ASCO 2017: Genomic Selection for Prostate Cancer: Are We Ready?
Dr. Bristow started by highlighting that one of the key messages of these three abstracts assessing genetic testing is treatment “Intensification” – bringing systemic therapies into earlier disease states to improve cure rates, in the appropriately identified patients. However, with genetic tests, a series of questions must be answered for each one: (i) Do we know the biology behind the test? (ii) Do we have a validated clinical-grade assay? (iii) Is it cheap and is it adoptable worldwide? (iv) Is it prognostic or predictive? (v) Does it better our clinical decision-making and change treatment? Some of the work from Dr. Bristow’s group has demonstrated poor outcomes associated with intraductal carcinoma and cribriform architecture is associated with a constellation of genomic instability, SChLAP1 expression, and hypoxia, leading to increased metastatic capacity [4]. Whether the model suggested by Spratt et al. [1] is able to identify these aggressive subpathologies is of concern, according to Dr. Bristow.
Given that we know that up to 25% gene repair defects occur in CRPC, circulating tumor DNA (ctDNA) with targeted sequencing is a reasonable way to track response to treatment. According to Dr. Bristow “ctDNA is probably a measure of bulk of ‘genetic instability’ as well as disease.” Not surprisingly, patients with DNA repair deletions (particularly BRCA2/ATM/p53) mutations do poorly. Dr. Bristow thinks there is supportive evidence relating to previous findings in localized disease of adverse prognosis in patients with DNA repair deletions using ctDNA as endpoints. However, he cautions that the assays do not always measure DNA repair deletion function. Highlighting the finding from the Hussain et al [2] abstract, Dr. Bristow notes that patients with DNA repair deletion tumors had better and more durable response compared to wild-type patients irrespective of treatment arm (abiraterone + prednisone +/- veliparib).
There are a number of challenges that lie ahead for localized prostate cancer with regards to sporadic vs BRCA prostate cancer according to Dr. Bristow. For both entities there are few clinically-actionable single-nucleotide variants in contrast to mCRPC, and a significant proportion of tumors have important genomic rearrangements for which there is unknown clinical significance. For sporadic disease, there are genetic tests accumulating for clinical use and the work by Spratt et al [1] begins to incorporate genomics with NCCN criteria in a practical manner, but whether it holds up to newer tests and intraductal carcinoma/cribriform pattern remains to be seen. For BRCA tumors, there are distinct hypomethylation patterns and gene pathways associated with mCRPC which are active before hormone therapy, and it is important to better understand these tumors and intervene earlier in the natural history of the disease.
Presented By: Robert G. Bristow, Princess Margaret Cancer Centre, Toronto, ON, Canada
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @zklaassen_md
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA
References:
1. Spratt DE, Zhang J, Santiago-Jimenez M, et al. Development and validation of a novel clinical-genomic risk group classification for prostate cancer incorporating genomic and clinicopathologic risk. J Clin Oncol 2017;35(suppl; abstr 5000).
2. Hussain M, Daignault S, Twardowski P, et al. Abiraterone + prednisone (Abi) +/- veliparib (Vel) for patients (pts) with metastatic castration-resistant prostate cancer (CRPC): NCI 9012 Updated clinical and genomics data. J Clin Oncol 2017;35(suppl; abstr 5001).
3. Chi KN, Annala M, Sunderland K, et al. A randomized phase II cross-over study of abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC). J Clin Oncol 2017;35(suppl; abstr 5002).
4. Chua MLK, Lo W, Pintilie M, et al. A prostate cancer “Nimbosus”: Genomic Instability and SChLAP1 Dysregulation underpin aggression of intraductal and cribriform subpathologies. Eur Urol 2017 May 13 [Epub ahead of print].