(UroToday.com) Stereotactic body radiotherapy (SBRT) is increasingly relevant as a definitive treatment option for men with localized prostate cancer. PREPARE-SBRT (PRE-ProstAtectomy MRI-GuidEd Stereotactic Body RadioTherapy for High-Risk Prostate Cancer Trial) is an ongoing clinical trial testing the safety of MRI-guided SBRT prior to radical prostatectomy (RP) (NCT03663218).
In this phase I study, men with clinically localized high-risk prostate cancer receive 5 days of MRI-guided treatment under a modified dose escalation study to determine recommended phase II dose. The investigators and authors of this abstract sought to compare transcriptomic profiles of irradiated tumors (via prostatectomy specimens) to better understand the biology of acutely irradiated human prostate cancer.
Twenty-four paired diagnostic pretreatment biopsies and radical prostatectomy specimens were analyzed from 12 patients. The median time from completion of SBRT to RP was 5 days. Decipher GRID (Veracyte, Inc.) was deployed to evaluate the transcriptional profiles before and after radiation. For control of the effects of tissue preservation between specimens, GRID profiles from 803 untreated biopsy samples with matching RP specimens were used.
Linear regression models were used for the interaction effect of cohort (SBRT vs control) and by procedure (Bx vs RP) to select signatures impacted by radiation treatment. Transcriptional signatures with interaction p-value of <0.01 and paired T-test value <0.05 were considered statistically significant. Examples of transcriptional signatures available via GRID include Androgen Receptor (AR) and DNA damage repair (DDR) pathways activity, as well as NADH-NADPH and glycogen metabolism.
Dr. Himanshu Nagar and colleagues report that radiation exposure significant downregulated AR activity (p=0.002), as compared to unirradiated biopsy specimens. Nucleotide excision repair (NER) and non-homologous endjoining (NHEJ), both DDR pathways, were significantly increased in post-SBRT specimens. In contrast, other pathways of genomic stability, including homologous recombination (HR) and mismatch repair (MMR), were not significantly altered.
Metabolic pathway activity was also impacted. Among these, pre-operative RT resulted in increased glycogen metabolism (p=0.008) and conversion of NADH-NADPH (p=0.001), a signature associated with radiation-induced oxidative damage. Markers of angiogenesis (p=0.0012) and stromal remodeling (p=0.0008) were also increased, consistent with upregulation of tissue response to radiation exposure.
With their intriguing and novel work, the authors demonstrate evidence of acute dynamic changes with paired transcriptomic analysis of pre-treatment and irradiated human prostate cancer specimens. Upregulation of specific DDR pathways and metabolic adaptations, and downregulation of AR signaling activity, support biological effect of neoadjuvant SBRT in high risk localized prostate cancer. Further investigations are underway to validate and expand these findings.
Presented by: Himanshu Nagar, MD, Weill Medical College of Cornell University/NewYork-Presbyterian Hospital, New York NY
Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at NewYork-Presbyterian Hospital. @DrJonesNauseef on Twitter during the 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 16 – Saturday Feb 18, 20223