APCCC 2021: DNA Repair Defect Aberrations – What Are the Differences Between Them and What Is the Impact on Patient Management?

(UroToday.com) The Advanced Prostate Cancer Consensus Conference 2021 virtual meeting session discussing PARP inhibitors and beyond included a presentation by Dr. Johann De Bono regarding differences between DNA repair defect aberrations and the impact on patient management. Dr. De Bono started by highlighting that >20-30% of advanced prostate cancer patients have DNA repair defect mutations, including BRCA2, ATM, PALB2, CDK12, MMR genes, BRCA1 and other genes. According to Dr. De Bono, the percentage of mutations likely increases with endocrine treatment resistance. Specific to germline DNA repair defects, 8-18% of advanced prostate cancer patients have germline mutations, with interesting variations in geography such that men in New York City have more mutations compared to men in London, compared to men in Seattle. Dr. De Bono also notes that PARP inhibitors have received regulatory approval for select cases of advanced prostate cancer, including:

 

  • EMA: advanced prostate cancer with BRCA (mainly BRCA2) deleterious alterations (olaparib)
  • FDA: advanced prostate cancer with BRCA post-chemotherapy (rucaparib)
  • FDA: advanced prostate cancer with multiple DNA repair defects including BRCA/ATM/PALB2 (pre- and post-chemotherapy)

 

According to Dr. De Bono, we need to pursue advanced prostate cancer molecular stratification in order to provide precision medicine

 

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Specifically, we need to look for advanced prostate cancer with DNA repair defects to identify tumors that may benefit from PARP inhibitors/platinum-based chemotherapy, and tumors that may benefit from immune checkpoint inhibitor strategies.

 

There are several key questions with regards to genetic testing: 

  1. When to test? According to Dr. De Bono, probably the earlier the better, but definitely by the first diagnosis of mCRPC, given that olaparib is approved for pre-chemotherapy mCRPC
  2. How to test? Targeted next generation sequencing allows testing of BRCA2, BRCA1, ATM, PALB2, MSH2, MSH6, MLH1, PMS2, CDK12, FANCA, RAD51, and other genes directly or indirectly involved in homologous recombination DNA repair. Of note, ATM detects DNA damage, activating DNA repair, but is not directly involved in homologous recombination. Loss of both alleles of these genes is usually necessary to sensitize to treatment, and detection of deletions is more challenging than detection of mutations. One BRCA2 mutation is usually (>80% of the time) associated with biallelic loss, and one ATM alteration is not commonly associated with biallelic loss. Other tests have been reported but not routinely used in clinical practice. The HRD score is the unweighted sum of three independent DNA-based measures of genomic instability (loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions) in the tumor, with data suggesting that this approach does not work well in prostate cancer perhaps secondary to high levels of stroma. The RAD51 IHC assay detects the presence of homologous recombination repair by measuring the number of RAD51 foci (but needs sufficient proliferating prostate cancer cells in the sample). Loss of RAD51 foci means absence of repair and does not detect ATM loss. Ultimately, Dr. De Bono notes that the devil is in the details:
    1. It is important to check the sample for tumor content since if there is <30% it will not provide a copy number
    2. If a mutation is detected, clinicians should check allele frequency, and if ~50% it may be a germline mutation
    3. If a mutation is frameshift/truncating, it is probably a deleterious mutation, however if it is a missense mutation, it may be tough to figure this out if it has not been previously described
    4. If mutation allele frequency is low (<10%), despite good tumor content, this may be sub-clonal and treatment targeting the mutation may not result in disease regression (ie. perhaps visceral (liver) metastasis, but not other locations)
    5. If one deleterious BRCA2 mutation is present, it is probably bi-allelic
    6. For ATM alterations, it is best to perform immunohistochemistry
    7. Tumors with homologous deletions of BRCA2 and maybe ATM may benefit more from treatment
  3. What to test? Targeted next generation sequencing of tumor biopsies gives the best test results, and should ideally have higher tumor content (>30%, ideally >50%), and there is evidence emerging that DNA repair defects appear at CRPC (fresh biopsies are required to detect this as, archival biopsies can have poor DNA preservation). Dr. De Bono cautions against dependence on plasma testing, given that 50% of circulating DNA samples have <30% tumor content and cannot detect deletions (patients that benefit the most have deletions). 

There are several important implications for treatment. First, biallelic loss of BRCA2, especially homologous deletions, is the most sensitizing to PARP inhibitors; PALB2, FANCA, and ATM are also sensitizing. ATM biallelic loss tumors can be sensitized to PARP inhibitors (albeit less than BRCA2), and if PARP inhibitors do not work, clinicians should consider platinum based chemotherapy. Second, MMR defective advanced prostate cancer can respond superbly to immune checkpoint inhibition, but no all patients respond. Third, CDK12 biallelic altered advanced prostate cancer are also muted to responding to immune checkpoint inhibitors. Finally, DNA repair defects in advanced prostate cancer may emerge in mCRPC with next generation hormonal therapy (ie. abiraterone, enzalutamide, etc), which may not be found on diagnostic biopsy, and should be considered if the disease behavior changes (ie. multiple visceral metastases in the setting of a low PSA).

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

  • Prostate cancer care is getting more complex
  • Molecular stratification is now standard of care for advanced prostate cancer, either with next generation sequencing or immunohistochemistry. At the latest, somatic testing is recommended at the time of mCRPC, and germline testing is recommended for all advanced prostate cancer (>10%) risk
  • Therapeutic implications include improved rPFS, OS, quality of life with PARP inhibitors for patients with BRCA/ATM tumors, and PARP inhibitors can also work against PALB2, FANCA, and other biallelic losses
  • DNA repair defects may evolve with endocrine therapy with chromosome 13 loss

As follows are several key references provided by Dr. De Bono based on his 15-year journey (2005-2021) with PARP inhibitors:

 

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Presented by: Johann S. de Bono, MD, MSc, PhD, FRCP, FMedSci, Division of Clinical Studies, Royal Marsden Hospital and The Institute of Cancer Research, London, UK

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 Advanced Prostate Cancer Consensus Conference, Saturday, October 9, 2021.

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