Pretreatment Genetic Test Predicts Recurrence in Prostate Cancer

Robert G. Bristow, MD, PhD, FRCPC

A novel 100-locus DNA signature obtained from pretreatment biopsies accurately classified 75% of patients with untreated prostate cancer as low- or high-risk, according to a study presented at the 2014 European Society for Radiotherapy and Oncology (ESTRO) annual conference.

The accuracy of the test was enhanced when the genetic signature was combined with intratumoral hypoxia data. Men with low levels of genetic changes and low hypoxia demonstrated the best outcomes, with a 5-year disease-free survival (DFS) rate of 93%. High-levels of genetic changes and hypoxia were associated with worse outcomes, with a DFS rate of 49%. The DNA-based assay could be used to determine whether active surveillance or more aggressive treatment is needed.

“This is the first report of a test using this information derived from biopsy samples that can predict with close to 80% accuracy which men are at high or low risk of their prostate cancer recurring,” Robert G. Bristow, MD, PhD, FRCPC, a senior scientist at the Ontario Cancer Institute, a clinician-scientist at the Princess Margaret Cancer Centre and a professor at the University of Toronto, Canada, the study’s lead investigator, said in a release. “Importantly, we found that when we combined the signature with the additional information about the tumor’s oxygen content, this made the genetic test even more accurate.”

In the study, pretreatment biopsy samples from 126 patients with clinically-staged intermediate-risk prostate cancer were examined by array comparative genomic hybridization (aCGH) prior to treatment with image-guided radiotherapy. At an average 7.8-year follow-up, findings from the pretreatment aCGH assays were used to correlate genomic indices, gene copy number alterations, or a generalized genomic instability score with overall outcomes.

Once identified, these variables were validated in a separate cohort of 154 patients treated with radical prostatectomy. This analysis showed that the genetic signature accurately defined risk in 75% of patients.

In a second analysis of the study, levels of glandular hypoxia were measured using an Eppendorff pO2 probe and categorized based on hypoxic percentages. The effect of hypoxia on the translation of more than 220 genes was measured using polysome-translation assays.

These tests demonstrated that hypoxia down regulates multiple genes involved in genome stability in patients with prostate cancer. When assessed together, the genetic test and hypoxia levels indicated an overall difference in the DFS of 44% between low and high-risk patients. These findings are being validated in larger studies that are expected to produce results in the next two to three years.

“If all goes well, then this will lead to a new test for cancer patients that can be turned around in three days and will tell doctors which patients will do well with local treatment alone — surgery or radiotherapy – and which will need extra treatment,” said Bristow. “Existing methods for identifying high-risk patients are imperfect, so new tests are required that are better at predicting which patients will have their cancer recur.”

A number of genomic-based tests are currently available for risk-assessment in prostate cancer, including Prolaris, Decipher, and the OncotypeDX prostate cancer test. The Prolaris and Decipher tests are used following prostatectomy to determine the risk of recurrence and metastases while the OncotypeDX test can be utilized on biopsy tissue to avoid unneeded invasive procedures.

In a validation study of the 17-gene Oncotype DX test, approximately 26% of patients with low-risk disease by PSA and Gleason scores were confirmed as “very low risk” by the test. Additionally, 10% of patients classified as low risk by clinical parameters were identified as high-risk by the test.

“This is exciting research because an accurate and quick test that can predict which men are most likely to need extra treatment to reduce the risk of a recurrence of their cancer is urgently needed,” Vincenzo Valentini, MD, the president of ESTRO and a radiation oncologist at the Policlinico Universitario A. Gemelli in Rome, Italy, said in a release. “If the utility of this genetic signature is confirmed in further research over the next few years, it could become an important tool for helping us to better target appropriate treatment according to the genetic make-up of each man’s tumor.”