Germline DNA Testing
1. DNA repair genes – Pritchard et al1 identified that almost 1 in 7 men with mCRPC had a hereditable deleterious mutation
- This was confirmed in other studies in other populations2,3 - ~6-8% rate of germline mutations
- There may be some ethnicity variation as each was in different populations
- Standardization and databases will be important as each utilized different assays
2. Consensus conference has supported this – all patients with mPCa should get genetic testing, BRCA2 genetic testing recommended
3. Even BRCA2 carriers are at increased risk of prostate cancer4
4. Patients with germline DNA repair defective CRPC still respond to abi/enza – but those with prior PARP-inhibitor exposure respond better (publication pending)
He has written a review recently of the current status of germline DNA mutations.5
Somatic DNA Testing
1. Mutational profile of primary localized disease vs advanced disease vs. metastases are very different – SU2C data, in press
2. MMR defective prostate cancers can benefit from immunotherapy
3. Consider trials of PARP-Inhibitors and carboplatin in patients with homologous recombination repair defective disease
Targeting Advanced Disease
1. The treatment has become more complex as there are more treatment options and growing number of disease spaces
- The cM0 space will continue to shrink due to PSMA-PET
- Abiraterone cM1 hsPCA trials did not ask the right question: earlier vs. later
- Important subtyping is emerging – repair defective disease, mismatch repair defective disease
2. Targeting PSMA using immunoconjugates and radioimmunoconjugates (alpha-emitters such as lutetium, and beta-emitters such as actinium and thorium)
- Study in JNM 2018 – 5/40 patients had >2year response with actinium, but 63% had >50% decline
- Abstract in ESMO 2017 – Lutetium therapy had similar PSA response (57% had >50% response)
Presented by: Johann S. De Bono, MD, PhD, FRCP, The Institute of Cancer Research and The Royal Marsden Hospital, London, UK
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto | @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
1. Pritchard CC, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. doi: 10.1056/NEJMoa1603144. Epub 2016 Jul 6.
2. Na R, et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur Urol. 2017 May;71(5):740-747. doi: 10.1016/j.eururo.2016.11.033. Epub 2016 Dec 15.
3. Annala M, et al. Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer. Eur Urol. 2017 Jul;72(1):34-42. doi: 10.1016/j.eururo.2017.02.023. Epub 2017 Mar 1.
4. Lecarpentier J, et al. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores. J Clin Oncol. 2017 Jul 10;35(20):2240-2250. doi: 10.1200/JCO.2016.69.4935. Epub 2017 Apr 27.
5. Mateo J, Boysen G, Barbieri CE, Bryant HE, Castro E, Nelson PS, Olmos D, Pritchard CC, Rubin MA, de Bono JS. DNA Repair in Prostate Cancer: Biology and Clinical Implications. Eur Urol. 2017 Mar;71(3):417-425. doi: 10.1016/j.eururo.2016.08.037. Epub 2016 Aug 31. Review.
6. Kratochwil C, Bruchertseifer F, Rathke H, Hohenfellner M, Giesel FL, Haberkorn U, Morgenstern A. Targeted Alpha Therapy of mCRPC with 225Actinium-PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control. J Nucl Med. 2018 Jan 11. pii: jnumed.117.203539. doi: 10.2967/jnumed.117.203539. [Epub ahead of print]