Specific clones may have the potential for grade conversion, research suggests.
Researchers using cutting-edge diagnostic techniques demonstrated that repeat sampling of the same clonal focus of prostate cancer can be achieved over time using magnetic resonance imaging/ultrasound fusion biopsy (“fusion biopsy”). In addition, their findings strongly suggest that high-grade prostate cancer may arise clonally from a low-grade cancer.
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“Our study provides the first definitive evidence that serial biopsies can be obtained from the same prostate cancer clonal focus through fusion biopsy, and so it supports use of this technique for following men during active surveillance,” said Ganesh S. Palapattu, MD, of the University of Michigan, Ann Arbor.
“It also raises the provocative idea that not all Gleason 6 prostate cancers may be indolent. Our findings point to the need for further research focusing on better characterizing these ‘high-risk low-grade’ cancers. Ultimately, these are the ones we need to follow.”
Conducted as a collaboration between urologists at the University of Michigan and the University of California, Los Angeles, the study included 31 men (mean age, 65 years, mean PSA at diagnosis, 4.6 ng/mL) with low-volume, Gleason 6 prostate cancer who were enrolled in an active surveillance program. All men underwent an initial diagnostic MR/fusion biopsy with individual needle core tracking and had a follow-up fusion biopsy of the same region. The median time between biopsies was 12 months.
Clonality of the initial and follow-up biopsies was assessed using immunohistochemistry to assay ERG status. In addition, targeted RNA/DNA next-generation sequencing (NGS) was performed to identify common oncogenic mutations in routine formalin-fixed paraffin-embedded biopsy tissues.
“Active surveillance for men with low-grade cancer is based on the notions that we are able to sample the same clonal focus of cancer over time and that low-grade disease can progress to high-grade disease,” said Dr. Palapattu.
“Ours is a first-in-kind study providing evidence to support these ideas through the use of sophisticated molecular techniques.”
Twenty-six of the 31 men had tissue that was evaluable for molecular studies at both the diagnostic and follow-up biopsies, and 10 men had progression to Gleason 7 or higher cancer on targeted surveillance biopsy.
Immunohistochemical analysis demonstrated ERG expression concordance between serially obtained samples in 25 (96%) of the 26 men with evaluable tissues and in all 10 men whose cancer progressed.
“The 96% ERG expression concordance between the initial and surveillance targeted biopsy is a much higher rate than could be attributable to chance, strongly suggesting that the same clonal focus was sampled over time,” Dr. Palapattu said.
“Furthermore, the concordance of ERG status between the samples from the men whose cancer progressed strongly suggests that the higher grade cancer originated from the Gleason 6 cancer.”
While approximately 50% of paired samples displayed oncogenic mutations, no consistent mutational event that predicted grade progression was observed.
“Our research is also noteworthy for establishing the feasibility of identifying somatic genetic alterations with high confidence using very minute tissue samples obtained through prostate biopsy as well as for showing that deleterious genetic alterations can be present in low-volume low-grade prostate cancer,” Dr. Palapattu said.
He acknowledged the study has two main limitations. One is its small cohort size, and the other relates to sampling bias, ie, the possibility that tissue assayed in the follow-up biopsy was in fact present at the initial biopsy but simply not sampled.
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