bluuebunny/crossref_metadata_2025 huggingface dataset:
Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-199 cohorts 4-5.
Authors: Graff Julie Nicole , Antonarakis Emmanuel S. , Hoimes Christopher J. , Tagawa Scott T. , Hwang Clara , Kilari Deepak , Ten Tije AJ , Omlin Aurelius Gabriel , McDermott Raymond S. , Vaishampayan Ulka N. , Elliott Anthony , Wu Helen , Kim Jeri , Schloss Charles , De Bono Johann S.
Published: February 2020

15

Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study. Cohort (C)4 (RECIST-measurable disease) and C5 (bone-predominant disease) consist of chemotherapy-naive patients (pts) with mCRPC treated with enza + pembro after progression with enza. Results for C4 and C5 presented. Methods: Pts with or without prior abiraterone had clinically meaningful response/benefit to enza followed by disease progression. Pts received pembro 200 mg Q3W with continuation of enza for up to 35 cycles or until progression/intolerable toxicity. Primary end point: ORR, blinded independent central review (C4). Secondary end points: DCR, PSA response rate (≥50% reduction), rPFS, OS, and safety (C4, C5); DOR (C4). Results: Of 126 pts (C4, 81; C5, 45), 107 discontinued, primarily due to progression. Median follow-up: 13.7 mo (C4, 11.8; C5, 18.6). ORR (95% CI) for pts with measurable disease was 12% (6-22) in C4; DCR for all pts: 51% (39-62) in C4 and 51% (36-66) in C5 (Table). Any grade/grade 3-5 treatment-related AEs occurred in 75%/26% pts in C4 and 69%/24% in C5. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any grade/grade 3-4 rash (regardless of treatment relatedness) was higher than previously reported for individual agents (33%/6%). All except one pt (grade 3 treated with IV steroids) were treated with oral/topical steroids or had no intervention. Conclusions: Addition of pembro to enza following enza resistance showed modest antitumor activity in pts with RECIST-measurable and bone-predominant mCRPC. Combination had manageable safety and is being evaluated in a phase 3 trial. Clinical trial information: NCT02787005. [Table: see text]
Improving data accessibility: New strategies towards implementation of a genomic data portal.
Authors: McNair Christopher , Knudsen Karen E.
Published: February 2020

159

Background: It is now standard practice to utilize genomic profiling as a mechanism to navigate cancer patients to more effective therapies and clinical trials. Despite routine use, there is no single solution to perform these tests at most institutions, neither in-house nor external. As such, a myriad of options continue to be utilized for molecular diagnostic purposes. Significantly, lack of standardization in testing results in difficulty developing consistent mechanisms for ingesting, organizing, and accessing the data resulting from these tests. Ultimately, the result is a substantial gap in the types of studies researchers are able to perform simply due to lack of data accessibility. Methods: Typical workflows for genomic profiling do not involve a data repository such as the EMR or data warehouse for reasons including: lack of EMR ability to store genomic data, no processes for genomic profiling results to be integrated. The SKCC Cancer Informatics team at Jefferson has utilized the open source cBioPortal platform as a means of organizing, visualizing, and increasing overall access to Jefferson patient-specific genomic data at SKCC, termed the Genomic Data Portal (GDP). Results: We have developed processes for ingesting and transforming test results from multiple sources including in-house and external vendors. Once ingested, results are integrated with patient-specific clinical information from the EMR and tumor registry in order to increase the power of the data. The GDP currently houses over 1200 samples, including over 80 samples from advanced prostate cancer patients, with these numbers growing as more patients receive testing. Genomic results for each patient include gene mutation, fusion, and CNV, in addition to TMB and MSI. Clinical information drawn from the EMR and tumor registry includes demographics, overall survival, as well as disease specific information such as Gleason Score. Conclusions: The GDP has shown utility for multiple purposes including translational research studies and clinical trial feasibility and design. Importantly, this workflow can be adopted by institutions with varying technical expertise and resources, further enabling the research community.
The effect of deep AR suppression with enzalutamide or apalutamide on endogenous glucocorticoids: Implications for adverse effects and development of combination therapies.
Authors: Sharifi Nima , Alyamani Mohammad , Li Jianbo , Patel Mona , Berk Michael , Taylor Susan , Przybycin Christopher , Posadas Edwin M. , Madan Ravi Amrit , Gulley James L. , Rini Brian I. , Garcia Jorge A. , Klein Eric A.
Published: February 2020

17

Background: Metabolic consequences of potent AR suppression with enzalutamide and apalutamide are unresolved. Endocrine perturbations induced by potent AR antagonists may promote adverse effects and impinge on the potential efficacy of combination therapies, including for example, immunotherapies. We hypothesized that enzalutamide and apalutamide will block 11β-HSD2, the major enzyme that inactivates cortisol in peripheral tissues and results in increased systemic exposure to endogenous active glucocorticoids. We further hypothesized that AR is co-expressed with 11β-HSD2, suggesting a mechanism of suppression. Methods: Cortisol and cortisol/cortisone ratio (substrate/product of 11β-HSD2) were measured in serum using mass spectrometry before and on-treatment in 3 clinical trials: 1) neoadjuvant apalutamide + leuprolide 2) enzalutamide +/- PROSTVAC for metastatic castration-resistant prostate cancer 3) enzalutamide +/- PROSTVAC for non-metastatic castration-sensitive prostate cancer. AR and 11β-HSD2 expression were assessed in kidneys of 13 men and 9 women. Results: A rise in cortisol concentration and cortisol/cortisone ratio occurs uniformly across all 3 trials of potent AR antagonists. For example, a rise in cortisol/cortisone ratio occurred in 23/25 (92%) patients (p<0.001), 30/38 (79%) patients (p=0.051), and 36/64 (67%) patients (p<0.001), in the 3 respective trials. AR is only expressed alongside 11β-HSD2 in the kidneys of men but not women. Conclusions: Treatment with enzalutamide or apalutamide increases systemic exposure to active glucocorticoids. This effect is likely mediated by AR suppression of 11β-HSD2 in the kidney. These findings have potential consequences for immune suppression, the efficacy of treatment combinations using next-generation AR antagonists, and adverse effects of these drugs.
Impact of baseline serum IL-8 on metastatic hormone-sensitive (mHSPC) prostate cancer outcomes in the phase III CHAARTED trial (E3805).
Authors: Harshman Lauren Christine , Wang Xin Victoria , Yamamoto Hidemi S. , Hamid Anis , Drake Charles G. , Carducci Michael Anthony , DiPaola Robert S. , Fichorova Raina N. , Sweeney Christopher
Published: February 2020

