Clinical and molecular characteristics and treatment outcomes of advanced right-colon, left-colon and rectal cancers: data from 1180 patients in a phase III trial of panitumumab with an extended biomarker panel.

Background

Primary tumor location (PTL) is being adopted by clinicians to guide treatment decisions in advanced colorectal cancer (aCRC). Here we test PTL as a predictive marker for panitumumab efficacy, and examine its relationship with an extended biomarker profile. We also examine rectal tumors as a separate location.

Patients and Methods

aCRC patients from the second-line PICCOLO trial of irinotecan versus irinotecan/panitumumab. PTL was classified as right-PTL, left-PTL or rectal-PTL. PTL was assessed as a predictive biomarker for irinotecan /panitumumab (IrPan) effect in RAS-wild-type (RAS-wt) patients (compared with irinotecan alone), then tested for independence alongside an extended biomarker profile (BRAF, epiregulin/amphiregulin (EREG/AREG) and HER3 mRNA expression).

Results

PTL data was available for 1180 patients (98.5%), of which 558 were RAS-wt. High HER3 expression was independently predictive of panitumumab OS improvement, but PTL and EREG/AREG were not.

IrPan PFS improvement compared with irinotecan was seen in left-PTL (HR=0.61,p=0.002) but not right-PTL (HR=0.98,p=0.90)(interaction p=0.05; RAS/BRAF-wt interaction p=0.10), or in rectal-PTL (HR=0.82,p=0.20)(interaction p=0.14 compared with left-PTL; RAS/BRAF-wt interaction p=0.04).

Patients with right-PTL and high EREG/AREG or HER3 expression, had IrPan PFS improvement (high EREG/AREG HR=0.20, p=0.04; high HER3 HR=0.33, p=0.10) compared with irinotecan. Similar effect was seen for rectal-PTL patients (high EREG/AREG HR=0.44, p=0.03; high HER3 HR=0.34, p=0.05).

Conclusions

RAS-wt patients with left-PTL are more likely to have panitumumab PFS advantage than those with right-PTL or rectal-PTL. However, an extended biomarker panel demonstrated significant heterogeneity in panitumumab PFS effect within a tumor location. AREG/EREG and HER3 mRNA expression identifies patients with right-PTL or rectal-PTL who achieve similar PFS effect with panitumumab as left-colon patients. Testing could provide a more reliable basis for clinical decision-making. Further validation and development of these biomarkers is required to optimise routine patient care.