Predicting response to anti-EGFR cancer therapy

Summary

Cetiximab and other anti-EGFR antibodies are effective late-line therapies for colorectal cancer, squamous cell cancers of the head and neck, and non-small cell lung cancer. Response rates are low (10-20%), but these response rates have been shown to be durable and do result in improved survival, particularly when combined with chemotherapeutic agents. The challenge now is to identify those patients who will best respond to these therapies.

Analysis

One of the challenges with biologic therapies is to identify responders prior to the initiation of treatment. Early identification of potential responders might allow for earlier treatment (i.e., prior to disease progression) and further improve survival. Furthermore, identification of non-responders would spare them the unnecessary time and expense of ineffective therapy, freeing those patients up for other treatments or clinical trials. Selection of appropriate patients is a judicious use of health care resources.

Although cetuximab targets EGFR, over-expression of the receptor and increased gene copy number do not correlate with clinical response to treatment. The biology of action is obviously more complex. As has been reported, a cutaneous rash is often used (or sought) as a marker predicting response to therapy. Yet such a clinical marker is imprecise and requires the initiation of therapy.

In colon cancer, KRAS mutation status can be used to select out non-responders to cetuximab. Patients who harbor KRAS mutations have been repeatedly shown to be unlikely to respond to therapy. The converse, however, is not true: those with normal KRAS contain both responders and non-responders. Unfortunately KRAS status is not useful in head and neck cancer patients.

Potentially more powerful are markers that indicate response. Increased expression of the EGFR ligands epiregulin and amphiregulin in pretreatment biopsies of metastatic colorectal cancer correlated with response to cetuximab. (e.g., Khamtabata-Ford, Journal of Clinical Oncology, 2007)

Given the complexity of the biology surrounding the EGFR pathway, it is reasonable to think that predicting response to anti-EGFR therapy will rely on a combination of multiple markers. Yet unraveling this very complexity may result in more precisely tailored treatments and improved responses to therapy. Anti-EGFR therapies and future companion diagnostics which guide their use may be an early step to realizing the potential of personalized medicine in cancer care.