The 17-gene Genomic Prostate Score assay as a predictor of biochemical recurrence in men with intermediate and high-risk prostate cancer.

The validated 17-gene Oncotype DX Genomic Prostate Score® (GPS™) assay risk-stratifies prostate-cancer patients with localized disease. The assay has primarily been utilized in lower risk patients deciding between active surveillance versus definitive therapy. In this retrospective cohort study, we analyze the association of the GPS result with time to biochemical recurrence post-prostatectomy in patients with National Comprehensive Cancer Network® (NCCN) intermediate and higher risk prostate cancer. The 141 patients included in the study were from the NorthShore University HealthSystem diagnosed 2014-2019 with NCCN intermediate (n = 109) or higher risk (n = 32) prostate cancer, treated with radical prostatectomy 2015-2019. The association of GPS result with time to biochemical recurrence was evaluated using univariable and multivariable Cox proportional hazards models in 120 patients with unfavorable intermediate or higher risk. Median (interquartile range) follow-up time was 28 (20 to 38) months. The GPS result was significantly associated with time to biochemical recurrence as both a continuous and dichotomous variable in univariable (hazard ratio [HR] per 20 GPS units 2.36, 95% CI 1.45-3.80, p < 0.001; HR for GPS result 41-100 vs 0-40 3.28, 95% CI 1.61-7.19, p < 0.001) and in multivariable models accounting for NCCN risk group (HR per 20 GPS units 2.14, 95% CI 1.31-3.46, p = 0.003; HR for GPS result 41-100 vs 0-40 3.00, 95% CI 1.43-6.72, p = 0.003) or biopsy Gleason Score and diagnostic PSA or PSA density. These results indicate that the GPS assay was a strong predictor of biochemical recurrence after radical prostatectomy in this unfavorable intermediate and higher risk prostate cancer patient population.

Heterogeneity of human prostate carcinoma-associated fibroblasts implicates a role for subpopulations in myeloid cell recruitment.

BACKGROUND: Carcinoma-associated fibroblasts (CAF) are a heterogeneous group of cells within the tumor microenvironment (TME) that can promote tumorigenesis in the prostate. By understanding the mechanism(s) by which CAF contributes to tumor growth, new therapeutic targets for the management of this disease may be identified. These studies determined whether unique sub-populations of human prostate CAF can be identified and functionally characterized. METHODS: Single-cell RNA-seq of primary human prostate CAF followed by unsupervised clustering was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. Potential communication between CAF and immune cells was analyzed using in vivo tissue recombination by combining CAF or normal prostate fibroblasts (NPF) with non-tumorigenic, initiated prostate epithelial BPH-1 cells. Resultant grafts were assessed for inflammatory cell recruitment. RESULTS: Clustering of 3321 CAF allows for visualization of six subpopulations, demonstrating heterogeneity within CAF. Sub-renal capsule recombination assays show that the presence of CAF significantly increases myeloid cell recruitment to resultant tumors. This is supported by significantly increased expression of chemotactic chemokines CCL2 and CXCL12 in large clusters compared to other subpopulations. Bayesian analysis topologies also support differential communication signals between chemokine-related genes of individual clusters. Migration of THP-1 monocyte cells in vitro is stimulated in the presence of CAF conditioned medium (CM) compared with NPF CM. Further in vitro analyses suggest that CAF-derived chemokine CCL2 may be responsible for CAF-stimulated migration of THP-1 cells, since neutralization of this chemokine abrogates migration capacity. CONCLUSIONS: CAF clustering based on DE gene expression supports the concept that clusters have unique functions within the TME, including a role in immune/inflammatory cell recruitment. These data suggest that CCL2 produced by CAF may be involved in the recruitment of inflammatory cells, but may also directly regulate the growth of the tumor. Further studies aimed at characterizing the subpopulation(s) of CAF which promote immune cell recruitment to the TME and/or stimulate prostate cancer growth and progression will be pursued.

Nanocytological field carcinogenesis detection to mitigate overdiagnosis of prostate cancer: a proof of concept study.

PURPOSE: To determine whether nano-architectural interrogation of prostate field carcinogenesis can be used to predict prognosis in patients with early stage (Gleason 6) prostate cancer (PCa), which is mostly indolent but frequently unnecessarily treated. MATERIALS AND METHODS: We previously developed partial wave spectroscopic microscopy (PWS) that enables quantification of the nanoscale intracellular architecture (20-200 nm length scale) with remarkable accuracy. We adapted this technique to assess prostate needle core biopsies in a case control study from men with Gleason 6 disease who either progressed (n = 20) or remained indolent (n = 18) over a ~3 year follow up. We measured the parameter disorder strength (Ld) characterizing the spatial heterogeneity of the nanoscale cellular structure and nuclear morphology from the microscopically normal mucosa ~150 histologically normal epithelial cells. RESULTS: There was a profound increase in nano-architectural disorder between progressors and non-progressors. Indeed, the Ld from future progressors was dramatically increased when compared to future non-progressors (1±0.065 versus 1.30±0.0614, respectively p = 0.002). The area under the receiver operator characteristic curve (AUC) was 0.79, yielding a sensitivity of 88% and specificity of 72% for discriminating between progressors and non-progressors. This was not confounded by demographic factors (age, smoking status, race, obesity), thus supporting the robustness of the approach. CONCLUSIONS: We demonstrate, for the first time, that nano-architectural alterations occur in prostate cancer field carcinogenesis and can be exploited to predict prognosis of early stage PCa. This approach has promise in addressing the clinically vexing dilemma of management of Gleason 6 PCa and may provide a paradigm for dealing with the larger issue of cancer overdiagnosis.

Invasive micropapillary carcinoma of the breast is associated with chromosome 8 abnormalities detected by comparative genomic hybridization.

Invasive micropapillary carcinoma (IMC) of the breast is a rare variant of invasive ductal carcinoma (IDC) characterized by unique histology and an extremely high incidence of lymph node metastases (approximately 95%). Comparative genomic hybridization (CGH) was used to characterize DNA extracted from 16 archival IMC cases to identify clonal genetic changes associated with this unique and highly metastatic cancer subtype. The average number of chromosomal alterations per IMC tumor was 7.4 +/-2.9 (3.4 gains and 3.9 losses), fewer than the number that we have observed in IDCs not otherwise specified (9.5 +/-6.6), IDCs with erbB-2 gene amplification (12.6 +/-5.9), and invasive lobular carcinomas (8.2 +/-5.5). The mean number of changes in IMC was significantly higher than we have observed in the rarely metastasizing tubular subtype of IDC (3.9 +/-2.3, P = 0.001), but less than the more aggressive subset of erbB-2-amplified IDC (P = 0.02). Remarkably, 100% of IMCs demonstrated loss involving the short arm of chromosome 8 (8p). Six cases showed loss of the entire 8p arm, whereas in 10 cases the loss was limited to the distal portion (8p21-pter) with localized gain of proximal 8p (8p11-p12). A reciprocal gain of 8q was detected in 14 cases (88%). Other common alterations included loss of 17p in 50% of tumors and loss of 16q in 50% of IMC cases. Gains of 17q (38%), 1q (31%), and 16p (25%) were also commonly detected. In comparison, IDCs (not otherwise specified), IDCs of the tubular subtype, and invasive lobular carcinomas showed only modest 8p loss (33%, 28%, and 13%, respectively). This region of chromosome 8 may contain 1 or more genes whose loss leads to this particular histology and/or the lymphotrophic phenotype associated with this histopathologic pattern.