In the current trial, we observed partial responses to the oral EGFR TKI erlotinib in patients with metastatic esophageal cancer with EGFR overexpression. Response was observed in 15% of squamous cancers of the esophagus, and we observed that nearly a third of patients with squamous cancers had protracted stable disease ranging from 8–24 months. No clear conclusion can be made about the impact of EGFR expression, as only 6 patients with EGFR negative tumors were treated on study. No responses were observed in 17 patients with adenocarcinoma, with nearly half of these patients progressing at the time of the first CT scan. EGFR over expression occurred to a lesser degree in adenocarcinoma (70%) compared to squamous cancer (92%). In the limited analysis in 5 patients for mutation of the EGFR, no mutations were observed, including one squamous cancer that achieved a partial response. No correlation of either response or stable disease with skin rash was observed.
How do these results compare with other recent trials of EGFR TKI’s in esophageal cancer? Our results are in close agreement with the study reported by Janmaat (14
). Gefitinib 500 mg daily was given to 36 patients all with prior chemotherapy treatment, including 26 patients with adenocarcinoma and 9 patients with squamous cancer. A response was seen only in squamous cancer, and a higher degree of response or stable disease was seen in females, in squamous cancers, and in patients with higher (3+) EGFR expression. K-ras mutation, recently identified as a potential marker of EGFr therapy resistance (15
), was tested and found in only 2 of 23 patients (9%), both of whom had early progressive disease on therapy. No EGFR mutations were found in 26 patients studied. High EGFR copy number was observed in two patients, one responder and one non responder.
In contrast to our study, Dragovich (16
) observed significant responses in 43 patients with adenocarcinoma of the GE junction treated with erlotinib 150 mg daily. Patients on this trial had no prior treatment for metastatic disease, in contrast to 53% of patients on our study receiving prior chemotherapy for advanced disease. Four responses were seen (9%) and stable disease was seen in 5 patients (12%). However, the median time on study was only 2 months, indicating that the majority of patients had rapid disease progression. These authors do not comment on characteristics of the responding patients. Potential predictive molecular markers of response were assessed, including EGFR mutation (none found) and amplification of EGFR (none found). Positive immunohistochemical staining for EGFR, pAKT, and TGF-alpha was observed in the majority of samples tested and there was no correlation with response. Another positive trial reported by Ferry (17
) evaluated gefitinib 500 mg daily in 26 patients with adenocarcinoma of the esophagus or gastroesophageal junction. Three responses were observed (12%), including one patient without prior therapy, and one patient each with prior adjuvant or prior advanced disease chemotherapy. Most patients, however, also had rapid disease progression (median time 1.9 months). In a separate report (18
), these authors reported the evaluation EGFR mutations in a cohort of 17 patients with adenocarcinoma and identified 2 with mutations (12%); both of these patients were treated with gefitinib and failed to respond. One patient with EGFR amplification treated on study responded to treatment.
Collectively the data for EGFR TKI’s suggest limited single agent activity in esophageal cancer, with most patients experiencing early disease progression. The median survival of 11.2 months for adenocarcinoma patients on our trial, despite rapid progression of disease on erlotinib, indicates a benefit from salvage treatment with further chemotherapy, and our patient survival exceeded reports of the other trials with median survivals of only 4.5–6.7 months. While the data for adenocarcinoma of the distal esophagus and GE junction for EGFR TKI’s appear to be conflicting, the data from our trial and others suggest a consistent signal of activity for EGFr TKI’s in esophageal squamous cancer. Our observation not only of responses but of protracted stable disease extending out 1–2 years supports the study of erolotinib as a potential adjuvant therapy in squamous cancer. Combining erlotinib with chemotherapeutic agents, however, to date has failed to improve outcome compared to chemotherapy alone in non small cell lung cancer (19
). Some investigators are now evaluating alternative dosing and scheduling of these agents with chemotherapy in non small cell lung cancer.
From the trials of TKI’s in esophageal cancer, there also is no clear molecular marker predictive of response to therapy, including K-ras or EGFR mutation, with the possible exception of either amplification of, or increased copy number of, the EGFR gene, which was observed in two responding patients. In our series, tissue study was limited to EGFR expression, and the majority of squamous cell and adenocarcinoma patients were over expressors; the limited number of EGFR negative patients accrued on our trial limits any conclusions about the efficacy of erlotinib in this patient subset. In other series, both K-ras mutation and EGFR mutations were rarely if ever observed in esophageal cancer; it is unlikely, therefore that these markers will have any significant application in this disease. This contrasts with the important role of K-ras mutation in identifying resistance to EGFR targeted agents in colorectal and non small cell lung cancers, and EGFR mutation in determining benefit for treatment with EGFR TKI’s in non small cell lung cancer. More promise in targeting the EGFR pathway in esophageal cancer may come from monoclonal antibodies blocking the binding of ligands to the receptor. Encouraging response rates and time to tumor progression reported for phase II trials in esophageal cancer combining antibodies such as cetuximab with combination chemotherapy (21