ASCO 2017: Next-generation sequencing of tissue and cell free DNA (cfDNA) to identify somatic and germline alterations in advanced prostate cancer

Chicago, IL ( As patient selection becomes a more critical part of prostate cancer management, particularly in advanced prostate cancer, there has been growing emphasis on using genomic data to help stratify patients. However, greater understanding regarding the genomic landscape of advanced prostate cancer is required, particularly in large datasets. In this study, the MSKCC and Cornell groups utilize a large combined dataset of 1038 prospectively collected tumors from 896 patients to help provide greater understanding of the genomic characterization of advanced prostate cancer.

Using a capture-based next-generation sequencing (NGS) assay (MSK-IMPACT) targeting 341–468 genes for all patients, the group also began offering formal germline analysis of 76 genes associated with heritable cancer risk for patients enrolled after May 2015. Additionally, they analyzed cell-free DNA (cfDNA) to assess the feasibility of identifying targetable alterations in patients for whom adequate tumor tissue was unavailable.

In a three year time frame, 576 primary tumors and 462 metastases were sequenced. Some of their key findings based on their analysis:
1. High frequency of known or likely pathogenic germline and somatic mutations in genes that regulate DNA damage response (DDR)
2. In the subset of patients with both tumor and germline analysis, 28.84% (169/586) had a DDR mutation identified compared to only 10.65% (33/310) of patients with somatic only analysis
3. In the subset of patients with tumor and germline analysis, 9.39% (55/586) had somatic only DDR mutations and 16.38% (96/586) had germline only DDR mutations, including 8 pts with two germline mutations
4. 3.07% (18/586) had co-occurring somatic and germline DDR mutations, with only 0.68% (4/586) involving the same DDR gene (all BRCA2)
5. Microsatellite instability (MSI) was measured using MSISensor, with MSI Score > 10 being consistent with MSI. Elevated MSI scores were noted even in a minority of patients who did not have an mismatch repair (MMR) mutation. One patient in particular had an elevated MSI score (26.2) and had a profound response to anti-PD-L1 therapy – durable partial response and complete PSA response.  
6. Interestingly, of all the solid tumors being assessed in this study, prostate cancer had the highest tissue failure rate. Bone biopsies were only successfully sequenced in 42% of patients, and cfDNA identified mutations in 4/32 (12.5%) patients without other tissue samples.

Ultimately, neither somatic mutations nor germline mutations completely captured the genomic profile of the patients completely. Both are required to adequately profile patients with advanced prostate cancer. cfDNA may add some value in patients for whom adequate tissue sampling was not available.

Presented By: Michael L. Cheng, Memorial Sloan-Kettering Cancer Center

Co-Author(s): Wassim Abida, Dana E. Rathkopf, Maria E. Arcila, David Barron, Karen A. Autio, Ahmet Zehir, Daniel Costin Danila, Michael J. Morris, Anuradha Gopalan, Victor E. Reuter, Philip W. Kantoff, Susan F. Slovin, Mark E. Robson, Liying Zhang, Diana Mandelker, Dana Tsui, Barry S. Taylor, David B. Solit, Howard I. Scher

Institution(s): Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical College, New York, NY             

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA