Renal Cell Cancer (2006)

An RNA—binding protein independently predicted metastasis and prognosis in renal cell carcinoma, according to a retrospective study published in Lancet Oncology (2006;7:556). The protein, IMP3 (IMP stands for insulin—like growth factor messenger—RNA binding protein), could be used to select patients who would most likely benefit from adjuvant treatment if the results are confirmed in a prospective clinical trial, said lead author Zhong Jiang, MD, Director of Urologic Pathology at the University of Massachusetts Medical School.figure: Zhong Jiang, MD, and colleagues also found that IMP3 indicates aggressive bladder cancer, and they plan to study its role in other cancers, including melanoma and prostate, breast, and colon cancers.While variables such as tumor stage, grade, histology, and necrosis are currently used to assess a patient's risk of metastasis, prognosis can still prove elusive, particularly with early—stage disease. “When people go for cancer surgery and they have clinically—only evidence of localized disease, we know in kidney cancer that somewhere between 10 percent and even up to 50 percent of patients can develop metastatic disease in the future,”said Allan Pantuck, MD, Associate Professor of Urology at the David Geffen School of Medicine at UCLA, who was not involved with the study. “We have limited tools to help us predict who those people are. Any biomarker, any technique that could help refine our ability to predict the patients who are at most risk would be helpful.” Data from Three Institutions Dr. Jiang and colleagues studied samples from 406 patients with primary renal cell carcinoma included in the archives of the University of Massachusetts Medical Center, Massachusetts General Hospital, and City of Hope National Medical Center who had had a radical or partial nephrectomy. Of those patients, 371 with Stage I—III disease and without metastasis during surgery were included in the survival analysis. IMP3 expression was significantly increased in metastatic tumors and in primary tumors that later metastasized, compared with tumors that did not, and it was not expressed in benign kidney tissue adjacent to tumors. Patients whose tumors tested positive for IMP3 were six times more likely to develop metastases after nephrectomy and four times more likely to die than were patients with IMP3—negative tumors, after adjustment for well—known clinical variables, such as tumor stage, size, grade, and subtype. The hazard ratios associated with IMP3 expression were much higher than those associated with other independent risk factors, Dr. Jiang said. Patients with IMP3—positive tumors had a 33% five—year metastasis—free survival rate, compared with 89% for patients with IMP3—negative tumors. Similarly, the five—year overall survival rates were 27% and 82%, respectively. The Case for IMP3 While the identification of IMP3 as a potential biomarker for renal cell cancer was incidental, occurring when the researchers observed a significant difference in the protein's expression between metastatic and primary tumors, several characteristics make it a particularly attractive candidate, Dr. Jiang noted.figure: Allan Pantuck, MD: “Essentially it looks to be quite promising in terms of predicting what patients are at higher risk to develop metastases or die from kidney cancer. The numbers look quite good, but it still is a relatively preliminary study.”For example, IMP3 expression was strongly associated with other indicators of aggressive renal cell cancer, such as high tumor stage and grade and large tumor size, in addition to being independently linked to death and metastasis. Also, immunohistochemical staining of IMP3 is a “simple, inexpensive, and reliable assay,”the team noted, and tumor tissue is usually readily available for staining, as surgery is the primary treatment for localized renal cell cancer. Testing for IMP3 can then be done after nephrectomy at initial diagnosis, the optimal time to consider adjuvant treatment for high—risk patients. That adjuvant treatment, though, still needs to be developed, Dr. Pantuck said. “The limitation currently with kidney cancer is that even if I could predict with 100% accuracy those patients who were going to develop metastatic disease, we don't have any treatments to immediately give them to prevent that from occurring.” He agreed that IMP3 has the potential to identify those patients—“Essentially it looks to be quite promising in terms of predicting what patients are at higher risk to develop metastases or die from kidney cancer. The numbers look quite good, but it still is a relatively preliminary study.” Since the tools currently used to predict prognosis do not require additional laboratory tests, Dr. Pantuck said he'd like to see an analysis of how much additional information testing for IMP3 could yield, which would help in understanding the costs versus the benefits of the test. Next Steps Results from independent data sets and prospective evaluation are needed before IMP3's role in renal cell cancer prognosis can be established, agreed another urologic cancer expert, Brian Rini, MD, of the Cleveland Clinic's Department of Solid Tumor Oncology and Urological Institute. “Whether this particular molecular marker is the most important or of what importance is unclear, but it's an example of the kind of work that's important in better quantifying a patient's risk of recurrence.” In addition to seeking to validate IMP3 through a clinical trial, Dr. Jiang said he plans to study the protein's role in other cancers, including melanoma and prostate, breast, and colon cancers. “Definitely this marker indicates aggressive behavior for bladder cancer, too,”he said, citing research that has not yet been published.figure: Brian Rini, MD: “Whether this particular molecular marker is the most important or of what importance is unclear, but it's an example of the kind of work that's important in better quantifying a patient's risk of recurrence.”Other potential projects for the researchers include studying targets of the protein and any factors that regulate it, which could uncover additional biomarkers, and investigating IMP3's mechanism. Evidence suggests that IMP3 is an oncofetal protein, expressed in fetal tissues early in development but at low or undetectable levels in normal adult tissues. The protein is also expressed in soft tissue sarcoma and in cancer of the pancreas, lung, stomach, and colon, and it has been shown to promote proliferation in leukemia cells. “I think that indicates that IMP3 is crucial for cell proliferation, but we'd like to do something in the kidney tumor, too, to see if this protein is crucial for the cells' proliferation and metastasis,”Dr. Jiang said.