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Background: IL-8 (CXCL-8) is a cytokine produced by leukocytes and tumor cells, which promotes inflammation, angiogenesis, anti-apoptosis, and metastasis. Our published training set identified serum IL-8 levels drawn within 28 days of androgen deprivation therapy (ADT) initiation as prognostic for shorter overall survival (OS). We sought to validate this finding using samples from CHAARTED patients treated with ADT +/- docetaxel for mHSPC. Methods: We assayed serum samples drawn ≤28 days from ADT initiation from 233 patients using the same Mesoscale multiplex ELISA assay as the training set. Multivariable Cox proportional hazards models adjusted for ECOG performance status, disease volume, and prior local therapy (radiation/prostatectomy vs. none) with IL-8 as continuous and binary variables. The training median 9.3 pg/mL was the a priori binary cutpoint. Fixed-effects meta-analysis of the training and validation sets was performed. Results: Higher IL-8 levels were prognostic for shorter OS and time to CRPC for ADT alone and ADT + docetaxel (Table) and were independent of disease volume or docetaxel use. Meta-analysis of binary IL-8 levels >9.3pg/mL from patients treated with ADT alone (training + validation cohorts) was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p= 0.007) and shorter time to CRPC (HR: 1.4, 95%CI: 0.99-1.9, p=0.057). The validation cohort’s baseline median IL-8 level was similar at 10 pg/mL. Conclusions: Higher IL-8 is prognostic for shorter time to CRPC and OS independent of docetaxel use, disease volume and presentation with metachronous or de novo metastatic disease. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.[Table: see text]
Plasma cell-free DNA (cfDNA) profiling of copy number variation (CNV) to identify poor prognostic biomarkers in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kwan Edmond Michael , Fettke Heidi , Bukczynska Patricia , Ng Nicole , Hauser Christine , Graham Lisa-Jane K. , Mahon Kate Lynette , Dai Chao , Xie Feng , Wang Xiaohong , Zhao Zhixin , Zhou Kemin , Du Peter , Yu Jianjun , Jia Shidong , Tan Winston , Horvath Lisa , Kohli Manish , Azad Arun
Published: February 2020

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Background: Multiple tumour tissue studies have demonstrated the prognostic utility of CNVs in mCRPC. However, accurate assessment of CNVs in plasma cfDNA remains challenging, and prognostic significance has not been well characterized. Using a large customized panel, we correlated plasma CNVs with clinical outcomes in a contemporary cohort of mCRPC patients. Methods: Deep targeted sequencing was performed using a 180-gene cfDNA panel (Predicine) in 56 patients commencing AR pathway inhibitors (enzalutamide or abiraterone; n = 34) or taxane chemotherapy (n = 22) at two Australian institutions. Kaplan-Meier estimates and Cox proportional-hazards models were used to correlate CNVs with progression-free survival (PFS) and overall survival (OS). Significant results were validated in an independent cohort (Mayo Clinic, n = 144). Results: Median follow-up was 19.4 months (mo; IQR 11.3-31.9). The most common CNVs in the Australian cohort are shown (Table). OS was significantly decreased in patients with PI3KCA gain (median 21.7 mo vs 6.6 mo, p < 0.0001), PTEN loss (24.8 mo vs 11.7 mo, p = 0.0019) and AR gain (21.7 mo vs 12.0 mo, p = 0.0083). Furthermore, all three alterations independently predicted for poor survival in multivariable analyses (MVA; Table). Findings in the independent cohort showed similar OS results in MVA: PIK3CA gain (HR 2.0, p = 0.07), PTEN loss (HR 1.7, p = 0.08) and AR gain (HR 1.7, p = 0.03). Conclusions: Sequencing of plasma cfDNA revealed that PTEN loss, and PIK3CA and AR gain are associated with inferior clinical outcomes in patients commencing contemporary systemic treatment. These data support therapeutic strategies co-targeting the PI3K and AR pathways in mCRPC.[Table: see text]
Copy number amplification of androgen receptor in cell-free DNA is a potential prognostic factor in patients with CRPC.
Authors: Hamano Itsuto , Hatakeyama Shingo , Yoneyama Tohru , Suzuki Yuichiro , Yamamoto Hayato , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: February 2020

