Purpose: Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based comprehensive genomic profiling. However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice. Experimental Design: We assessed the landscape of 16,812 liquid profiles across 49 cancer types using the Caris Assure assay, a whole-exome and whole-transcriptome next-generation sequencing workflow that independently sequences both plasma-derived cell-free total nucleic acids and the white blood cell DNA and RNA from the buffy coat. The variant source was identified algorithmically by comparing plasma and buffy coat variant frequency and read quality metrics. Results: Of 16,812 patients, 42.3% presented at least one CH variant among reportable clinical genes. We found 39% of BRCA2 variants to be of CH origin, as well as 37.9% of CHEK2, 27.4% of BRCA1, 20.1% of ATM, 7.3% of NRAS, 5.8% of BRAF, 2.1% of EGFR, 2.1% of KRAS, and 18.5% of TP53. For patients aged 65 to 69 years, the median proportion of CH variant classification was 20%, whereas it was 33% for patients aged 70 to 74 years, 33% for ages 75 to 79 years, and 50% for ages 80+ years. We found high rates of CH detected in what would be otherwise druggable targets in many cancer types typically treated with PARP inhibitors, including breast, female genital tract, ovarian, pancreatic, prostate, and endometrial cancers. Conclusions: This large study highlights the need for thorough CH classification during liquid biopsy to appropriately recommend therapies, especially PARP inhibitors. See related commentary by Bernard and Micol, p. 2545

Androgen-indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse, and AIPC remains a poorly understood malignancy. Utilizing the Oncology Research Information Exchange Network (ORIEN) database, we enriched for tumors with features of AIPC using previously described characteristics. Our AIPC cohort included three subgroups: aggressive variant prostate cancer (AVPC), neuroendocrine PC (NEPC), and double-negative PC (DNPC). Of 1496 total PC patients available for analysis, we identified 323 (22%) as MCRPC. Of those, 39 (12%) met AIPC criteria (17 AVPC, 13 NEPC, 9 DNPC) and 284 (88%) were non-AIPC. Forty-three percent of AIPC patients had de novo metastatic disease vs. 15% for non-AIPC (p = 0.003). Homologous recombination deficiency (HRD) and tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) were significantly higher in AIPC (p = 0.019). Using Gene Set Enrichment Analysis (GSEA), we found that genes defining response to androgens and genes involved in oxidative phosphorylation were the most downregulated, whereas genes involved in epithelial–mesenchymal transition (EMT) and immune signaling were significantly upregulated in AIPC vs. non-AIPC. Our study demonstrates the potential for predefined criteria that aim to enrich for AIPC and suggests opportunities for therapeutic investigation.

PURPOSE: Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC). METHODS: Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response. RESULTS: Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP -mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (≥8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP- mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02). CONCLUSION: SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP -mutated PC support its consideration as a unique molecular subtype with prognostic implications.