1. Samson, Kurt

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BOSTON-Three new prostate cancer subtypes have been independently identified that correlate with distant metastasis-free survival (DMFS) in the largest genome study of its kind to date.

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If the findings are confirmed, the new subtypes would be the first-ever biomarkers that clinicians could use to help predict how individual prostate cancer patients will respond to radiotherapy, according to a presentation at the 58th Annual Meeting of the American Society for Radiation Oncology.


Daniel E. Spratt, MD, lead author of the study, and Chief of the Genitourinary Radiotherapy Program at the University of Michigan in Ann Arbor, said the findings could be used to both diagnose and determine the best treatment course for individual patients, a major step toward personalized prostate cancer treatment (Radiat Oncol 2016;96;2 Supplement:S3-S4).


The researchers used high-throughput analysis of RNA expression patterns in 4,236 samples from nine groups of primary prostate cancer patients treated with radical prostatectomy, including two prospective cohorts.


A profile of 100 distinct genes characterized the three subtypes. These were associated with androgen receptor activity, expression of the ERG oncogene, as well as other known drivers of tumor growth and progression, including clusters of genes known to regulate protein degradation, RNA processing, cell death, the cell cycle, adenosine triphosphate synthesis, and a large cluster of genes relating to protein localization.


No association was found between the subtypes and mutations or genetic rearrangements.


Study Findings

The investigators, from a number of research institutions, reported DMFS rates at 10 years were significantly different between the subtype groups.


In subgroup A, DMFS was 57.1 percent, 64.4 percent for subtype B, and 73.6 percent for subtype C. Their analysis also indicated that subtypes B and C shared a significant correlation with response to post-operative radiation therapy (RT).


"We were surprised to find that prostate cancer subtyped into only three very distinct subtypes and that subtype A had the most favorable prognosis," said Spratt. "The three clusters were highly reproducible across all cohorts. For clinicians, it is important to know what these subtypes mean for patients. We knew that primary prostate cancer was a relatively quiet tumor genomically, but similar cancers that are endocrine-driven, like breast cancer, have been shown to be able to be clustered into a finite number of subtypes."


Prostate tumors that appear similar under a microscope can behave very differently from a clinical standpoint, Spratt noted. "One promise of genomic analyses is to elucidate subtypes of cancer based on the genetics of the tumor rather than merely how they look or what size they are."


The researchers also validated the subtypes across six additional retrospective cohorts representing a variety of RNA sequencing platforms and tissue storage methods, and two prospective cohorts totaling 2,610 patients.


"We have discovered and independently validated a highly stable 100-gene intrinsic molecular profile of prostate cancer that is both prognostic and predictive for radiation therapy," said Spratt.


"We believe that these subtypes reflect truly distinctive underlying biology and that this work represents a significant advance in our understanding of prostate cancer biology," he continued. "Moreover, our findings identify numerous genes and enriched biologically active pathways in prostate cancer that have been underappreciated to date but may be potential targets to improve cure rates in this disease by developing new targeted therapies."


Spratt noted that current prostate cancer assessment relies on "imperfect tools," such as the digital rectal exam, biopsy, and PSA testing that do not give specific information about disease biology, recurrence risk, or whether a patient will benefit from a specific therapy. According to Spratt, clinical trials of the subtypes to stratify patients will be the next step.


Fortunately, genomic tests currently exist that can be used to screen for the subtypes once they have been incorporated in such screening tools, and the researchers are already working with gene testing companies to include the subtypes in tests, Spratt explained.


Practice Implications

Session moderator Colleen Lawton, MD, Professor and Vice-Chair of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, said the findings could one day have broad implications for prostate cancer patients and research, although for clinical purposes the findings "are not yet ready for prime time."


"Rough and imperfect," is how she characterized current prostate cancer screening techniques. "This is exactly the type of research that we truly need and I can't wait to see how we can incorporate this kind of information into the mainstream and into all of our RTOG [Radiation Therapy Oncology Group] trials," Lawton said in a briefing.


"Once we have this information, we are going to treat differently. This is tapping into information we did not have before," she continued. "For example, a low-risk patient under active surveillance might actually be at higher risk genomically, and if so, should receive treatment."


Also commenting on the findings, David F. Jarrard, MD, Professor and Chair in Urologic Oncology and Associate Director of the University of Wisconsin School of Medicine Carbone Cancer Center, said the researchers have made several interesting discoveries.


"These subtypes were associated with several known pathways, but were not driven by mutation or rearrangement suggesting epigenetic alterations might play a role," he told Oncology Times. "This formidable undertaking represents the largest cohort to date analyzed by RNA gene arrays with extensive 10-year follow-up."


The biostatistical evaluation organized the cohorts into three groups of 100 genes that predicted increased risk of metastasis-free survival, as well as response to postoperative radiation.


"One question not addressed by the present study is risk of death, an elusive endpoint given the long natural history of many prostate cancers," explained Jarrard. "This massive RNA microarray study should permit, with further validation, predicting the possibility of metastatic failure after surgery as well as response to radiation for individual patients."


Kurt Samson is a contributing writer.