ctDNA Alterations Correlate with Survival in Patients with Metastatic Castration-Resistant Prostate Cancer

Circulating tumor DNA (ctDNA) analysis is a useful sequencing platform in metastatic castration-resistant prostate cancer (CRPC), and ctDNA alterations are detected in most patients with this type of prostate cancer, according to Justin Shaya, MD, Hematology/Oncology Fellow, UC San Diego Moores Cancer Center, CA.

In addition, the type, number, and frequency of alterations are potentially prognostic of overall survival (OS) in this patient population.

The number of alterations and maximum allelic fraction do not appear to correlate strongly with prostate-specific antigen level, suggesting that they could serve as a noninvasive biomarker for outcomes in patients with metastatic CRPC, noted Dr Shaya, at the virtual 2020 American Urological Association Virtual Annual Meeting.

“There has been considerable interest in a better understanding of the genomic landscape of metastatic CRPC to better develop targeted therapies in this space,” he added.

Tissue next-generation sequencing (NGS) is often difficult to obtain because of bone-predominant disease and significant genomic heterogeneity between the primary prostate tumor and metastatic sites in metastatic CRPC. Given this fact, liquid biopsy by ctDNA NGS platforms have been of increasing interest.

Dr Shaya and colleagues sought to examine the real-world experience of the use of ctDNA in metastatic CRPC through a retrospective analysis of patients treated at UC San Diego who underwent ctDNA analysis from 2014 to 2019. Forty-six patients were identified, 42 (91.3%) of whom had hormone-sensitive metastatic disease before the development of M1 metastatic CRPC.

At the time of ctDNA collection, median patient age was 71 years, and all patients had CRPC. Bone metastases were present in 100% of patients and visceral metastases in 17.3%. The median time from CRPC diagnosis to ctDNA collection was 13 months, and median follow-up time from CRPC diagnosis was 17.5 months.

Forty-three (94%) patients had ≥1 detected genomic alterations, with a median of 2 genomic alterations and the median maximum allelic fraction was 5.1%. Slightly more than half (54.3%) had undergone tissue NGS, with the most common source of tissue being the prostate (76%).

The most common alterations present were TP53 mutation (41.3%), AR amplification (30.4%), AR point mutation (21.7%), and CDK6 amplification (21.7%). Actionable mutations in BRCA1 (4.3%), BRCA2 (4.3%), ATM (2.2%), and PMS2 (2.2%) were detected at low frequencies.

Median OS of the entire cohort was 10 months from the time of ctDNA collection. When measured from the diagnosis of metastatic CRPC to death or last follow-up, the median OS was 36 months.

“The presence of a tumor suppressor mutation in P53, RB1, or PTEN was associated with inferior survival that was statistically significant. A similar finding has been described in a tissue NGS cohort and so this is concordant with that,” noted Dr Shaya.

The presence of AR amplification or AR point mutation was not associated with numerically worse OS (median of 8 months with presence of alteration vs 19 months with absence of alteration) but did not achieve statistical significance (P = .12).

The presence of >2 genomic alterations or >5% mutation allelic frequency on ctDNA analysis was associated with inferior OS. Median OS was 24 months with <2 genomic alterations compared with 6 months with >2 alterations (P <.001). Median OS was 24 months in the presence of an allelic fraction ≤5% compared with 8 months with an allelic fraction >5% (P = .001).

The number of detected alterations remained a strongly significant predictor of mortality in multivariate analysis.

There was no statistically significant association between the number of detected alterations or maximum allelic fraction and prostate-specific antigen at the time of ctDNA analysis.

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