1252P - Liquid biopsy to track KRAS G12C mutation at progressive disease in patients with advanced non-small cell lung cancer (NSCLC)

Background

In the era of precision medicine, molecular testing is mandatory to guide therapeutic choice. Although tissue biopsy represents the gold standard in clinical decision-making, the genomic profile of the tumor might differ at progressive disease (PD). Thus, liquid biopsies arise as a precious tool to monitor temporal-based tumor dynamics. With the recent identification of several KRAS G12C inhibitors, KRAS mutational status in advanced NSCLC is progressively gaining a novel predictive significance. For this reason, we investigated the utility of two different blood-based KRAS G12C genotyping test at PD to better match patients to interventional biomarker-targeted therapies.

Methods

Thirty-eight patients with advanced NSCLC were enrolled for liquid biopsy testing at PD after first-line immunotherapy treatments. In all patients, mutational analyses of primary tumor tissues had been previously performed through Next Generation Sequencing (NGS). Blood samples were centrifuged at 1500 RPM for 10’. Plasma was removed, centrifuged at 13000 RPM for 1’ and screened for KRAS G12C mutation through real-time polymerase chain reaction (Idylla^TM). Plasma samples were further sequenced using the Oncomine^TM Lung Cell-Free Total Nucleic Acid Research Assay.

Results

KRAS G12C (not previously detected on tumor tissues at diagnosis) was acquired in 9/38 (24%) plasma samples at PD using both Idylla^TM and NGS assays. KRAS G12C co-existed with EGFR mutations in 2 cases, MAP2K1 in 2 cases, p53 in 2 cases, BRAF in 1 case, PIK3A in 1 case. G12C co-occurred with other KRAS mutations in 1 case. All patients harboring KRAS G12C mutation in baseline tissue became negative in ctDNA at PD. The presence of other somatic mutations in these samples allowed to exclude that the absence of KRAS G12C mutation at PD might be due to the scarce release of ctDNA.

Conclusions

We demonstrated through liquid biopsy that KRAS G12C mutation can be acquired or lost at the time of PD due to cancer clonal evolution. Our results underline the limitation to restrict biomarker studies to the analysis of primary tumor tissue for clinical trial stratification of cancer patients at PD, particularly if the tissue biopsy used for biomarker evaluation has been performed long before PD.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Sapienza Università di Roma.

Disclosure

All authors have declared no conflicts of interest.