bluuebunny/crossref_metadata_2025 huggingface dataset:
Liquid biopsy AR/enhancer alteration detection before AR-targeted therapy and correlation with survival in metastatic castrate-resistant prostate cancer patients.
Authors: Shiang Alexander , Chauhan Pradeep S. , Dang Ha X. , Webster Jace , Ledet Elisa M. , Babbra Ramandeep K , Feng Wenjia , Harris Peter K. , Jaeger Ellen B. , Miller Patrick , Caputo Sydney , Cittolin Santos Giordano Fabricio , Pachynski Russell Kent , Sartor A. Oliver , Maher Christopher , Chaudhuri Aadel A
Published: February 2022

171

Background: Patients with metastatic castrate-resistant prostate cancer (mCRPC) have a variety of different systemic therapy options, yet survival outcomes remain poor. To minimize the chance of rapid resistance, it is critical to be able to personalize therapy upfront. We previously developed a cell-free DNA liquid biopsy assay that tracks alterations in the androgen receptor ( AR) locus, including its upstream enhancer (EnhanceAR-Seq). This assay demonstrated the ability to stratify patients based on resistance to AR-directed agents after treatment started (Dang and Chauhan et al., JCO PO, 2020). Here we evaluated if the same approach can accurately risk-stratify patients with mCRPC prior to the initiation of first-line AR-targeted therapy. Methods: We performed EnhanceAR-Seq on plasma cell-free DNA samples from 55 mCRPC patients prior to the initiation of AR-targeted therapy. Forty-seven patients were treated with Abiraterone and eight with Enzalutamide. Five patients were excluded due to having already received AR-targeted therapy or being lost to follow-up. Kaplan-Meier analysis was performed, and progression-free survival (PFS) and overall survival (OS) were assessed in relation to AR/enhancer locus status (wild-type vs. altered). Results: Median follow-up time was 30 months. EnhanceAR-Seq noninvasively detected AR/enhancer locus alterations in 36% (18/50) of the patients in our cohort, while 64% (32/50) were determined to be wild-type. Alterations detected by the assay were AR amplification (12/18), AR nonsynonymous single nucleotide variants (4/18), AR truncation (2/18), and AR enhancer amplification (13/18). Eleven patients had both AR gene body and enhancer amplifications present. Strikingly, patients with AR/enhancer alterations detected in plasma cell-free DNA were found to have significantly worse outcomes, with median PFS of 16.3 (wild-type) vs. 10.8 months (altered) (p = 0.046; HR = 2.10), and OS trending toward significantly different with median 34.3 (wild type) vs. 24.7 months (altered) (p = 0.19; HR = 1.05). Conclusions: AR/enhancer locus alterations in patients with mCRPC, as detected noninvasively by EnhanceAR-Seq, corresponded with significantly worse PFS and trended toward significantly worse OS. Our results support the role of cell-free DNA AR/enhancer locus alterations as prognostic, and potentially predictive, biomarkers that enable more precise upfront risk stratification and treatment personalization.
Underutilization of standard of care (SOC) treatment intensification in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) by specialty.
Authors: Swami Umang , Hong Agnes , El-Chaar Nader N. , Nimke David , Ramaswamy Krishnan , Diessner Brandon , Sandin Rickard , Agarwal Neeraj
Published: February 2022

183

Background: Intensification of androgen deprivation therapy (ADT) with docetaxel (DOC) or novel hormone therapies (NHTs) [abiraterone, enzalutamide, or apalutamide] has shown to improve survival outcomes and is SOC in men with mCSPC.1 However, recent evidence indicates that most pts still only receive ADT ± first-generation non-steroidal antiandrogens (NSAA).2-4 This is one of the first studies to assess the real-world utilization of intensified treatments as first-line (1L) therapies for pts with mCSPC by physician specialty. Methods: This retrospective study used the Optum health insurance claims database, which includes pt claims data from commercially insured and Medicare Advantage populations. Adult pts (≥18 years) had ≥2 claims for prostate cancer (PC) and ≥1 claim for metastasis (the first claim was index date) within 90 days (d) prior to, or any time after, the first claim for PC from January 2014– June 2019. 1L treatments included any systemic treatment for mCSPC within 90 d pre-index, plus any other treatment received within 180 d of the first. Physician specialty was determined from medical or pharmacy claims during 1L treatment and categorized as Urologist; Oncologist; urologists and oncologists (Both); or other specialties (Other). Treatment patterns and pt characteristics across specialties were analyzed descriptively. Results: Of 4,675 mCSPC pts identified, 16% received care from Urologists, 20% from Oncologists, 63% from Both, and 1% from Other. Pts seen by Urologists were more likely to be older and have Medicare compared to pts seen by the Oncologists or Both. Treatment intensification with NHT and/or DOC was numerically higher among Oncologists and Both compared with Urologists. However, all specialties prescribed ADT ± first-generation NSAA most frequently for 1L mCSPC treatment, even in patients with visceral metastases (Table). Conclusions: Despite evidence of improved survival with intensified treatment for pts with mCSPC, we observed its underuse by all specialties and even among pts with visceral metastases. Our results highlight a great need to advance the implementation of evidence-based medicine in mCSPC. 1. Sayegh N et al. JCO Oncol Pract 2021; OP2100206. 2. Ryan CJ et al. J Urol 2021; Online ahead of print. 3. Freedland S et al. Ann Oncol 2021; 32: S650-S651. 4. Freedland S et al. J Clin Oncol 2021; 39(Suppl 15): e5073.[Table: see text]
Genomic characterization of patients (pts) with de-novo high-volume metastatic castration-sensitive prostate cancer (dn-hv-mCSPC) compared to those without dn-hv-mCSPC.
Authors: Sayegh Nicolas , Jo Yeonjung , Tripathi Nishita , McFarland Taylor Ryan , Kessel Adam , Nussenzveig Roberto , Chigarira Beverly , Li Haoran , Tandar Clara , Sahu Kamal Kant , Haaland Benjamin , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj
Published: February 2022

