Barcelona, Spain (UroToday.com) In this educational session, Dr. De Bono discussed how prostate cancer genomic studies are important for the development of biomarkers to stratify disease. He broke these down into three categories: Pre-diagnosis, pre-treatment, and post-treatment. Pre-diagnosis biomarkers can include risk biomarkers such as germline DNA defects and diagnostic biomarkers such as prostate MRI and DNA circulating in the blood or in the urine. Pre-treatment biomarkers include prognostic (how the patient will do), and predictive (how the patient will respond to therapy). Post-treatment biomarkers include pharmacodynamic indicators, response to therapy, and the identification of true surrogates for outcomes such as metastatic progress-free survival.
The discussant then offered three main perspectives, the first being that validation of preclinical biology and biomarkers matters. For example, with regards to detection of AR-V7 splice variants, it must be determined whether simply detecting the presence of this variant is enough to stratify patients, or whether a more quantitative and dynamic scale of detection is necessary to truly understand a patient’s clinical status. The ultimate validation of a biomarker such as AR-V7 would be a prospective trial utilizing an anti-cancer drug that specifically targets AR-V7 biology.
The second perspective Dr. De Bono discussed was multiplicity. First, he discussed that biomarkers can be multi-purpose, serving as both predictive and prognostic biomarkers. Second, he considered that certain biological readouts such as mismatch repair deficiency can require multiple orthogonal assays. Immunohistochemistry is the standard assay for determining the status of mismatch repair protein, but this can be supplemented by genomic sequencing for clinical benefit. Dr. De Bono described a patient seen in his clinic with advanced prostate cancer for whom mismatch repair IHC was normal, but genomic sequencing detected an MSH6 deleterious mutation. The patient went on to have an exceptional response to immunotherapy. Third, he discussed how given multiple mutations seen in tumors, a predictive hierarchy is required to determine which mutations ought to be the focus of targeted therapy.
The third perspective discussed was regarding next-generation sequencing. While incredibly informative, care must be taken with the interpretation of variant calling. Specifically, one must consider corrections for tumor purity and ploidy to accurately call mutations. Functional validation and/or improved predictive algorithms are required to understand the true significance of a variant. Simply because a mutation is predicted to be truncating and deleterious to the function of a protein does not make it so.
Finally, after providing numerous molecular stratification parameters that either already impact or are likely to impact therapy decisions (DNA damage repair, AR pathway, PI3K/AKT pathway, SPOP mutations), Dr. De Bono concluded that though we want simplicity in molecular stratification, ultimately we cannot avoid complexity. There is much work to be done, but it is an exciting time for prostate cancer research and treatment, with many new advances likely in the near future.
Presented by: Johann De Bono, MD, Ph.D., Regius Professor of Cancer Research at the Institute for Cancer Research and the Royal Marsden Hospital, London, United Kingdom
Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain