Carbone, David P. MD, PhD
James Thoracic Center, International Association for the Study of Lung Cancer, The Ohio State Wexner Medical Center, Columbus, Ohio.
Disclosure: The author has received consulting honoraria from Genentech, Roche, Clovis, and AstraZeneca relevant to this article.
Address for correspondence: David P. Carbone, MD, PhD, James Thoracic Center, President-Elect, International Association for the Study of Lung Cancer, The Ohio State Wexner Medical Center, Columbus, OH 43026.
In 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,1,2now 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. A reasonable step to take now is to add carrier status as an eligibility criterion for low-dose computed tomography screening, but it is completely unclear at what age to start this screening, as although most cases would fall in the age range of 55 to 70 years, cases in much younger patients have been identified. Management of patients with sometimes multiple ground-glass lesions is complicated under the best of circumstances, but more so when the patient is known to have a germline T790M. Current practice of intervening only when these lesions start to turn solid is reasonable, but demands prospective study. One exciting possibility is to initiate a clinical trial using one of the new T790M selective drugs as chemopreventives in this population.
There are many other unanswered questions, including the effect of this allele on the development of other cancers. Both of the families I have identified also have a large number of breast cancer cases, as was the case in one of the families studied by Yu et al.,1 begging the question of whether the incidence of breast cancer may be increased in carriers. Clinical geneticists now need to be made aware of this syndrome for them to be informed and partner with oncologists in following these patients and their families.
Many intriguing scientific questions remain unanswered. Linkage studies to study founder effects would be interesting, but most interesting to me is explaining the fact that this same exact amino acid substitution is the most frequently acquired resistance mutation after therapy with TKIs, and is even present at subclonal levels in some tumors before therapy, portending a worsened progression-free survival. The fraction of tumor cells with this allele seems to increase during therapy and decrease if the selection pressure is removed, suggesting some disadvantage to clones with both traditional activating and T790M alleles. Thus this allele seems to be both tumor-promoting and tumor-inhibiting, depending on the context. What is special about this alteration that it not only persists in the germline in multiple populations, but also is apparently strongly and specifically selected for after therapy with TKIs? These two observations are not likely to be the result of chance, but more likely some key unknown function of this alteration or feature of the DNA or chromatin at this location in the genome that drives this convergent evolution.
Lung cancer has thus grown up from a depressing, monotonous, and uniformly awful disease to one in which, while still frequently awful, there is a rapidly advancing molecular understanding, rationally targeted therapeutics, effective screening, and now improving risk stratification including germline genetics. It has been an exciting ride.
1. Yu A, Arcila M, Fleischut MH, et al. Germline EGFR T790M mutation found in multiple members of a familial cohort. J Thorac Oncol. 2014;9(4):554–558
2. Gazdar A, Robinson L, Oliver D, et al. Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations. J Thorac Oncol. 2014;9(4):456–463