An era of lung cancer iconoclasts.

®n the old days, non–small-cell lung cancer was simple—there were no effective screening test, no functionally important subtypes, it was a disease of smokers, was rarely curable, and the medical therapy options were limited to nonexistent, and neither familial nor somatic genetics was relevant. When diagnosed with lung cancer one of the first questions acquaintances and physicians ask is “Did you smoke?” expecting a positive answer. Many physicians, if they asked about family history in lung cancer patients at all, generally ignored the information even if lung cancer was found in first-degree relatives, because of the high prevalence of this disease. Now everything has changed. In the span of a generation, it is now recognized that most cases of lung cancer occur in nonsmokers and many in never-smokers. Computed tomography screening can detect it early and save lives, and genetically informed therapy selection is now standard of care with dramatic clinical benefit usually observed when therapy can be matched to specific gene mutations. However, somatic genetics has not played a role in this revolution to date. Perhaps presciently, during discussions of lung cancer genetics in the clinic, informed family members who know about breast cancer suseptibility gene (BRCA) testing for breast cancer or adenomatous polyposis coli syndrome (APC)/hereditary non polyposis colorectal cancer syndrome (HNPCC) testing for colon cancer usually ask me whether this gene mutation we have found in the tumor can be passed to their children. Physicians previously could confidently say no. The two reports in this issue of Journal of Thoracic Oncology discussing germline epidermal growth factor receptor (EGFR) T790M, 1,2 now break this last icon, and report a very high risk of lung cancer in never-smoking carriers of this allele. These studies now solidify the fact that routine clinical management of lung cancer now has to include the awareness of this inherited cancer syndrome. Lung cancer genetic analysis should thus routinely include not only EGFR T790M, but also some measure of allele frequency, as we have now implemented in the routine genetics reports at my institution. Through this awareness over the past several years I have found two unrelated families with this syndrome in my own clinical practice, so I am sure the vast majority of these cases are currently being missed. There is, however, much remaining to clarify about this syndrome, both clinically and scientifically. Because it is currently most often detected in lung cancer patients, the most pressing questions are two: defining the optimal acute and chronic management of lung cancer in these people, and clarification of the penetrance and optimal management of affected family members. For the first question, it seems clear that these patients are likely to respond differently to first-generation EGFR tyrosine kinase inhibitors (TKIs) than nongermline patients, and testing of the latest generation of T790M selective inhibitors for therapy is an obvious choice. In addition, exclusion or stratification of these patients from patients without germline T790M is imperative in clinical trials targeting this gene. Less obvious is how to manage family members, including children, inheriting this gene. This can only be clarified by prospective studies such as the ongoing Addario Lung Cancer Medical Institute–sponsored Investigating Hereditary Risk for T790M (INHERIT) trial, and it is important to enroll patients in this trial to improve our understanding of this syndrome.