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Background: A circulating cell-free DNA (cfDNA) has been suggested as a potential biomarker for castration-resistant prostate cancer (CRPC). However, clinical implication of the parameters in cfDNA remains unclear. We aimed to investigate the impact of copy number variation (CNV) of androgen-receptor amplification (AR-amp) in cfDNA on prognosis in patients with CRPC. Methods: We retrospectively evaluated AR-amp in cfDNA in 154 patients with prostate cancer between April 2018 and September 2019. We compared AR-amp between the patients with CRPC and non-CRPC. An optimal cutoff point was defined using receiver operating characteristic (ROC) curve. The effect of AR-amp on prognosis was evaluated between the CRPC patients with AR-amp high and low. Results: The median age and initial PSA was 75 years and 34 ng/mL, respectively. The number of patients with abiraterone acetate, enzalutamide, docetaxel, cabazitaxel was 24, 15, 21, and 2, respectively. No significant association was observed between the AR-amp and serum prostate-specific antigen (PSA) level at AR-amp measurement. Of 154, 73 (47%) patients developed to CRPC. The AR-amp was significantly higher in the patients with CRPC than that in the non-CRPC (1.07 vs. 0.97, respectively, P<0.001). The cutoff value of AR-amp was defined 1.16 with area under the ROC curve of 0.672. Overall survival was significantly shorter in the patients with AR-amp low (≤1.16, n=46) than that with AR-amp high (>1.16, n=27) (8.9 vs. 9.6 months, respectively, P < 0.001). The AR-amp was not significantly different between the pre- and post-docetaxel status in patients with CRPC. Conclusions: AR-amp in cfDNA might be a potential biomarker for poor prognosis in patients with CRPC who were treated with life-prolonging therapies.
Efficacy of cabazitaxel second-line and beyond.
Authors: Vengalil Salil , Nolan Emma , Sultana Nasira , Joseph Shibu , Bhana Rajanee , El-Helw Loaie
Published: February 2020

226

Background: Prostate cancer accounts for the 2nd most common cause of cancer deaths in males in the UK. Cabazitaxel (CBZ) is a third generation taxane with activity demonstrated even in docetaxel resistant cases. Results of the TROPIC study established survival benefit for CBZ in metastatic castrate resistant prostate cancer (mCRPC) patients but there was also a higher incidence of febrile neutropenia (FN) reported. We studied the efficacy of CBZ in mCRPC patients treated in our centre and assessed FN rates with the use primary granulocyte colony stimulating factor (GCSF) support. Methods: We conducted a retrospective audit of mCRPC patients treated with CBZ from January 2016 – January 2019. We analysed treatment outcomes, FN rates and potential prognostic factors. Results: There were 42 patients in total with a median age of 70 years (range; 54-91). The median follow up was 9.5 months (range; 2-34 months). Most of our patients had extensive disease, with bone and visceral metastases seen in 88% and 31% respectively. CBZ was given as second line treatment in 15 (35.7%) patients on progression following docetaxel and as third line in 27 (64.3%) patients. Majority of our patients (95%) had WHO PS of either 0 or 1. Median number of cycles of CBZ administered was 6 and 31% of patients completed 10 cycles of treatment. Median biochemical progression free survival (PFS) for patients who received at least 3 or more cycles of CBZ was 6 months and median overall survival (OS) was 11 months. Median OS for patients who received CBZ as 2nd line and 3rd line treatments were 9 and 13 months respectively. Patients with visceral metastases had a median OS of 9 months. Median OS for patients with Haemoglobin (Hb) ≥12gm/dl and lower Hb were 19 and 9 months respectively (p = 0.004). Patients in favourable prognostic group (Normal Hb, Normal albumin and no visceral metastases) had a median OS of 24 months compared to 10 months for those in less favourable group. There were no episodes of FN reported in our group with the use of primary GCSF prophylaxis. Conclusions: CBZ is effective as a 2nd or 3rd line treatment option in patients with mCRPC. Neutropenic complications can be significantly reduced with the use of primary GCSF prophylaxis. Low pre-treatment Hb seems to be a predictor for poor overall survival.
Prevalence of ARV7 in Asian metastatic castrate-resistant prostate cancer (mCRPC) patients using multiple detection platforms.
Authors: Chan Johan , Ong Whee Sze , Ng Quan Sing , Toh Chee-Keong , Rajasekaran Tanujaa , Tan Wan Ling , Tan Hui Shan , Tan Min-Han , Lim Kiat Hon , Lee Yifang , Wong Siew Wei , Wong Alvin SC , Saad Marniza Bte , Ng Chi-Fai , Chansriwong Phichai , Horie Shigeo , Kanesvaran Ravindran
Published: February 2020

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Background: The presence of AR-V7 in metastatic castrate resistant prostate cancer (mCRPC) men has been associated with worse outcome in men initiated on 2nd generation androgen receptor signalling inhibitors (ARSI) in the Caucasian population. A multinational study was conducted to investigate this in the Asian population. Methods: mCRPC patients were recruited prospectively across 5 countries. Blood samples were collected and processed from patients with progressive disease immediately before the initiation of a new treatment and at progression. AR-V7 detection were performed using 3 methods: CTC enrichment followed by automated immunofluorescent staining (Clearbridge [CB]), CTC enrichment followed by reverse-transcription PCR analysis (IBN), and the AdnaTest Prostate Cancer(Adna) platform for CTC analysis and detection. Only blood samples collected in Singapore underwent all 3 methods of detecting AR-V7. Comparison of AR-V7 prevalence using the 3 detection methods were done on patients with the AdnaTest platform as gold standard. We examined associations between AR-V7 status and PSA response rates, PSA progression free survival and overall survival(OS). Results: 102 patients were recruited. 72 patients had ARSi while 30 patients had chemotherapy. 66 patients were included for the comparison of AR-V7 detection methods. AR-V7 prevalence rate was 14.3% (95% CI 4.8-30.3), 21.6% (95% CI 12.9-32.7) and 33.7% (95% CI 24.6-43.8) based on Adna, CB and IBN respectively. Concordance between Adna and CB was 75% while Adna and IBN was 68%. AR-V7- patients had a trend towards higher PSA response, lower risk of PSA progression as compared to AR-V7+ patients. AR-V7- patients had a significantly lower risk of death as compared to AR-V7+ patients detected by Adna and IBN platforms but not the CB platform. The association between ARV7 status and outcomes did not vary when compared across treatment groups. Conclusions: AR-V7 positivity in Asian mCRPC patients is consistent with the data reported in Western populations with lower PSA response rates, PSA progression free survival and OS. This data suggest that ARV7 is more likely a prognostic than a predictive biomarker. Clinical trial information: 2015/2797.
Association of PI-RADS categories and PSA density with active surveillance progression in patients with prostate cancer.
Authors: Wang Alex Z. , O'Connor Luke P. , Yerram Nitin , Zeng Johnathan , Mehralivand Sherif , Harmon Stephanie , Gurram Sandeep , Chalfin Heather , Telfer Siobhan , Lebastchi Amir H. , Ahdoot Michael , Gomella Patrick H. , Merino Maria J. , Turkbey Baris , Wood Bradford J. , Choyke Peter L. , Pinto Peter A.
Published: February 2020

