Additional value of EGFR downstream signaling phosphoprotein expression to KRAS status for response to anti‐EGFR antibodies in colorectal cancer

Abstract

KRAS mutations are a strong predictive marker of resistance to anti-epidermal growth factor receptor (EGFR) antibodies in advanced colorectal cancer (CRC) but only a subset of wild-type (WT) KRAS patients are responders, suggesting the existence of additional markers of resistance to this treatment. The activation of EGFR downstream signaling pathways may be one of these ones. In a series of 42 patients with advanced CRC treated with cetuximab/panitumumab, for whom KRAS status was previously determined, we retrospectively analyzed the intratumor expression of EGFR downstream signaling phosphoproteins of the RAS/MAPK and PI3K/AKT pathways (pERK1/2, pMEK1, pAKT, pP70S6K and pGSK3b) using Bio-Plex V R phosphoprotein array. Association with tumor response, progression-free survival (PFS) and overall survival (OS) was assessed. The expression of all the phosphoproteins was higher in KRAS mutated tumors than in WT tumors. The expression of pP70S6K was lower in responders than in nonresponder patients. In univariate analysis, patients with high pMEK1 or pP70S6K expression had a shorter PFS than those with low expression. Patients with high pP70S6K expression also had a shorter OS. In multivariate analysis, PFS was shorter for patients with high pMEK1 or pP70S6K expression, independently of KRAS status, as OS for patients with high pP70S6K expression. Therefore, WT KRAS patients with high pP70S6K expression had a shorter survival than those with low expression. Our results suggest the importance of EGFR downstream signaling phosphoproteins expression in addition to KRAS status to define the subgroup of patients who will not benefit from anti-EGFR therapy.Recent progress has been made in the treatment of colorectal cancer (CRC) with the introduction of new therapies targeting the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor. Monoclonal antibodies represent one of the most important options for the inhibition of EGFR.

KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer

“…First, we collected individual data on the ORR from 7 studies 6,13,14,18-21 that did not perform a comparison between patients with the KRAS p.G13D mutation and KRAS codon 12 mutations, which significantly increased the statistical power of the analysis. Second, except for 2 abstracts, 16,17 all fulltext studies 6,[13][14][15][18][19][20][21] were of high quality, with an average NOS score of 7. Third, no heterogeneity was observed in any comparison.…”

“…The articles were published between 2005 and 2011. Three studies 6,19,20 were conducted in France, 3 studies 13,18,21 were conducted in Italy, 1 study 14 was conducted in Switzerland, 1 study 17 was conducted in Figure 1. This is a flow chart of study selection for the current analysis.…”

“…Cetuximab was received as first-line treatment in 1 study 17 and as firstline or subsequent treatment in 9 studies. 6,[13][14][15][16][18][19][20][21] Patients received cetuximab plus chemotherapy in 5 studies 14,16,17,19,21 and cetuximab-based treatment (cetuximab monotherapy or cetuximab plus chemotherapy) in the remaining 5 studies. 6,13,15,18,20 Quality-Assessment Results…”

“…Individual data were extracted from 7 studies 6,13,14,[18][19][20][21] that included the available data for ORR but did not perform a comparison between 2 groups of patients.…”

Massively Parallel Tumor Multigene Sequencing to Evaluate Response to Panitumumab in a Randomized Phase III Study of Metastatic Colorectal Cancer

“…In addition to KRAS mutations, multiple other genes are known to be somatically mutated in mCRC and have been assessed as biomarkers of response to anti-EGFR therapy (8)(9)(10)(11)(12)(13). Recent studies have suggested that mutations in BRAF (8,9,13), as well as mutations in PI3KCA and loss of PTEN expression (8,9,(11)(12)(13), may be associated with poor outcome in patients with mCRC treated with agents targeting the EGFR. In a retrospective analysis of tumor samples from patients with mCRC treated with cetuximab plus chemotherapy, mutations in BRAF, NRAS, and PIK3CA exon 20 were associated with low response rates in patients with wild-type KRAS tumors (14).…”