BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype

Fettke, Heidi; Dai, Chao; Kwan, Edmond M.; Zheng, Tiantian; Du, Pan; Ng, Nicole; Bukczynska, Patricia; Docanto, Maria; Kostos, Louise; Foroughi, Siavash; Brown, Stephen; Graham, Lisa-Jane K.; Mahon, Kate; Horvath, Lisa G.; Jia, Shidong; Kohli, Manish; Azad, Arun A.

doi:10.1016/j.ebiom.2023.104738

Cited by 11 publications

(2 citation statements)

References 50 publications

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“…Fettke and colleagues in this issue of eBioMedicine provide some additional insights into the landscape of DDR defects in mCRPC analyzing liquid biopsy and germline samples from a total of 375 men from the US and Australia using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) panel assay which targets sequencing of 152 cancer driver genes including 27 individual DDR genes. 7 From the 34% of the total cohort that exhibited DDR alterations, consistent with other studies, the most common altered gene was BRCA2 (17%). Also consistent with some previous reports in BRCA2 mutated mCRPC, clinical outcomes including PSA response, PFS and OS were found to be inferior with ARPI treatments.…”

supporting

confidence: 85%

Cell-free DNA sequencing sheds additional insights on BRCA-altered metastatic castration-resistant prostate cancer

et al. 2023

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supporting

confidence: 85%

Cell-free DNA sequencing sheds additional insights on BRCA-altered metastatic castration-resistant prostate cancer

et al. 2023

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“…Interestingly, HOXB13 is highly expressed in circulating tumor cells and predicts early death following AA treatment [ 75 ]. Similarly, BRCA genes have been associated with a high risk of prostate cancer and poor prognosis [ 89 , 90 ]. While this pilot study involves a small patient cohort, miRS data indicate a potential new companion diagnostic for AA, currently absent in clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Plasma microRNA Signature as Companion Diagnostic for Abiraterone Acetate Treatment in Metastatic Castration-Resistant Prostate Cancer: A Pilot Study

Detassis,

Precazzini,

Grasso

et al. 2024

IJMS

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Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug’s efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.

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Combination of PARP Inhibitors and Androgen Receptor Pathway Inhibitors in Metastatic Castration-Resistant Prostate Cancer

Kostos,

Tran,

Azad

2024

Drugs

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Despite recent advances in the treatment of metastatic prostate cancer, progression to a castration-resistant state remains inevitable for most and prognosis is limited. Genetic testing for homologous recombination repair pathway alterations is recommended for all patients with advanced prostate cancer given that a mutation is present in up to 25% of cases. Poly(ADP-ribose) polymerase (PARPis) are now approved for use in patients with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor pathway inhibitor (ARPI) and harbour a germline or somatic homologous recombination repair mutation. Preclinical data support a synergistic effect with an ARPI and PARPi, and various ARPI-PARPi combinations have therefore been explored in phase III clinical trials. Despite heterogeneous findings, a clear hierarchy of benefit is evident, with patients harbouring a BRCA mutation deriving the greatest magnitude of benefit, followed by any homologous recombination repair mutation. The benefit in homologous recombination repair-proficient cohort is less clear, and questions remain about whether ARPI-PARPi combination therapy should be offered to patients without a homologous recombination repair mutation. With ARPIs now considered standard-of-care for metastatic hormone-sensitive prostate cancer, ARPI-PARPi combination therapy is currently being explored earlier in the treatment paradigm. The purpose of this review is to discuss the rationale behind ARPI-PARPi combination therapy, summarise the results of key clinical trials, and discuss clinical considerations and future perspectives.

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BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype

Cited by 11 publications

References 50 publications

Cell-free DNA sequencing sheds additional insights on BRCA-altered metastatic castration-resistant prostate cancer

Cell-free DNA sequencing sheds additional insights on BRCA-altered metastatic castration-resistant prostate cancer

Plasma microRNA Signature as Companion Diagnostic for Abiraterone Acetate Treatment in Metastatic Castration-Resistant Prostate Cancer: A Pilot Study

Combination of PARP Inhibitors and Androgen Receptor Pathway Inhibitors in Metastatic Castration-Resistant Prostate Cancer

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