A Phase II Exploratory Study to Identify Biomarkers Predictive of Clinical Response to Regorafenib in Patients with Metastatic Colorectal Cancer Who Have Failed First-Line Therapy.

Single-agent regorafenib is approved in Canada for metastatic colorectal cancer (mCRC) patients who have failed previous lines of therapy. Identifying prognostic biomarkers is key to optimizing therapeutic strategies for these patients. In this clinical study (NCT01949194), we evaluated the safety and efficacy of single-agent regorafenib as a second-line therapy for mCRC patients who received it after failing first-line therapy with an oxaliplatin or irinotecan regimen with or without bevacizumab. Using various omics approaches, we also investigated putative biomarkers of response and resistance to regorafenib in metastatic lesions and blood samples in the same cohort. Overall, the safety profile of regorafenib seemed similar to the CORRECT trial, where regorafenib was administered as ≥ 2 lines of therapy. While the mutational landscape showed typical mutation rates for the top five driver genes (APC, KRAS, BRAF, PIK3CA, and TP53), KRAS mutations were enriched in intrinsically resistant lesions. Additional exploration of genomic-phenotype associations revealed several biomarker candidates linked to unfavorable prognoses in patients with mCRC using various approaches, including pathway analysis, cfDNA profiling, and copy number analysis. However, further research endeavors are necessary to validate the potential utility of these promising genes in understanding patients' responses to regorafenib treatment.

Preparation of saccade sequences and eye programming affect endogenous covert attention.

Endogenous attention can be allocated in parallel to at least two saccade target locations of a planned sequence, but attentional resources are larger in the location of the first than the second saccade. The meridian effect that is observed in endogenous attention can be explained by eye programming, but it is not known how eye-movement preparation and eye programming can together affect endogenous attention during sequential saccades. We used a double-task paradigm to investigate this issue. In two experiments, we confirmed the relation between the preparation of sequential saccades and attentional selection and also showed that eye programming could eliminate deterioration of attentional resources in the second saccade location. The finding of the meridian effect in both the saccadic task and the target discrimination task additionally indicates the important role of eye programming in endogenous attention. The results were discussed in terms of the Premotor Theory of Attention.