High HER3 Expression in Advanced CRC Related to Anti-EGFR Activity

HER3 messenger RNA expression may serve as a biomarker for patients with RAS wild type colorectal cancer who will benefit from treatment with the anti-EGFR therapy panitumumab, according to the results of a study published in JAMA Oncology.

“We found no evidence for HER3 as a prognostic marker but found HER3 overexpression to be significantly associated with benefit from panitumumab,” wrote Jenny F. Seligmann, PhD, of Leeds Institute of Cancer and Pathology in the United Kingdom, and colleagues.

According to the study, previous research has shown that high EGFR ligand expression was predictive of panitumumab benefit in advanced colorectal cancer. Here, the researchers looked at the role of HER3 tumor RNA expression in samples of advanced colorectal cancer to try to determine if HER3 expression could further refine the RAS wild type population that will benefit from anti-EGFR agents.

The researchers used data taken from the PICCOLO trial, which tested irinotecan therapy with or without panitumumab in patients with KRAS wild type advanced colorectal cancer who had failure with prior fluoropyrimidine treatment. HER3 was assessed as a prognostic marker, then as a predictive biomarker. The primary endpoint was progression-free survival (PFS).

Of the 308 patients enrolled, 209 were wild type for all KRAS/NRAS codons, and this was the primary population for the study. In these patients, HER3 expression was not significantly associated with RAS mutation status. However, it was lower in those patients with BRAF and PIK3CA mutations compared with wild type.

Among RAS wild type patients, increasing HER3 expression was predictive of PFS benefit with irinotecan/panitumumab (hazard ratio [HR], 0.71; 95% CI, 0.61–0.83 per 2-fold increase; P < .001) but not in those treated with irinotecan alone (HR, 0.96; 95% CI, 0.82–1.13; P = .65). There was significant interaction between biomarker and treatment (P = .001). Similarly, HER3 expression was also predictive of overall survival in panitumumab-treated RAS wild type patients (HR, 0.73; 95% CI, 0.64-0.83; P < .001) but not in those treated with irinotecan alone (HR, 0.93; 95% CI, 0.83–1.05; P = .25), again with a significant interaction between biomarker and treatment (P = .004).

The researchers established a cut point for HER3 high and HER3 low expression at the 66th percentile. Using this cut point, there was no PFS benefit from panitumumab in low expressers (median PFS, 3.3 months with irinotecan/panitumumab vs 4.3 months with irinotecan alone; HR, 0.96; 95% CI, 0.67–1.38; P = .84). However, there was a clear benefit for high expressers (HR, 0.33; 95% CI, 0.19–0.58; P < .001).

“Furthermore, in our combined HER3-and-ligands model, patients with high-HER3, high-AREG/EREG tumors achieved marked and significant overall survival benefit with panitumumab (HR, 0.36; 95% CI, 0.18–0.73; P = .004),” the researchers wrote. “These findings are interesting but must be treated with caution, especially given that the HER3 cut point for dichotomization was derived internally from this data set.”