, seem to have turned a corner toward better times ahead. Exciting new results of randomized controlled trials that targeted the arachidonic acid pathway, including a celecoxib trial reported by Mao and colleagues in this issue of the journal (beginning on page 984) and a trial of the prostacyclin analog iloprost, complement recently reported 20%–30% lung cancer mortality reductions, either with aspirin in targeting the arachidonic acid pathway or with computed tomography screening. The new results show encouraging activity personalized to former smokers and/or people expressing predictive biomarkers. These trials and technological advances in molecular profiling and imaging herald substantial clinical advances on the horizon of this field. Cancer Prev Res; 4(7); 949–53. ’2011 AACR. "It was the best of times, it was the worst of times...it was the spring of hope, it was the winter of despair" —Charles Dickens (A Tale of Two Cities) The well-known litany of disappointments in clinical lung- cancer prevention includes the Alpha-Tocopherol, Beta- Carotene (ATBC) trial, Carotene and Retinol Efficacy Trial (CARET), Lung Intergroup Trial (LIT), and the finding that, important as smoking cessation is, half of all new lung cancers arise in former smokers (1–5). Furthermore, a very recent randomized controlled trial (RCT) of selenium to prevent new cancer in resected early-stage lung-cancer patients reported negative outcomes (6). The worst of times. For people living with an increased risk of lung cancer, however, the glass is starting to look somewhat fuller. Reversing decades of disappointing results of lung cancer early detection research with chest–X-ray screening (7), the definitive randomized controlled National Lung Screening Trial (NLST) showed that screening high-risk current or former smokers with computed tomography (CT) scans reduced lung-cancer mortality by 20%, a remarkable but far from bloodless success (8). CT scanning became the most contentious debate of the lung cancer field—one side asserting that it should be implemented without delay on the heels of strong early data (including those of Henschke and colleagues; ref. 9) for reducing lung- cancer mortality, the other side asserting that it should be implemented only after a definitive RCT has confirmed benefit (8). Success has many "fathers," and both camps claimed affirmation, even vindication, by the NLST results. Meanwhile, and more subtly, analyses of RCTs of daily aspirin to reduce the risk of vascular disease found a 30% reduction in lung-cancer mortality in people taking daily aspirin for five or more years (10). The early-2011 report of this clinical targeting of the arachidonic acid pathway is prelude to three trials reported in the past year showing that targeting the same pathway with different agents is effective in reversing proliferation or histologic changes in the lungs of former smokers (11–13). These three trials effectively targeted arachidonic acid metabolic pathways with the cyclooxygenase-2 (COX-2)– specific inhibitor celecoxib or the prostacyclin analog ilo- prost in former and/or current smokers. Celecoxib reduced the proliferation marker Ki-67 in former smokers but had no significant effects on histology, and iloprost reversed histologic abnormalities in the lungs of former smokers, all of which not only reinforces the importance of smoking cessation for risk reduction (14) but also introduces the potential of personalizing prevention to former smokers. Indeed, as will be discussed later, one of the celecoxib trials took personalization a step further with the identification of potential molecular predictive markers for this agent. These markers and the activity involving former smokers are the first important personalizing steps of lung cancer chemoprevention, and together with the NLST, represent important strides toward reducing the national and world- wide burden of lung cancer, which has largely eluded the grasp of cancer therapy and prevention to date (15, 16). A number of explanations have been given for several decades of clinical failure to translate epidemiologic clues into successful chemoprevention approaches for lung cancer. Although each of these numerous explanations is valid in its own right, none of them alone is adequate to completely explain the litany of defeats suffered by clin- ical investigators in this domain (17). They include inadequate mouse models of respiratory premalignancy, Author's Affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia Corresponding Author: Fadlo R. Khuri, FACP, Chair, Department of Hematology and Medical Oncology, Deputy Director, Winship Cancer Institute, Emory University School of Medicine, 1365 C Clifton Road, NE, Atlanta, GA 30322. Phone: 404-778-4250; Fax: 404-778-1267; E-mail: fkhuri@emory.edu doi: 10.1158/1940-6207.CAPR-11-0278 ’2011 American Association for Cancer Research. 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