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Purpose/objective(s): Radiotherapy (RT) with or without androgen deprivation therapy (ADT) plays a key role in the salvage treatment of prostate cancer recurrent after prostatectomy. However, not all patients benefit from salvage therapy, and there is an unmet need for biomarkers to distinguish responders from non-responders. Prostate cancer depends on androgen receptor (AR) signaling, and expression of AR splice variants (ARVs) that enable androgen-independent AR signaling is associated with resistance to ADT in the metastatic setting. Recent in vitro data suggest that ARVs also mediate DNA repair after irradiation, suggesting that ARV expression may also be a biomarker of resistance to RT. However, the landscape of ARV expression in primary prostate cancer and its effect on treatment outcomes remain unexplored. Here, we hypothesized that ARVs may be detectable in primary prostate cancer and furthermore may modulate response to salvage RT+ADT.Materials/methods: We retrospectively identified 46 prostate cancer patients treated with prostatectomy followed by salvage RT+ ADT at a single institution from 1995 to 2012. Median age at salvage was 64.5 years. The indication for salvage therapy was biochemical failure after an undetectable post-operative PSA in 72%, gross local recurrence in 17%, and persistently elevated PSA after surgery in 11%. Median RT dose was 64.8 Gy, and all patients received concurrent ADT. We comprehensively interrogated the landscape of ARVs by performing ultra-deep targeted RNA-seq of archival formalin-fixed paraffin-embedded prostatectomy samples. Using a custom library of > 3000 primers spanning all AR exons and introns, we evaluated 21 native splice junction sites and 20 splice variants with a mean depth of coverage of > 5000x. We tested for association between splice variant expression and clinical outcomes using the log-rank test and Cox proportional hazards model.Results: In total, 76% of patients had one or more detectable AR splice variants. The most commonly detected variants were AR-45 (exon 1b-2) in 41%, AR-V9 (exon 3-cryptic exon (CE) 5) in 20%, and AR-V7 (exon 3-CE3) in 13%. At a median follow-up of 33.8 months, biochemical progression-free survival (BPFS) at 3 years was 60%, distant metastasis-free survival was 90%, and overall survival was 100%. Among detected splice variants, only AR-V7 was associated with differential clinical outcomes, with a median BPFS of 10.9 months in AR-V7 positive vs 73.4 months in AR-V7 negative patients (P = 0.0020, HR 5.23, 95% CI 1.62-16.87).Conclusion: Using a custom ultra-deep targeted RNA-Seq approach, we provide among the first comprehensive descriptions of the AR splice variant landscape in primary prostate cancer. Moreover, we show that detectable AR-V7 expression in prostatectomy specimens was associated with inferior outcomes following subsequent salvage RT+ADT, suggesting for the first time that AR-V7 may modulate outcomes for localized as well as metastatic disease. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Recent autopsy data from patients with glioblastoma (GBM) has demonstrated that pronounced brainstem infiltration is now a common pattern of disease progression near the end of life. The present study evaluated the association of disease proximity to the brainstem on imaging, both at diagnosis and at recurrence, with overall survival (OS).Materials/methods: 140 patients with IDH wild-type GBM treated definitively with resection and adjuvant chemoradiation at a single institution from 2013-2019 were retrospectively analyzed. Disease proximity to brainstem was calculated from measurements made on T1 post-contrast MRI brain obtained at diagnosis postoperatively and at recurrence. Tumor volume was approximated by the resection cavity plus adjacent extrinsic enhancement, measured during target delineation at time of treatment delivery. The Kaplan-Meier method was used to estimate OS, and multivariable analysis was performed using the Cox proportional hazards model. Logistic regression was used to assess the effect of tumor volume on brainstem involvement, and the relationship between tumor volume and proximity to brainstem was assessed by the Spearman correlation.Results: Median distance of disease to brainstem was 22.4 mm (range 0-54) at diagnosis, with 2.1% (n = 3) having brainstem involvement. At 56-month median follow-up, 87% of patients had recurrence; 2-year OS was 38.6%. Median distance of disease to brainstem was 20.8 mm (range 0-63) at recurrence, with 5.7% (n = 8) having brainstem involvement at recurrence. Controlling for resection status, MGMT methylation, and Karnofsky performance status, there was no noted association of brainstem invasion (P = .60) or proximity at diagnosis (P = .14) with OS. However, at recurrence, distance from the brainstem was significantly associated with improved OS when measured continuously (HR: .97, 95% CI: .95-.99, P = 0.001) and when compared by group (20-40 mm vs. ≤20 mm: HR .59, 95% CI: .35-.99, P = 0.05; > 40 mm vs. ≤20 mm: HR .16, 95% CI: 0.05-.55, P = 0.003). While volume of tumor at diagnosis was not found to be independently associated with brainstem involvement (P = .99) or OS (P = .90) at recurrence, tumor volume at diagnosis was found to be significantly associated with disease proximity to brainstem at the time of recurrence (P = 0.037), with larger volume disease more likely to recur close to the brainstem.Conclusion: GBM proximity to the brainstem at diagnosis was not found to be prognostic, whereas disease proximity to the brainstem at recurrence was associated with worse OS. Tumor volume at diagnosis was found to be associated with disease proximity at recurrence, with higher volume disease at diagnosis associated with greater proximity to the brainstem at recurrence. These findings may have ramifications for upfront and salvage radiation treatment design.Author Disclosure: A. Bajaj: None. E.T. Benishay: None. I.B. Helenowski: None. R. Savoor: None. M.R. Drumm: None. N. Rammohan: None. S. Sachdev: None. C.M. Horbinski: None. T. Kruser: Employee; Northwestern Memorial Hospital. Honoraria; Elsevier, OncLive. Speaker's Bureau; AstraZeneca. Advisory Board; AstraZeneca. [ABSTRACT FROM AUTHOR]