Genomic Instability Linked To Prostate Cancer Biochemical Recurrence

Genomic analysis may identify patients with localised prostate cancer who are at high risk of biochemical recurrence

medwireNews: Research suggests that the degree of genomic instability, combined with the level of tissue hypoxia, may indicate the prognosis of patients with localised prostate cancer undergoing image-guided radiotherapy or surgery.

“This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome”, say Robert Bristow, from the University of Toronto in Ontario, Canada, and co-authors in The Lancet Oncology.

“Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials”, they recommend.

The team examined data from 126 patients with low-to-intermediate risk prostate cancer who had biopsies taken before radiotherapy, as well as two validation cohorts consisting of 154 and 117 samples, all taken from patients undergoing radical prostatectomy.

Analysis revealed four distinct genomic profiles among the patients – gain of chromosome 7 (subtype 1), deletion of 8p and gain of 8q (subtype 2), loss of 8p and 16q (subtype 3), and a “quiet genome” with few alterations (subtype 4).

Patients with subtype 4 had a significantly better prognosis than those with subtypes 1, 2 or 3, with a 5-year biochemical relapse-free survival rate of 89% versus 58%, 55% and 53%, respectively.

The researchers further investigated the impact of genomic instability on prognosis by using the percentage of the genome showing a copy number alteration as a proxy.

This revealed significant variation in genome alteration between patients, independent of Gleason score, T stage and prostate-specific Antigen. Each 1% increase in genome alteration was associated with a 5% to 8% decrease in 5-year biochemical relapse-free survival, the team reports.

The median percentage of genome alteration differed significantly between the four genomic profile subtypes. Subtypes 2 and 3 remained significant prognostic factors in multivariate analysis, “suggesting that their prognostic ability stems from both specific genetic aberrations and general genomic instability”, the researchers comment.

And prognostic accuracy of the high or low genome alteration was improved when the researchers further stratified patients using validated hypoxia RNA signatures.

Patients with low genome alteration and high hypoxia had good prognoses after surgery or image-guided radiotherapy, whereas patients with high alteration and high hypoxia had the worst prognosis – this group potentially “could benefit from treatment intensification”, the authors write.

Finally, the team devised a biopsy-driven, 100-loci, 276-Gene DNA signature, enriched for lipid metabolism genes, that could predict biochemical failure and guide clinical decision-making.

In a validation patient group, 58% of patients classified by the signature as having a poor prognosis remained free from biochemical relapse after 5 years compared with 89% of those with a good prognosis, with a significant hazard ratio of 6.1 after adjusting for clinical factors.

In addition, the signature was also able to discriminate patients in the two validation groups who had a good prognosis and those who were at risk of relapse within 18 months of treatment or were likely to develop metastases.

Noting their DNA signature outperformed previously reported RNA signatures, the researchers conclude: “Once our assays undergo clinical quality assurance protocols within a hospital setting, clinicians can use this assay to divert patients to appropriate clinical trials.”

In an accompanying comment, a team from the University of Southern California in Los Angeles, USA, says that while the study requires validation, it provides “strong evidence” that the prostate cancer genome is linked to patient outcomes and that the DNA signature “represents a great stride” in prostate cancer characterisation.

“Although still strictly hypothesis-generating, risk strata are not only an important biological accomplishment, but might also have therapeutic implications”, David Quinn and co-authors write.

“Actionable Mutations can be targeted while hypoxia might be modulated in various ways, each with the goal of improving response and outcome. Much work still needs to be done to formulate the best combination of targeted therapy for the cancer cell and modification of the microenvironment to optimise some of our oldest therapies, including radiation.”

References

Lalonde E, Ishkanian AS, Sykes J, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol; Advance online publication 13 November 2014 doi:10.1016/S1470-2045(14)71021-6

Ballas LK, Hu BR, Quinn DI. Chromoplexy and hypoxic microenvironment drives prostate cancer. Lancet Oncol; Advance online publication 13 November 2014 doi:10.1016/S1470-2045(14)71114-3

medwireNews (www.medwireNews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2014