There is a potential for molecular and genomic biomarker application across several prostate cancer disease states. Among men with localized disease (i) affirming stage (organ-confined), (ii) predicting treatment response (XRT sensitivity, need for adjuvant treatment, etc), and (iii) predicting risk of progression on active surveillance. For men with metastatic disease (i) affirming metastatic volume and (ii) predicting treatment response, for example, selecting the ideal therapy in mCSPC and/or selecting treatment sequence in CRPC. In the latest version of the NCCN guidelines for systemic therapy for M1 CRPC, recommendations suggest consideration for metastatic lesion biopsy and to consider tumor testing for MSI-high or mismatch repair deficiency (dMMR) mutations. Furthermore, these guidelines recommend germline genetic testing for all men with high-risk, very-high-risk, regional or metastatic prostate cancer.
Dr. Garraway notes that there are several prognostic/predictive genomic biomarkers that have been previously described:
- DDR/homologous recombination DNA repair gene mutations: BRCA1, BRCA2, ATM, PALB2, and CHEK2. If these are positive, men should be considered for a clinical trial or treatment with a PARP inhibitor or platinum-based chemotherapy.
- dMMR or MSI-high variants: men should be treated with pembrolizumab if these alterations are found
- CDK12 loss: consider testing mCRPC cases for enrollment in immunotherapy clinical trials
- AR amplification/AR-V7: predicts abiraterone/enzalutamide resistance
- Tumor suppressor genes: RB, PTEN, TP53. These are associated with a poor prognosis, as they are currently treatment resistant
For the CHAARTED study assessing HSD3B1 and OS in men with low-volume metastatic prostate cancer, multivariable analysis showed that HSD3B1(1245C) genotype demonstrated (i) shorter time to CRPC: HR 1.89 (95% CI 1.13-3.14), and (ii) lower overall survival: HR 1.74 (95% CI 1.01-3.00). For high volume men, there was no association between genotype and clinical outcomes.
Finally, the study assessing genomic predictors of the benefit of docetaxel and next-generation hormonal therapy in mCRPC found that PTEN alterations were associated with worse time to treatment failure on next-generation hormonal therapy, but not docetaxel; a similar trend was observed with BRCA2. Biallelic RB1 loss was strongly predictive, conferring significantly shorter time to treatment failure on both next-generation hormonal therapy (HR 1.76, 95% CI 0.96-3.21) and docetaxel (HR 2.30, 95% CI 1.10-4.81).
Dr. Garraway noted several take-home points from these three studies:
- RB1 loss is a poor prognostic sign in mCRPC
- Compound loss of PTEN + RB1 and TP53 + RB1 demonstrates significantly worse outcomes to mCRPC treatments compared to single or no ‘hits’
- HDSB31(1245C) variant consistently demonstrates value as a prognostic/predictive biomarker, showing ADT-resistance and shorter OS in Caucasian men with low volume mCSPC
- PTEN/TP53 and DNA damage repair alterations are enriched in mCSPC primary tumors
Presented by: Isla Garraway, MD, PhD, David Geffen School of Medicine, UCLA, Los Angeles, California
Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA