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Researchers identify genomic drivers of poor survival, enzalutamide resistance in advanced prostate cancer
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SAN FRANCISCO — Integrated genomic analysis of castration-resistant prostate cancer metastasis biopsies revealed RB1 loss as a driver of poorer survival, according to results of a prospective cohort study presented at Genitourinary Cancers Symposium.
Further, the Wnt/beta-catenin pathway and CTNNB1-activating mutations appeared associated with resistance to enzalutamide (Xtandi; Astellas, Pfizer Oncology).
Although researchers have recently tried to identify genomic alterations in metastatic castration-resistant prostate cancer, their clinical implications have not yet been understood.
William S. Chen, BS, third year medical student at Yale School of Medicine and who, for this project, is also affiliated with UC San Francisco Helen Diller Family Comprehensive Cancer Center, and colleagues used whole-genome sequencing of metastasis biopsies to analyze the association between key driver gene alterations and OS among 101 men (median age, 71 years) with metastatic castration-resistant prostate cancer. They integrated the resulting mutation, copy number and structural variant calls to determine functional copy number status of candidate genes for downstream clinical analyses.
The most common mutations they identified included TP53 (46%), PTEN (36%) and RB1 (12%).
However, only RB1 loss was associated with poor OS (median, 14.1 months vs. 42 months, P < .001).
Researchers also conducted whole-transcriptome RNA sequencing to identify potential mechanisms of resistance to enzalutamide.
When researchers compared samples from enzalutamide-resistant vs. -naive patients, they identified the Wnt/beta-catenin pathway as the most frequently differently expressed pathway among enzalutamide-resistant patients.
CTNNB1 (beta-catenin)-activating mutations also occurred exclusively in enzalutamide-resistant patients (11.4% vs. 0%: P = .013) and predicted poor OS (median 13.6 months vs. 41.7 months, P < .001). Three of four of these CTNNB1 mutations occurred at known pathogenic mutational hotspots.
“These data should be interpreted with caution, as there were only four patients with beta-catenin mutations, which is not surprising, given that these mutations are rare,” Chen said. – by Alexandra Todak
Reference:
Chen WS, et al. Abstract 146. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.
Disclosures: Chen reports no relevant financial disclosures. Please see the abstract for all other authors' relevant financial disclosures.
Perspective
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Michael Schweizer, MD
The presentation by Chen and colleagues represents an important step toward better understanding the drivers of enzalutamide drug resistance.
In this study, researchers analyzed whole-genome sequencing, RNA sequencing and clinical data from the StandUp2Cancer West Coast Dream Team project to determine key molecular features associated with survival and enzalutamide resistance. Not surprisingly, they confirmed that RB1 mutations define an aggressive subgroup of prostate cancer and that loss-of-function mutations in this gene are associated with poor OS.
More interestingly, gene set enrichment analysis revealed that the Wnt/beta-catenin pathway was highly differentially expressed in patients resistant to enzalutamide compared with enzalutamide-naive patients. Similarly, whole-genome sequencing demonstrated that activating mutations in CTNNB1 were present only in enzalutamide-resistant patients, and that the presence of these mutations was associated with decreased OS.
It is important to note that only four patients included in this study had activating CTNNB1 mutations, and additional work is needed to better understand the role Wnt/beta-catenin-signaling plays in mediating enzalutamide resistance. If Wnt/beta-catenin pathway activation is indeed confirmed to be a driver of enzalutamide resistance, this could have direct implications for future drug development efforts and would support testing Wnt/beta-catenin pathway inhibitors (eg, porcupine inhibitors) in men who have become resistant to enzalutamide.
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