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Background: Active surveillance (AS) is now considered a well-accepted alternative for low-favorable intermediate risk prostate cancer over definitive therapy. Few studies have incorporated the use of multi-parametric MRI (mpMRI) into the treatment paradigm. In this study we investigate imaging findings that are predictive of a patient dropping off AS. Methods: Our institutional database was queried for all patients who met criteria for active surveillance from 11/2003 to 5/2017. Criteria for inclusion included ≥ 2 mpMRIs, ≥ 2 prostate biopsies, and a diagnosis of Gleason Grade group (GG) 1 or higher. Patients were excluded if they received any other therapy for the treatment of their prostate cancer such as radiation, chemotherapy, focal therapy, or immunologic therapy. Patient demographics, mpMRI, biopsy and most recent follow-up data were recorded. Factors, including PSA density (PSAD), PSA, lesion size, and PI-RADS category, associated with AS progression were evaluated in Cox Proportional Hazards Model. Results: An analysis of a total of 212 patients were performed during the study time interval. 88 patients were dropped from AS during this time and of those patients the median amount of time before removal was 4.70 years (range, 0.7-10.5). On univariable analysis, PI-RADS category (HR, 1.302 for every increase in 1 unit of the PI-RADS category; 95% CI, 1.046-1.62, p = 0.01) and PSAD (HR, 4.98 for every increase in 0.001 ng/mL/cc; 95% CI, 2.127-11.66; p < 0.001) were found to be associated with being removed from AS. On multivariable analysis, both PI-RADS score (HR, 1.281 for every increase in 1 unit of the PI-RADS category; 95% CI, 1.025-1.6; p = 0.003) and PSAD (HR, 4.188 for every increase in 0.001 ng/mL/cc; 95% CI, 1.640-10.7; p < 0.001) remained associated with being removed from AS. Conclusions: PI-RADS categories and PSAD predict the risk of a patient to drop off active surveillance. AS. Patients with these criteria should be considered high risk in any current AS protocol.[Table: see text]
A randomized phase II study of apalutamide (APA), androgen deprivation therapy (ADT), or APA + ADT in patients (pts) with biochemically relapsed (BCR) prostate cancer (PC).
Authors: Aggarwal Rahul Raj , Alumkal Joshi J. , Szmulewitz Russell Zelig , Higano Celestia S. , Bryce Alan Haruo , Lopez-Gitlitz Angela , McCarthy Sharon Anne , Miladinovic Branko , McQuarrie Kelly , Thomas Shibu , Small Eric Jay
Published: February 2020

320

Background: While there is no standard therapy for BCR PC following local therapy, intermittent ADT is widely used. We evaluated utility of APA alone, ADT (luteinizing hormone–releasing hormone agonist [LHRHa]) alone, or APA + LHRHa in ADT-naïve BCR PC pts. Methods: Pts with BCR PC after primary definitive local therapy and prostate-specific antigen (PSA) doubling time (PSADT) ≤ 12 mo were randomized 1:1:1 to open-label 240 mg APA daily, LHRHa alone, or APA + LHRHa for 12 mo, followed by a 12-mo observation period off therapy. Pts were stratified by PSADT (< 6 vs 6-12 mo) and age (≤ 70 vs > 70 y). Primary end point: mean change from baseline (BL) in health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy-Prostate total score at 12 mo. Secondary end points included PSA nadir < 0.2 ng/mL by 7 mo, time to PSA progression (TTPpsa), and time to testosterone (T) recovery. Results: 90 pts (APA, n = 29; LHRHa, n = 30; APA + LHRHa, n = 31) were treated for median of 12 mo with similar distribution of BL characteristics across groups: 67% age ≤ 70 y; 67% PSADT < 6 mo. There was no significant difference in HRQoL in APA vs LHRHa at 12 mo, or between LHRHa vs APA + LHRHa groups. At median follow-up of 30-33 mo, TTPpsa in APA, LHRHa, and APA + LHRHa groups was 26 mo, 31 mo, and 36 mo, respectively. Compared to LHRHa alone, APA + LHRHa resulted in a trend toward improved TTPpsa (HR [95% CI] 0.56 [0.23-1.36], p = 0.196), and APA alone resulted in a trend for shorter TTPpsa (HR 1.09 [0.49-2.43], p = 0.824). PSA nadir < 0.2 ng/mL was reached in 89%, 89%, and 97% in APA, LHRHa, and APA + LHRHa pts. Median time to T recovery was similar in LHRHa and APA + LHRHa groups (23 mo vs 24 mo). Grade 3-4 adverse events (AEs) occurred in 17% of APA, 14% of LHRHa, and 29% of APA + LHRHa pts. The only grade 3-4 AE reported in > 1 pt per group was hypertension (APA, 3%; LHRHa, 0; APA + LHRHa, 13%). Conclusions: Addition of APA to LHRHa resulted in a trend for longer TTPpsa and a higher proportion of pts achieving optimal PSA nadir without significant difference in HRQoL or time to T recovery. Observed AEs were consistent with known safety profiles. Results support further evaluation of APA + LHRHa for a specified duration in BCR PC. Clinical trial information: NCT01790126.
Biochemical relapse in very high-risk prostate cancer after radical prostatectomy and DC-vaccine loaded with tumor RNA, hTERT, and survivin.
Authors: Lilleby Wolfgang , Tryggestad Anne Merete , Bigalke Iris , Brennhovd Bjørn , Axcrona Karol , Josefsen Dag , Axcrona Ulrika , Kvalheim Gunnar , Dueland Svein
Published: February 2020

