Circulating CD133: A Promising Biomarker, but What Are We Measuring?

Effective biomarkers should predict outcome in a way that has significant impact on treatment recommendations; however, in the treatment of malignancies, such biomarkers have proven elusive. This is particularly true for biomarkers predicting outcome after hepatic resection in resectable metastatic colorectal cancer. While many clinical scoring systems that use pathologic and clinical characteristics may be used to stratify patients into groups with different survival rates, it is rare that these systems are able to identify subgroups with such poor survival that we probably should not be operating on them. At our institution, the clinical risk score (CRS) has been used for many years and is a reasonably good predictor of outcome. Unfortunately, a high CRS does not preclude the possibility of long-term survival or cure and in reality does not greatly affect treatment recommendations. While the degree of differential survival predicted by the CRS may be useful for devising neoadjuvant chemotherapy strategies, in reality, patients with resectable hepatic metastases are often exposed to extensive chemotherapy before and after surgery, regardless of their risk status. Furthermore, neoadjuvant treatment consisting of modern chemotherapy, especially in ‘‘high-risk’’ patients, has not been shown to be an effective strategy since most respond, very few progress, and there are no differences in survival rates. To make things worse, there are numerous CRS systems and they have not universally proven to be reliable predictors of outcome across institutions, further limiting their utility. Even the paradigm of excluding patients with extrahepatic disease from resection has been recently challenged, since a well-selected subset of these patients experience longterm survival following resection. By contrast, some very effective predictors of outcome do exist. For example, patients with gallbladder cancer and jaundice are rarely resectable, and in our experience, all patients die of their disease within 2 years—a very strong argument against resection indeed. A second example is tumor k-ras mutation status and the use of cetuximab in the treatment of metastatic colorectal cancer. A recent prospective trial demonstrated that patients with mutated k-ras derive no benefit from this chemotherapy; we can therefore spare these patients from what we know will be a completely ineffective therapy. In this edition of the Annals of Surgical Oncology, Pierluigi et al. retrospectively evaluated prospectively collected preoperative peripheral blood for circulating biomarkers in patients undergoing complete resection of metastatic colorectal cancer to the liver. Seven genes were analyzed, chosen for their known expression on epithelial and/or malignant cells and their role in malignancy. Ultimately, after controlling for clinical factors with the CRS in a multivariable model, the expression of CD133 was determined to be the only independent predictor of survival. Perhaps most important, patients with high CD133 expression did very poorly—so poorly, in fact, that if the results were validated, one would have to consider alternative therapies in this patient group. With a median follow-up time of 36 months (for the whole cohort), there were no 4-year survivors in the group of patients with high CD133 expression in the peripheral blood. Simply put, expression of CD133 in the peripheral blood is a very promising biomarker for patients with resectable hepatic metastases. Of course, these data require close scrutiny. There are some interesting aspects to this study. First, in an era of effective chemotherapy, the patients included in this study were exposed to very little. No patient received adjuvant chemotherapy and less than one-half received preoperative therapy. Second, only 44% of patients had a preoperative Society of Surgical Oncology 2011