November 2013, Vol 2, No 7
Understanding Molecular Subtypes Is Basis for Genomic Medicine in Prostate Cancer
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. â€śAs in lung cancer, we can define prostate cancer molecular subtypes,â€ť said Tomlins, assistant professor, pathology and urology, University of Michigan Medical School, Ann Arbor. â€śThe 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.â€ť
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%.
â€śWe have things in prostate cancer that we know are potentially targetable, but there hasnâ€™t been the momentum to do whatâ€™s been done in lung cancer, where we looked for these patients to find them,â€ť he said.
â€śInterestingly, there are almost no high-level focal amplifications in prostate cancer until the posttreatment setting. There is a high level of genomic aberrations, and weâ€™re seeing these as you start to do whole genome studies.â€ť
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. â€śIt is as specific for prostate cancer as we can get,â€ť 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.
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.
â€śProstate cancer has a low mutational burden, but you do see patients with high numbers of mutations,â€ť 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 Whatâ€™s Actionable
To translate these findings into potentially targetÂable actions for individual patients, a clinical sequencing program for advanced cancers was started at the University of Michigan: the Michigan Oncology Sequencing Center. â€śWe 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],â€ť 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.
Biomarker Development and Validation Crucial to Use of Emerging Treatments in Solid Tumors and Hematologic Malignancies
Biomarker development and validation are essential for the rational use of emerging cancer treatments, said presenters at the second annual Global Biomarkers Consortium conference. â€śIf we donâ€™t identify biomarkers, weâ€™re likely to miss a therapeutic effect,â€ť said Rob Coleman, MD, MBBS. â€śWe want to separate our patients into those that [ Read More ]
Combinations of targeted therapies will be key to overcome resistance that occurs in tumor cells that leads to eventual failure of a single targeted agent, said Alex Adjei, MD, PhD, at the second annual Global Biomarkers Consortium conference. â€śTumor heterogeneity is the predominant reason for therapeutic failure in cancer,â€ť he [ Read More ]