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Background: Patients with very high-risk prostate cancer (VHR-PC) features experience worse outcome after radical prostatectomy. This study was designed to assess biochemical failure and toxicity of adjuvant dendritic cells vaccine (DCV) in prostate cancer patients who are at greatest risk for cancer progression. Methods: Twenty patients with pathological stage pT2 - pT3b and Gleason score 7B-10, pN0, pN+ or pNx were enrolled into the approved study DC-005. The primary end point was clinical failure. Ten patients were tested for disseminated tumor cells (DTCs) to the bone marrow before inclusion to the study. Three patients out of 10 patients had positive DTCs detection in bone marrow. The mean age of the cohort was 63 years (SD 6.9 years), and three patients had postsurgical pN1 status. Eighteen patients had two or more high-risk factors (ISUP grade 5, T3- stage and or PSA > 20 ng/mL). Autologous dendritic cells were transfected with mRNA for hTERT, survivin and tumor mRNA. The DCV product was applied intradermally after curative intended surgery once per week the first months, then once per months the first year, thereafter every 3 months for two years or until biochemical progression (PSA relapse cut-off ≥ 0.3). Results: After 5 years follow-up (FU) 62% (12/20 patients) had not biochemically progressed and with a median FU of 69 months all patients included in the study are alive. Five patients were treated with salvage and one patient with adjuvant radiation treatment, three patients received limited ADT, and three patients are on first line ADT, none of those eight patients have experienced castration resistant prostate cancer. The toxicity was mild with no serious adverse event related to DCV. Conclusions: Adjuvant DCV mitigates the time to biochemical progression. These results appear favorably compared to historical controls in VHR-PC. The clinical outcomes of this study warrants a future enlarged clinical trial. Clinical trial information: NCT01197625.
Adjuvant docetaxel for high-risk localized prostate cancer: Update of NRG Oncology/RTOG 0521.
Authors: Sandler Howard M. , Karrison Theodore , Sartor A. Oliver , Gomella Leonard G. , Amin Mahul B. , Purdy James , Michalski Jeff M. , Garzotto Mark , Pervez Nadeem , Balogh Alexander G. , Rodrigues George , Souhami Luis , Reaume M. Neil , Williams Scott , Hannan Raquibul , Jones Christopher U. , Horwitz Eric M. , Rodgers Joseph P. , Feng Felix Y , Rosenthal Seth A.
Published: February 2020

333

Background: High-risk, localized prostate cancer has a poor prognosis. We hypothesized that adj docetaxel (D) and prednisone and long-term (24 mos) androgen suppression (AS) and radiation therapy (RT) would improve overall survival (OS) and tested this in NRG/RTOG 0521. Results with med follow-up of 5.7 yrs were reported (JCO 37:1159, 2019), showing a benefit of D (HR=0.69, 90% CI: 0.49-0.97, 1-sided p=0.034). Med follow-up is now 10.4 yrs and we report updated results for OS and metastasis (DM). Methods: NRG/RTOG 0521 opened 12/05 and closed 8/09 with targeted accrual of 600 and designed to detect a HR of 0.49, based on improvement in 4-yr OS from 86 to 93%. With 0.05 1-sided type I error and 90% power >78 deaths were required. Pts were stratified by predefined risk groups. Group 1: Gl 9-10, any T; Group 2: Gl 8, PSA<20, T≥T2; Group 3: Gl 8, PSA≥20, any T; Group 4: Gl 7, PSA≥20, any T. maxPSA ≤150. RT dose was 75.6 Gy. Chemo consisted of 6, 21-day cycles of D starting 28 days after RT. Results: Of 612 accrued, 563 were eligible/available for analysis. By risk group 1-4, there were 297, 116, 64, and 86 pts. Med PSA 15 ng/mL. 10-yr OS rates were 64% [95% CI: 58-70%] for AS+RT and 69% [95% CI: 63-75%] for AS+RT+CT (HR = 0.89, 90% CI: 0.70, 1.13, 1-sided p=0.22). However there was evidence of non-proportional hazards (Grambsch-Therneau test, p=0.016). Thus survival was alternatively evaluated with restricted mean survival time (RMST). The difference in RMST at 10 yrs was 0.42 yrs (90% CI: 0.07-0.77, 2-sided p=0.048). Cumulative incidence of DM at 10 yrs was 22% [95% CI: 17-27%] for AS+RT and 20% [95% CI: 15-25%] for AS+RT+CT (2-sided log-rank p=0.29). At 10 years most deaths occurred in risk group 1: 62 in AS+RT and 50 in AS+RT+CT (HR= 0.93, 95% CI: 0.66-1.32, 2-sided log-rank p=0.16). There was no new related Grade 5 toxicity. Conclusions: OS findings, reported after follow-up of 5.7 yrs, demonstrated a small beneficial effect of adding D to AS and RT. With longer follow-up the benefit of D remains, but the HR varies over time and the OS curves have converged. Support: U10CA180868 (NRG Operations), U10CA180822 (NRG SDMC), U24CA180803 (IROC) from the NCI and Sanofi-Synthelabo Int. Clinical trial information: NCT00288080.
Fraction genome altered (FGA) to regulate both cell autonomous and non-cell autonomous functions in prostate cancer and its effect on prostate cancer aggressiveness.
Authors: Chakraborty Goutam , Ghosh Arnab , Nandakumar Subhiksha , Armenia Joshua , Mazzu Ying Zhang , Atiq Mohammad Omar , Lee Gwo-Shu Mary , Mucci Lorelei A. , Merghoub Taha , Wolchok Jedd D. , Kantoff Philip W.
Published: February 2020

