WCLC: New Study Reveals Genomic Architecture of EGFR Mutations in Lung Cancer
Epidermal growth factor receptor (EGFR) mutations are one of the most common driver oncogenes in lung cancer, typified by high response rates when treated with tyrosine kinase inhibitors and median progression-free survival of 10 months, commonly due to emergence of T790M. The genomic architecture and spectra of EGFR-positive tumors may provide insights to mechanisms of treatment failure.
A research team led by Daniel S. W. Tan, of the National Cancer Centre Singapore and Genome Institute of Singapore, undertook a study performing whole-exome and RNA sequencing to determine the genomic architecture of treatment-naive EGFR-mutant lung cancers, as well as to elucidate mechanisms of resistance from analysis from a series of tyrosine kinase inhibitor–resistant biopsies. Dr. Tan presented his group's findings at the 16th World Conference on Lung Cancer (WCLC) hosted by the International Association of the Study of Lung Cancer.
“As emerging data implicate tumor evolution in drug resistance, we sought to gain insights into the mechanisms of clonal selection in EGFR-mutant NSCLC [non–small cell lung cancer], in order to develop strategies to overcome early treatment failure,” he said.
Sequencing Results
The team found that EGFR mutations consistently occur in trunks and that these tumors generally had a low-mutation burden across the exome (median 48, range 9–98). The investigators also observed short trunks and high clonal diversity among East Asian patients with lung cancer. Trunk mutations are found across all regions of a particular tumor, whereas private or branch mutations are found only in certain parts of the tumor.
Multiregion sequencing further identified coexisting driver trunk alterations as a possible mechanism for primary resistance to EGFR tyrosine kinase inhibitors, which is seen in 10% to 20% of patients with activating EGFR mutations.
Finally, sequencing tyrosine kinase inhibitor–resistant samples highlighted a subgroup of tumors with a high-mutation burden, associated with a history of smoking. “It is likely that additional subgroups within T790M-positive and -negative patients, such as those with high mutation burden, will further emerge and may form the basis for novel therapeutic approaches, including immunotherapy,” Dr. Tan concluded.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
