Background: Mutational analysis has become standard of care in lung cancer. However, many patients do not have tissue available due to lack of tissue, or more commonly due to tissue exhaustion by previous tissue analysis. Next generation sequencing of circulating cell-free DNA (cfDNA) provides a non-invasive alternative. EGFR point mutations and indels are well reported in this manner, however gene copy number amplification is more challenging. Here we present a cases where MET amplification has been detected and guided highly efficient therapy in advanced lung cancer patient.
Methods: Guardant360TM is a targeted cfDNA NGS panel using hybrid capture and complete exon sequencing exons for single nucleotide variant detection in 68 genes, copy number amplifications (CNA) in 16 genes, and selected indels and fusions. CNA has been validated against cell lines with known amplifications.
Results: A 70 y old former light smoker (15 PY) with pulmonary fibrosis and moderate pulmonary hypertension was diagnosed with a 30 mm RMB lung adenocarcinoma that was treated by stereotactic beam radiotherapy due to poor pulmonary reserve. After 5 months, mediastinal, liver and multiple bone metastases were diagnosed. Genomic analysis of the primary tissue biopsy yielded a rare EGFR mutation (I744F) and afatinib therapy was started to cover uncommon EGFR mutations. However, 2 months later, a significant progression has occurred and the patient had severe local progression with respiratory near-failure. The patient was not a candidate for chemotherapy and there was no further tissue available for molecular testing. Therefore cfDNA testing was performed finding no residual EGFR mutation in the blood but a MET amplification reported above the 90th percentile for the Guardant Health laboratory with copy number of 53.6 in the blood.
Upon this result, crizotinib 250 mg BID was started with immediate clinical improvement, followed with a dramatic imaging response on CT/PET scans. Currently, the patient is in PS-0 and free of any symptoms, 3 months since treatment has been started.
Conclusion: cfDNA detection of MET amplification as a key resistance mechanism after EGFR TKI therapy is feasible in patients where tissue is not accessible or was undergenotyped and may be accompanied by a fast and dramatic clinical improvement.
Citation Format: Nir Peled, Anna Belilovski, Lior Soussan-Gutman, Richard B. Lanman, AmirAli Talasaz. Salvage MET amplification detection and therapy through cell-free DNA NGS in a progressing lung cancer patient. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 491.