AUA 2021: Genetic Testing in Advanced Prostate Cancer 

(UroToday.com) The American Urologic Association (AUA) annual meeting’s evolving landscape of advanced prostate cancer treatment session included a talk by Dr. Leonard Gomella discussing genetic testing in advanced prostate cancer. Dr. Gomella notes that there have been rapid advances in prostate cancer genetic testing, reflected in changes made to the NCCN guidelines from 2016-2020. Before 2016, prostate cancer and BRCA were only discussed in the Hereditary Breast and Ovarian Cancer (HBOC) Guidelines, followed by early 2016 guidelines noting the first mention of a family history of BRCA1/2 for screening patients. The 2017 prostate cancer guidelines noted the first familial/hereditary genetic considerations, emphasizing that the following should be considered “brother or father or multiple family members diagnosed with prostate cancer at less than 50 years of age, germline DNA repair gene abnormalities, especially BRCA2 mutation or Lynch Syndrome (germline mutations in MLH1, MSH2, MSH6, or PMS2) and/or strong family history for breast or ovarian cancer (suggests the possibility of BRCA2 mutation) or colorectal, endometrial, gastric, ovarian, pancreatic, small bowel, urothelial, kidney, or bile duct cancer (suggests the possibility of Lynch syndrome).” In the 2018 NCCN prostate cancer guideline, there was the first “consideration” for germline testing based on risk, and in 2020, there was a change in terminology to germline testing being “recommended” based on risk.

Dr. Gomella emphasized that there are several basic concepts in genomics and genetic testing. In the traditional sense, genetics is defined as the study of individual genes and their inheritance, whereas the modern definition of genetics is in the study of multiple genes and their inheritance pattern. The genome is defined as the entire set of genes in an organism and genomics is defined as the analysis of multiple genes interacting with each other and the environment (ie. cancer, diabetes). Importantly, modern genetic testing relies on genomics. The difference between germline and somatic mutations is as follows:

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There are several important aspects of prostate cancer genetic/genomic testing:

  • Genomic profiling: tissue-based biopsies and proprietary molecular signatures (ie. Decipher, Prolaris, OncotypeDx, ConfirmMDX)
    • Used for treatment and management decisions
  • Genomic tumor sequencing: tissue or “liquid biopsy”, with extensive testing of tumor-specific mutations (300+) (ie. Foundation Medicine, Caris)
    • Used for direct targeted therapies and assessing clinical trial eligibility
  • Inherited cancer risk testing: identifying inherited mutations by buccal/blood testing and assessing for increased cancer risk (ie. Ambry, Myriad, Invitae, GeneDX, Color, etc)
    • Used for cancer screening and prevention, genetic testing in close relatives, and informing treatment decisions and clinical trial eligibility

Deep sequencing, also known as next-generation sequencing, takes many hours to days to perform and involves sequencing a region many times in order to minimize errors using “gene chip” technology. More sequencing certainly is more expensive to perform but is more accurate.

Dr. Gomella then discussed prostate cancer and inherited risk, noting that prostate cancer is hereditary in ~10-15% of cases, often due to a single inherited genetic mutation and greatly increasing the lifetime risk of prostate cancer (ie. BRCA1, BRCA2, Lynch syndrome, HOXB13). Inherited mutated genes (ie. BRCA1/2) do not cause cancer but increase cancer risk, with these pathogenic genes interacting with other genes/environment to increase risk. Familial prostate cancer includes ~15-20% of cases, with some features of hereditary cancer, but no detectable mutation identified and close family members being at increased risk. It is possible that familial prostate cancer represents an interaction between genetic and environmental risk factors. Sporadic prostate cancer represents ~70-80% of cases with no exact cause, no features of hereditary or familial cancer, and no increased risks for close family members.

It is important to perform genomic/genetic germline testing, given that it has the potential to impact therapeutic options, identifying “actionable genes” and the ability to guide treatment in the era of “precision medicine”. Additionally, it has the potential to screen and prevent other cancers in the patient and protect/screen at-risk members in the family. As follows is a summary of gene mutations, prostate cancer risk associated with mutation, and the mechanism of action:

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With regards to germline mutation in metastatic prostate cancer, BRCA-2 is the best-studied for potential screening and treatment; males with BRCA-2 mutated prostate cancer have more aggressive disease. There is a 2-6 fold increased risk of lifetime risk of prostate cancer (BRCA2 >BRCA1), and an 8.6 fold increased risk by age 65 (BRCA2). Initial studies suggest that germline mutations occur in 11.8% of metastatic disease compared to 4.6% of localized disease,1 whereas later studies indicate this may be as high as 25% in mCRPC.

