San Francisco, CA USA (UroToday.com) Dr. Robert Bristow of the Princess Margaret Cancer Centre in Toronto presented data from work by the International Cancer Genome Consortium that attempted to characterize patients by molecular patterns to allow risk stratification of men with intermediate risk localized prostate cancer (T2b-T2c, Gleason score 7, or PSA 10-20 ng/mL). He assessed DNA, RNA, and
protein levels, as well as the epigenetic state and hypoxia levels to distinguish groups with varied risk of disease progression, essentially defining “response” and “non-response” biopsy-driven signatures to identify intermediate risk patients in which therapy should be escalated or de-escalated accordingly. In this study, these findings were combined with clinical outcome data from 150 patients treated with radiation and 250 patients treated with radical prostatectomy followed for > 7 years to identify risk groups.
The team completed whole genome sequencing and ExomeSeq on 180 and 458 tumors, respectively. There were high levels of heterogeneity in single nucleotide variants, gene re-arrangements, and copy number alterations among patients of each Gleason grade (3+3, 3+4, and 4+3). They found striking heterogeneity in degree of gene rearrangements (fusions and translocations) between patients with equivalent T-stage, Gleason score, and PSA level, demonstrating variation beyond traditional prognostic data that may be associated with variation in clinical outcome. Additionally they compared biochemical relapse-free rate between men with less than versus greater than 7.5% genome alteration (7.5% = median genome alteration) to evaluate overall genomic instability. Among men treated with radiation and radical prostatectomy, greater genome alteration was associated with more rapid development of metastatic disease than less genome alteration, with each 1% of percent genome alteration corresponding to a 5-6% increased risk of failure. A high level of percent genome alteration was associated with development of metastatic disease (p<0.004). The group also developed a copy number alteration signature present in 18% of men with intermediate risk prostate cancer that was associated with rapid failure within 18 months of treatment (>30% failure rate). Men without this signature had < 7% chance of disease progression within the same 18-month period. This work is being validated in additional populations.
In addition, Dr. Bristow’s team sought to create an assay that could predict a patient’s expected DNA damage response to identify patients that may be more or less responsive to radiation treatment. They found that mutations occurred in very few DNA repair genes in localized prostate cancer (p53 and ATM), unlike the 20% rate of DNA repair gene mutation reported in other studies in castration-resistant prostate cancer. They also demonstrated that a specific mutation in NIBRIN, a protein associated with repair of double strand DNA breaks, was associated with rapid failure of radiation and may be used in the future to help direct patients to avoid radiation for treatment of localized prostate cancer.
Finally, the team evaluated the tumor microenvironment and assessed the relationship between hypoxia and failure of disease control among men treated with radiation. They assessed the degree of hypoxia within the prostate using a transrectal ultrasound evaluating a specific mRNA signature. The investigators found that men with both high genetic instability and high levels of hypoxia experienced more rapid disease progression than men with lower levels. They reported that this was true both for men treated with upfront radiation as well as men treated with upfront surgery.
The authors conclude that this work may contribute to risk assessments in the future, with men with intermediate risk localized prostate cancer with high levels of genetic instability potentially benefiting from treatment with prolonged androgen deprivation therapy (ADT) rather than short term ADT, or more aggressive treatment generally. Alternately they suggest that men with low levels of genetic instability and low levels of hypoxia may be sufficiently treated without ADT. They are assessing this currently in a clinical trial in their center. Finally, they postulate that men with intermediate risk features but very low genetic instability may potentially be followed with active surveillance alone. Ultimately their findings are hypothesis generating, but further evidence gathered from prospective trials will likely be required to change the current standard of care. This elegantly designed evaluation is the first of many steps towards personalizing the treatment approach, and may lead to more or less aggressive therapies for disease that is regarded as higher or lower risk among men with intermediate risk prostate cancer.
Presented By:
Dr. Robert G. Bristow, MD, PhD
Princess Margaret Cancer Centre
Reported By:
Dr. Alicia K. Morgans, MD, at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Assistant Professor of Medicine Medical Oncologist
Vanderbilt - Ingram Cancer Center