Concomitant genomic alterations in KRAS mutant advanced lung adenocarcinoma.

OBJECTIVES: KRAS mutations are one of the most prevalent alterations in non-small cell lung cancer. However, patients with this driver alteration present heterogeneous clinical outcomes. In this study, we have explored the potential clinical impact of coexisting alterations in this subset of patients. MATERIALS AND METHODS: Samples from a cohort of 69 lung adenocarcinoma patients homogenously treated with platinum doublet as first-line therapy were evaluated using targeted next generation sequencing (NGS). Mutations and copy number alterations were assessed in 37 advanced KRAS-mutant (KRASm) and in 32 KRAS wild-type (KRASwt). RESULTS: TP53 was the most frequent additional alteration found in both cohorts. Interestingly, TP53 mutations were more frequent in KRASwt than in KRASm patients (80 % vs. 34 %; p <  0.05) as well as STK11 mutations (17 % vs 8 %, p=NS). FGFR3 mutations were only found concomitantly with KRASm (11 %). No genomic co-alteration had an impact on overall survival within the KRASm patients treated with chemotherapy. CONCLUSIONS: KRAS mutated lung adenocarcinoma is a heterogeneous entity and comprehensive characterization of co-alterations using NGS may lead to more accurate patient stratification.

Dynamics of EGFR Mutation Load in Plasma for Prediction of Treatment Response and Disease Progression in Patients With EGFR-Mutant Lung Adenocarcinoma.

BACKGROUND: The assessment of epidermal growth factor receptor (EGFR) mutations is crucial for the management of patients with lung adenocarcinoma. Circulating tumor DNA (ctDNA)-based assessment offers advantages over tumor as a minimally invasive method able to capture tumor heterogeneity. PATIENTS AND METHODS: Consecutive patients diagnosed with EGFR-mutant lung adenocarcinoma in tumor biopsy were included in this study. Plasma samples were obtained at different time points during the course of the disease. EGFR mutations in plasma were quantified using BEAMing (beads, emulsions, amplification, and magnetics) or digital PCR and were correlated with mutations in tumor and with radiologic response and progression. RESULTS: Two hundred twenty-one plasma samples from 33 patients were analyzed. EGFR mutations in plasma were detected in 83% of all patients and 100% of those with extrathoracic metastases. The dynamics of the EGFR mutation load predicted response in 93% and progression in 89% of cases well in advance of radiologic evaluation. Progression-free survival for patients in whom ctDNA was not detected in plasma during treatment was significantly longer than for those in whom ctDNA remained detectable (295 vs. 55 days; hazard ratio, 17.1; P < .001). CONCLUSION: The detection of EGFR mutations in ctDNA showed good correlation with that in tumor biopsy and predicted tumor response and progression in most patients. The liquid biopsy for ctDNA-based assessment of EGFR mutations is a reliable technique for diagnosis and follow-up in patients with EGFR-mutant lung adenocarcinoma in routine clinical practice.