National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 20, 2009 • Volume 6 / Number 20

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Cancer Research Highlights

Minimally Invasive Prostate Cancer Surgery Shows Benefits, Shortcomings

Minimally invasive surgeries to remove the prostate in men with prostate cancer, including procedures performed with a surgical robot, are superior to standard “open” prostate removal surgeries by some measures but fall short on several other important outcomes, including risk of incontinence and erectile dysfunction. The study was published October 14 in the Journal of the American Medical Association.

From 2003 to 2007, the number of minimally invasive radical prostatectomy (MIRP) procedures increased from 1 percent to more than 40 percent of all prostatectomies, an increase that the researchers believe has been largely driven by the rapid proliferation of robotic surgery. Currently, robotic prostatectomy accounts for 70 percent of all MIRP procedures, said the study’s lead author Dr. Jim C. Hu of Brigham and Women’s Hospital in Boston.

The study was not a randomized clinical trial. Rather, the researchers used billing and diagnostic data from NCI’s SEER Medicare database, identifying 1,938 men who underwent MIRP and 6,899 men who underwent open surgery. After accounting for differences in physician and patient characteristics in men receiving MIRP versus open procedures, the researchers found that men who underwent MIRP had shorter hospital stays (2 days versus 3 days), far fewer blood transfusions, and a lower risk of respiratory and other surgical complications. But they also had more than twice the risk of genitourinary complications, a 30 percent increased risk of incontinence, and a 40 percent increased risk of erectile dysfunction 18 months after the procedure.

The need for additional cancer therapies was roughly equivalent between the groups, Dr. Hu explained, suggesting that neither procedure is superior in terms of cancer control. The study also revealed several disparities related to MIRP, including less frequent use by African American and Hispanic men.

Given the available data on standard open surgery compared to MIRP, said Dr. Hu, open surgery should remain the “gold standard” for men who opt for surgery to treat localized prostate cancer.

Liver Cancer Study Finds Potential Marker for Treatment

A small RNA molecule in liver tumors could be a biological marker for assessing a patient’s prognosis and might also be used to select candidates for treatment with the biological therapy interferon, according to a study in the October 8 New England Journal of Medicine. The molecule is one of approximately 1,000 microRNAs in the human genome. Each microRNA is thought to regulate the activitiy of several hundred genes.

The researchers found that patients whose tumors had reduced levels of a microRNA called miR-26 tended to have a poor prognosis but were more likely to benefit from interferon than other patients. MicroRNAs are thought to regulate the activity of hundreds of genes, and some have been linked to cancer.

“We think this microRNA could be quite useful for helping clinicians determine how aggressive a tumor will be and also to identify patients who will benefit from interferon to prevent relapse,” said lead investigator Dr. Xin Wei Wang, head of NCI’s Liver Carcinogenesis Section. The study was done with investigators at Fudan University, Shanghai; the University of Hong Kong in China; and Ohio State University.

The study’s original aim was to see whether differences in microRNA levels, or expression, could help explain the different outcomes seen in males and females with a form of liver cancer called hepatocellular carcinoma. The analysis found clear differences in the expression of miR-26 between males and females and also between patients with more or less aggressive tumors.

Overall, both male and female patients with low levels of miR-26 did not live as long as patients with higher levels of the microRNA. The difference in survival was about 4 years between the groups. But while patients with low levels of miR-26 had a poor prognosis, these patients were more likely to benefit from interferon as an adjuvant therapy. This group survived at least 7.7 years longer than patients with low tumor levels of miR-26 who did not receive interferon therapy. Patients with normal levels of miR-26 in their tumors did not benefit from interferon.

The association between miR-26 and prognosis or treatment response does not imply cause and effect, but a recent study in mice provided evidence that miR-26 may act as a tumor suppressor, noted Dr. Wang. Future studies will assess the microRNA in additional populations and explore its potential use as a therapeutic target in the disease, he added.

Gene Mutation Linked to Aggressive Childhood Cancer

Rhabdomyosarcoma (RMS), an aggressive childhood cancer caused by mutations in genes that control the development of skeletal muscle tissue, has often spread (metastasized) by the time it is diagnosed in children, leading to poor survival rates. Researchers have now identified mutations in the fibroblast growth factor receptor 4 (FGFR4) gene that are associated with metastasis and poor outcomes in patients with RMS. The FGFR4 protein belongs to a family of proteins known as receptor tyrosine kinases, which are involved in cellular signaling processes that help regulate cell growth, maturation, and survival. The gene, the researchers believe, may provide a target for therapy. The results appeared online October 5 in the Journal of Clinical Investigation.

Researchers from NCI; the National Heart, Lung, and Blood Institute; The Children’s Hospital at Westmead, Australia; and the Nationwide Children’s Hospital in Columbus, OH, were involved in the project. Their previous research, and that of others, has shown that FGFR4 is highly expressed in RMS. Because the gene is active during muscle development and not in mature muscle, the team investigated whether expression of FGFR4 might contribute to RMS. Using mouse models, the researchers showed that the growth and spread of human RMS cells to the lungs was inhibited by suppressing FGFR4 expression. After sequencing the FGFR4 gene in human RMS tumor samples, they found that more than 7 percent of the tumors had mutations in the tyrosine kinase portion of the protein. Some of these mutations caused the protein to become overly active. Mutations that increase receptor tyrosine kinase activity have been found in other cancers, but the researchers note that this is the first time that mutations in a receptor tyrosine kinase have been found in RMS.

With a series of lab and animal studies, they confirmed that two of the FGFR4 mutations caused increased tumor growth, reduced RMS cell death, and enhanced the ability of RMS cells to metastasize.

The mutations, which were found in both types of RMS, alveolar and embryonal, appeared to act via the STAT3 pathway. Mouse RMS cells harboring these mutations were also more sensitive to treatment with drugs that inhibit FGFR4, which has “direct implications for personalized therapy and for patients with metastatic RMS, for whom long-term prognosis remains poor,” said lead author Dr. Javed Khan of NCI’s Pediatric Oncology Branch.

Primary and Metastatic Tumors from Same Patient Sequenced

Using next-generation DNA sequencing technology, researchers in Canada have compared the genetic changes in two breast tumors collected from the same patient 9 years apart. The secondary tumor (metastasis) included genetic changes not present in the tumor sample collected at diagnosis, suggesting that “significant evolution can occur with disease progression,” the researchers reported in the October 8 Nature.

“The cancer evolved significantly in terms of its genome content, but moreover, the primary cancer was heterogeneous from the start,” said lead investigator Dr. Samuel Aparicio of the BC Cancer Research Center in Vancouver. “We’ve known that cancer cells must be heterogeneous for many decades, but now we’re seeing it up close.”

The researchers found 32 genetic mutations in the secondary tumor, 19 of which were not in the primary tumor. (It was not known whether these 19 mutations were a consequence of radiation therapy or of innate tumor progression.) Knowing which alterations are present in a primary tumor prior to therapy and to metastasis could make it easier to uncover the genetic factors responsible for the initial cancer, the researchers said.

When asked about the findings, Dr. Joan Massagué of Memorial Sloan-Kettering Cancer Center said that because cancers essentially happen by accident and evolve in the body any way they can, one would expect to see many different paths of evolution. Studies like the current one show how tumor evolution “may happen in one situation or another,” but he cautioned against drawing broader conclusions from any particular report.

Dr. Massagué made his comments at a recent press briefing on metastasis hosted by the American Association for Cancer Research.

Prostate Tumor Microenvironment Found to Change Immune Cell's Function

Much remains unknown about the process tumors undergo to evade attack by the immune system. Now a team including researchers from NCI’s Center for Cancer Research and the Fred Hutchinson Cancer Research Center has shown that tumor-specific immune cells that have migrated to the mouse prostate tumor microenvironment can switch from their normal antitumor activity to an immune suppressor function. Their report appeared in the October 15 Journal of Immunology.

The researchers found that, once within the microenvironment of mouse prostate tumors, tumor-specific CD8+ T cells actually began to block the normal immune response: a call for nonspecific T cells to multiply and attack the tumor.

This immune-suppressive activity appeared to be caused, in part, by substances secreted by the CD8+ T cells in the tumor microenvironment. One of these substances, TGF-β, is a protein that controls cell proliferation and differentiation and plays a role in cancer and other diseases. When the researchers used an antibody to block TGF-β, the CD8+ cells were prevented from switching to a suppressor role.

While it’s not clear whether TGF-β is required for this process, the researchers did note that CD8+ T cells only suppressed other immune cells after they had infiltrated the tumor microenvironment. In contrast, CD8+ T cells isolated from elsewhere (in this case from the lymph nodes of the same mice) were unable to suppress the growth of nonspecific T cells. The research team also found that they could disrupt suppressive immune signaling within the tumor microenvironment by introducing CD4+ T cells into the region. When CD4+ T cells were added, CD8+ T cells isolated from the prostate tumors no longer suppressed the proliferation of other T cells, and they produced less TGF-β.

With these findings, the authors concluded that “new approaches to block these pathways will enhance our ability to generate more sustained and effective antitumor T cell responses.”

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