American Association for Cancer Research
10780432ccr150137-sup-143844_4_supp_3187546_nwb2bd.docx (1.66 MB)

Supplementary Figures 1-8, Supplementary Tables 1-6 from The Initial Detection and Partial Characterization of Circulating Tumor Cells in Neuroendocrine Prostate Cancer

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posted on 2023-03-31, 18:51 authored by Himisha Beltran, Adam Jendrisak, Mark Landers, Juan Miguel Mosquera, Myriam Kossai, Jessica Louw, Rachel Krupa, Ryon P. Graf, Nicole A. Schreiber, David M. Nanus, Scott T. Tagawa, Dena Marrinucci, Ryan Dittamore, Howard I. Scher

Figure S1: Examples of a decision boundary that separate class A (red) from class B (blue) in 1 dimension (figure 1A) and 2 dimensions (figure 1B); Figure S2: Schematic of the supervised learning process (A) and leave one out cross validation (B); Figure S3: Single iteration of Leave-One-Out Cross-Validation performed at the blood sample level; Figure S4: An example of concordance of AURKA amplification in tumor and CTCs; Figure S5: (A) Kernel Density Estimate (KDE) curves of the classifier output are plotted for each patient sample colored by their diagnosis: NEPC (red) and CRPC (blue); Figure S6: Cell-level NEPC classifier (A) Receiver-Operating-Characteristic (ROC) curve generated on the classifier's single-cell output after LOOCV; Figure S7: To address whether the CTC classifier is simply stochastic, a reflection of an overall higher CTC count, linearity was assessed with a Pearson's coefficient showing a weak relationship between frequency of NEPC CTCs and total cell count; Table S1: A summary of cell-level features utilized to train Random Forest cell-level classifiers in both the LOOCV and for the classification of CTCs in the test cohort; Table S2: Patient characteristics (discovery cohort) including prior systemic therapies, serum markers including PSA (ng/ml), Chromogranin (ng/ml), NSE (ng/ml) and CTC counts; Table S3: Liver metastases in NEPC vs. CRPC; Table S4: The median concentration of CK-negative and AR-negative CTCs in CRPC, atypical CRPC, and NEPC patients; Table S5: Confusion matrix for the ability of CD56 staining to discriminate patients diagnosed with Small Cell Carcinoma NEPC vs CRPC; Table S6: Example of results from a single tube of blood.


Department of Defense

Damon Runyon-Gordon Family Clinical Investigator Award



Purpose: The transition of prostate adenocarcinoma to a predominantly androgen receptor (AR) signaling independent phenotype can occur in the later stages of the disease and is associated with low AR expression +/− the development of small-cell or neuroendocrine tumor characteristics. As metastatic tumor biopsies are not always feasible and are difficult to repeat, we sought to evaluate noninvasive methods to identify patients transitioning toward a neuroendocrine phenotype (NEPC).Experimental Design: We prospectively studied a metastatic tumor biopsy, serum biomarkers, and circulating tumor cells (CTC, Epic Sciences) from patients with castration-resistant prostate cancer (CRPC) including those with pure or mixed NEPC histology present on biopsy. CTCs labeled with the patient's clinical status were used to learn features that discriminate NEPC patients, which was then applied to an independent cohort.Results: Twenty-seven patients with CRPC including 12 NEPC and 5 with atypical clinical features suggestive of NEPC transition were studied. CTCs from NEPC patients demonstrated frequent clusters, low or absent AR expression, lower cytokeratin expression, and smaller morphology relative to typical CRPC. A multivariate analysis of protein and morphologic variables enabled distinguishing CTCs of NEPC from CRPC. This CTC classifier was applied to an independent prospective cohort of 159 metastatic CRPC patients and identified in 17/159 (10.7%) of cases, enriched in patients with high CTC burden (P < 0.01) and visceral metastases (P = 0.04).Conclusions: CTCs from patients with NEPC have unique morphologic characteristics, which were also identified in a subset of CRPC patients with aggressive clinical features potentially undergoing NEPC transition. Clin Cancer Res; 22(6); 1510–9. ©2015 AACR.

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