ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non–Small Cell Lung Cancer

Abstract

Introduction Chromosomal rearrangements involving the ROS proto-oncogene 1 receptor tyrosine kinase gene (ROS1) define a distinct molecular subset of non-small cell lung cancer (NSCLC) with sensitivity to ROS1 inhibitors. Recent reports have suggested a significant overlap between ROS1 fusions and other oncogenic driver alterations, including mutations in epidermal growth factor receptor (EGFR) and KRAS proto-oncogene (KRAS). Methods We identified patients at our institution with ROS1-rearranged NSCLC who had undergone testing for genetic alterations in additional oncogenes, including EGFR, KRAS, and anaplastic lymphoma kinase (ALK). Clinicopathologic features and genetic testing results were reviewed. We also examined a separate database of ROS1-rearranged NSCLCs identified through a commercial FoundationOne assay. Results Among 62 patients with ROS1-rearranged NSCLC evaluated at our institution, none harbored concurrent ALK fusions (0%) or EGFR activating mutations (0%). KRAS mutations were detected in two cases (3.2%), one of which harbored a concurrent non-canonical KRAS I24N mutation of unknown biological significance. In a separate ROS1 FISH-positive case, targeted sequencing failed to confirm a ROS1 fusion, but instead identified a KRAS G13D mutation. No concurrent mutations in BRAF, ERBB2, PIK3CA, AKT1, or MAP2K1 were detected. Analysis of an independent dataset of 166 ROS1-rearranged NSCLCs identified by FoundationOne demonstrated rare cases with co-occurring driver mutations in EGFR (1/166) and KRAS (3/166), and no cases with co-occurring ROS1 and ALK rearrangements. Conclusions ROS1 rearrangements rarely overlap with alterations in EGFR, KRAS, ALK, or other targetable oncogenes in NSCLC.

Recent Advances in Targeting ROS1 in Lung Cancer

“…However, conflicting findings have subsequently been reported, with some later studies suggesting a co-occurrence of ROS1 rearrangements and mutations in EGFR (28, 44), KRAS (44), or BRAF (44). In the most recent and largest series to date, a total of 220 cases of ROS1 -rearranged NSCLCs were examined (45). Amongst these tumors, ROS1 fusions did not overlap with ALK fusions, and rarely co-occurred with oncogenic EGFR mutations (0.5%; 1/220) or KRAS mutations (1.8%; 4/220) (45).…”

“…In the most recent and largest series to date, a total of 220 cases of ROS1 -rearranged NSCLCs were examined (45). Amongst these tumors, ROS1 fusions did not overlap with ALK fusions, and rarely co-occurred with oncogenic EGFR mutations (0.5%; 1/220) or KRAS mutations (1.8%; 4/220) (45). Therefore, ROS1 rearrangements generally define a unique molecular subset of NSCLC.…”

“…While FISH can be performed on a small amount of formalin-fixed, paraffin-embedded (FFPE) tissue, the assay can be challenging to interpret, particularly for fusions arising from small intrachromosomal deletion events. Therefore, false-negative and false-positive FISH results can occur (45). …”

“…IHC results may also be falsely positive due to aneuploidy leading to aberrant expression. Thus, albeit useful as a screening tool, ROS1 IHC by itself may be insufficient to diagnose ROS1 -rearranged NSCLC, and testing typically requires confirmation using an orthogonal method such as FISH or NGS (45). …”

Targeting ROS1 rearrangements in non-small cell lung cancer with crizotinib and other kinase inhibitors

“…Although, ROS1 rearrangements and ALK rearrangements are mutually exclusive (3,5,17), they share similar clinicopathological features (3,6). Both are generally seen in younger patients with light or never smoking history and have a preponderance for adenocarcinoma histology.…”