186

Background: Dn-hv-mCSPC have the poorest survival outcomes among various subsets pts with mCSPC (Fizazi, Lancet Oncol 2019). However, the molecular underpinnings behind the poor prognosis is not entirely understood. In this study, we aimed to assess the tumoral genomic characteristics in pts with dn-hv-mCSPC. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: patients with mCSPC with availability of tumor comprehensive genomic profiling (CGP) from a CLIA-certified lab before start of ADT. Clinically relevant genes previously reported to be associated with prognosis in metastatic prostate cancer were included: TP53, PTEN, RB1, BRCA2, CDK12, MYC, PIK3CA, SPOP, APC, CTNNB1, and, ATM. Variants of unknown significance and genomic aberrations present in < 5% pts were excluded. High-volume disease was defined per CHAARTED criteria. Genomic aberration prevalence was compared using a Chi-square test and was adjusted for false discovery (Benjamini-Hochberg). Results: 304 pts were eligible: dn-hv-mCSPC (N = 100) vs non-dn-hv-mCSPC (N = 204); median age 67 vs 63 years, median PSA at baseline 35 vs 14 ng/mL, median Gleason score 9 vs 9, visceral metastases 15% vs 3%. 41% and 27% of pts had ≥2 mutations in the dn-hv-mcSPC and non-dn-hv-mCSPC respectively (P = 0.01). Overall, most commonly mutated genes were TP53, TMPRSS2, and PTEN. Pts with dn-hv-mCSPC had higher frequency of TP53 (P = 0.016) and BRCA2 (P = 0.03) mutations. Conclusions: In this real-world patient population, dn-hv-mCSPC pts were shown to have a greater number of clinically relevant genomic aberrations. Detailed genomic landscape of these pts will be presented in the meeting. These hypotheses-generating data need external validation.
Randomized phase II trial of neoadjuvant abiraterone plus or minus cabazitaxel in high-risk prostate cancer: ACDC-RP.
Authors: Fleshner Neil E. , Hansen Aaron Richard , Chin Joseph , Winquist Eric , Van Der Kwast Theodorus , Lajkosz Katherine , Kenk Miran , Berlin Doron , Veloso Rosette , Sridhar Srikala S. , Hamilton Robert James , Kulkarni Girish S. , Finelli Antonio , Zlotta Alexandre R. , Joshua Anthony M.
Published: February 2022

224

Background: High-risk prostate cancer has a significant risk of recurrence when treated with unimodal therapy. The utility of neoadjuvant therapy prior to radical prostatectomy (RP) has yet to be defined. The ACDC-RP study investigated the use of abiraterone acetate (AA) + prednisone (P) + leuprolide (LHRH) with or without cabazitaxel prior to RP in high-risk patients. Methods: This phase II trial randomized patients to Arm A (AA/P + LHRH + cabazitaxel 20 mg/m2 with peg-filgrastim 6 cycles) or Arm B (AA/P + LHRH) for 6 months prior to RP. The primary objective was to compare the rate of pathological complete response (CR) or minimal residual disease (MRD) between treatment arms. MRD was defined as ≤5% of prostate volume involved by tumor. We present RP pathological outcomes, safety signals, and early biochemical response data. Results: Out of 78 randomized participants, 70 completed the full course of study treatment and underwent RP. Across both treatment arms, 31 (44%) men achieved either CR or MRD; 5 men had CR (2 in Arm A) and an additional 26 men exhibited MRD (15 in Arm A), p = 1 between Arm A and B. Kaplan-Meier analysis demonstrated no difference in biochemical-free survival (BFS) rate between the two treatment groups. Patients who achieved a CR/MRD experienced significantly longer BFS. Conclusions: Study findings indicate significant tumor response with 44% of patients exhibiting CR/MRD, with no significant difference observed between the two treatment arms. Patients who exhibit CR/MRD experienced better BFS rates. Genomic efforts are underway to determine predictors of response. Clinical trial information: NCT02543255. [Table: see text]
The lexicon of PET/CT reports in prostate patients: Evaluating confidence.
Authors: Baumgartner Jessica , Tward Jonathan David
Published: February 2022

232

Background: Pet/CT scans are increasingly used to evaluate prostate cancer patients with biochemical failure following surgery or radiation therapy for localized prostate cancer. We assessed the language used in report impressions to characterize the reader's confidence for lesions in various anatomic sites. Methods: Between 2015 and 2021, 419 fluciclovine PET/CT scan reports were identified in our institutional outcomes database. Thirteen phrases routinely used in the report impression section by radiologists at least once to characterize a lesion of interest were identified. The phrases were categorized in the following confidence categories: Definitive (positive, negative), Likely (consistent with, most likely, favors, probable), and Unsure (suspicious for, concerning for, non-specific, conspicuous, compatible with, borderline, unknown). The final analysis set included 353 reports where the prescan PSA value was known within the prior 90 days of the scan. Descriptive statistics, stratified by prescan PSA value, were used to characterize this language for the following anatomic regions: bone, regional lymph nodes, prostate fossa, prostate gland/seminal vesicles, other soft tissue. Results: Overall, definitive language was used between 34.6% to 87.1% of the time, depending on the anatomic context (table). The intact prostate was the least likely site to use definitive language (34.6%), whereas bone was most likely (87.1%). Intact prostates in post-radiation patients had the most uncertainty to the persistence of disease (42.3% unsure, 23.1% likely). The highest degree of definitive certainty occurred in impressions of persons with PSA <0.5 (89.2%), whereas the least definitive certainty was in patients with PSA >1 (66.2%). Overall, definitive, likely and unsure findings were reported in 68.6, 9.7%, and 21.7% of scans. Conclusions: Fluciclovine PET/CT scans routinely result in equivocal findings, which vary by anatomic site of interest and prescan PSA level. The language utilized in these reports has not been standardized. Future work aims to create a clear confidence level lexicon standard to assist radiologists and providers in reporting standardization.[Table: see text]
Bladder volume variation in hypofractionated prostate radiotherapy.
Authors: Joyce Ronan , Murphy Jake , O'Neill Eoin , Lyons Ciara A.
Published: February 2022

