Publications

BACKGROUND

A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3βHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-abiraterone synthesis in patients.

METHODS

First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5α-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics.

RESULTS

Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002).

CONCLUSION

Increased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition.

FUNDING

Prostate Cancer Foundation Challenge Award, National Cancer Institute.

BACKGROUND

Multiple sclerosis (MS) incidence has increased recently, particularly in women, suggesting a possible role of one or more environmental exposures in MS risk. The study objective was to determine if animal, dietary, recreational, or occupational exposures are associated with MS risk.

METHODS

Least absolute shrinkage and selection operator (LASSO) regression was used to identify a subset of exposures with potential relevance to disease in a large population-based (Kaiser Permanente Northern California [KPNC]) case-control study. Variables with non-zero coefficients were analyzed in matched conditional logistic regression analyses, adjusted for established environmental risk factors and socioeconomic status (if relevant in univariate screening),± genetic risk factors, in the KPNC cohort and, for purposes of replication, separately in the Swedish Epidemiological Investigation of MS cohort. These variables were also assessed in models stratified by HLA-DRB1*15:01 status since interactions between risk factors and that haplotype have been described.

RESULTS

There was a suggestive association of pesticide exposure with having MS among men, but only in those who were positive for HLA-DRB1*15:01 (OR pooled = 3.11, 95% CI 0.87, 11.16, p = 0.08).

CONCLUSIONS

While this finding requires confirmation, it is interesting given the association between pesticide exposure and other neurological diseases. The study also demonstrates the application of LASSO to identify environmental exposures with reduced multiple statistical testing penalty. Machine learning approaches may be useful for future investigations of concomitant MS risk or prognostic factors.