In the emerging model for metastatic prostate cancer, the tumor, plasma, and germline tissue are being evaluated therapy is then selected on tumor and germline findings genetic counseling is based on tumor and germline findings. Dr. Pritchard notes that the landscape of metastatic disease has evolved, for example with 20% of patients in the mCRPC setting having DNA repair mutations, treatable with platinum-based chemotherapy and PARP inhibitors. Furthermore, in these patients we know that 11.8% of patients have germline mutations in 16 DNA repair genes. There are emerging precision targets, most notably homologous recombination DNA repair mutations (ie BRCA1/2) with a 20% frequency as mentioned, and mismatch DNA repair mutations (ie MSH2) with a ~5% frequency and treatable with immunotherapy.
When it comes to genomic cancer panels, methods matter according to Dr. Pritchard. Somatic mutation panels include (i) hotspot panels, which are typically 1kb-200kb, for partial gene sequencing, multiplex PCR-based enrichment, and uncommonly CNV/fusion detection, and (ii) comprehensive sequencing panels, which are 200kb-2,000kb, allow full gene sequencing, capture-based environment, and where CNV/fusion detection is common. However, in Dr. Pritchard’s opinion, a 200 gene hotspot panel is not equivalent to a 200 gene comprehensive panel.
One must also deal with specimen sample issues. Dr. Pritchard notes that whether the specimen is fresh tumor tissue, fixed tumor tissue or plasma ctDNA, there are issues and challenges with regards to quality, quantity, tumor content, false negatives, and false positives. Furthermore, somatic mutations in the blood increase with age – older men have clones in their blood and plasma. Thus, with plasma ctDNA, sources of somatic mutations may not be from the cancer of interest.
There are a number of reporting considerations researchers should be aware of. For analytical reporting (i) the types of mutations validated, (ii) limits to detection, (iii) pseudogenes, and (iv) platform-specific considerations are important. For clinical reporting, (i) the clinical context is important (ie. post abiraterone or enzalutamide), (ii) having a strategy for poorly characterized variants, (iii) identifying the specimen source, and (iv) the net benefit or harm. To guide somatic variant interpretation, AMP/ASCO/CAP have released the following tiered guidelines: Type I – variants of strong clinical significance; Type II – variants of potential clinical significance; Type III – variants of unknown clinical significance; Type IV – benign or likely benign variants . However, Dr. Pritchard cautions that the germline interpretation does not equal the somatic interpretation. For germline interpretation, the ACMG/AMP guidelines are a rules-based algorithm , and the IARC guidelines are probability-based .
In summary, Dr. Pritchard notes that many new precision targets have been identified in prostate cancer through genomic sequencing efforts. It is important for oncologists to understand how methods, specimen considerations, and interpretation impact clinic tumor sequencing assay performance. Accurate clinical lab reporting is the practice of medicine, relying on expert review by providers with knowledge of both germline and somatic cancer genetics, in addition to the specific patient scenario.
Presented By: Colin Pritchard, University of Washington, Seattle, WA, USA
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA
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