Abstract
Simple SummaryKRAS G12C mutations are important oncogenic mutations in lung cancer that can now be targeted by allosteric small molecule inhibitors. We assessed the imaging features and patterns of metastases in these lung cancers compared to other mutated lung cancers. We found that KRAS G12C NSCLC has distinct primary tumor imaging features and patterns of metastasis when compared to those of NSCLC driven by other genetic alterations. These distinct imaging features may offer clues to its presence and potentially guide management in the future.KRAS G12C mutations are important oncogenic mutations that confer sensitivity to direct G12C inhibitors. We retrospectively identified patients with KRAS+ NSCLC from 2015 to 2019 and assessed the imaging features of the primary tumor and the distribution of metastases of G12C NSCLC compared to those of non-G12C KRAS NSCLC and NSCLC driven by oncogenic fusion events (RET, ALK, ROS1) and EGFR mutations at the time of initial diagnosis. Two hundred fifteen patients with KRAS+ NSCLC (G12C: 83; non-G12C: 132) were included. On single variate analysis, the G12C group was more likely than the non-G12C KRAS group to have cavitation (13% vs. 5%, p = 0.04) and lung metastasis (38% vs. 21%; p = 0.043). Compared to the fusion rearrangement group, the G12C group had a lower frequency of pleural metastasis (21% vs. 41%, p = 0.01) and lymphangitic carcinomatosis (4% vs. 39%, p = 0.0001) and a higher frequency of brain metastasis (42% vs. 22%, p = 0.005). Compared to the EGFR+ group, the G12C group had a lower frequency of lung metastasis (38% vs. 67%, p = 0.0008) and a higher frequency of distant nodal metastasis (10% vs. 2%, p = 0.02). KRAS G12C NSCLC may have distinct primary tumor imaging features and patterns of metastasis when compared to those of NSCLC driven by other genetic alterations.
Highlights
The discovery of genetic drivers of lung cancer has led to a dramatic paradigm shift in therapeutic strategies for patients with advanced non-small cell lung cancer (NSCLC)
Recent advances in the development of covalent inhibitors of G12C, which take advantage of the cysteine 12 residue to lock the protein in its inactive guanosine diphosphate (GDP) bound conformation, have demonstrated promising signals of activity in clinical trials and are poised to dramatically change the treatment landscape for patients with Kristen rat sarcoma viral oncogene (KRAS) G12C mutations owing to the relative high frequency of this alteration [6,7,8]
A higher frequency of lung metastasis was noted at initial diagnosis in G12C KRAS NSCLC compared to that of non-G12C KRAS NSCLC (38% vs. 21%; p = 0.043)
Summary
The discovery of genetic drivers of lung cancer has led to a dramatic paradigm shift in therapeutic strategies for patients with advanced non-small cell lung cancer (NSCLC). Recent advances in the development of covalent inhibitors of G12C, which take advantage of the cysteine 12 residue to lock the protein in its inactive GDP bound conformation, have demonstrated promising signals of activity in clinical trials and are poised to dramatically change the treatment landscape for patients with KRAS G12C mutations owing to the relative high frequency of this alteration (approximately 13% of lung cancer) [6,7,8]. One direct G12C inhibitor, sotorasib, recently gained approval by the United States Food and Drug Administration for treatment of patients with KRAS G12C-mutated NSCLC who have received at least one prior line of therapy [9]
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