Genetic Factors May Predict Prostate Cancer Recurrence

ATLANTA—Specific genetic factors may be involved in the progression and differential tumor response in men with intermediate-risk prostate cancer who fail radiotherapy or radical prostatectomy (RP), new findings presented at the American Society for Radiation Oncology's 55th annual meeting suggest.

“There are some hot spots for mutations and gene alterations and basically it may be possible to tell the urologist which patients need intensified treatment beyond surgery or radiotherapy alone,” study investigator Alireza Fotouhi Ghiam, MD, a radiation oncology resident at the University of Toronto, told Renal & Urology News

Study results indicate that patients who have abnormal levels of breaks at common fragile sites (CFSs) within the chromosomes sensitive to DNA damage are more likely to have their cancer return, Dr. Ghiam said. These CFS break abnormalities are usually associated with instability of the cell's DNA.

He and his colleagues evaluated the outcomes of 280 PCa and reviewed the DNA “fingerprints” of each patient's tumor using the patient's initial diagnostic core biopsy to determine if gene copy number alterations (CNAs) or breaks in CFSs were related to poor treatment outcomes. 

The study population was divided into two groups: 126 patients with localized intermediate-risk PCa and who received image-guided radiation therapy (IGRT) with a mean dose of 74.6 Gy and 154 patients with localized low-, intermediate- and high-risk PCa who had undergone RP.

Using an array comparative genomic hybridization (aCGH) database, DNA from frozen needle biopsies of the radiotherapy patients was analyzed for 13 previously characterized CFSs. The data revealed a pattern in which the patients who failed treatment had abnormal levels of CNAs at CFSs. In the radiotherapy group, CNAs in CFSs occurred frequently, with 80 (64%) of the patients having a CNA in one or more CFS locations (median was 1, range 0-10). On univariate analysis, the five-year biochemical relapse-free survival rate was significantly lower among those with a CNA in at least one CFS than in patients without genetic alteration in CFSs (64% vs. 90%). In multivariate analysis, a CNA in a CFS was associated with a significantly increased likelihood of decreased response to radiation therapy and higher incidence of recurring cancer.

“We thought that patients who have CFS breaks might be more sensitive to radiation therapy-induced DNA damage,” said lead investigator Robert Bristow, MD, PhD, a professor in the radiation and medical biophysics departments of the University of Toronto. “We now think that the CFS breaks are a signal that the cancer cell has acquired numerous genetic changes that lead to more aggressive cancer cells that can spread early and outside the prostate gland.”

Approximately 30% of intermediate-risk PCa patients will fail radiotherapy or RP. This study suggests that analyzing CFS in tumor biopsy specimens may help improve the management of these patients and help lower morbidity and mortality. “If we validate this study in similar but larger groups of patients, we can develop a test based for CFS breaks,” Dr. Bristow said. “The results would allow us to place patients in one of two categories: those whose tumors do not have CFS breaks and who would likely do well with local treatment alone, such as radiotherapy or surgery, and those patients whose tumors do have CFS breaks and would need a more complex treatment protocol.” 

Results from the 154 patients in the RP group were compiled using the Memorial Sloan-Kettering Cancer Center aCGH database of patients. Of these patients, 81 (53%) had a CNA in one or more location (median 1, range 0-6). In multivariate analysis, a CNA in a CFS was not a significant predictor of cancer recurrence.

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