234

Background: A full bladder for prostate radiotherapy treatment limits overall dose to the bladder and displaces bowel from high dose regions. There is currently no clear consensus on optimum bladder volume for prostate radiotherapy. Inconsistent bladder volumes can cause dosimetric uncertainty, distress, treatment delay and negative toxicity outcomes for patients. To identify potential ways to improve bladder filling consistency we retrospectively analysed bladder volume variation over the course of patients’ treatment and its relationship to various patient and treatment factors. Methods: We included all patients treated with 60gy in 20 fractions to the prostate only over a 1-year period. Standard fractionation, palliative, post-operative, and whole pelvis treatment regimens were excluded from our study. Patient, tumour, and treatment characteristics were collected retrospectively. We recorded patient reported IPSS scores that were completed pre and post treatment. Daily bladder volumes were recorded from cone beam CT (CBCT) retrospectively for a subset of 34 patients and included in correlative analyses with various treatment and patient factors. Results: 69 men were included in this study with a mean planning CT bladder volume of 272ml (79-574). Patients were divided into large ( > 180ml) and small subgroups (N = 46 vs 23). Smaller bladders resulted in a greater post treatment IPSS score (10.2 vs 7.7 (p = 0.2)) and greater change in IPSS (+3.3 vs +1.4 (p = 0.23). The variation of daily bladder volumes as measured by the standard deviation was positively associated with planning CT volume (p < 0.05), variation in daily treatment time (p < 0.05) and urinary symptoms (p = 0.29). Greater discordances between planning CT time and mean radiotherapy time resulted in a greater average difference between CBCT bladder volume and planning CT volume (p = 0.16). There were no appreciable seasonal or diurnal associations for all recorded bladder volumes. Conclusions: Smaller bladder volumes at planning CT are associated with increased urinary symptoms whereas larger volumes undergo more daily variation. This data suggests an optimal planning bladder volume of 200-400ml to minimise on treatment variation. This is the first study to demonstrate a relationship between variation in daily treatment times and daily bladder variation. Synchronisation of planning CT time with patient treatment time preference will enable patients to better replicate planning CT bladder volumes. This, along with several other areas for improvement highlighted by this study have formed the basis for a prospective single centre pilot study.
Comparative study of RARP and carbon ion radiotherapy sexual functional changes for prostate cancer using the propensity score matching method.
Authors: Miyazawa Yoshiyuki , Oka Daisuke , Koike Hidekazu , Kawamura Hidemasa , Miyasaka Yuhei , Syuto Takahiro , Arai Seiji , Sekine Yoshitaka , Matsui Hiroshi , Ohno Tatsuya , Suzuki Kazuhiro
Published: February 2022

236

Background: We mainly perform Robotic-Assisted laparoscopic Radical Prostatectomy (RARP) and Carbon Ion Radiotherapy (CIRT) as curative treatment for prostate cancer. Several factors such as cancer control and quality of life after treatment are considered to be important, but there are few reports comparing sexual function changes before and after treatment between RARP and CIRT. We performed retrospective study comparing the evaluation of sexual function after RARP and CIRT cases using the propensity score matching method. Methods: 127 patients treated by RARP from 2014 to 2018 and 190 patients treated by CIRT monotherapy from 2010 to 2019 were evaluated. We evaluated Expanded Prostate Cancer Index Composite (EPIC) score before and after treatment. The EPIC was compared before, 12 months, and 24 months after treatment. Propensity score matching was performed using the age at treatment, PSA value, T stage, and pretreatment EPIC comprehensive score of sexual function as covariates. A cohort of 101 patients in each group was prepared and examined. This study was approved by the Institutional Review Board of Gunma University Hospital (No. IRB2020-050, 1839). Results: The mean ± standard deviation of each of the RARP and CIRT groups were age; 65.1 ± 5.9, 65.3 ± 6.5 years, PSA value; 6.31 ± 2.07, 6.34 ± 2.46 ng/ ml, pretreatment EPIC sexual function overall score; 46.4 ± 15.6, 48.2 ± 16.2. In both groups, T1N0M0 was 16%, T2N0M0 was 83%, and T3N0M0 was 1%. The total EPIC sexual function scores before, 12 months, and 24 months after treatment were 46.4, 27.9, 28.2 in the RARP group, and 48.2, 41.4, 41.6 in the CIRT group, respectively. In both groups, there was a significant decrease in score after 12 months and 24 months compared to before treatment (p < 0.05). At 12 and 24 months, the total EPIC sexual function score in the CIRT group was significantly higher than RARP group (p < 0.001). Conclusions: In prostate cancer cases adjusted by propensity score matching, the decrease in EPIC sexual function score was significantly smaller in the CIRT group than RARP group. The results of this study seemed to be useful information for decision making with patients.
Prostate specific antigen dynamics and prostate cancer risk: A population-based study.
Authors: Hird Amanda Elizabeth , Saskin Refik , Del Giudice Lisa , Kulkarni Girish S. , Nam Robert
Published: February 2022

