PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients

Abstract

To evaluate whether the epidermal growth factor receptor (EGFR), K-Ras and PTEN, all members of the EGFR signalling pathway, may affect the clinical response in cetuximab-treated metastatic colorectal cancer (mCRC) patients. Twenty-seven cetuximab-treated mCRC patients were evaluated for drug response and investigated for EGFR protein expression and gene status, K-Ras mutational status and PTEN protein expression. Ten patients achieved a partial response (PR) to cetuximab-based therapy. All 27 patients showed EGFR protein overexpression. Epidermal growth factor receptor gene amplification was observed in eight out of 27 (30%) and chromosome 7 marked polysomy in 16 (59%) patients. Partial response was observed in six out of eight patients with EGFR gene amplification, four out of 16 with marked polysomy and none out of three with eusomy ( P <0.05). The K-Ras wild-type sequence was observed in 17 patients, and nine of them experienced a PR. Conversely, K-Ras was mutated in 10 cases, of which one patient experienced a PR ( P <0.05). The PTEN protein was normally expressed in 16 patients, and 10 of them achieved a PR. In contrast, no benefit was documented in 11 patients with loss of PTEN activity ( P <0.001). Patients with EGFR gene amplification or chromosome 7 marked polysomy respond to cetuximab. In addition to K-Ras mutations, we demonstrate for the first time that the loss of PTEN protein expression is associated with nonresponsiveness to cetuximab.

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

“…Cell lines deficient in PTEN expression are more resistant to cetuximab in vitro than those with normal PTEN expression [46]. The loss of PTEN protein expression negatively predicts efficacy of cetuximab therapy in patients with metastatic colorectal cancer [50]. In this study, 63% (10/16) of patients with tumors that showed normal PTEN expression were able to achieve a partial response whereas no response was documented in 11 patients with tumors that lacked PTEN expression [50].…”

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.…”

“…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.…”

“…12 Second, a few patients who have tumors with KRAS mutations occasionally respond to anti-EGFR treatment. 1,13,14 The tumors from those responsive patients predominantly harbored codon 13 mutations, and all codon 13 responders have p.G13D mutation. These findings indicate that the KRAS p.G13D mutation and KRAS codon 12 mutations may have a different effect on cetuximab efficacy.…”