SAN FRANCISCO—Colorectal cancers that do not express epidermal growth factor receptor (EGFR) may still have overactivation of the EGFR signaling pathway, new data show. In addition, activation of the signaling pathway in the primary tumor is not a reliable indicator of its activation in metastases. "Although many treatment options targeting EGFR are being explored in solid tumors, and in some cases have reached clinical practice, we are still unable to identify molecular or clinical markers reliable and predictive for response or resistance to such a treatment strategy, and, therefore, we are unable to select the appropriate treatment for the individual patient," lead author Mario Scartozzi, MD, said at the 2006 Gastrointestinal Cancers Symposium (abstract 223).
Dr. Scartozzi and his colleagues immunohistochemically measured the expression of the activated (phosphorylated) forms of two of the main effectors of the EGFR signaling pathway—Akt and MAPK—in primary colorectal cancers and in their corresponding metastases. The EGFR status of the primaries and metastases was already known. The study included 98 patients who underwent resection of their primary tumor and at least one metastasis. The primary tumor was in the colon in 75% of patients and was an adenocarcinoma in 94%.
Overall, 52% of primary tumors were positive for EGFR, 74% were positive for Akt, and 70% were positive for MAPK, said Dr. Scartozzi, an oncologist at the Azienda Ospedaliera Ospedali Riuniti, Ancona, Italy. "More or less the same proportions of patients had positivity for EGFR, Akt, and MAPK in liver metastases, whereas the proportion of positivity for these molecular markers is different in lungs, in brain, and in the only bone metastasis, probably because of the small sample size analyzed," he noted.
The majority of the EGFR-negative primary tumors were nonetheless positive for Akt (75%) and positive for MAPK (75%). Similarly, the majority of the EGFR-negative metastases were still positive for Akt (73%) and for MAPK (64%). These findings suggest that even when EGFR expression is absent, its signaling pathway may still be overactivated, Dr. Scartozzi commented.
In a final analysis, the investigators compared the Akt and MAPK status of the primaries with that of the metastases and found a substantial rate of discordance. Specifically, the Akt status was positive in the primary but negative in the metastasis in 16% of cases and negative in the primary but positive in the metastasis in 13% of cases. Similarly, the MAPK status was positive in the primary but negative in the metastasis in 13% of cases, and negative in the primary but positive in the metastasis in 12% of cases.
"Taken together, we can say that in almost 30% of the patients, there is a shift, a change, in Akt and MAPK among primary tumor and corresponding metastatic sites," Dr. Scartozzi said.Implications for Treatment
Overall, the study's results have implications for selecting treatment and predicting the response to biological agents targeting EGFR in patients with colorectal cancer, he noted. "The EGFR downstream signaling pathway can be overactivated even in the absence of EGFR expression in a considerable proportion of patients. In these cases, we can postulate that the use of a treatment strategy including tyrosine kinase inhibitors that can interfere with the EGFR downstream pathway could be more appealing," Dr. Scartozzi said. As for the discordance between primaries and metastases in Akt and MAPK status, he commented: "Since in our practice, we treat metastatic disease with anti-EGFR treatment options, we should conclude that, in metastases, only the EGFR downstream signaling pathway status would be relevant for predicting a response or activity."
