Understanding Molecular Subtypes Is Basis for Genomic Medicine in Prostate Cancer

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Incorporating genomics into the practice of medicine requires demonstration of the ability of biomarkers to impact clinical decision making and ensuring that patients receive the best therapy based on genomic findings. Scott Tomlins, MD, PhD, reviewed efforts to realize genomic medicine into prostate cancer diagnosis and management at the second annual Global Biomarkers Consortium conference.

Genomic medicine starts with understanding basic molecular subtypes. Numerous microarray studies, array CGH studies, and characterization of the prostate cancer transcriptome and genome have identified common alterations. “As in lung cancer, we can define prostate cancer molecular subtypes,” said Tomlins, assistant professor, pathology and urology, University of Michigan Medical School, Ann Arbor. “The easiest way to do this is to look for the presence of ETS gene fusions. Like an ALK rearrangement, these are chromosomal rearrangements that occur in prostate cancer, but they occur in about 50% of prostate cancers.”

More than 50% of prostate-specific antigen (PSA)-screened prostate cancers harbor fusions between the TMPRSS2 and ERG genes.

No clear individual driver has been identified in prostate cancer patients without an ETS fusion.

Exome sequencing of prostate tumor and normal pairs has discovered focal loss in common tumor suppressor genes such as PTEN, TP53, and RB1. Point mutations have been found in several genes including TP53, SPOP, PTEN, FOXA1, and MED12, each with a prevalence of <10%.

“We have things in prostate cancer that we know are potentially targetable, but there hasn’t been the momentum to do what’s been done in lung cancer, where we looked for these patients to find them,” he said.

“Interestingly, there are almost no high-level focal amplifications in prostate cancer until the posttreatment setting. There is a high level of genomic aberrations, and we’re seeing these as you start to do whole genome studies.”

A TMPRSS2:ERG fusion serves as a urine biomarker for prostate cancer. It has been shown to improve on serum PSA for predicting cancer in men undergoing diagnostic biopsy. “It is as specific for prostate cancer as we can get,” he said.

A urine-based test developed at the University of Michigan uses quantification of TMPRSS2:ERG and PCA3 along with PSA to calculate the prostate cancer risk on needle biopsy. Rather than provide a positive or negative value, the test will provide the risk of having cancer and high-grade cancer, with estimates of what constitutes low, intermediate, and high risk, said Tomlins.

Mutational Landscape

Integrative profiling of lethal castration-resistant prostate cancer (CRPC) has been conducted at the University of Michigan in an effort to characterize mutations present. The exomes of 50 lethal, heavily pretreated metastatic CRPCs obtained at rapid autopsy were sequenced.

“Prostate cancer has a low mutational burden, but you do see patients with high numbers of mutations,” he said. The exome data revealed 9 genes that were significantly mutated, 6 of which are recurrently mutated in prostate cancer: TP53, AR, ZFHX₃, RB1, PTEN, and APC. Three of the mutated genes did not have roles in prostate cancer: MLL₂, OR₅L₁, and CDK₁₂.

Clinical Sequencing Program: Finding What’s Actionable

To translate these findings into potentially target­able actions for individual patients, a clinical sequencing program for advanced cancers was started at the University of Michigan: the Michigan Oncology Sequencing Center. “We do profiling of the normal germline as well. We do full exome and transcriptome studies, and we do the exome of the normal sample, run it through pipelines, and we present the results to a sequencing tumor board [now called a precision medicine tumor board],” said Tomlins. The board discusses actionable results and sends a report to the genetic counselor and the referring physician. A multidisciplinary tumor board determines which biomarker candidates are actionable.

The University of Michigan has recently initiated one of the first genetically stratified clinical trials (a multi-institution randomized phase 2 trial) in which ETS gene fusions are assessed (ERG by immunohistochemistry and ETV1 by fluorescence in situ hybridization), and patients are stratified to treatment with either an antiandrogen alone or a PARP inhibitor plus an antiandrogen.

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