347

Background: Our ability to distinguish lethal from non-lethal forms of prostate cancer (PC) is limited. Given prostate tumors’ genetic heterogeneity, is it unlikely that a single somatic variant is prognostic. Herein we investigated fraction of genome altered (FGA; percentage of copy number altered chromosome regions out of measured regions; cBioportal) and tumor mutational count (TMC; number of mutational events per case) harbored by the primary tumor as two tumor-specific factors posited to influence disease aggressiveness or responsiveness to certain therapeutic agents. Methods: We used the TCGA data (n= 490 primary PC) and MSKCC-IMPACT (n=717, Zehir et al 2017) PC datasets to analyze the correlation between FGA and TMC in PC. GSEA was performed with transcriptomes used to identify signaling pathways associated with these two measures. We then categorized 490 primary PC patients from TCGA dataset into 4 groups based on FGA and TMC levels (based on the median values) to assess associations with outcomes. Results: Primary PC patients who harbor FGAhighTMClow exhibited shorter disease-free survival (High Risk). We observed attenuation of the androgen signaling pathway and induction of cell proliferation pathways associated with this aggressive form of disease. We used results from CIBERSORT algorithm and deep learning methods of TCGA data and observed that quantities of tumor infiltrating lymphocytes was higher in the FGAhighTMClow group (p=0.038). However, we also observed significantly reduced immune effector signaling-pathway signaling in this high-risk FGAhighTMClow group suggesting the presence of immune-suppressive networks in primary disease associated with a high risk of progression. Conclusions: A greater understanding of molecular features of aggressive primary PC (FGA/TMC) will be important in developing management strategies. Based on our preliminary analyses, we hypothesize that patients whose primary PC harbors FGAhighTMClow have a higher likelihood of aggressive disease due to their impact on PC cell proliferation and dedifferentiation (cell autonomous), and subdued immune responses (non-cell-autonomous).
The prevalence of cardiovascular disease and its risk factors among prostate cancer patients treated with and without androgen deprivation.
Authors: Pinthus Jehonathan H. , Shayegan Bobby , Klotz Laurence , Siemens D. Robert , Luke Patrick P. , Niazi Tamim , Fradet Vincent , Fradet Yves , Duceppe Emmanuelle , Lavallee Luke , Mousavi Negareh , Hamilton Robert James , Brown Ian , Chin Joseph , Gopaul Darin , Violette Philippe , Davis Margot , Mian Rajibul , Karampatos Sarah , Leong Darryl ,   RADICAL-PC Investigators
Published: February 2020

364

Background: Cardiovascular disease (CVD) is the second most common cause of death in prostate cancer (PC) patients, yet the prevalence of CVD and its risk factors have been incompletely described in this population. Androgen deprivation therapy (ADT) is a risk factor for CVD. The objective of this study were to describe the CVD characteristics and risk factors in PC patients and the relationship between CVD risk and how ADT is used in real-world practice. Methods: RADICAL-PC (Role of Androgen Deprivation Therapy in CArdiovascular Disease – A Longitudinal Prostate Cancer Study) is an ongoing prospective cohort study. We recruited 2395 consecutive men (mean age 68 years) with newly diagnosed PC or with a plan to prescribe ADT for the first time. Cardiovascular risk was estimated by calculating Framingham risk scores. A Framingham score >17 (corresponding with a predicted 10-year CVD risk of >30%) was considered high-risk. Multivariable logistic regression was performed with ADT use as the outcome variable and CVD risk factors as the exposures of interest. Results: The prevalence of known CVD for the entire cohort was 22% and 35% had a Framingham risk score >17. Most participants (58%) were current or former smokers; 16% had diabetes; 45% had hypertension and 23% had high blood pressure but had not received a diagnosis of hypertension; 31% were obese (BMI ≥30kg/m2); 24% had low levels of physical activity. There was a positive relationship between each major cardiovascular risk factor and the use of ADT. However, after adjustment for age, education, alcohol use, BMI and time from PC diagnosis to eligibility assessment, these associations were significantly attenuated. Participants in whom ADT was planned had higher Framingham risk scores than those not intending to receive ADT. This risk was abolished after adjustment for confounders. Conclusions: One in three men with PC is at high cardiovascular risk. Men receiving ADT are a priori at higher CVD risk than PC patients whose treatment strategy does not include ADT. These differences are explained by confounding factors. Clinical trial information: NCT03127631.
Utilization of androgen deprivation therapy (ADT) and stereotactic body radiation therapy (SBRT) for localized prostate cancer (PC) in the United States (US).
Authors: Royce Trevor Joseph , Switchenko Jeffrey M. , Zhang Chao , Spratt Daniel Eidelberg , Chen Ronald C. , Jani Ashesh B. , Patel Sagar Anil
Published: February 2020

