Clinical and pathological features associated with circulating tumor DNA content in real‐world patients with metastatic prostate cancer

Abstract

Background Liquid biopsy is a powerful tool that can enable treatment decisions for metastatic prostate cancer patients with difficult‐to‐biopsy tumors. However, the detection of genomic alterations via liquid biopsy is limited by the fraction (tumor fraction [TF]) of circulating tumor DNA (ctDNA) within the total cell‐free DNA content. While prior work has preliminarily correlated TF with clinical features of prostate cancer, we sought to validate and provide additional resolution, such that a clinical practitioner might anticipate the probability of successful liquid biopsy profiling leveraging commonly assessed clinical and laboratory features. Methods A total of 813 liquid biopsy specimens were assessable, with 545 associated with a PSA prostate specific antigen measurement, collected in standard‐of‐care settings across approximately 280 US academic or community‐based cancer clinics from September 2018 to July 2021. Deidentified data were captured into a real‐world clinico‐genomic database (CGDB). Comprehensive genomic profiling (CGP) was performed on extracted cell‐free DNA from liquid biopsy samples. Results In multivariable models, higher PSA level, lower hemoglobin, lower albumin, higher alkaline phosphatase (all p < 0.001), and collection of liquid biopsy blood draw within 60 days of new treatment initiation (p = 0.002) were the most strongly associated features with higher TF. At PSA levels of <5 ng/ml, 43% of patients had a TF of <1% indicating an increased likelihood of unevaluable results. Conversely, at PSA levels of >5 ng/ml, 78% of patients had a TF of at least 1% and 46% had a TF of ≥10%, suggesting improved sensitivity for detection of targetable alterations. Conclusions Universal genomic profiling of prostate cancers will require complementary use of liquid biopsy and tumor tissue profiling for suitable patients. The likelihood of adequate ctDNA shedding into plasma is one consideration when deciding whether to pursue CGP via liquid biopsy versus tumor profiling. Our real‐world data suggest that PSA < 5 ng/ml is associated with lower ctDNA yield on liquid biopsy, potentially increasing the incidence of negative results or a need for confirmation with tissue testing.

Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound

“…Genomic sequencing techniques such as low-pass whole-genome sequencing may be able to identify genomic alterations (including homozygous deletions) in samples of low tumor fraction percentages (39); however, the evidence highlighting the clinical utility of such techniques in precision oncology is limited (40). Although there is considerable evidence related to the prognostic potential of ctDNA tumor fraction assessment in mCRPC (32,41,42), these data, as well as other research (43), highlight that additional work is needed to optimize and standardize quantification, particularly when tumor fraction/shedding rates are particularly low.…”

Tumor Fraction Correlates With Detection of Actionable Variants Across > 23,000 Circulating Tumor DNA Samples

“…LBx is therefore likely to be most useful in patients with an increased likelihood of ctDNA shed, generally patients with advanced cancer who are untreated or progressing on therapy higher levels of ctDNA shed were associated with a higher prostate-specific antigen level and collection of LBx within 60 days of new treatment initiation, whereas prostatespecific antigen , 5 was associated with lower ctDNA shed. 22 Optimal clinical use of LBx will require additional efforts to identify clinical features that identify patients who may be better served by tumor tissue profiling.…”

Recent Advances in Blood-Based Liquid Biopsy Approaches in Prostate Cancer

“…Publications with the highest level of evidence were selected for review. This yielded 60 articles for which full text evaluation was performed and included in the final review 12–71 . A flow diagram of the article evaluation process is shown in Figure 1.…”

“…Thus, a comparison of a major commercial ctDNA sequencing assay (Guardant360) with an academic laboratory-based gene panel identified very good concordance at 1% ctDNA fraction or above, below which alteration calls became considerably discordant/questionable 27 . When correlated to serum PSA, 4 of every 5 PCa patients with a PSA of >5 ng/mL were higher than the 1% ctDNA tumor fraction threshold, as opposed to fewer than half of patients with a PSA <5 ng/μL 26 . Comparison of ctDNA findings to those in matched, synchronous tissue biopsies as the benchmark method has continued to be studied.…”

“…27 When correlated to serum PSA, 4 of every 5 PCa patients with a PSA of >5 ng/mL were higher than the 1% ctDNA tumor fraction threshold, as opposed to fewer than half of patients with a PSA <5 ng/ μL. 26 Comparison of ctDNA findings to those in matched, synchronous tissue biopsies as the benchmark method has continued to be studied. In a de novo metastatic, castration-sensitive cohort, ctDNA was 80% concordant with tissue in detecting genomic alterations, indicating complementarity between the 2 approaches.…”