Molecular Diagnosis and Clinical Outcome of a Lung Cancer Patient with -E285K Mutated Li-Fraumeni Syndrome Harboring a Somatic -KDD Mutation

Objectives: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition, mostly caused by germline mutations. Lung adenocarcinoma (ADC) has been identified as the most frequent LFS-related cancer outside the common LFS core spectrum. EGFR-kinase domain duplication (KDD) is rare in lung cancer and the effective therapy for LFS patients with -KDD mutated ADC is unclear. This study reports the first case of a -mutated LFS patient with confirmed family history, developing advanced lung ADC harboring -KDD.

Materials And Methods: The patient's lung tumor, lymph nodes, liquid biopsies and germline control sample at various disease stages were subjected to next-generation sequencing (NGS). The germline mutation was confirmed using the peripheral blood of the patient's relatives by Sanger sequencing.

Results: A rare -KDD somatic mutation that was missed in the routine hotspots test, and a -E285K temperature-sensitive germline mutation were identified by NGS. The patient was diagnosed with breast cancer in 2006 and her family cancer history review revealed that seven out of 13 relatives were diagnosed or died from LFS-spectrum cancers before the age of 45 years. Three of the six relatives were positive for the -E285K germline mutation. This patient received multi-line chemotherapy followed by anlotinib, a multi-target tyrosine kinase inhibitor, upon the identification of -KDD, and achieved an overall survival of 18 months.

Conclusions: Our study highlights the importance of NGS in discovering rare genetic alterations to guide treatment decision-making, and provides meaningful insight into the potential treatment options for LFS patients with -KDD mutations.