Lung cancer awareness

Abbreviation: COX-2 = cyelooxygenase-2

It is both an honor and a challenge to summarize this year's Aspen Lung Conference, organized by York Miller and Bob Keith, with the capable assistance of Jeanne Cleary. They haw, managed to attract an outstanding variety of leading investigators from around the world working on all of the major aspects of this topic, and no summary can do justice to the wealth of information presented or the quality of the scientific interactions that took place.

It is a particular pleasure for me to both attend and summarize this particular conference, as it is organized and run by pulmonologists, and I am a medical oncologist. The fact that this conference focuses on lung cancer signifies an era of increasing awareness and collaboration between pulmonary medicine and the ontology specialties that is desperately important if we are to make real progress in fighting this disease. This has not always been the case.

There are many obstacles to overcome in order to make progress in reducing the morbidity and mortality attributable to lung cancer, and only some of them are scientific. Others are sociological or political. For example, there has been the perception that patients with lung cancer are to blame for their disease, so it is not important to try to cure or prevent it. However, over half of patients with lung cancer diagnosed today are never smokers or ex-smokers, and I strongly feel that even smokers do not "deserve" lung cancer. The opinion that there are no effective therapies is also being chipped away with the advent of new drugs such as Iressa (gefitnib) and Alimta (pemetrexed), and a positive adjuvant chemotherapy trial al this year's American Society of Clinical Oncology. The lack of a powerful advocacy group has also led to a relative understanding for lung cancer research, with no Department of Defense grants, and only approximately one tenth the funding of breast cancer per cancer death. The fact that many states use their multimillion-dollar tobacco settlements to balance their budgets and not to combat tobacco-related disease is also a travesty of justice.

My particular enthusiasm for this year's conference relates to the fact that there has also been a historical lack of interest in lung cancer by some pulmonologists, the specialty usually responsible for its diagnosis. The quality and progress reflected by this conference is evidence that these historical barriers to progress are being overcome. I will thus attempt to summarize the highlights of this meeting from the perspective of a researcher and a lung cancer medical oncologist.

CONFERENCE THEMES

The central theme of this year's Aspen conference was crystallized by Wilbur Franklin, who proposed the concept of premalignancy as the disease and cancer as only the end point. It is clear that unless completely surgically resectable, lung cancers are very hard to treat, and thus we need to focus on prevention and earlier intervention, the focus of this conference. I hope that eventual understanding of the genetic and environmental basis of lung cancers will allow us to identify high-risk populations and to develop effective prevention, early detection, and chemoprevention strategies.

A secondary theme for this conference for me was not just the increasing recognition of the complexity of lung cancers, preneoplasia, and populations at risk, but of the availability of emerging technologies capable of grappling with that complexity. Not all lung cancers are the same; every individual's genetic background and individual environmental exposures factor into their personal risk of acquiring lung cancer. Beyond recognizing these facts that have long been clinically suspected, we now have data on the mechanisms of this heterogeneity, and most importantly the tools to begin to quantify and understand what is going on.

INHERITED RISK MODIFIERS

Ann Schwartz described her efforts to identify genes associated with lung cancer risk through the Genetic Epidemiology of Lung Cancer Consortium. To date, this consortium has identified approximately 40 families of a planned 85 with a familial clustering of cases. She emphasized the distinction between the genetics of a single, low-prevalence, high-penetrance gene and a high-prevalence, low-penetrance susceptibility gene. Their data suggest that such a single gene may exist, and the families being collected by this consortium should help map the location of this putative gene. The relative risks for family members of a ease range from 1.3 to 4.8 for all cases, or up to 6.1 for family members of young nonsmokers with lung cancer, all significant levels of risk that justify vigorous pursuit of the putative genes. (1)

Both Dr. Schwartz and Jonathan Samet reviewed the data on susceptibility genes in lung cancer. The genes analyzed to date are primarily those associated with variability in the handling of environmental carcinogens, including phase I, phase II, and DNA repair genes. Single genes tended to be associated with risks of 1.3 to 2.0, but the combination of CYP1A1 with GSTM1 had an overall risk of 3.0 to 5.8. Dr. Schwartz reported on a population study in nonsmoking and early-onset disease based on the Detroit Surveillance, Epidemiology, and End Results registry. This study involved nonsmokers aged 40 to 84 years, and has identified 325 cases and 141 biological samples. Also identified were those with early onset disease appearing at age < 40 years, with 641 cases and 372 samples obtained. There were 181 eases of early onset disease in nonsmokers. The strongest risk identified to date was for CYP1B1 with an odds ratio of 5.5 (CI, 3.4 to 9.1) in nonsmokers. This gene is involved in metabolism of polycyclic aromatic hydrocarbons and estrogen metabolism. It is perhaps counterintuitive, however, that a phase I enzyme association should be found to strongest in nonsmokers, as it is thought to be important in handling the carcinogens associated with cigarette smoking. One possible interpretation is that high doses of carcinogens from smoke overwhelm inherited variability in the phase I enzymes, and that these are manifest only with lower-level exposures that occur in nonsmokers.

It was pointed out by Dr. Samet that since these studies all adjust for tobacco exposure, it is also possible that genetic susceptibility to nicotine addiction would not be detected in these studies. There are data, in fact, suggesting a linkage between dopamine receptor polymorphisms and tobacco use. These sorts of associations should be further explored.

If the observed associations with these genes hold up in larger studies, they could have individual clinical predictive significance, but it is clear that risk associations in smokers may involve whole pathways of genes rather than single genes due to the complexity of carcinogens in tobacco smoke and their various metabolic pathways. In the future, use of bioprobes for entire pathways or comprehensive single nucleotide polymorphism analysis of large numbers of genetic polymorphisms may be useful for more accurately estimating individual risks.

MECHANISMS OF GENETIC ALTERATION

Dr. Samet reviewed the history of the evidence linking environmental factors to lung cancer. While there were many who suspected a link much earlier, solid data associating smoking with lung cancer started with the studies of Ernst Wynder, Morton Levin, and Richard Doll in the 1950s. The links to radon, asbestos, and atmospheric factors such as diesel exhaust were also reviewed. Dr. Samet emphasized the concept of joint causation--the fact that individual cases might be caused by a combination of genetic and environmental factors. Thus, if a single factor is associated with 10% of the cases, elimination of this cause will not cause a 10% drop in incidence, but something less (the concept that "100 minus 10 is not 90"). The role of passive smoking is still somewhat controversial, but most studies place the risk at approximately twofold to fourfold.