370

Background: Randomized trials have demonstrated improved survival with the addition of ADT to conventionally fractionated radiotherapy (RT) for men with unfavorable intermediate risk (UIR) and high-risk (HR) prostate cancer (PC). The benefit of ADT with SBRT is unknown. The purpose of this study is to examine ADT utilization with SBRT in the US. Methods: Men > 40 years old with localized PC treated with external beam RT for curative intent between 2004-2015 were analyzed from the National Cancer Database. Patients who received brachytherapy, surgery, or lacked ADT or risk stratification data were excluded. A total of 7,559 men treated with SBRT (≥5Gy/fraction; ≤5 fractions; dose ≥25Gy) versus 133,825 men treated with moderate or conventional RT (≤3Gy/fraction; dose ≥60Gy) were included. Patients were stratified by risk: low (LR), favorable intermediate (FIR), UIR, and HR using NCCN criteria. Differences between RT and SBRT were determined via Chi-square test. Results: Among all PC treated with RT, SBRT use increased from 2004 to 2015 across risk groups – overall: 0.9% to 10.3%; LR: 0.9% to 21.6%; FIR: 1.1% to 13.7%; UIR: 0.6% to 10.8%; HR: 0.8% to 2.8%; p < 0.001. Among all PC treated with RT, ADT use declined from 2004 to 2015 for LR (22.8% to 5.5%), FIR (51.7% to 40.0%), UIR (53.4% to 49.5%), but not HR (78.9% to 84.2%); p < 0.001. Patients with EBRT were more likely to receive ADT compared to those with SBRT across risk groups (Table). Conclusions: The majority of patients receiving SBRT for UIR and HR disease in the US do not receive concurrent ADT, despite national guideline recommendations and the lack of level 1 evidence to support this practice pattern. The omission of ADT may result in inferior oncologic outcomes, and randomized trials are needed to establish the safety of omitting ADT with SBRT for higher risk PC.[Table: see text]
Evaluation of the oncologic benefit of adjunctive surgery at time of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Authors: Nestler Tim , Paffenholz Pia , Pfister David , Hiester Andreas , Nini Alessandro , Albers Peter , Heidenreich Axel
Published: February 2020

388

Background: PC-RPLND for advanced nonseminomatous germ cell tumors aims to resect all remaining metastatic tissue. The resection of adjacent visceral or vascular organs is commonly performed to achieving complete resection of the residual masses. However, the frequency of metastatic involvement of those organs with teratoma or vital cancer is currently unknown. Methods: We reviewed a cohort of 1181 patients who underwent PC-RPLND between 2008 and 2018 as a 2-center study and identified 235 (20%) cases of adjunctive surgery during PC-RPLND. We analysed the pathohistological presence of germ cell tumor elements in the resected organs: viable tumor (V), teratoma (T) or necrosis / fibrosis (N). Surgery associated complications were reported according to the Clavien-Dindo classification. Outcomes of subgroups were compared by using log-rank test. Results: V, T, N was present in 51 (21%), 91 (39%) and 93 (40%) of all patients with adjunct resected organs. In 235 patients, 316 adjunct organs were resected with 64 (27%) of these patients receiving a resection of multiple organs. The kidney was the most often resected organ (n = 74; V: 27% T: 39% N: 34%), followed by V. Cava (n = 66; V: 24% T: 36%, N: 40%) and partial liver resections (n = 48; V: 15%, T: 31%, N: 54%). Intraoperative complications occurred in 21% of patients (VT 32% vs N 17%, p = 0.021). Postoperative complications occurred in 35% of which 22% were Clavien Grad III-V showing no significant differences between VTN p = 0.093. 27% of all patients suffered from a relapse during a median follow-up of 22 months [0-180]. Patients with T or V in the resected specimens had a significantly reduced 5-year RFS compared to patients with only N (39%, 81%, p < 0.001). Conclusions: This study shows for the first time that 40% of all resections of adjunct organs are oncologically unnecessary due to the presence of N only in the pathological specimens. In case of doubt we propose an organ safe procedure with multiple intraoperative frozen section to avoiding oncologically unnecessary adjunctive surgeries especially nephrectomies and vascular resections. Additionally, a more accurate presurgical workup is required to spare patients with N from PC-RPLND.
Prognostic impact of LDH and HCG levels in marker-positive seminomas.
Authors: Seidel Christoph Alexander , Daugaard Gedske , Nestler Tim , Tryakin Alexey , Fankhauser Christian Daniel , Hermanns Thomas , Aparicio Jorge , Heinzelbecker Julia , Paffenholz Pia , Heidenreich Axel , De Giorgi Ugo , Cathomas Richard , Lorch Anja , Bremmer Felix , Giannatempo Patrizia , Necchi Andrea , Aurilio Gaetano , Casadei Chiara , Oing Christoph , Bokemeyer Carsten
Published: February 2020

392

Background: The prognostic impact of LDH and HCG serum levels in marker positive metastatic seminoma patients is uncertain. This analysis evaluated the association between LDH and HCG levels with oncological outcomes in this patient population. Methods: Seminoma patients with elevated HCG levels were retrospectively analyzed. After stratification according to tumor marker levels pre- and post-orchiectomy, outcomes of subgroups were compared using log-rank test and cox-regression analysis. Study endpoints were cancer specific- (CSS) and recurrence-free survival (RFS). Results: In total, 429 HCG-positive metastatic seminoma patients (stage II n=291; stage III n=138) diagnosed between 1981 and 2018 were included. LDH + HCG levels ranged from 124 U/l to 8833 U/l (median: 619; IQR: 955) + 2 IU/l to 283,782 IU/l (median: 20; IQR: 63) pre- and from 107 U/l to 8650 U/l (median: 324; IQR: 481) + 0 IU/l to 36700 IU/l post-orchiectomy (median: 30; IQR: 121), respectively. Five-year CSS and RFS rates were 90% and 79%, respectively. Patients with LDH levels pre-orchiectomy <1.5 UNL (n=142) had a 5-year CSS (RFS) rate of 97% (88%), compared to 86% (81%) for ≥1.5 to 3 UNL (n=40), 83% (77%) for >3 to 5 UNL (n=44) and 83% (72%) for >5 UNL (n=44) (CSS p <0.001; RFS p=0.142). Concerning LDH levels post-orchiectomy this stratification was not significant but patients with LDH levels ≥3 UNL (n=77) displayed an impaired prognosis associated with a 5-year CSS (RFS) rate of 85% (79%) compared to 94% (82%) for levels <3 UNL (n=186) (CSS p=0.025; RFS p=0.447). Patients with HCG levels ≥2000 IU/l (n=17) pre- but not post-orchiectomy had a 5-year CSS (RFS) rate of 73% (60%) compared to 94% (79%) for patients with HCG levels <2000 IU/l (n=855) (CSS p=0.09; RFS p=0.04). In cox-regression analysis LDH ≥1.5 UNL (p=0.037; HR 3.32, CI95%1.08-10.26) and HCG levels ≥2000 IU/l (p=0.044; HR 3.69, 95%CI1.04-13.13) pre-orchiectomy were confirmed as prognostic factors for CSS. Conclusions: LDH levels inversely correlate with survival outcomes, suggesting ≥1.5 UNL pre- and ≥3 UNL post-orchiectomy as potential cut-off values for further risk assessment. Patients with extensive HCG elevations may represent an unfavorable subgroup concerning RFS and CSS, but only few patients were affected.
Germline alterations in patients with testicular cancer.
Authors: Ramamurthy Chethan , Esplin Edward D. , Yang Shan , Liss Michael , Tomlinson Gail Elizabeth , Sonpavde Guru
Published: February 2020