239

Background: Baseline prostate specific antigen (PSA) is a strong predictor of clinically significant prostate cancer. In a large cohort of patients undergoing opportunistic testing, our objective was to assess the association between first serum PSA in combination with other PSA predictors and risk of prostate cancer. Methods: This was a retrospective, population-based study in Ontario, Canada between 2010-2019. Men 40-75 years of age who underwent incident PSA testing with at least two PSA tests during the study period were included. Among men who underwent PSA testing, the PSA levels of patients who were diagnosed with prostate cancer were compared to patients who were not. Univariable and multivariable logistic regression analysis was used to compare any prostate cancer and clinically significant prostate cancer diagnosis (International Society of Urological Pathology [ISUP] grade group 2-5) between groups. Results: A total of 508,238 patients were included in our cohort (12,444 cases and 495,794 controls). The median follow-up time was 8.2 years (IQR: 7.0-9.1). Patients who were diagnosed with prostate cancer were older (median age 62 [IQR: 56-67] versus 56 years [IQR:50-63], standardized difference [SD]:0.61) and had a higher first PSA than patients who were not (median 4.79 [IQR:3.29-6.96] versus 0.96 ng/mL [IQR:0.58-1.69], SD:1.93). Fewer than 0.1% (248/261,463) of patients with a first PSA less than 1.0 ng/mL were diagnosed with prostate cancer during the study period. Our final multivariable model revealed that a first PSA above 2.0 ng/mL (adjusted odds ratio [OR] 6.64, 95%CI: 6.13-7.20, p < 0.001), a final PSA between 4.0 to 9.9 ng/mL and 10.0 to 20.0 ng/mL (adjusted OR 22.09, 95%CI: 20.58-23.71, p < 0.001 and adjusted OR 47.46, 95%CI: 43.28-52.05, p < 0.001, respectively) and change from first to final PSA per 365 days of 20.0 to 99.9% (adjusted OR 3.40, 95%CI: 3.21-3.60, p < 0.001) and more than 100% (adjusted OR 6.91, 95%CI: 6.29-7.59, p < 0.001) were strongly associated with the diagnosis of prostate cancer. The model performed well when predicting any prostate cancer, clinically significant prostate cancer, and when stratified by age. Conclusions: This study suggests that first PSA in combination with final PSA and rate of change can be used to predict prostate cancer diagnosis. Future studies will be conducted to determine the association with metastatic and lethal prostate cancer.
Contemporary outcomes of a systematic prostate cancer active surveillance program: Results from the Niagara Health System, Ontario, Canada.
Authors: Mesci Aruz , Tsakiridis Nicole Niki , Gouran-Savadkoohi Mohammad , Faught Brent , Brown Ian , Tsakiridis Theodoros
Published: February 2022

241

Background: Surgery and radiotherapy are standard therapies for patients with early-stage prostate cancer (PrCa). However, studies show that patients with low-risk localized PrCa (Gleason 6; Grade Group (GG) 1 and prostate-specific antigen (PSA) <10) could be safely monitored with active surveillance (AS), if intense patient follow up and re-biopsy schedules are utilized. Here, we reviewed clinical outcomes of AS of a program associated with the Niagara Health System (NHS) PrCa diagnostic program, which provides centralized diagnosis, systematic follow up, re-biopsy and multi-disciplinary consultation clinics for all patients in the Niagara region, Ontario, Canada. Methods: After receiving appropriate ethics approval, NHS databases were searched for patients that underwent more than one biopsy of the prostate in the period Jan. 2015 (program inception) to Dec. 2020. Cases were reviewed for clinical stage, biopsy results and treatment record data. Data were then codified for anonymity and analyzed. Criteria for inclusion into the analysis involved, i) a minimum of two PrCa biopsies before treatment and ii) detailed reporting of biopsy and clinical results (number of positive cores, % of core involvement, and PSA). Results: A total of 343 AS patient cases were identified in the initial search. Of those 52 cases did not meet inclusion criteria. The baseline GG score distribution in the 291 cases included in the analysis was, GG0: 27 (cases with negative biopsies but high PSA), GG1: 247 and GG2: 17 (patients refusing treatment). A total of 144 cases (49.5%) progressed at re-biopsy. Rates of progression to higher GG category in the three groups were 100%, has 46.5% and 50%, respectively. The average time to progression was 23.3+15.5 months. The rate of progression to treatment after entering AS was 39.17% (114/291). Average time from first biopsy to treatment was (28.4+14.5 months). Amongst those that received treatment the overall rate of progression to high-intermediate or high-risk PrCa, was 29.8%, with 20.8% of cases (30/144) progressing to GG>3 (Gleason Score 7: 4+3 or higher) and 9.0% (13/144) progressing to PSA > 20. Of the treated patients, 70 (61.4%) patients received radiotherapy, 42 (36.8%) combined radiotherapy and androgen deprivation therapy and (31.3%) underwent radical prostatectomy. Conclusions: This retrospective study provides contemporary real-world systematic AS outcomes from a Canadian program with unique features of systematic urological follow up and centralized diagnosis and multi-disciplinary patient assessment. We observe increased rates of disease progression and need for earlier utilization of treatment compared to those reported by other studies. Further analysis examines factors predicting increased risk for disease progression.
Outcomes and factors associated with reclassification in a multiethnic cohort enrolled in active surveillance for prostate cancer.
Authors: Zhu Denzel , Loloi Justin , Shreck Evan , Abeshouse Marnie , Sankin Alexander , Watts Kara , Stern Joshua M. , Aboumohamed Ahmed A. , Kovac Evan
Published: February 2022

