Clinicopathologic, genomic and protein expression characterization of 356ROS1fusion driven solid tumors cases

Abstract

Based on the approvals of crizotinib and entrectinib by the Food and Drug Administration for the treatment of ROS1 positive nonsmall cell lung cancer (NSCLC), we sought to examine the mutational profile of a variety of solid tumors (excluding sarcomas) with ROS1 fusions that underwent comprehensive genomic profiling. A review of our database was performed to extract all nonsarcoma patients with ROS1 fusions that were discovered by the hybrid capture‐based DNA only sequencing assays. We examined the coalterations representing potentially targetable biomarkers, resistance alterations and other alterations in these cases. In addition, we examined the histologic characteristics and protein expression with immunohistochemistry (IHC). From a series of clinically advanced nonsarcoma solid tumors, 356 unique cases with ROS1 fusions included 275 (77.2%) NSCLC and 81 (22.8%) non‐NSCLC. Ten novel ROS1 fusions were discovered. Importantly, the NSCLC ROS1 fusionpos tumors had a higher PD‐L1 IHC expression positivity when compared to the NSCLC ROS1 fusionneg population (P = .012, Chi‐squared). The frequency of known and likely anti‐ROS1 targeted therapy resistance genomic alterations in NSCLC was 7.3% (20/275) and in non‐NSCLC was 4.9% (4/81). Overall, the coalteration profile of ROS1 fusionpos NSCLC and non‐NSCLC was similar with only three genes altered significantly more frequently in non‐NSCLC vs NSCLC: TERT, PTEN, APC. In our study, we characterized a large cohort of ROS1 fusionpos NSCLC and non‐NSCLC solid tumors and discovered 10 novel ROS1 fusions.

Interstitial Deletions Generating Fusion Genes

“…It contained the FERM domain of the EZR protein joined to the transmembrane and kinase domains of ROS1 (178). Additional studies confirmed the recurrence of EZR-ROS1 in lung cancer and also that the finding was clinically important: the chimeric protein could be the target of kinase inhibitors with very good results (160,161,167,169,(179)(180)(181)(182)(183)(184).…”

“…In 2016, a review of ROS1 fusions in cancer reported 26 genes as having been found to fuse with ROS1 (159) whereas a similar recent review reported the number of ROS1 fusion partners to be 54 (160). In 2020, the year before the review by Drilon et al (160) was published, another 14 novel ROS1 fusion partner genes were added to the list (161)(162)(163)(164)(165), raising the total currently known number of ROS1 chimeras to 68. Regardless of their large number and variability, ROS1 chimeras encode chimeric ROS1 proteins which are constitutively active kinases and which, consequently, may be targets for treatment with kinase inhibitors (13, 160,[166][167][168][169][170][171].…”

“…Recently, three novel in-frame ROS1 chimeric transcripts were detected (161, 164) using high throughput technology, probably corresponding to microdeletions between ROS1 (as the 3'-end partner gene) and 5'-end partner genes (161,164). In the first chimeric transcript, found in a melanoma of the skin, the SFT2 domain containing 1 (SFT2D1) gene was fused to ROS1 (161).…”

“…Recently, three novel in-frame ROS1 chimeric transcripts were detected (161, 164) using high throughput technology, probably corresponding to microdeletions between ROS1 (as the 3'-end partner gene) and 5'-end partner genes (161,164). In the first chimeric transcript, found in a melanoma of the skin, the SFT2 domain containing 1 (SFT2D1) gene was fused to ROS1 (161). In the second transcript, found in a serous carcinoma of the ovary, an invasive ductal breast carcinoma, and in a carcinoma of unknown origin, the protein tyrosine phosphatase receptor type K (PTPRK) gene was fused to ROS1 (161).…”

“…In the first chimeric transcript, found in a melanoma of the skin, the SFT2 domain containing 1 (SFT2D1) gene was fused to ROS1 (161). In the second transcript, found in a serous carcinoma of the ovary, an invasive ductal breast carcinoma, and in a carcinoma of unknown origin, the protein tyrosine phosphatase receptor type K (PTPRK) gene was fused to ROS1 (161). In the third transcript, found in a leiomyosarcoma, the mannosidase alpha class 1A member 1 (MAN1A1) gene was fused with ROS1 (164).…”