Two studies provide new insight into a germline epidermal growth factor receptor (EGFR) T790M mutation in familial non-small cell lung cancer (NSCLC). The findings suggest the need for tailored approaches for early detection and treatment, as well as for genetic testing to identify carriers.   

Germline EGFR T790M mutation causes a rare hereditary lung cancer syndrome associated with a 31% risk for the disease in persons who have never smoked.

In the first study, lead author Adi Gazdar, MD, of the Department of Pathology, University of Texas Southwestern Medical Center in Dallas, and colleagues studied five generations (14 persons) of a family with germline EGFR T790M mutations. They combined their observations with data obtained from a literature search (15 persons) and found that the mutation occurred in approximately 1% of NSCLCs and in less than one in 7,500 subjects without lung cancer.

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Females who had never smoked were overrepresented in the family cohort. Among 13 persons for whom gender and smoking status were known, nine were females who had never smoked, two were males who had never smoked, and two had a history of smoking (one male and one female).

“Unaffected carriers with this mutation are at increased risk for the development of lung cancer regardless of their smoking status and should be followed by increased surveillance, including low-dose computed tomography,” said Gazdar. This study was published in the Journal of Thoracic Oncology (2014; doi:10.1097/JTO.0000000000000130).

In the second study, Helena A. Yu, MD, of Memorial Sloan-Kettering Cancer Center in New York, New York, and colleagues identified the germline EGFR T790M mutation in a 44-year-old female who had never smoked. The researchers tested eight family members and found the mutation in two additional family members (mother and daughter) who had never smoked. Metastatic lung cancer developed in the patient’s mother, and the radiographic appearance of the lung cancer was the same for both women, with bilateral ground-glass opacities and pulmonary nodules.

“Germline EGFR T790M mutations are present in approximately 50% of all patients with baseline EGFR T790M identified in their tumor specimens before treatment,” said Yu. “In our practice, we recommend that all patients with baseline EGFR T790M identified in their lung tumor tissue be referred to clinical genetics to discuss EGFR T790M germline testing.”

The presence of a germline EGFR T790M mutation also is predictive of resistance to standard tyrosine kinase inhibitors (TKIs), which adds complexity to treatment. Until newer third- and fourth-generation TKIs designed to overcome T790M-mediated resistance become available, standard chemotherapy may be the preferred first-line therapy option in the absence of another known or suspected molecular target. This study was published in the Journal of Thoracic Oncology (2014; doi:10.1097/JTO.0000000000000052).