The Genomic Landscape of Prostate Cancer Brain Metastases

Abstract

Lethal prostate cancer commonly metastasizes to bone, lymph nodes, and visceral organs but with more effective therapies, there is an increased frequency of metastases to the brain.Little is known about the genomic drivers of prostate cancer brain metastases (PCBM). To address this, we conducted a comprehensive multi-regional, genomic, and targeted transcriptomic analysis of PCBM from 28 patients. We compared whole-exome and targeted RNA sequencing with matched primary tumors when available (n = 10) and with publicly available genomic data from non-brain prostate cancer metastases (n = 416). In addition to common alterations in TP53, AR, RB1, and PTEN, we identified highly significant enrichment of mutations in NF1 (25% cases (6/28), q = 0.049, 95% CI = 2.38 -26.52, OR = 8.37) and RICTOR (17.9% cases (5/28), q = 0.01, 95% CI = 6.74 -480.15, OR = 43.7) in PCBM compared to non-brain prostate cancer metastases, suggesting possible activation of the druggable pathways RAS/RAF/MEK/ERK and PI3K/AKT/mTOR, respectively. Compared to non-brain prostate cancer metastases, PCBM were almost three times as likely to harbor DNA homologous repair (HR) alterations (42.9% cases (12/28), p =0.016, 95% CI = 1.17 -6.64, OR = 2.8). When considering the combination of somatic mutations, copy number alteration, and Large-scale State Transitions, 64.3% of patients (18/28) were affected. HR alterations may be critical drivers of brain metastasis that potentially provide cancer cells a survival advantage during re-establishment in a special microenvironment. We demonstrate that PCBM have genomic dependencies that may be exploitable through clinical interventions including PARP inhibition.

Mismatch repair–deficient prostate cancer with parenchymal brain metastases treated with immune checkpoint blockade

“…Therefore, it is unclear whether our patient's dMMR status contributed to his development of brain metastases. Of note, this patient's brain metastases also exhibited alterations in PTEN as well as NF1, which may support prior work suggesting a correlation between PTEN and NF1 inactivation and brain metastases in prostate cancer (Mota et al 2019;Rodriguez et al 2020).…”

“…Given the rarity of prostate cancer with brain metastases, little is known about its molecular characteristics and its interaction with the immune microenvironment. Initial studies suggested that PTEN loss and DNA homologous repair (HR) mutations may be common in this entity (Mota et al 2019;Rodriguez et al 2020), however relatively few tumors have undergone DNA sequencing to date. Moreover, the immune cell composition of brain metastases from prostate cancer has not previously been described.…”

Dural spread from metastatic prostate cancer

“…Dural metastases thus represent a late manifestation of disease across all cancer subtypes and are more frequently seen in those treated with a number of lines of therapy 8. Additionally, emerging data suggests BRCA mutated cancers including prostate cancers are more likely to develop central nervous system metastases 10…”