3094 - Circulating tumor cell (CTC) genomic landscape in neuroendocrine prostate cancer (NEPC) by single cell copy number analysis

Background

Cell-to-cell heterogeneity is a major driver of cancer evolution, progression, and drug resistance. NEPC is an aggressive variant of prostate cancer that may develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. Loss of tumour suppressors RB1, TP53, PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinoma. Through single-cell CTC genomics of men with castration resistant adenocarcinoma (CRPC-Adeno) and NEPC, we aimed to characterize the clonal heterogeneity that underlies these resistance scenarios.

Methods

CTCs were assessed using Epic Sciences platform for morphology and expression of adenocarcinoma (AR) and NEPC (DLL3) markers. Low pass whole genome sequencing was performed on individual cells/clusters. CTC copy number alterations (CNAs) were compared with whole exome sequencing data of patient-matched tumor biopsies.

Results

A total of 182 CTCs from 13 pts (5 CRPC, 8 NEPC) with matched biopsies were analyzed for 87 commonly altered prostate cancer genes. 11 pts (7 NEPC and 4 CRPC-Adeno, 177 CTCs) had at least 3 CTCs with one or more gene CNA. Concordance of these alterations with matched biopsy was 90.9%. All 7 NEPC pts had at least one tumor RB1,TP53, or PTEN loss; 71.4% (5/7) pts had loss of > two tumor suppressors, of which 40.6% (43/106) of CTCs harbored alterations in the same cell (vs. different cells). In contrast, only 2/4 CRPC-Adeno pts had one RB1/TP53/PTEN loss and loss of > 2 occurred in none. Combined loss of RB1, TP53 and/or PTEN in CTCs was associated with lower AR expression and higher DLL3 expression in CTCs. Other CNAs showed similar trends, with higher concordance of alterations across CTCs in individuals with NEPC.

Conclusions

Prostate cancer associated CNA profiles of single cell CTCs was consistent with matched metastatic tumor biopsies in our cohort. Combined loss of tumour suppressor genes is more frequent in NEPC than in CRPC-Adeno and more often co-occurs in individual cells. Overall there is higher concordance, or less diversity (heterogeneity), across CTCs in NEPC. Analysis of additional patients including serial CTC assessment is ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Prostate Cancer Foundation, National Cancer Institute SPORE P50-CA211024, and Epic Sciences.

Disclosure

V. Conteduca: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Sanofi. Y. Wang: Full / Part-time employment: Epic Sciences. L. Fernandez: Full / Part-time employment: Epic Sciences. M. Kearney: Full / Part-time employment: Epic Sciences. J. Lee: Full / Part-time employment: Epic Sciences. R. Jiles: Full / Part-time employment: Epic Sciences. A. Rodriguez: Full / Part-time employment: Epic Sciences. R. Dittamore: Full / Part-time employment, Officer / Board of Directors: Epic Sciences. H. Beltran: Advisory / Consultancy: Janssen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Astellas. All other authors have declared no conflicts of interest.