397

Background: There are limited data for the association of testis cancer (TC) with hereditary cancer genes. We report the prevalence of germline mutations among men with TC completing germline genetic testing through a large, commercial laboratory. Methods: We reviewed a de-identified dataset of men from across the USA with history of TC who underwent testing of 1 to 130 genes via massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. P/LP variants including single nucleotide variants/indels/copy number variants are reported. Fisher’s Exact test was used to analyze categorical variables. Results: The cohort of 250 men was 84% White/Caucasian. The median number of genes tested was 48. P/LP variants were found in 18% (n = 45) of subjects. P/LP variants occurred in several moderate to high penetrance genes, including CHEK2 (n = 10 [4.0%]), BRCA1/2 (n = 6 [2.4%]), ATM (n = 6 [2.4%]) and Lynch syndrome genes (n = 4 [1.6%]). Heterozygous MUTYH (n = 6) and NTHL1 (n = 1) mutations were also found. DNA damage repair (DDR) mutations were found in 14.8% (n = 37) of subjects. Of the 45 carriers, 18 (40%) had no other personal cancer history while 27 (60%) had an additional primary cancer, but there was no significant association between having another primary and risk of carrying a mutation (p = 0.253). CHEK2 was the single most frequently mutated gene, with 2 of the low penetrance I157T mutations identified, but 8 other higher penetrance variants, including 2 1100delC mutations. Conclusions: A high percentage of hereditary cancer gene mutations were found in testicular cancer patients, many which were not associated with a history of another malignancy. Several mutations were in high penetrance DDR genes such as BRCA1/2 and Lynch genes, which may also serve as actionable targets. CHEK2 mutations were common, supporting prior data suggesting an association with testicular cancer. Further multigene panel testing in unselected patients and the study of association with histologic subtype, race, stage and family history is warranted.
Treatment compliance and early toxicity in SAKK 01/10: Single-dose carboplatin and involved-node radiotherapy for treatment of stage IIA/B seminoma.
Authors: Papachristofilou Alexandros , Bedke Jens , Hayoz Stefanie , Fischer Natalie , Schiel Xaver , Schratzenstaller Ulrich , Krege Susanne , Lorch Anja , Aebersold Daniel M. , Putora Paul-Martin , Berthold Dominik R. , Zihler Deborah , Azinwi Ngwa C. , Zengerling Friedemann , Dieing Annette , Mueller Arndt-Christian , Cathomas Richard
Published: February 2020

405

Background: Standard treatment options for stage IIA/B seminoma include either extensive paraaortal/pelvic radiotherapy or intensive chemotherapy with 3x BEP or 4x EP. Both treatment modalities are associated with excellent efficacy but also a high rate of acute and late toxicities. Therefore, de-escalation strategies appear warranted for this patient group aiming to minimize acute and long-term toxicities while maintaining efficacy. SAKK 01/10 is a joint project of the Swiss Group for Clinical Cancer Research and the German Testicular Cancer Study Group. Methods: Patients with stage IIA/B seminoma (de novo or relapse on active surveillance) were eligible for participation in this single arm phase II trial. A repeat scan was advised in patients with equivocal lymph node enlargement. Treatment consisted of one cycle carboplatin AUC7 followed by involved-node radiotherapy with 30 Gy in stage IIA and 36 Gy in stage IIB disease. The primary endpoint of the trial is 3-year progression free survival. We report on treatment compliance and early toxicity during treatment and within 30 days. Results: 120 patients with stage IIA/B seminoma were recruited from 10/12 until 06/18 in 20 study centers in Switzerland and Germany. 116 patients were eligible and initiated treatment per protocol (40% stage IIA, 60% stage IIB). All patients received chemotherapy (CT) with a median applied dose of 984 mg (range: 560-1920 mg). The median planning target volume (PTV) for radiotherapy (RT) was 297 cm3 (range: 24-1047 cm3). RT was delayed/interrupted in two patients due to adverse events. During CT, grade 2 and grade 3 adverse events were seen in 21% and 2% of all patients respectively (most common grade 2 events: neutropenia 6%, nausea 5%). During RT, grade 2 and grade 3 adverse events were seen in 26% and 6% of all patients respectively (most common grade 2 events: neutropenia 15%, nausea 6%). One case of transient creatinine increase was reported as a severe adverse event, resolving without sequelae. Conclusions: Treatment with one cycle carboplatin AUC7 and 30-36 Gy involved-node radiotherapy for stage IIA/B seminoma is feasible and demonstrates a very favorable early toxicity profile. Clinical trial information: NCT01593241.