(UroToday.com) The Society of Urologic Oncology (SUO) 2021 annual meeting in Orlando, FL hosted an overview of integrating somatic and germline next generation sequencing results into the clinical management of patients with advanced prostate cancer, presented by Dr. Kara N. Maxwell, MD, PhD.
Dr. Maxwell began her presentation by giving a brief overview of the definitions of germline and somatic mutations.
- Germline cancer risk mutations (e.g. BRCA 1/2): mutations or set of mutations in all cells from birth, inherited in families that lead to increased risk of development of cancer- typically assayed on blood or saliva
- Somatic alteration (e.g. ERG fusions): acquired mutations in a tumor that are likely not involved in tumor formation and are a result of the oncogenic process - traditionally assayed on tumor material
- Next Generation Sequencing (NGS): typically refers to massively parallel sequencing of genomic DNA using hybrid capture or multiplexed amplicon based sequencing
- Targeted panels of selected genes or genomic regions
- Whole exome sequencing
- Whole genome sequencing
- NOT: expression-based profiling (i.e. Decipher®, Oncotype®)
Next, Dr. Maxwell addressed the question of what genes should we be sequencing for germline risk? The table below provides a panel of genes that are associated with increased risk of prostate cancer. An inverse linear parabolic relationship exists between the frequency of mutations in the population and the subsequent risk of cancer (i.e. mutations in TP53, PTEN, BRCA1/2 are rare and significantly increase risk of cancer development). Previously AmbryScore-Prostate from AmbryGenetics® was based on 72 single nucleotide polymorphisms (SNPs) and was able to predict risk of prostate cancer based on one’s composite score. This test is currently off the market (since Oct 2021) due to concerns about inherent racial biases with this test.
Why should we find germline carriers? The answer is a clear one as BRCA1/2 carriers for example have increased risk of multiple prostatic, breast, ovarian and pancreatic cancers that may impact screening, prevention, family planning and targeted treatment. The same concept applies to Lynch (MLH1, MSH2, MSH6, PMS2) carriers.
Which patients should undergo germline genetic testing? The National Comprehensive Cancer Network (NCCN) currently recommends germline genetic testing for patients with:
- Metastatic disease
- Nodal disease
- Very-high risk and high risk localized disease
- Any stage with AJ descent
- Any stage with personal history of breast cancer
- Any stage with various family history criteria
Such testing may be considered for:
- Intermediate risk with intraductal/cribriform histology
- Prostate and certain other primary cancers
DNA repair gene mutation rates have been estimated to be ~10-15% in metastatic patients and ~5% in patients with localized disease. There are a number of tests available for germline genetic sequencing as illustrated in the image below.
What genes should we be sequencing in metastatic prostate cancer? The frequency plot in the image below provides clues as to the most important genes to target (BRCA2, ATM, CDK12, PIK3CA)
Dr. Maxwell conversely asked: What genes should be sequenced in localized prostate cancer? The answer appears to be “none at this point” due to their relatively low frequency in the localized disease space compared to the metastatic setting.
Why should we be sequencing our prostate cancer patients’ tumors? Currently, there are targeted treatment options that depend on the patient’s underlying genetic alterations.
- Homologous recombination alterations (BRCA1/2, ATM, CHEK2, etc.): olaparib, rucaparib
- Mismatch DNA repair alteration (MSI or MMR): Pembrolizumab
There are also currently numerous examples of molecularly directed clinical trials in prostate cancer.
Dr. Maxwell went on to ask whether one can sequence circulating tumor DNA(ctDNA) in cell-free DNA (cfDNA) instead? cFDNA is derived from lymphocytes, but can be altered in many disease states (e.g. renal disease, surgery, trauma), be fetal derived, or tumor-derived (ctDNA). Thus, the proportion of ctDNA in cfDNA can vary widely (as low as zero to as high as 90%). Dr. Maxwell went on to caution about the perils of Chromatin Immunoprecipitation (ChIP) and the probability of erroneous, confounding results as illustrated in the image below.
She concluded her talk by advising that if you must do tumor-only sequencing, be aware that:
- Mutations that you find could be from the tumor, but could also be germline or due to ChIP
- Guidelines exist for which genes should be referred for germline testing due to high probability of being germline
- A tumor variant can have variant allele frequency <50% and still be germline
- ~8% of pathogenic germline variants are missed by tumor sequencing
Presented by: Kara N. Maxwell, MD, PhD, Assistant Professor of Medicine, Hematology Oncology and Genetics, Penn Medicine, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA
Written by: Rashid Sayyid, MD, MSc – Urology Chief Resident, Augusta University/Medical College of Georgia, @rksayyid on Twitter during the 2021 Society of Urologic Oncology (SUO) Winter Annual Meeting, Orlando, FL, Wed, Dec 1 – Fri, Dec 3, 2021.