There are several practical considerations in genetic testing for prostate cancer. Urologists should become more focused on a patient’s detailed family history, including relatives that are affected by breast cancer, prostate cancer, breast cancer, Lynch syndrome, and male breast cancer, etc in order to inform the need for genetic testing/counseling in men diagnosed with prostate cancer. Common prostate cancer-specific genetic testing panels are as follows:

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Additionally, other common prostate cancer-specific genetic testing panels include the Myriad “myRisk” 28 gene panel that screens for several cancers, and the Color Genomics/Genome Dx hereditary panel of 30 genes. There are several results that may occur when testing for germline mutations with different interpretations:

  • “Pathogenic” or “likely pathogenic” mutation (ie. BRCA2 c.1411G>T/(p.Glu471Ter) – these patients should be referred for genetic counseling after a detailed review of their family history. Additionally, it may be recommended that testing be performed on family members for “cascade” testing
  • “Benign” or “likely benign” – no pathogenic mutations definitively identified
  • “Variant of unknown significance” – these patients can be considered a “negative” test but requires follow-up and ongoing review for newly identified mutations. GenBank (https://www.ncbi.nlm.gov/genbank/) maintains a central repository of reported genes

Somatic tumor DNA testing includes several modalities with tissue biopsy being the most common technique, including lymph node, liver, bone, or the primary lesion. Liquid biopsy techniques are increasing, including circulating tumor cells and circulating tumor cell DNA, which may be advantageous due to tumor instability over time and providing better “real-time” results of genetic profiles versus archival biopsies. Somatic tumor testing is the most commonly used modality used for identifying “actionable” genes for clinical trials, including the key trials for approving rucaparib and olaparib, as well as pembrolizumab for identifying MSI-H, mismatch repair deficient, or tumor mutational burden > 10 Mb.

Dr. Gomella notes that there are several emerging roles of genetic testing in prostate cancer. This includes screening, active surveillance, treatment decisions at all stages, prostate biopsy confirmation, and precision medicine for advanced therapeutics. Perhaps the most common example of genomic profiling to guide treatment is DNA repair genes and candidacy for PARP inhibitors. For example, the indication for rucaparib is in adults with a deleterious BRCA mutation (germline and/or somatic) and mCRPC who have been treated with androgen receptor-directed therapy and taxane-based chemotherapy. Other indications for rucaparib include ovarian and fallopian tube cancers. The advanced prostate cancer AUA/ASTRO/SUO 2020 Guideline suggests that clinicians should offer a PARP inhibitor to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or taxane-based chemotherapy. Platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor.

Several key organizations, including the American College of Medical Genetics and Genomics (ACMG), the National Society of Genetic Counselors (NSGC), the Philadelphia Prostate Cancer Consensus 2017/2019, and the NCCN 2020 guidelines recommend consideration for genetic germline testing and/or genetic counseling for the following patients:

  • >=2 cases of prostate cancer age <= 55 years in close relatives regardless of risk category
  • >= 3 family relatives with prostate cancer regardless of risk
  • Aggressive (Gleason >7) prostate cancer
  • >=2 cases of breast, ovarian, and/or pancreatic cancer in close relatives
  • Metastatic prostate cancer or mCRPC
  • Intraductal/cribriform prostate cancer
  • Somatic tumor sequencing with mutation in hereditary cancer genes
  • Ashkenazi Jews
  • Family history of cancer at an early stage of diagnosis: breast cancer <45 years of age, uterine or colon cancer < 50 years of age, ovarian cancer < 60 years of age

Dr. Gomella concluded his presentation with the following take-home messages:

  • There are rapidly evolving recommendations for prostate cancer genetic testing and decision making
  • The most critical inheritable prostate cancer genes today are: BRCA1/2, HOXB13, ATM, and CHEK2
  • There is a high prevalence of germline mutations (>11%, possibly up to 25%) in mCRPC
  • All mCRPC/high-risk disease should have germline testing with consideration for somatic testing as well (to assess for candidacy for PARP inhibitors, etc)
  • There is an increasing role for somatic tumor testing, including liquid biopsy of cell-free DNA
  • Clinicians should strongly consider referral for genetic testing and counseling for high-risk patients/family concerns
  • Many new advanced prostate cancer therapies are under investigation, with most being associated with genomic markers

Presented by: Leonard G. Gomella, MD, Thomas Jefferson University, Philadelphia, PA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.

References:

  1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453.
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