242

Background: Active surveillance (AS) is the standard of care for low-risk prostate cancer (PCa). However, there is limited data exploring factors associated with reclassification among non-Hispanic Black (NHB) and Hispanic men enrolled in AS. In this study, we examined factors associated with reclassification among men enrolled in AS within a multiethnic population. Methods: We identified men enrolled in AS from 2005-2019 at our institution, and collected demographic/clinical data. We then compared characteristics among men who experienced pathologic reclassification while on AS vs men who did not. Reclassification was defined as either type 1 (Grade Group (GG) 1 to GG2) or type 2 (GG1 to ≥GG3). Our AS protocol generally consists of biannual prostate specific antigen (PSA) testing and prostate biopsy every 1-3 years. Prostate MRI is used to guide decisions on selective basis. Logistic regression was used to determine factors associated with reclassification. Results: Among 197 men enrolled into an AS protocol within our institution, 133 (67.5%) did not experience reclassification by the end of follow-up while 64 (32.5%) did (Table). Median follow-up time was 12 months (IQR: 7-20), and 2-year overall reclassification-free rates were 59.3% (95% CI: 59.2-59.4). 2-year deferred treatment rates were 26.4% (95% CI: 26.3-26.5) for radical prostatectomy (RP) and 16.9% (95% CI: 16.8-17.0) for radiation therapy (RT). NHB and Hispanic men composed 87 (44.2%) and 70 (35.5%) of our cohort, respectively. Higher PSA at diagnosis was associated with adverse reclassification (OR=1.02, 95% CI: 1.01-1.05, p=0.002), and there was a trend towards NHB men having higher odds of experiencing reclassification (OR=2.78, 95% CI: 0.85-9.10) although the result was not statistically significant (p=0.09). Conclusions: In a diverse, multiethnic cohort, rates of adverse reclassification on AS were relatively low. The only factor predictive of reclassification while on AS was higher median PSA at diagnosis; however, NHB men did have a trend towards a higher odds of reclassification. Our results suggest that men who are NHB or have higher PSA at diagnosis may benefit from increased surveillance intensity, as they are more likely to experience reclassification while on AS.[Table: see text]
Discordance of patient- and physician-reported toxicities in two prospective trials of stereotactic body radiotherapy (SBRT) for localized prostate cancer.
Authors: Patel Akshat , Badia Rohit R , Amini Armon , Kung Christopher , Kusin Samuel B. , Neufeld Sarah , Mannala Samantha , Garant Aurelie , Hannan Raquibul , Timmerman Robert D. , Zelefsky Michael J. , Folkert Michael Ryan , Desai Neil Bipinchandra
Published: February 2022

245

Background: SBRT for localized prostate cancer (PCa) is the focus of several ongoing and reported high-impact trials, which often focus on physician-reported toxicity (P-Tox) when comparing regimens. Patient-reported quality of life (PR-QoL) may differ and provide a more sensitive comparative metric of treatment burden, especially with fewer provider interactions during SBRT than during protracted RT courses. We evaluated the concordance of prospective genitourinary (GU) and gastrointestinal (GI) P-Tox and PR-QOL in men receiving SBRT for PCa. Methods: Data from two concurrently-enrolled prospective trials of SBRT in high-risk (Phase I Safety Endpoint, NCT01896271) and low-intermediate risk (Phase II GI Toxicity Endpoint, NCT02353832) PCa were used. Matching standardized schedules of collected PR-QoL [Expanded Prostate Cancer Index Composite (EPIC)] and P-Tox (CTCAE v5.0) were analyzed over the first 18 months of follow up, where symptoms are most pronounced. We assessed concordance of Grade≥2 GU/GI physician reported toxicity with PR-QoL declines exceeding anchor based minimal clinically important difference (MCID) thresholds (-6 urinary and -5 bowel summary scores, respectively) for each patient at each time point. Patients without baseline PR-QoL data were excluded in full, while time points with missing PR-QoL or P-Tox were excluded individually without imputation. Concordance was evaluated by Cohen’s kappa statistic. Results: From 101 patients, there were 256 (64%) follow up observations through 18 months with both PR-QoL and P-Tox at the time point and baseline. Concordance of PR-QoL and P-Tox was low at all time points for both GU and GI toxicity domains (mean kappa 0.093; Table). MCID was more often reported by patients than Grade≥2 toxicity by physicians (38% vs 17% for GU and 44% vs 10% for GI). There was little overlap of PR-QoL and P-Tox reporting: Grade≥2 P-Tox reported in 17% of observations with MCID in PR-QoL, while MCID in PR-QoL reported in 54% of observations of Grade ≥2 P-Tox. Mean concordance was similarly low when analyzing sub-groups of trial, investigator, and an alternative 2xMCID threshold. Conclusions: P-Tox and PR-QoL differed dramatically in two prospective studies of SBRT despite toxicity primary endpoints. This may reflect subjective and varying intervention thresholds driving P-Tox reporting, rather than actual patient burden. These data strongly support use of PR-QoL rather than P-Tox for SBRT comparative study endpoints and guidelines in this rapidly evolving space. [Table: see text]
Late, persistent, substantial, treatment-related symptoms (LAPERS) following low-dose-rate brachytherapy for prostate cancer.
Authors: Ong Wee Loon , Millar Jeremy Laurence
Published: February 2022

