SNPs Identified for Further Study in Association With QOL in Men With Prostate Cancer Treated With Radiation

Phoebe Starr

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Investigators at Harvard Medical School have identified candidate single nucleotide polymorphisms (SNPs) in genes associated with inflammation that will be explored further with regard to their associations with long-term quality-of-life (QOL) effects of radiation therapy (RT) in men with prostate cancer. The authors found 7 SNPs significantly associated with long-term QOL outcomes after RT, but these SNPs did not retain statistical significance in a comparator group of men treated with radical prostatectomy.

“Men with prostate cancer have significant decrements in quality of life, which may be related to genetic differences. In particular, inflammation-related genes may impact long-term toxicity following radiation therapy, including esophagitis and pneumonitis,� stated presenting author Jonathan Schoenfeld, MD, Harvard Radiation Oncology Program, Boston, Massachusetts. “We have confirmed significant associations with SNPs and quality of life in men treated with radiotherapy, and these associations require prospective assessment regarding their relationship to QOL.�

The study was based on blood samples collected from men diagnosed with prostate cancer and treated with RT between 1982 and 2006. All men were enrolled in the prospective US Physicians’ Health Study (USPHS), a randomized trial of aspirin and beta-carotene. Forty- three SNPs in 10 inflammation-related genes (previously found to be associated with prostate cancer) were genotyped and analyzed using the additive model.

Men with confirmed cases of prostate cancer (n=264) were given questionnaires at intervals during the years 2005 and 2007, a median of 6 years after diagnosis. The questionnaires followed QOL outcomes for the following symptoms experienced over the years since diagnosis and RT: decreased force of urinary stream, increased urinary frequency or urgency, rectal urgency, and impotence.
Medical records were obtained and reviewed as well.

The first cohort was specifically limited to men with nonmetastatic prostate cancer treated with definitive RT. A second cohort of 337 men treated with definitive radical prostatectomy served as a comparison group.
“We limited excluded analysis to Caucasian men, and excluded other races,� said Dr Schoenfeld.
The first cohort of 264 men treated with RT had a median age of 72 years and were predominantly low-risk patients. Sixty-one percent had Gleason scores <7; 98% were early clinical stage.

The investigators identified 13 SNPs significantly associated with QOL. On multivariate analysis, 7 remained statistically significant. The SNPs were found on the following genes: IL8 (1 SNP), NFKB (2 SNPs), RNASEL (2 SNPs), CRP (1 SNP), and TLR10 (1 SNP).
Between 20% and 29% reported severe urinary and rectal symptoms, and 72% reported severe impotence. Between 71% and 80% reported mild/never urinary and rectal symptoms, and 28% reported mild/never impotence.

In the second cohort of 337 men from the USPHS treated with radical prostatectomy, 71% had Gleason scores <7 and 95% were early stage.

Unfortunately, baseline characteristics and QOL results between the RT and surgical patients were not comparable. Between 9% and 15% had urinary or rectal symptoms and 82% had moderate to severe impotence.
“None of the 7 SNPs that were statistically significantly associated with the 4 parameters of QOL retained their statistical significance in men treated with radical prostatectomy,� Schoenfeld said.

Schoenfeld told the audience that the study had several limitations, including lack of pretreatment data and no correction for multiple testing. “The study is hypothesis generating. The mechanism of action of the selected genes is currently unknown. We performed incomplete sequencing of SNPs we tested.�

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