Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery.

Background: Pulmonary metastasectomy is one of the cornerstones in the treatment of oligometastatic colorectal cancer (CRC). However, the selection of patients who benefit from a surgical resection is difficult. Mutational profiling has become an essential part of diagnosis and treatment of malignant disease. Despite this, comprehensive data on the mutational profile of CRC and its clinical impact in the context of pulmonary metastasectomy is sparse. We therefore aimed to provide a complete mutational status of CRC pulmonary metastases (PM) and corresponding primary tumors by targeted next-generation sequencing (tNGS), and correlate sequencing data with clinical outcome variables.

Methods: Case-matched, formalin-fixed paraffin embedded surgical specimens of lung metastases (n=47) and matched primary CRC (n=24) were sequenced using the TruSeq Amplicon Cancer Panel (Illumina platform). Penalized Cox regression models were applied to identify mutations with prognostic impact.

Results: Mutations were found most frequently in APC , TP53 and KRAS , in both PM and matched primary tumors. Concordance between primary tumors and PM was 83.5%. Adaptive elastic-net regularized Cox regression models identified mutations being prognostic for time to pulmonary recurrence ( EGFR , GNAQ , KIT , MET , and PTPN11 ) and for overall survival (OS) ( PDGFRA , SMARCB1 , and TP53 ).

Conclusions: Our findings suggest that CRC PM harbor a variety of conserved and de novo mutations. We could identify a mutational profile predicting clinical outcome after pulmonary metastasectomy. Moreover, our data provide a rationale for future targeted therapies of patients with CRC lung metastases.