246

Background: The late, persistent, substantial treatment-related symptoms (LAPERS) is a novel methodological approach to identify clinically relevant and long-lasting symptoms after treatment. It was first reported in a cohort of women with cervical cancer in the EMBRACE study. We applied the LAPERS methodology to report long-term outcomes following low-dose-rate brachytherapy (LDRBT) for prostate cancer (PCa). Methods: We studied a cohort of men with PCa treated with LDRBT in a single Australian institution, who completed the Expanded Prostate Cancer Index Composite short-from 26 (EPIC26) questionnaire before LDRBT, and at regular intervals after LDRBT. For LAPERS analyses, 1) we limited the analyses to men with baseline EPIC26, and at least 3 ‘late’ follow-up EPIC26 (from 6 months post-LDRBT onwards); 2) ‘substantial’ symptoms were defined as either ‘moderate’ (score 25) or ‘big problem’ (score 0) in EPIC26 urinary and bowel domain questions which assess the degree of symptom bother; 3) ‘persistent’ symptoms were defined as ‘substantial’ symptoms that present in at least half of the ‘late’ follow-up EPIC-26 assessments. This provides a binary (yes/no) LAPERS outcome. We estimated cumulative incidence of substantial symptom with the Kaplan-Meier methods. We reported on 1) proportion of men with LAPERS, 2) proportion with baseline-corrected LAPERS, 3) prevalence of substantial symptoms at specified timepoint, and 4) cumulative incidence of substantial symptoms. Results: 177 men were included in the study. The median follow-up was 60 months (IQR: 36-74 months). For overall urinary function, the proportion of men with LAPERS was 2.3% (baseline corrected LAPERS 2.3%). The prevalence of substantial urinary symptoms at 12, 24, 36, 48, and 60 months were 5.9%, 4.4%, 2.9%, 0.7%, 1.8%, and 5-year cumulative incidence was 17.8% (95%CI = 12.7-24.6%). For overall bowel function, the proportion of men with LAPERS was 2.3% (baseline-corrected LAPERS 1.7%). The prevalence of substantial bowel symptoms at 12, 24, 36, 48, 60 months were 7.6%, 3.0%, 3.6%, 3.6% and 2.2%, and 5-year cumulative incidence was 16.2% (95%CI = 11.3-23.2%). Conclusions: We observed considerable differences between LAPERS, prevalence and cumulative incidence of substantial symptoms in men with PCa treated with LDRBT. Cumulative incidence (‘time-to-first event’ analyses) may overestimate the burden of late toxicities as considerable proportion of patients do not experience persistent symptoms over time, and LAPERS is more reflective of ‘true’ late toxicities, taking into account the duration of symptoms.
Impact of rectal spacer on toxicity reduction in men treated with proton versus photon therapy.
Authors: Dhere Vishal Ramesh , Jani Ashesh B. , Fischer-Valuck Benjamin Walker , Cooper Sherrie , Shelton Joseph W. , Hershatter Bruce Warren , Goyal Subir , Liu Yuan , Godette Karen D. , Patel Pretesh R. , Patel Sagar Anil
Published: February 2022

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Background: Dose escalation in prostate cancer (PCa) radiotherapy (RT) is limited by toxicity to surrounding tissue, including the rectum. Rectal spacers improve bowel toxicity in men treated with photons (i.e. IMRT). However, the relative benefit of rectal spacers in men treated with protons remains unknown. Further, proton therapy may result in high-dose exposure to the anterior rectal wall due to lateral penumbra with conventional opposed lateral beam arrangement. We hypothesize that rectal spacers will confer greater toxicity benefit in the setting of proton therapy compared with photon therapy. Methods: We conducted an IRB approved, single institution, retrospective review of patients receiving definitive conventional or moderate hypofractionated photon IMRT or pencil-beam scanning proton RT for localized PCa from 2018-2021. Four cohorts were compared: Photon with (Ph+RS) or without (Ph-RS) rectal spacer, and proton with (Pr+RS) or without (Pr-RS) rectal spacer. Rates of pelvic nodal treatment were equivalent between protons and photons within the +/- rectal spacer cohorts. Acute (<3 months) and late (≥ 3 month) toxicity was compared amongst the four cohorts. Cumulative incidence of physician-reported grade 1-2 gastrointestinal (GI) toxicity (CTCAE V5.0) was compared using Chi-square or Fisher’s exact test. Patient-reported bowel toxicity was evaluated using International Prostate Expanded Prostate Composite Index- Clinical Practice (EPIC-CP) and compared using linear mixed modeling. Results: 164 patients were eligible for analysis: 38 Ph-RS, 50 Ph+RS, 26 Pr-RS, & 50 Pr+RS. Median follow-up was 17.6 months. In men treated with protons, physician-reported acute G1-2 GI toxicity was significantly lower in men with versus without rectal spacer (6.12 vs 30.77%, Pr+RS vs Pr-RS, respectively; p=0.009) and there was a trend towards lower late G1-2 GI toxicity (8.51 vs 26.09%, Pr+RS vs Pr-RS, respectively; p=0.08). In men treated with photons, there were no significant differences in physician-reported acute or later GI toxicity with versus without rectal spacer. No significant differences in patient-reported outcomes were observed with versus without spacer in the proton or photon cohorts. Conclusions: Rectal spacer use was associated with a lower CTCAE grade 1-2 acute GI toxicity in men treated with protons, and this difference was not observed in men treated with photons. While this study is limited by low sample size, a relatively greater benefit of rectal spacer with proton vs. photon therapy was observed. Further prospective analyses in larger cohorts are ongoing to validate these hypothesis-generating findings.
Validation of the STAR-CAP clinical prognostic system for predicting biochemical recurrence after radical prostatectomy in a Japanese cohort.
Authors: Miura Noriyoshi , Miyauchi Yuki , Kikugawa Tadahiko , Oka Akihiro , Sawada Yuichiro , Tomida Ryotaro , Matsumura Masafumi , Hashine Katsuyoshi , Yanagihara Yutaka , Ninomiya Iku , Kan Masaharu , Yano Akira , Tacho Takatoshi , Yanagaki Takahiro , Takeda Hajime , Watanabe Yuichi , Saika Takashi
Published: February 2022

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Background: An international staging collaboration for cancer of the prostate (STAR-CAP) was recently established and used for predicting oncological outcomes for patients with prostate cancer. However, the validation of STAR-CAP has not yet been performed in the Japanese cohort. Our study aimed to assess the STAR-CAP prognostic model for Japanese patients with prostate cancer and compare it to the CAPRA score for the prediction of biochemical recurrence (BCR) after radical prostatectomy. Methods: We retrospectively analyzed data from a multi-institution database of 1,645 patients who underwent radical prostatectomy between 2010 and 2020. We excluded patients with inadequate follow-up duration ( < 1 year), missing or incomplete perioperative clinical parameters relevant for STAR-CAP, and patients who received neoadjuvant therapy. BCR was defined as two consecutive prostate-specific antigen values ≥ 0.2 ng/mL. The 3-year BCR-free survival was assessed by Kaplan-Meier analyses and log-rank test. The performance of both models to predict 3-year BCR-free survival was assessed using the area under the curve (AUC). Results: The 3-year BCR-free survival ranged from 47.3% (high risk) to 93.5% (low risk) in the STAR-CAP classification ( p< 0.001) and from 62.5% (high risk) to 94.6% (low risk) in the CAPRA classification ( p< 0.001). AUCs for the 3-year BCR prediction were 0.756 and 0.784 for STAR-CAP and CAPRA, respectively. Conclusions: In Japanese patients, both STAR-CAP and CAPRA prognostic systems provide sufficient stratification and their predictive ability for 3-year BCR-free survival is comparable, with a small advantage for CAPRA (2.8%).
Long-term outcomes of a pilot study on highly hypofractionated intensity-modulated radiation therapy over three weeks for localized prostate cancer.
Authors: Nakamura Kiyonao , Ikeda Itaru , Inokuchi Haruo , Aizawa Rihito , Akamatsu Shusuke , Kobayashi Takashi , Mizowaki Takashi
Published: February 2022

