Genomic correlates of clinical outcome in advanced prostate cancer

Abstract

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.

Keywords: biomarkers; castration-resistant prostate cancer; clinical outcomes; integrative genomics.

Fig. 1.

Overview of sample and patient characteristics for 444 tumors from 429 patients with mCRPC. (A) Site of mCRPC tumors profiled. (B) Histopathologic classification of profiled tumors. Tumors were classified by central review as adenocarcinoma, pure small-cell/neuroendocrine cancer, adenocarcinoma with neuroendocrine features (also included mixed acinar/neuroendocrine carcinoma), or could not be classified due to scant material or no tumor visible on the slides that were available for review despite successful sequencing. (C) Patient exposure status to next-generation AR signaling inhibitors (abiraterone acetate, enzalutamide, or ARN509) and to taxanes at the time of biopsy for the 444 profiled tumors. (D) Overall survival (OS) from the date of biopsy of the profiled tumor. OS was longer for tumors from ARSI- and taxane-naive patients compared with patients who had received an ARSI before the biopsy (P < 0.01, log-rank test). Survival was shortest when the patient had received both an ARSI and taxane chemotherapy at the time of biopsy.

Fig. 2.

Landscape of genomic alterations in 444 tumors from 429 patients with mCRPC. (A) Genomic alterations of potential biologic relevance by frequency. (A, Top) Frequency of alteration by gene. Frequency of ETS gene alterations applies to the subset of 323 patients who underwent tumor RNA sequencing, where fusion status could be determined. (A, Bottom) Frequency of alteration by pathway (SI Appendix, Table S2). (B) Fraction of SNVs considered to be likely oncogenic for genes harboring mutations. Genes colored in red are putative oncogenes, genes colored in blue are putative tumor suppressor genes (TSGs), and genes colored green are currently unknown. (C) Co-occurrence or mutual exclusivity between the most commonly altered genes. The significance of the relationship is represented by gradient. Relationships with P value < 0.05 with multiple hypothesis correction are shown. Associations involving ETS genes (*) apply only to cases where RNA-sequencing data are available.

Fig. 3.

Alteration in PI3K and homologous recombination repair genes and association with clinical outcomes. (A) Oncoprint of genomic alterations in PI3K pathway genes. (B and C) Kaplan–Meier analysis showing overall survival (B) and time on treatment with a first-line ARSI (C) in PI3K pathway altered (red) versus unaltered (black) tumors. (D) Oncoprint of genomic alterations in BRCA2, BRCA1, and ATM. (E) Kaplan–Meier analysis showing time on treatment with a first-line ARSI in BRCA2/1/ATM–altered (homozygous deletion or somatic or pathogenic germline mutation) (red) versus unaltered (black) tumors.

Fig. 4.

Androgen receptor alterations and outcome. (A) AR splice variant landscape. LBD, ligand binding domain. (B) AR pathway expression score in AR-amplified (n = 168) versus nonamplified (n = 159) tumors. ***P < 0.001. (C) AR amplification frequency in ARSI-naive versus exposed tumors. (D) Kaplan–Meier analysis showing time on treatment with a first-line ARSI in AR-amplified versus nonamplified tumors. (E) Association between ARV7 expression and time on treatment with a first-line ARSI. o, censored event; x, off-treatment event.

Fig. 5.

Integrative analysis incorporating histopathology, transcript-based assessment of AR signaling and NEPC score, TP53 and RB1 genomic status, and clinical outcomes. (A) Kaplan–Meier analysis showing overall survival from the start of a first-line ARSI versus genomic status for TP53 and RB1 in n = 128 patients who received a first-line ARSI and underwent tissue profiling at baseline (before or within 90 d of therapy start). (B and C) Kaplan–Meier analysis showing time on treatment with a first-line ARSI by genomic status for RB1 and TP53. P values were generated from the log-rank statistic. (D) Frequency of histopathologic neuroendocrine features in pre- versus post-ARSI samples, among patients who received an ARSI at some point during their treatment history. Patients who were not reported to have received an ARSI at any point were excluded. **P < 0.01. (E) NEPC expression score in pre- (n = 118) versus post- (n = 152) ARSI samples, as in D. NS, not significant. (F) AR and NEPC expression scores, histopathology (CRPC-Adeno, no NE features; CRPC-NE, histopathologic NE features) and TP53/RB1 genomic status (circle, wild type for both; diamond, both altered) for the 332 tumors with RNA-sequencing data. Ten cases (3%, blue box) had low AR and low NEPC expression scores. (G–J) Representative cases of CRPC-Adeno (G), CRPC-NE, small-cell type (H), CRPC-Adeno showing intermediate transcriptomic scores (I), and CRPC-Adeno showing a high NEPC score/low AR signaling score (J). Tumors represented in I and J were noted to have distinct nuclear features, including various degrees of nuclear pleomorphism, irregular nuclear membrane contours, and/or high mitotic activity. (Scale bars, 25 μm.)