Challenge and opportunity of targeted lung cancer chemoprevention.

Impacting lung cancer mortality remains among the most formidable of challenges in basic, translational, and clinical cancer investigation. While early detection has been the focus of research efforts resulting in recent notable achievements, lung cancer chemoprevention has lagged behind. Both smoking prevention and cessation are key elements of an overall strategy for lung cancer prevention, but they do not address the problem of the increasing population of former smokers who remain at elevated risk. To address this problem, attention has focused on chemoprevention. Despite extensive efforts, agents evaluated in the majority of the lung cancer chemoprevention phase III clinical trials have been found to be ineffective or even harmful. As a result, current guidelines do not recommend agents for lung cancer chemoprevention. In the article that accompanies this editorial, Karp et al describe a phase III assessment of the capacity of selenium supplementation to prevent second primary tumors in individuals following surgical resection of non–small-cell lung cancer (NSCLC). This double-blind, placebo-controlled, multicentered lung cancer chemoprevention trial involved six cooperative groups in the United States and Canada, accruing more than 1,700 patients in nearly a decade-long investigation. Here they report that selenium resulted in no benefit over placebo in the prevention of second primary tumors. The authors are commended for the organization of this large, complex trial in an important clinical context. Selenium has been suggested to prevent tumor development by multiple potential mechanisms that impact distinct stages of carcinogenesis. In antioxidant systems, selenium can participate by incorporation as selenocysteine into more than 25 selenoproteins, such as glutathione peroxidase and thioredoxin reductase. Studies have suggested that selenium may also play a role in minimizing DNA damage as well as augmenting DNA repair capacity. Overall, however, studies evaluating the potential for selenium in the prevention of lung cancer have yielded conflicting results in both preclinical and clinical investigations. For example, in studies using in vitro and animal model systems, low, nontoxic levels of selenium protected against lung cancer, suggesting possible benefits of selenium in humans. However, these results were not consistently identified by others. For example, while selenium was effective in blocking the in vivo effects of a single tobaccospecific carcinogen such as 4-(methylnitrosamino)-1-(3-pyridyl)1-butanone (NNK), it was not effective against exposure to whole cigarette smoke in murine models. The epidemiological literature has suggested an inverse association between selenium intake and cancer incidence for several malignancies. A recent comprehensive review of the data from 26 prospective observational studies reported that there was a reduction in lung cancer as well as mortality with higher selenium. This systematic review and meta-analysis also included a broad array of clinical studies and randomized controlled trials. Based on available evidence, the authors concluded that there appears to be a differential chemopreventive effect dependent on baseline selenium status, such that selenium supplementation may reduce risk of lung cancers in populations with lower baseline selenium status but increase risk of lung cancers in those with higher selenium. The study by Karp et al was not powered to evaluate the interaction between selenium level and treatment; their study involved subjects from a broad geographic area and was not concentrated in areas in which individuals are known to have low selenium levels. Previous clinical trials investigating surrogate biomarkers of lung cancer risk found that subjects with low selenium responded to supplementation with increases in glutathione and augmentation of immune function. However, prospective studies in subjects who were replete in selenium at baseline have not shown efficacy. How can this study inform future investigation in clinical lung cancer chemoprevention? The numerous negative phase III studies suggest the portal of entry for an agent to this level of investigation should now be guided by specific criteria. It is suggested that evidence supporting efficacy of a chemopreventive intervention should be derived from multiple objective research sources, including mechanistic, observational, preclinical and phase II studies with intermediate or surrogate end points. Most importantly, individuals at risk for lung cancer should enter into a chemoprevention trial based on selected biologic features that both help define the heterogeneity of those at elevated risk and suggest their response to a particular agent. Major clinical breakthroughs in advanced stage lung cancer have been facilitated by the recent advent of patient selection based on tumor mutational profiles that have fostered a personalized medicine approach for patients with NSCLC. This paradigm shift has not yet fully reached clinical lung cancer chemoprevention, however, there is increasing recognition that the molecular determinants inherent in the early pathogenesis of the disease must be mined to develop risk assessment, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 33 NOVEMBER 2