ASCO GU 2023: Use of a Navigable Interface for Integrated Whole Genome and Transcriptome Sequencing as a Platform for Pursuit of Therapeutic Targets in Advanced Prostate Cancers

( Nauseef et al. describe the use of a navigable interface for whole genome and transcriptome sequencing as a platform to identify therapeutic targets in patients with advanced prostate cancer.

As the authors note, metastatic castration-resistant prostate cancer (mCRPC) is the deadliest form of prostate cancer (PC). Among these patients, there are a subset of tumors that are androgen-indifferent; indeed, the most aggressive often manifests with variant histology, including neuroendocrine or small cell changes. Neuroendocrine PC can be de novo (NEPC) or develop in response to therapy as treatment emergent (CRPC-NE). But, currently effective durable treatments for NEPC are lacking. Hence, the authors aimed to identify additional targets in CRPC/NEPC using an integrative platform of whole genome (WGS) and transcriptome sequencing (RNAseq).

Using cases from their Weill Cornell Medicine Englander Institute for Precision Medicine cohort of advanced PC, whole genome sequencing (WGS) was performed on 55 tumor/normal pairs (CRPC-Ad, n= 32; CRPC-NE, n=13; de novo NEPC, n=7; metastatic hormone naïve, PC n=3) from 48 patients. RNAseq data were available in a subset of 21 samples. They employed the Isabl GxT analytic platform and manually curated single base substitution (SBS, COSMIC v3) molecular signatures and structural variants (SV) that involved tumor suppressor genes and oncogenes. Cases were then reviewed by Medical Oncology, Computational Biology, and Pathology teams.

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The cohort utilized is summarized below:

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Jumping to their results, they observed 184 events in cancer-associated genes and targets in 38 cases. Non-canonical ETS fusions were identified in 2 CRPC-Ad patients (MSMB-ERG and YWHAE-ETV4). Other rare events included SVs affecting ALK (SLC45A3-ALK) and FGFR1 amplification in 1 patient each.  

Pathogenic germline alterations occurred in 15% of patients with equal frequency in each clinicopathological state. These variants included genes such as BRCA1, BRCA2, and ATM, and other genes of uncertain relevance for prostate cancer (e.g.,PPM1D and MUTYH). SBS genomic signatures associated with homologous recombination deficiency (HRD) were observed in 15% of the patients (7 cases): 3 harbored germline BRCA1/2mutations, 2 with somatic BRCA2 mutations, and 2 without alteration in BRCA1/2 (1 of these CRPC-Ad had a complex SV disrupting RAD51B) without apparent enrichment for any histology, and a majority of both histologies were enriched in Mismatch repair (MMR)-associated SBS.

One subject with CRPC-NE and amphicrine character, which displayed a complete response to immune checkpoint blockade, harbored driver mutations in AR and CTNNB1, and homozygous loss of MSH2/6. This, and two other cases in which actionable targets were identified are highlighted below:


Further, molecular signatures of potential clinical relevance were detected at varying contributions and included CDK12-type genomic instability (CRPC-Ad, n=2) (4%) and MMR deficiency with POLD1 proofreading (CRPC-Ad) who also experienced a durable response to pembrolizumab.

Based on this, they concluded that using an integrated and navigable platform WGS/RNAseq in CRPC and NEPC helps identify genomic signatures associated with HRD and MMR, complex SVs in oncogenes, and non-canonical ETS fusions. 184 events in cancer-associated genes were detected in 67% of cases and 15% contained pathogenic variants in BRCA1, BRCA2, and/or ATM. Expansion of their analysis is underway with enhanced integration of clinical metadata and RNAseq for rational trial design for aggressive variant CRPC and NEPC.

Presented by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at New York - Presbyterian Hospital.

Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis @tchandra_uromd on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.

Related Content: 
An Integrative Platform of Whole Genome and Transcriptome Sequencing to Identify Additional Targets in Castration-resistant Prostate Cancer and Neuroendocrine Prostate Cancer - Jones Nauseef