University of Utah Hunstman Cancer Institute, Salt Lake City, UT
Andrew W Hahn , David Michael Gill , Peter Hale , Austin Poole , Roberto Nussenzveig , Sara Wilson , James M. Farnham , Robert A Stephenson , Benjamin Louis Maughan , Lisa Cannon-Albright , Neeraj Agarwal
Background: Predictive biomarkers of response to AA in advanced prostate cancer are needed. SLCO2B1 encodes a protein that mediates transport of AA into tissue. A pre-clinical study showed that variant alleles in select single nucleotide polymorphisms (SNPs) for SLCO2B1, rs12422149 and rs1789693, result in higher tumor tissue AA levels (Mostaghel EA, Clin. Can. Res., 28389510). In an exploratory analysis, we found a non-significant trend towards improved progression-free survival (PFS) in men with variant alleles for rs12422149 but not for rs1789693 on AA in mCRPC patients. Here, we interrogate the correlation of variant alleles in rs12422149 with PFS on first-line therapy with AA in men with new mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah. Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was PFS on first-line AA in men with mCRPC. We performed a pre-specified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 on PFS on AA. Results: Of 401 men with advanced prostate cancer genotyped. 323 were homozygous wild type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line AA for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared to the homozygous group (8.9 months vs. 6.3 months, HR 0.46, 95% CI 0.23-0.94, p=0.03) (Table). Conclusions: In this first clinical validation of pre-clinical data reported by Mostaghel, et al., variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line AA In men with mCRPC. These findings need external validation.
rs12422149 GG (n=63) | rs12422149 AG (n=16) | rs12422149 AA (n=0) | p value* | ||
---|---|---|---|---|---|
log PSA at AA Initiation | 3.22 (1.47) | 3.60 (1.40) | NA | 0.36 | |
Gleason | 0.35 | ||||
4 | 2 (3%) | 0 | 0 | ||
5-6 | 4 (6%) | 3 (19%) | 0 | ||
7 | 14 (22%) | 2 (12%) | 0 | ||
8-10 | 43 (69%) | 11 (69%) | 0 | ||
Cox Regression results: | |||||
Median PFS (months) | 6.3 | 8.9 | NA | ||
Hazard rate | 1.0 | 0.462 (p=0.034) | NA | ||
HR CIs | NA | 0.23-0.94 | NA |
*p values are comparisons across the two observed genotypes
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