Fisher’s exact tests and unpaired
t tests were performed in R (3.5.0) and GraphPad Prism software as indicated. For the analysis shown in
Fig. 2B, enrichment analysis using a binomial distribution test was performed as previously described (45 (
link)) to identify genes that had a significant fraction of known or likely oncogenic alterations (as defined by OncoKB) among all identified SNVs. Multiple hypothesis test correction was applied using the Benjamini–Hochberg method, with
q values of <0.05 considered significant for enrichment of oncogenic mutations among all SNVs identified for a gene. Kaplan–Meier analysis was performed from time of biopsy to death for all samples. Overall survival analysis was performed for the
n = 128 subjects who received an ARSI (abiraterone, enzalutamide, or apalutamide) in the first-line setting before a taxane, either alone or in combination with another agent in a clinical trial, and where the profiled tissue was obtained before the start of therapy or within 90 d after starting first-line therapy. Time on treatment analysis was evaluated for a subset of
n = 108 patients (of the 128 above), who received an ARSI in the first-line setting without another agent, so as not to confound the interpretation of response to the ARSI.
P values for individual (univariate) association tests between genomic status and survival/time on treatment were generated from the log-rank statistic. In cases where a data-driven threshold value was used to determine the genomic status, the
P value was computed from the maximum log-rank statistic. When a genomic class contained a small number of events, the
P value was produced using a permutation log-rank test. A concordance probability estimate provided a metric to assess the level of separation between the Kaplan–Meier curves and is reported in relevant cases. Multivariate analyses were performed for the association of common genomic characteristics shown in
Table 1 with overall survival and time on a first-line ARSI, with relative risk reported based on the Cox proportional hazards model. Kendall’s tau, derived from the Clayton copula, was used to evaluate the level of association between the time on therapy end point and overall survival.
Abida W., Cyrta J., Heller G., Prandi D., Armenia J., Coleman I., Cieslik M., Benelli M., Robinson D., Van Allen E.M., Sboner A., Fedrizzi T., Mosquera J.M., Robinson B.D., De Sarkar N., Kunju L.P., Tomlins S., Wu Y.M., Nava Rodrigues D., Loda M., Gopalan A., Reuter V.E., Pritchard C.C., Mateo J., Bianchini D., Miranda S., Carreira S., Rescigno P., Filipenko J., Vinson J., Montgomery R.B., Beltran H., Heath E.I., Scher H.I., Kantoff P.W., Taplin M.E., Schultz N., deBono J.S., Demichelis F., Nelson P.S., Rubin M.A., Chinnaiyan A.M, & Sawyers C.L. (2019). Genomic correlates of clinical outcome in advanced prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 116(23), 11428-11436.
