Dana-Farber Cancer Institute, Boston, MA
Anis Hamid , Himisha Beltran , Atish Dipankar Choudhury , Christopher Sweeney
Background: Predictive genomic biomarkers in mCRPC remain elusive. Prior studies suggest that tumor suppressor (TS) loss is prognostic, and may result in less benefit from NHT, but no impact on D efficacy. We assessed genomic predictors of differential benefit of androgen receptor-targeted therapy and chemotherapy for mCRPC. Methods: Patients with mCRPC and targeted exome sequencing of biopsies obtained after metastatic diagnosis were identified (n=109). Patients with pure small cell histology (n=6) were excluded. Time from NHT or D start to clinical/radiographic progression (time to treatment failure, TTTF) was estimated by Kaplan-Meier method, with censoring at next therapy or last follow-up for non-progressors. Results: 80.1% of patients had bone and/or lymph node-only metastases at mCRPC diagnosis. In total, 87/103 (84.5%) and 61/103 (59.2%) received NHT and D for mCRPC, respectively. Median overall survival was 4.5 years from first mCRPC. The frequency and predictive association of selected recurrently-altered genes are detailed in the table. PTEN alterations (alts) were associated with worse TTTF on NHT, but not D, and a similar trend was observed with BRCA2. Biallelic RB1 loss was strongly predictive, conferring significantly shorter TTTF on both NHT and D. A score based on presence of tumor PTEN alt (1) and/or biallelic RB1 alt (1) was predictive of TTTF on NHT (median TTTF of score 0 vs 1 vs 2: 14.7 vs 12 vs 3.8 months; log rank p=0.003). Conclusions: The presence of single or compound PTEN and RB1 alts predict poorer outcomes with NHT for mCRPC. Chemotherapy may be a preferred therapeutic strategy for this patient population.
Abiraterone/Enzalutamide N=86 Median TTTF=12.2 mo | Docetaxel N=61 Median TTTF=5.1 mo | ||||
---|---|---|---|---|---|
Gene | N=103 | HR | p-val | HR | p-val |
PTEN mo/bi | 59.2% | 1.68 | 0.029 | 0.83 | 0.52 |
PTEN bi | 32% | 1.25 | 0.39 | 0.96 | 0.89 |
TP53 mo/bi | 65% | 1.17 | 0.52 | 0.84 | 0.55 |
TP53 bi | 47.6% | 1.1 | 0.67 | 0.96 | 0.87 |
RB1 mo/bi | 65% | 1.29 | 0.28 | 1.04 | 0.88 |
RB1 bi | 12.6% | 2.86 | 0.003 | 3.17 | 0.007 |
BRCA2 | 11.7% | 1.83 | 0.088 | 0.31 | 0.091 |
ATM | 5.8% | 0.84 | 0.7 | 0.52 | 0.37 |
AR amplification | 30.1% | 1.02 | 0.92 | 0.81 | 0.46 |
AR mutation | 10.7% | 0.36 | 0.017 | 1 | 0.99 |
Key: mo/bi, monoallelic or biallelic loss; bi, biallelic loss only.
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