The MSKCC in New York has just published a genetic analysis of prostate cancer which will help in identifying which prostate cancers need aggressive treatment and which do not. This is an achievement which I have been discussing for the past several years. The article is in the current Cancer Cell.
An excellent analysis is presented in Eureka as follows:
"Genomic studies in other cancer types have resulted in new drug targets and strategies to classify patients into clinically meaningful subgroups that improve treatment decisions," said senior study author Charles Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSKCC and a HHMI investigator. "This first -ever database of its type brings us one step closer to achieving that goal in prostate cancer."
The study, published early online on June 24 in the journal Cancer Cell, provides a previously unavailable genomic analysis whose scope and size offers new insight leading to more effective diagnostic tests as well as future treatment options for prostate cancer patients.
"We have used all of our expertise and resources to complete a large-scale study of the changes in the genomes of patients' prostate cancers," says Dr. Sawyers, who explains that prostate tumor cells are very difficult to work with despite the fact that prostate cancer is the most common cancer in men. Consequently, there have been fewer genomic studies in prostate cancer compared to other tumor types such as lung cancer. "The ability to collect and analyze these tumor samples is a testament to the collaboration and expertise across many disciplines."
The MSKCC team, composed of members of the Human Oncology and Pathogenesis Program, urology, medicine and genitourinary oncology services, pathology, computational biology, and statistics departments, used an integrated, comprehensive approach to analyze 218 primary and metastatic samples and 12 cell lines. All samples were procured from patients treated by radical prostatectomy at MSKCC. The analysis revealed a much higher frequency of alterations in the androgen receptor pathway than previously suspected. Also, the pattern of DNA copy number alterations identified defined subsets of low-and high-risk disease beyond what is revealed by Gleason score.
"One of the holy grails of prostate cancer is to identify which tumors need to be aggressively treated and which don't," said Dr. Sawyers. "Ultimately, what we have learned could lead to the creation of a genetic-based test to determine which prostate cancers might become more virulent and require aggressive treatment and which tumors may not." According to Dr. Sawyers, "This data clarifies the role of several known cancer pathways and provides important clues into others. We have gained insight into the importance of androgen receptor status—and why some men respond to hormone therapy and others don't."
The MSKCC portal for the gene analysis is located at the following. This is a major step forward. The challenge will be in getting the clinical physicians to test this as well as getting the CMS to accept it as well. It will result in great reductions in morbidity and mortality.The NCI also has an excellent summary as well
Researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) have completed the largest genomic analysis of prostate tumors to date. The results, based on clinical and genomic information collected from 218 patients, provide an overview of the common genetic changes in the disease and point to new directions for research, including a way to potentially differentiate aggressive tumors from those that are not life threatening. The researchers have made the data available to the community through a public Web site, and a summary of the results appeared online last week in Cancer Cell.
“We now have a much better picture of the common genetic alterations in prostate cancer,” said lead investigator Dr. Charles Sawyers. Although more samples need to be analyzed, he continued, the results could provide a roadmap for designing future clinical trials in this disease. “When it comes to developing and testing targeted cancer drugs, you need to be able to subclassify patients, and you can’t do this intelligently until you know what the alterations are.”
The authors continue:The analysis also revealed a striking association between changes in DNA copy number and the risk of recurrence after surgery, and this association could not be explained entirely by Gleason score. “This was one of the most exciting findings from the study,” said Dr. Scardino. “It offers the possibility of a biomarker that could be used to characterize the aggressiveness of prostate cancer, which is something we greatly need.”
Doctors currently do not have a way to distinguish between prostate cancers that require aggressive treatment and those that will cause no harm if left alone. Consequently, many men receive treatment unnecessarily. Genomic tests can provide prognostic information in breast cancer, for example, but none yet exists in this disease.
The new findings, if confirmed, represent a prototype for developing these kinds of prognostic tests for prostate cancer, said Dr. Jonathan Simons, CEO and president of the Prostate Cancer Foundation. “This would change how doctors talk to patients about the disease and the need for adjuvant therapy or not, which is why this finding is so exciting,” he added.
Dr. Scardino runs the Specialized Program of Research Excellence (SPORE) in prostate cancer at MSKCC, and his group has launched follow-up studies. The current work was done using frozen tumor specimens collected during prostatectomies. The researchers will now see whether copy-number changes are informative using paraffin-embedded tissues. If the answer is yes, they will test cells obtained from a needle biopsy.
The genome analysis also revealed that some patients whose tumors include a fusion of the genes TMPRSS2 and ERG are also missing part of chromosome 3. This fusion gene occurs in about half of all prostate cancers, and researchers have suspected that other genes also play a role in these cases.
“This deletion on chromosome 3 appears to be very strongly associated with the fusion,” said Dr. Sawyers. “The next steps are to see which genes in the region that is deleted are involved in the disease. We have a clear path forward.”
The TMPRSS2-ERG fusion was discovered in 2005 by University of Michigan researchers supported by NCI’s Early Detection Research Network. At the time, fusions were thought to be limited to cancers of the blood, but it is now known that these alterations are present in common cancers as well. About two dozen have been identified in prostate cancer.
I have tested it for PTEN and the results are:
- Pathway: Prostate cancer pathway (280 genes)
- Total number of input genes: 1
- Case Set: Prostate All: All prostate cancer samples (230 samples)
- Total number of cases selected: 230
Mutation Details:
PTEN: [Mutation Rate: 0.87%]
| Case ID | Mutation Status | Mutation Type | Validation Status | Sequencing Center | Amino Acid Change | Predicted Functional Impact** | Alignment | Structure | |
|---|---|---|---|---|---|---|---|---|---|
| LNCaP | No matched normal | frameshift_del | Valid | MSKCC | K6fs | | |||
| LNM971 | No matched normal | frameshift_del | Valid | MSKCC | K6fs | |
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