ASCO 2021: Complementary Detection of Genomic Alterations in Metastatic Castration Resistant Prostate Cancer From CheckMate 9KD Through Analyses of Tumor Tissue and Plasma DNA

( There has been a proliferation in treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) in the last 10 years. While there are many available treatment options, to date, we have been unable to widely operationalize rationale treatment selection in this disease space. While tumor tissue is the richest source of somatic genomic information, plasma-based assessment is much more convenient and may allow for longitudinal assessment. In the Prostate, Testicular, Penile Poster session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Mark Sausen presented results of a comprehensive comparative analysis across three next-generation sequencings (NGS) platforms, using samples from patients enrolled in CheckMate 9KD, a phase 2 study of nivolumab combined with docetaxel, rucaparib, or enzalutamide for patients with confirmed mCRPC (NCT03338790).

The authors performed retrospective integrated analyses of sequence and structural alterations identified through comprehensive genomic profiling (CGP) of DNA obtained from formalin-fixed, paraffin-embedded tissue specimens and cell-free DNA obtained from plasma among patients enrolled on the CheckMate 9KD trial. Tissue-based analysis was performed using the FoundationOne assay (F1, 395 genes), while the FoundationACT (FACT, 70 genes) and GuardantOMNI (OMNI, 500 genes) assays were used for plasma-based analysis.

To allow for comparisons between NGS platforms, analysis was performed on samples from 103 patients in whom data from all 3 assays were available. The inter-platform analysis considered variants with ≥ 0.50% variant allele fraction and common to the shared pairwise targeted regions while excluding synonymous variants.

The authors confirmed previously identified recurrent alteration of AR, TP53, PTEN, and TMPRSS2 fusion with ETS genes, through broad profiling of DNA obtained from tissue and plasma. In addition, they found that a significant proportion of patients harbored a combination of germline and somatic mutations in homologous recombination repair pathway genes, with some variation between NGS platforms: 42% (F1), 45% (FACT), and 34% (OMNI).


Inter-platform variant analyses demonstrated concordance of 52% for F1 vs FACT, 40% for F1 vs OMNI, and 75% for FACT vs OMNI.


The authors further examined the proportion of variants identified in tissue and plasma-derived samples. They found a trend towards higher comparability between tissue and blood-based analyses when concentrations of ctDNA were higher. When ctDNA levels were low, a greater proportion of SNVs was found on the F1 assay than the OMNI assay.

Across all samples, the median tumor mutational burden was 3.5 mutations per megabase (mut/Mb) by F1 and 8.6 mut/Mb by OMNI.

The authors concluded that these data demonstrate the value of integrated tissue and liquid biopsy profiling in mCRPC. However, there was meaningful discordance between different NGS platforms which may be explained by technical and biological sources of variation, including panel size, mutation detection algorithms, variant annotation, and reporting analytical performance, circulating tumor DNA levels, and tumor heterogeneity. As a result, continuing exploration and harmonization addressing the source of variation are needed given the increasing role of genetic and genomic testing in the management of patients with mCRPC.

Presented By: Mark Sausen, Associate Director, Clinical Genetics and Genomics at Bristol Myers Squibb in Pennington, New Jersey

Written By: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021