MedicalResearch.com Interview with:
Dr. Azi Gazdar, MD
UT Southwestern Medical Center
W. Ray Wallace Distinguished Chair in Molecular Oncology Research
Hamon Center for Therapeutic Oncology, Pathology
MedicalResearch.com: What are the main findings of the study?
Dr. Gazdar: We describe the characteristics of lung cancers arising in subjects who inherited a germline mutation that predisposes to lung cancer. The mutation is rare in the general populations, and is inherited equally by both sexes. However it is a potent predisposing gene, and one third of the never smoking carriers will develop lung cancer. Thus, about 1% of patients who develop lung cancer carry the germline mutation. This figure may rise as awareness of the condition and its link to lung cancer is raised among doctors diagnosing lung cancer. However, lung cancers mainly develop in women who are lifetime never smokers. Lung cancer development is much less common among smokers and men, although accurate figures are not yet available. So the risk among carriers is somewhat similar to the BRCA genes predisposing to breast cancer, where a female carrier has about a 50% lifetime chance of developing breast cancer.
The specific germline mutation (known as T790M) occurs in a gene known as epidermal growth factor receptor (EGFR) gene. Sporadic mutations in this gene usually predict for effective responses to a class of drugs known as tyrosine kinase inhibitors (TKIs), which are widely used in the treatment of lung cancer. However, the T790M mutation, when it occurs in sporadic tumors not associated with germline inheritance are resistant to TKI therapy. Thus the prediction is that lung cancers arising in carriers with the germline mutation would also be resistant to TKI therapy.
MedicalResearch.com: Were any of the findings unexpected?
Dr. Gazdar: These findings are surprising, because, in the general population, heavy smokers have about a 40 fold greater risk of developing lung cancer than lifetime never smokers. Also, men form the majority of cases with lung cancer worldwide, although there are geographic and ethnic differences.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Gazdar: Physicians should be aware of this germline mutation and its link to lung cancer. When it occurs in newly diagnosed cancers, they should determine whether its occurrence was sporadic or germline by testing the blood of the patient. If a germline mutation is present, the patient and family members should be referred to a medical geneticist for counseling and mutation testing. Patients should not be treated with the current FDA approved TKIs. Mutation carriers should be followed by regular medical visits and CT scans.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Gazdar: There are many unanswered questions. What is the optimal method of preventing cancers in carriers, of detecting them early and of treating them? What do we advise carriers regarding smoking and other lifestyle decisions? Can some of the new generation of TKIs, some of which target T790M, be useful for treating the cancers as well as preventing them in carriers? Some of these questions will only be answered by detailed studies of more families, and such organized studies have already begun.
For more information about the study, please visit: http://bit.ly/1h1FG6S.
Inherited mutation predisposes to lung cancer in women and never smokers.
Gazdar, Adi MD*†; Robinson, Linda MS‡; Oliver, Dwight MD†; Xing, Chao PhD§; Travis, William D. MD‖; Soh, Junichi MD¶; Toyooka, Shinichi MD¶; Watumull, Lori MD#; Xie, Yang PhD**; Kernstine, Kemp MD††; Schiller, Joan H. MD‡‡