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Lost PTEN expression linked to EGFR inhibitor resistance in colorectal metastases

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The loss of PTEN expression in colorectal metastases may predict resistance to treatment with cetuximab plus irinotecan, according to data from a retrospective study. Taken together the use of PTEN immunohistochemistry and KRAS mutational analyses may help identify patients with metastatic colorectal cancer who have a greater chance of benefiting from EGFR inhibitors.

Researchers tested 102 patients with irinotecan-refractory metastatic colorectal cancer for PTEN immunoreactivity, pAKT immunohistochemistry and KRAS mutations; patients had been treated with cetuximab (Erbitux, Imclone) plus irinotecan. The researchers analyzed primary tumors and metastases and examined the association among immunohistochemistry, mutational results and treatment outcomes.

Fifty-eight percent of primary tumors were PTEN positive and 40% were pAKT-positive. Concordance levels between primary tumors and metastases and PTEN was 60%; it was 68% for pAKT and 95% for KRAS. PTEN status did not predict response or PFS on primary tumors; pAKT status did not predict response or PFS on primary tumors or metastases.

Thirty-six percent of patients with PTEN-positive tumors responded on metastases compared with 5% of PTEN-negative tumors (P=.007). Patients with PTEN-positive tumors had increased median PFS (4.7 months vs. 3.3 months) compared with patients with PTEN-negative metastases (HR=0.49; P=.005). Compared with other patients, those with PTEN-positive metastases and KRAS wild-type had longer PFS (3.8 months vs. 5.5 months; HR=0.42; P=.001).

“It is urgent to plan adequately dimensioned trials to confirm and to prospectively validate the integrated analyses of EGFR signaling pathways, eventually combined with other promising predictive factors (ie, EGFR polymorphisms and EGFR ligand expression) as useful tools to select patients undergoing cetuximab-containing treatments,” the researchers wrote.

Loupakis F. J Clin Oncol. 2009;doi: 10.1200/JCO.2008.20.2796