In his opinion, germline (patient) and somatic (tumor) testing can now be recommended for all men with advanced prostate cancer. This can help inform family cascade testing and treatment selection decisions (ie PARP inhibitors, immunotherapy, etc). However, he understands that not all systems and practices are able to do this regularly.
1) When to obtain testing?
Arguably testing should be done at diagnosis to appropriately plan future care and prognostication, as well as start family cascade testing when appropriate (as 1:10 to 1:7 will have a risk of germline mutation).
At the very least it should be done at the time of diagnosis of castration resistance disease. However, he does note that sub-clonal genomic alterations at chromosome 13 may arise following AR targeted therapy (abi, enza, apa, daro). To detect these you may need to re-biopsy and re-test.
2) How to test?
The most likely tests that are going to be done in real world practice are
a) Targeted Next-Generation Sequencing (NGS)
- Testing for BRCA2, BRCA1, PALB2, ATM, MMR genes, CDK12, AR, PTEN, SPOP, TP53, RB1, others.
- Best done on tumor biopsies and not plasma DNA – targeted NGS of ctDNA testing has a significant risk of missing BRCA2 homozygous deletion if tumor fraction in plasma is <30% (which is the case in at least 50% of mCRPC patients)
- Testing for PTEN, ATM
Research tests (not yet in regular practice) include exome, RNA-seq (transcriptome) and whole genome NGS
3) What do you need to know from the tests?
a) Is there a BRCA2 homozygous deletion (biallelic loss)
- These patients respond best to PARP inhibition – much longer responses to BRCA mutations
b) Is there a mutation in BRCA 1 or 2?
- is this definitely deleterious with loss of function? Is a truncating or frameshift mutation? Is the slice site?
- what is the allele frequency? Is this truncal or less common sub-clone?
- To elucidate this, you must know sample tumor fraction and mutation allele frequency.
3) is there any other relevant mutation? Ie PALB2, ATM, RAD51, FANCA
- these can also sensitize to PARP inhibition or carboplatin
He finished off with some new data to be aware of.
1. Sumanisuriya et al.1 – recent work by Dr. De Bono and colleagues. They pursued low plasma pass whole genome sequencing from patients on taxane therapy from the FIRSTANA and PROSELICA trial.
- Found that following next generation hormonal agents (but not taxanes!), prostate cancer has increased genomic instability – mainly associated with chromosome 13 loss at RB1, BRCA2 but does not appear to depend on BRCA2 loss
2. Carreira et al.2 – In this other work by Dr. De Bono and colleagues looking at biomarker data from TOPARP-B study, they demonstrate that biallelic loss of BRCA2 have the best outcomes with PARP-inhibitors (rPFSA and OS).
Based on the above, he concludes with the following:
1. Molecular testing of prostate cancer is now part of the standard of care and should be done for all men with advanced prostate cancer and should be done at least once on tumor tissue with next generation sequencing and IHC.
- the detail does matter – BRCA2 homozygous deletion responds best to PARP inhibitors
- BRCA2 loss, genomic instability may evolve after endocrine/AR targeted therapy
2. This should include consideration of germline and tumor testing
- Plasma ctDNA testing has limitations – tissue remains the gold standard
3. Molecular data can lead to the identification of key alterations
Presented by: Johann de Bono, MB ChB FRCP MSc Ph.D. FMedSci. Professor Johann de Bono is Regius Professor of Cancer Research and a Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.
1. Sumanasuriya S, Seed G, Parr H, et al. Elucidating Prostate Cancer Behaviour During Treatment via Low-pass Whole-genome Sequencing of Circulating Tumour DNA. Eur Urol. 2021 Jun 5:S0302-2838(21)01799-1. doi: 10.1016/j.eururo.2021.05.030. Epub ahead of print. PMID: 34103179.
2. Carreira S, Porta N, Arce-Gallego et al. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer Discov. 2021 May 27:candisc.0007.2021. doi: 10.1158/2159-8290.CD-21-0007. Epub ahead of print. PMID: 34045297.