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Background: A number of reports have been published on both moderately hypofractionated intensity-modulated radiation therapy (IMRT) for localized prostate cancers using 2.4 – 3.4 Gy per fraction over 4 – 6 weeks, and ultrahypofractionation over 1 – 2 weeks using 6 Gy or more per fraction. However, long-term outcomes have sparsely been reported using doses between these two fractionations (3.4 – 6.0 Gy per fraction) over 2 – 3 weeks (high hypofractionation). Therefore, we performed a pilot study of highly hypofractionated IMRT in 15 fractions using 3.6 Gy per fraction over 3 weeks for localized prostate cancer. We now report the long-term outcomes of the study. Methods: Twenty-five patients with low- to intermediate-risk prostate cancer were enrolled in this prospective study from April 2014 to September 2015. Fifty-four Gy in 15 fractions (3.6 Gy per fraction) was delivered over three weeks using IMRT with CBCT-based image guidance without intraprostatic fiducial markers. Based on an estimated alpha/beta ratio for prostate cancer of 1.5 Gy, the EQD2 was 78.7 Gy for the present dose fractionation. Neoadjuvant hormonal therapy (HT) was administered to intermediate-risk patients for 4 – 8 months, but was not mandatory in patients with low-risk disease. Adjuvant HT was not provided for any patient. Biochemical relapse-free survival (BRFS), clinical relapse-free survival (CRFS), overall survival (OS), and the cumulative incidence rate of late toxicities were analyzed using the Kaplan Meier method. Results: Twenty-four patients were treated with highly hypofractionated IMRT, except one case switched to conventionally fractionated IMRT because we could not meet the dose constraint of the small bowel in treatment planning. Among the 24 patients, 17 % had low-risk, and 83% had intermediate-risk disease. Neoadjuvant HT was administered to 23 patients, and the median duration of HT was 5.3 months. The median follow-up period was 77 months (range, 57–87 months). BRFS, CRFS, and OS were 91.7%, 95.8% and 95.8% at 5 years, and 87.5%, 86.3% and 95.8% at 7 years, respectively. No patient died of prostate cancer, but one patient died due to the other cancer. Neither grade ≥2 late gastrointestinal toxicity nor ≥3 late genitourinary toxicity was observed. Grade 2 late genitourinary toxicity did not occur during the first 4 years, but was developed in 5 patients after more than 4-year follow-up. The cumulative incidence rate was 12.9% and 22.8% at 5 and 7 years, respectively. Conclusions: Highly hypofractionated IMRT delivering 54 Gy in 15 fractions over 3 weeks for prostate cancer without intraprostatic fiducial markers demonstrates favorable oncological outcomes with no severe complications. This treatment approach could be a possible alternative of moderate hypofractionation, although further studies will be mandatory.
Early initiation of salvage radiotherapy is associated with improved metastasis-free survival in patients with relapsed prostate cancer following prostatectomy.
Authors: Lee Emerson , Singh Tanmay , Han Misop , Deville Curtiland , Halthore Aditya , Greco Stephen C. , Tran Phuoc T. , DeWeese Theodore L. , Song Danny
Published: February 2022

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Background: Salvage radiation therapy is a recognized management option for patients who develop biochemical failure following radical prostatectomy. However, given the documented long natural history of biochemically relapsed prostate cancer after prostatectomy, questions remain on the value of early salvage intervention vs initial expectant management, especially with regards to more critical clinical rather than biochemical endpoints. We sought to determine the impact of early salvage radiotherapy (initiated at PSA 0.2 - 0.5 ng/ml) on metastasis-free survival in patients who receive salvage radiotherapy following prostatectomy for clinically localized prostate cancer. Methods: Using tumor registry data, we identified 408 patients who received salvage radiation therapy between 1986 – 2016 at our institution. We analyzed association between survival outcomes and prognostic factors, including pre-treatment and nadir prostate-specific antigen (PSA), interval between prostatectomy and initiation of salvage RT, use of neoadjuvant/concurrent hormonal suppression, and adverse pathologic features, including Gleason score, extraprostatic extension, seminal vesicle invasion, nodal involvement, and margin status. Univariate analyses and multivariable-adjusted Cox proportional hazards models were constructed to assess association between these clinical and pathologic features and duration of biochemical relapse-free survival (bRFS) and metastasis-free survival (MFS). Construction of Kaplan-Meier survival curves stratifies survival by predictive features. Results: Overall, 187 (45.8%) patients received salvage radiotherapy while PSA levels were 0.2 - 0.5 ng/ml (early salvage). One hundred thirty three (32.6%) patients received neoadjuvant/concurrent androgen deprivation therapy (ADT). Median radiation dose was 68.4 Gy and did not differ significantly between treatment subgroups. Independent of pathologic features and use of ADT, early-salvage at lower PSA levels was the most significant predictor of improved bRFS and MFS, HR = 0.52 (95% CI [0.35, 0.79], p = 0.002), and HR = 0.58 (95% CI [0.37, 0.91], p = 0.02), respectively. Seminal vesicle invasion was associated with shorter interval to biochemical failure (HR = 1.79 (95% CI [1.07, 2.98], p = 0.03), but not significant difference in MFS. Conversely, nodal involvement was a significant predictor of worse MFS, with HR = 2.18 (95% CI [1.04, 4.57], p = 0.04). Notably, interval between prostatectomy and initiation of salvage radiation was not a significant prognostic factor for bRFS or MFS. Conclusions: Independent of pathologic features and use of ADT, the initiation of salvage radiation therapy early after biochemical relapse (PSA ≤ 0.5 ng/ml) following prostatectomy is associated with increased metastasis-free as well as biochemical relapse-free survival.
The role of spatial transcriptomic profiling to determine androgen receptor signaling and immune infiltration in prostate cancer
Authors: Patel Parth , Nallandhighal Srinivas , Scoville David , Tran Lynn , Cotta Brittney , Udager Aaron M. , Rao Arvind , Palapattu Ganesh S. , Dadhania Vipulkumar , Pitchiaya Sethu , Salami Simpa
Published: February 2022

