Investigating the Potential of Targeted Therapies for Patients With Colorectal Cancer

While targeted therapies have demonstrated potential for patients with metastatic colorectal cancer, researchers have noted that their effect is deterred by a rapid emergence of resistance.

A study from Rona Yaeger, MD, and colleagues published in Clinical Cancer Research sought to determine the connection between genetic mechanisms and intrinsic tumor characteristics and new therapeutic approaches that may eventually enable the prevention of resistance.

To discover the molecular and clinical factors connected to time on treatment (TOT), researchers evaluated the data of 52 patients with paired pretreatment and progression samples who underwent therapy targeting EGFR (n=17), BRAF V600E (n=17), KRAS G12C (n=15), or amplified HER2 (n=3).

Of the patients, 23 reported regression following targeted therapy, 28 reported stable disease, and 1 demonstrated primarily refractory disease.

Dr. Yaeger and colleagues noted that all patients ended treatment due to progression, with no variance in TOT according to oncogenic driver (P=.5). A decreased TOT was found to relate to baseline disease burden (P=.02), presence of hepatic metastases (P=.02), and gene amplification on baseline tissue (P=.03). A shorter TOT was also associated with copy-number changes (P=.008) and increased number of acquired alterations (P=.040).

Patients with baseline MAPK pathway amplifications and acquired gene amplifications demonstrated chromosomal instability (CIN) upon progression. An increased amount of emergent alterations upon resistance and enrichment of mutations involving receptor tyrosine kinases was found in patients with hepatic metastases.

“Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression,” researchers wrote. “Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.”