(UroToday.com) In the session of the 2022 Advanced Prostate Cancer Consensus Conference focusing on the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), Dr. Chi presented on the somewhat mundane but critical task of reading a genomics report. He emphasized that this is increasingly important as clinicians, rather than genetic counsellors, are ordering testing more and more commonly. It’s notable that most clinicians report no formal training in the interpretation or communication of tumor genomic profiling results and risks.
Dr. Chi highlighted that there are numerous features that can be gleaned from a genomics repots including the genes and regions covered; types of mutations detectable and the limits of detection; the mutation status of genes of interest; variant allele frequency; and microsatellite instability. He noted that a higher variant allele frequency (a higher number of times that a variant is seen among the total number of times that region was sequenced) is consistent with a truncal/driver mutation that may be a useful therapeutic target whereas a lower variant allele frequency is more in keeping with passenger or subclonal mutation.
In reviewing tumor genomic testing, Dr. Chi used an example of a FoundationOne CDx test report. He noted that first among the report outcomes is a list of FDA-approved therapeutic options based on the result of the genomic features identified for this patient. Other alterations, that may not be as immediately therapeutically actionable, are then enumerated.
Subsequently, pertinent negative findings, therapies with clinical benefit, NCCN categories of evidence and consensus, and potentially relevant clinical trials are highlighted.
Dr. Chi noted that not seeing an alteration doesn’t mean there isn’t one there. False negatives may arise as some panels only test for certain types of variants. Thus, it is particularly important for clinicians to know what is covered by the specific test being ordered. Further copy number changes and structural rearrangements that have lower tumor cellularity contribute to false negative results.
Dr. Chi then discussed variants of unknown clinical significance (VUS). These are variants that are known or presumed to alter normal gene function, without convincing evidence of a predictive, prognostic, or diagnostic association. With increasingly large panels and whole exome and whole genome sequencing emerging, the likelihood of finding VUSs increases.
Following identification of a variant beginning with a tumor test, he emphasized the importance of considering follow-up germline testing. While a variant allele frequency (VAF) of 50% of suggests a germline variant, he noted that this is not reliable and that there may be errors in both directions. Further, where history suggests germline testing would be indicated, he emphasized that we should not allow negative tumor results to stop germline testing. Additionally, he noted that non-actionable findings, such as HOXB13 may not be included in many panels but will have implications for families.
Dr. Chi then discussed cell free DNA (cfDNA) and circulating tumor DNA (ctDNA), noting that the vast majority of cfDNA is derived from white blood cells. A subset of this, in people with tumors, may come from the cancer.
He noted that the ctDNA fraction (the proportion of cfDNA that is derived from cancer) is highly variable between patients, ranging from 1 to 89%. This ctDNA fraction is highly associated with metastatic burden. Thus, it may be useful as a longitudinal measure of treatment response as a large proportion of patients have a significant drop in ctDNA levels 4 weeks following the start of treatment.
He noted the importance of clearly reporting and identifying when a low ctDNA fraction precludes the ability to identify mutations or deletions. Further, he emphasized that the FoundationOne Liquid CDx assay does not detect heterozygous deletions or copy number losses/homozygous deletions in ATM. He cited data from the PROfound trial demonstrating that deletions may be missed by a low ctDNA fraction. However, ctDNA can detect variants that are not identified in tissue testing.
Dr. Chi noted that commercial assays do not incorporate white blood cell samples (as matched normals) into the analysis. Thus, this limits the ability to discriminate germline from somatic alterations. Further, clonal hematopoiesis can result in false positives. A relatively high proportion of DNA repair gene variants identified in the plasma of patients with advanced prostate cancer are attributable to CHIP, rather than underlying cancer.
In summary, Dr. Chi emphasized that tumor genomics is now a standard part of the evaluation of patients with advanced prostate cancer. As a result, medical genetics is now a key member of the prostate cancer care team. Understanding the genomics report, and its limitations is key to translating this to clinically actionable results for our patients.
Presented by: Kim Chi, MD, Senior Research Scientist, Vancouver Prostate Centre, Chief Medical Officer & Vice President, BC Cancer, Medical Oncologist, BC Cancer – Vancouver, Professor, Department of Medicine, UBC