IHC May Be Viable Alternative to FISH Screening for Identifying ROS1 Lung Cancers

British researchers have validated an immunohistochemical (IHC) screening tool for more quickly and inexpensively identifying patients who should undergo crizotinib (Xalkori) therapy for lung cancer, than is currently possible with standard fluorescence in situ hybridization (FISH) screening.

Crizotinib targets the proto-oncogene 1 receptor tyrosine kinase (ROS1) gene, rearrangements of which are harbored in up to 2% of lung adenocarcinoma cases. 

Researchers with the Cancer Research UK-Stratified Medicine Project (CRUK-SMP) screened tissue samples from 170 patients for ROS1 translocations using FISH and the Dako EnVision IHC system, using semi-quantitative IHC categories (negative, weakly-positive, moderately-positive, or strongly-positive) and recording positive-cell percentages.

Two patients with adenocarcinoma tested ROS1-rearrangement-positive with IHC, of which only one tested positive using FISH analysis, the team reported. Four additional archived samples that had previously been determined to be positive for ROS1 rearrangements with FISH analyses were added to the study.

In this small cohort validation study, IHC staining was 100% sensitive and 83% specific to ROS1 translocations, the researchers reported in the Journal of Thoracic Oncology.

“Patients with ROS1 gene rearrangements were younger and typically never-smokers, with the tumors all being adenocarcinomas with higher-grade architectural features and focal signet ring morphologic features (two of five),” the study authors reported. “Four patients treated with crizotinib showed a partial response, with three also showing a partial response to pemetrexed. Three of four patients remain alive at 13, 27, and 31 months, respectively.”

Discordant ROS1 test results, such as IHC staining-positive findings but negative FISH results, “may have implications for treatment selection,” the authors wrote. “This phenomenon is described in some patients with abnormalities in relation to the ALK gene in whom a clinical response to crizotinib has still been found.”

The authors wrote that to their knowledge, patients have not yet been treated with ROS1-targeting agents following discordant IHC and FISH test results for ROS1, but anticipated that “it is only a matter of time before this happens as ROS1 IHC assessment becomes more routinely implemented.”

“An alternative option for such patients would be to undertake additional polymerase chain reaction [PCR]-based testing or next-generation sequencing based-testing because, as in the case of ALK fusions, some tumors have been found to show IHC staining and polymerase chain reaction positivity for ROS rearrangements whereas the FISH test results have proven negative.”

The small number of ROS1-positive cases was “the main limitation of the study,” the authors noted .

“However, only one prior publication has more than 10 cases, highlighting the rarity of this gene rearrangement and the need for cost-efficient screening,” they added. “With a high sensitivity rate and relatively high specificity rate, IHC screening to identify patients that might harbor ROS1 gene rearrangements is feasible and would be less expensive and time consuming that FISH testing, which could be reserved for a confirmatory second step.”