Abstract
This abstract is available on the publisher's site.
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PURPOSE
To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi).Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models.
RESULTS
Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001).
CONCLUSIONS
In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.
TAKE-HOME MESSAGE
Precision targeting within the androgen signaling pathway remains critical in the care of patients with metastatic castration-resistant prostate cancer (mCRPC). The authors of this study evaluated outcomes in 168 men with mCRPC prior to treatment with androgen receptor signaling inhibitors (abiraterone, enzalutamide). These outcomes were correlated with androgen receptor and TP53 sequencing in circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). On multivariable analysis, no single androgen receptor perturbation was associated with a worse prognosis. However, predictors of adverse outcomes included TP53 inactivation and tumor burden, as measured by CTC count, ctDNA fraction, and radiographic visceral metastases. As a result, the authors conclude that TP53 and tumor burden status outperforms androgen receptor perturbations in predicting clinical outcomes.
These data demonstrate that androgen receptor perturbations are not the strongest predictor of outcomes. The study, however, is limited by its heterogeneous patient population, such as prior chemotherapy exposure, metastatic burden, and prior androgen receptor signaling inhibitor therapy. In addition, evaluation of ctDNA and CTC are still emerging technologies with inherent limitations.
– Michael H. Johnson, MD
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About TP53:
"The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.
The p53 protein is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.
Because p53 is essential for regulating cell division and preventing tumor formation, it has been nicknamed the "guardian of the genome."
