Dr. Nelson notes DNA may be affected by different types of damage, different mechanisms of repair, and that distinct genes/proteins may be involved. With regards to prostate cancer, Dr. Nelson notes that inactivation of DNA repair genes occurs in >20% of patients with metastatic CRPC and these patients may have homologous recombination-mediated repair (HR) or mismatch repair (MMR) defects. Common genes implicated include BRCA2, CHD1 and SPOP, among others. Specifically, SPOP DNA repair mutations have been demonstrated to lead to genomic instability in prostate cancer. MMR genes represented a prostate cancer hyper-mutation subtype that is primarily driven by structural alterations (MSH2, MSH6, etc)
Germline DNA repair gene alterations are also common in mCRPC, as previous studies have demonstrated that 11.8% of patients may have deleterious germline mutations in 16 DNA repair genes. The reason germline HR defects are clinically important is that these deletions may predict response to PARP inhibitors and platinum-based chemotherapy regimens. Recent studies have also suggested that MMR deficiencies such as MSH2/6 may play a role in the PD1/PDL1 blockade pathway.
Dr. Nelson notes that we are missing a number of aspects prior to truly being able to offer precision medicine. Questions that remain to be answered include (i) Does a DNA repair mutation always confer DNA repair deficiency? (ii) Are all DNA repair mutations equal? (iii) Are we missing other DNA repair gene mutations/events? (iv) Are there other genomic modifiers of DNA repair gene mutations? (v) What is the mechanism of resistance? Dr. Nelson notes that among the University of Washington experience, 32% of patients with CRPC have ‘some’ HRs, 18% have high HRs, 44% with high HR somatic signature have at least one HR mutation or homozygous deletion, and 37% of HR signature tumors have aa bonafide HR mutation. Recent research has also reported that an MMR signature can in fact mask an HR signature, even though the HR genes are mutated.
In summary, HR gene aberration does not always confer a ‘read out’ of HR deficiency and that there may be an HR signature present in a subset of tumors that do not have a clear HR gene aberration. Ultimately, which assays best indicate HR deficiency and consequently susceptibility to PARP inhibitors and chemotherapy remains to be fully elucidated.
Presented by: Peter Nelson, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA