ALK AND ROS1 IN COLORECTAL CANCER

ALK and ROS1 gene rearrangements, which are known to drive subsets of lung cancer, appear to be present in some colorectal cancers as well, according to the results of a study published in Molecular Cancer Research. The findings by Aisner et al suggest that therapies used to target these two oncogenes in lung cancer may have potential applications in treating colorectal cancers that share the same mutations.

Study Details

To determine whether a subset of colorectal tumors may harbor genetic alterations predictive of response to targeted therapies such as crizotinib (Xalkori), the investigators evaluated the frequency of ALK andROS1 gene rearrangements in specimens from patients with metastatic colorectal cancer through the use of fluorescence in situ hybridization. They also attempted to identify fusion partners in rearranged specimens using reverse-transcriptase polymerase chain reaction assays.

Colorectal cancer tissue specimens were obtained from 268 patients enrolled in the randomized phase III MAX study, which was conducted by the Australian Gastrointestinal Trials Group. All patients had histologically confirmed colorectal adenocarcinomas.

Evidence of ROS1 and ALK Gene Fusions

Of the original 268 patient samples included in the tissue microarray, 236 had evaluable fluorescence in situ hybridization results defined as at least 50 tumor cells in two cores. Patterns consistent withROS1 gene rearrangement were noted in two of the tumor samples, and a pattern consistent with ALKgene rearrangement was demonstrated in one case. For both ALK and ROS1, other signal variants were identified. The investigators detected EML4 as the fusion partner for ALK and SLC34A2 as the fusion partner for one of the ROS1-positive cases; the second ROS1-positive case was negative for all known fusion partners.

The researchers also found that these gene alterations in colorectal cancer tended to coexist with other molecular alterations, which contrasts with the predominant findings in non–small cell lung cancer. For example, tumors that were positive for ALK gene rearrangements were also positive forKRAS, and the ROS1 mutations were found to occur alongside BRAF in one sample. Thus, the investigators surmised that more than one alteration may be found in a single specimen and that not all cells within a single tumor are necessarily driven by the same oncogene.

Furthermore, marked intratumoral heterogeneity was displayed for both KRAS mutation and ALK gene rearrangement status, which the investigators called “surprising.” Moreover, the identification of an area of high-grade dysplasia harboring both molecular alterations was unexpected, they noted. However, with respect to ROS1 gene rearrangement, no evidence of intratumoral heterogeneity was identified.

Clinical Implications

Originally found to be associated with anaplastic large cell lymphoma, the rearrangement of the ALKgene has been linked to lung adenocarcinomas. According to the investigators, the importance of this molecular diagnosis is that it may be predictive of benefit from targeted kinase inhibitors. For instance, the ALK inhibitor crizotinib has yielded clinical responses in patients with ALK-positive lung cancers and in those with ROS1 gene rearrangements.

As for colorectal cancer, KRAS mutation analysis has become an accepted molecular approach, and it is used to exclude patients unlikely to benefit from targeted therapy. Although ALK gene fusions in colorectal cancer have been rare, admitted the investigators, their findings suggested a low but detectable rate. Furthermore, this study is reportedly the first to show a similarly low but detectable rate of ROS1 gene rearrangement in colorectal cancer.

“Even though the percentage of colorectal cancer patients with these gene rearrangements is small, the benefit to these few patients could be dramatic,” noted study author Robert C. Doebele, MD, PhD, of the University of Colorado Cancer Center, in a statement. “It’s worth following this line of reasoning to see if colorectal cancer patients will also benefit from drugs proved effective in lung cancer.”

Marileila Varella-Garcia, PhD, of the University of Colorado Cancer Center, is the corresponding author of the article in Molecular Cancer Research.

This study was supported in part by research grants from Abbott Molecular, Boettcher Foundation, and the National Cancer Institute. Among the study authors, Dr. Varella-Garcia and Dara L. Aisner, MD, PhD, are on the speakers bureau of Abbott Molecular.