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Background: Prostate cancer (PCa) in the transition zone (TZ) accounts for approximately 30% of disease and tends to present with higher PSAs with a lower risk of seminal vesicle invasion, extra-capsular extension, and risk of biochemical recurrence compared with peripheral zone (PZ) tumors. The underlying biological mechanism for these differences is poorly understood. Here, we performed spatial transcriptomic profiling to elucidate the molecular differences between TZ and PZ PCa. Methods: We identified three patients who underwent radical prostatectomy for PCa (one each with PZ only, TZ only, and both PZ and TZ tumors) and used the NanoString’s Digital Spatial Profiling (DSP) platform to quantify whole transcriptomic gene expression data (17,128 genes) in multiple regions of interest (ROI) per patient (42 cancer and 8 normal samples). Four morphology markers to facilitate ROI selection in both cancer and normal areas (SYTO13 for nucleus, PanCK for epithelium, SMA for stroma and CD45 for immune cells) were selected. Raw counts for 17,128 genes were imported to R v.4.1.0 for downstream data analyses. Counts were Q3 normalized and scaled (Z-score) to enable plotting of all genes on the same axes. Differential gene expression analysis using a linear model fit by empirical Bayes moderation, gene set enrichment analysis (GSEA) by cancer hallmarks, XCell gene sets for pathway enrichment and immune cell deconvolution using CIBERSORT was performed. Results: There were grade group (GG) 4 (n=10) and 5 (n=10) tumors in PZ and GG 3 (n=10), 4 (n=11) and 5 (n=1) cancers in TZ regions. We observed distinct gene expression profiles between PZ (n = 20) and TZ (n=22) tumors. Interestingly, androgen receptor (AR) signaling was significantly higher in TZ PCa ROIs compared to PZ ROIs in both GSEA (false discovery rate < 5%) and the androgen subcomponent of the genomic prostate score (p<0.001), regardless of grade, epithelial, stromal or immune component of the region. To standardize the comparison, CIBERSORT’s absolute immune signature scores were only computed for GG4 tumors and found to be significantly higher in PZ GG4 tumors compared to TZ GG4 tumors. Notably, CD4+ memory T cells were significantly higher in PZ GG4 regions compared to TZ GG4 tumor regions (p<0.05). Conclusions: Here, we demonstrate distinct gene expression profiles of PZ and TZ PCa. Specifically, we observed higher AR signaling in TZ cancers and higher levels of immune infiltration on PZ cancers. This is in concordance with prior knowledge that TZ tumors may be associated with higher serum PSA and PZ tumors may be associated with inflammation. Further studies are needed to discern the biological and clinical significance of the different molecular features of PZ and TZ PCa.
Longitudinal ctDNA alterations in germline positive CRPC patients.
Authors: Huang Minqi , Jaeger Ellen B. , Caputo Sydney , Fleming William , Light Malcolm , Manogue Charlotte , Sussman Isabelle P. , Lieberman Alex , Lewis Brian E. , Barata Pedro C. , Layton Jodi Lyn , Ledet Elisa M. , Sartor A. Oliver
Published: February 2022

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Background: Circulating tumor-derived DNA (ctDNA) is an accessible method for characterizing somatic alterations. We report longitudinal ctDNA screenings of mCRPC patients (pts) who have had germline testing. Methods: Patients with both germline testing and ctDNA assessment were included. Germline testing was performed with a multi-gene cancer panel from Invitae (50-83 genes) and somatic alterations in ctDNA were identified by testing with Guardant 360 (70-83 genes). ctDNA alterations were characterized as deletions, frameshift, missense, nonsense, and other mutations. A total of 177 patients in various stages of therapy had both ctDNA and germline DNA tested. Results: From 2015-2021, 177 mCRPC patients were included and had an average of 3 ctDNA tests. 11.3% (20/177) had pathogenic or likely-pathogenic germline mutations. The common pathogenic germline mutations were in BRCA2 (25%; 5/20), ATM (10%; 2/20), and MSH2 (10%; 2/20). In ctDNA, missense mutations were the most prevalent type of gene alteration in germline negative (n = 539/790, 68%) and germline positive (n = 124/218, 57%) followed by frameshift mutations at 22% (n = 48/218) in germline positive and 10% (n = 80/790) in germline negative patients. Germline positive patients were more likely to have somatic frameshift mutations (OR = 2.09, 95% C.I. (1.3792, 3.1618), p = 0.001) and less likely to have missense mutations (OR = 0.61, 95% C.I. (0.4519, 0.8351), p = 0.002). Other alterations including deletions, nonsense, and other mutations were not significantly different. Of the germline positive pts, BRCA2 mutation was associated with the highest number of somatic alterations. Conclusions: Germline positive CRPC patients were more likely to have frameshift mutations and less likely to missense mutations compared to germline negative CRPC patients. Patients with germline mutations in BRCA2 and TP53 had the highest number of somatic alterations detected in ctDNA over the course of ctDNA evaluation.