NEW YORK (GenomeWeb) – HER3 expression levels can distinguish colorectal cancer patients with wild-type RAS tumors who will respond to anti-EGFR therapy, according to a new study.
While RAS testing can identify colorectal cancer patients who won't respond to treatment with an anti-EGFR therapy like panitumumab, it doesn't necessarily identify patients who will benefit from such treatment.
Using samples and data from the PICCOLO trial, researchers from the US and the UK examined whether levels of HER3 mRNA could predict which patients would do well on the topoisomerase inhibitor irinotecan in combination with panitumumab, as compared to irinotecan alone. As they reported in JAMA Oncology today, the researchers found colorectal cancer patients with high HER3 mRNA levels benefited from the addition of panitumumab, while those with low levels did not.
"HER3 appears to be a helpful test — in about half the patients who might otherwise receive panitumumab, it shows that the drug would be ineffective or even harmful, and these patients could instead be offered another treatment option," first author Jenny Seligmann, from the University of Leeds, said in a statement.
The randomized, multi-center PICCOLO trial sought to determine whether adding panitumumab to irinotecan treatment would help patients with advanced colorectal cancer and wild-type KRAS. The trial results, reported in 2013, indicated that it did not.
But in the new study, the researchers retrospectively examined whether HER3 expression analysis could separate out patients who did benefit from the added therapy. They extracted RNA from tumor samples from 331 patients from the trial that had been stored as FFPE-fixed tissue sections. Using RT-PCR, they were able to gauge HER3 mRNA levels in 308 of the samples. Of these, 208 had wild-type RAS.
Broadly, the researchers found that higher HER3 expression was weakly prognostic for overall survival, though not progression-free survival.
But for patients with wild-type RAS, increasing levels of HER3 expression was associated with prolonged overall survival and progression free-survival on combined panitumumab and irinotecan treatment, but not irinotecan alone.
Seligmann and her colleagues also split the patients into two groups. Patients expressing HER3 below the 66th percentile were dubbed low expressers, while those above that cut-off were considered high HER3 expressers. When sliced this way, low expressers showed no benefit in progression-free survival when given panitumumab in conjunction with irinotecan, while high expressers did.
In particular, patients with high HER3 levels experienced an average four months longer stabilization of their disease and overall survival when also given panitumumab. High expressers also had longer overall survival when given panitumumab.
The researchers had previously found that high levels of the EGFR ligands epiregulin (EREG) and amphiregulin (AREG) could also predict response to panitumumab treatment in patients with wild-type RAS. Combining the markers together could refine patient classification, the researchers have now reported.
Patients with high HER3 and high EREG and AREG levels responded the best to added panitumumab treatment, while patients with low levels of those markers showed no benefit to the added treatment. Patients with mixed HER3 and EREG and AREG levels had an intermediate response to treatment.
"And if we combine both indicators — HER3 and ligands — we can identify the 20 percent of patients for whom panitumumab is the most effective in prolonging cancer control, making it a compelling treatment choice for them," Seligmann said.
She and her colleagues cautioned, however, that validation of the findings and refinement of the cut-off value is needed.