bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA damaging therapies in patients (pts) with prostate cancer (PC) and pathogenic alterations in homologous recombination repair (HRR) genes.
Authors: Graham Laura , Green Edward , Park Joseph J. , Kellezi Olesia , Hwang Clara , Barata Pedro C. , Bilen Mehmet Asim , Kilari Deepak , Clingerman Melissa , Tripathi Abhishek , Labriola Matthew , Rothstein Shoshana , Garje Rohan , Koshkin Vadim S , Patel Vaibhav G. , Dorff Tanya B. , Armstrong Andrew J. , McKay Rana R. , Alva Ajjai Shivaram , Schweizer Michael Thomas
Published: February 2022

129

Background: Pathogenic HRR gene mutations may confer sensitivity to PARP inhibitors (PARPi) and/or platinum chemotherapy (chemo). While pts harboring mutations in BRCA1/2 appear to benefit from these DNA damaging therapeutics, outcomes data for those with non- BRCA1/2 mutations are less robust. We evaluated outcomes in men with HRR gene-mutated PC who received treatment with PARPi and/or platinum-based chemo stratified by type of HRR alteration. Methods: Retrospective data from the PROMISE Consortium was utilized (PMID: 34363009). PC pts with pathogenic HRR mutations who received PARPi and/or platinum-based chemo were included. Differences in PSA progression-free survival (PFS), clinical/radiographic PFS (rPFS), and overall survival (OS) between those with BRCA1/ 2 mutations (Cohort A) and those with mutations in HRR genes that do not directly interact with the BRCA complex (Cohort B: ATM, CDK12, CHEK1, CHEK2, FANCL) were evaluated. We also evaluated outcomes in pts with HRR gene mutations known to interact with the BRCA complex aside from BRCA1/2 (Cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, BRIP1). Results: Of 361 pts identified with HRR gene alterations, 89 received PARPi and 70 received platinum-based chemo. Prior therapy and metastatic disease sites were similar between cohorts. PSA PFS, rPFS, and OS were significantly improved in Cohort A vs. Cohort B with PARPi but not platinum-based chemo (Table). Sample size in cohort C was too small to allow for statistical comparison, although PSA PFS, PFS and OS were reasonably long. Conclusions: PC pts with BRCA1/2 mutations had improved outcomes to PARPi compared to those with mutations in HRR genes not directly interacting with the BRCA complex. Platinum-based chemo appeared effective regardless of which HRR gene was affected. [Table: see text]
Evaluating the optimal sequence of immunotherapy and docetaxel in men with metastatic castration-sensitive prostate cancer.
Authors: Chandran Elias Bin Aris , Atiq Mohammad O. , Donahue Renee Nicole , Karzai Fatima , Bilusic Marijo , Marte Jennifer L. , Arlen Philip M. , Cordes Lisa M. , Owens Helen , Hankin Amy , Williams Monique , Figg William Douglas , Dahut William L. , Schlom Jeffrey , Gulley James L. , Madan Ravi Amrit
Published: February 2022

130

Background: Docetaxel is a standard of care for metastatic castration-sensitive prostate cancer (mCSPC). PROSTVAC is a pox viral-based therapeutic cancer vaccine encoding for PSA and three T-cell co-stimulatory molecules. Pox viral-based vaccines had previously demonstrated potential immune synergy with docetaxel. This clinical trial evaluated the optimal sequence of immunotherapy and chemotherapy in mCSPC. Methods: Key eligibility criteria were mCSPC within 4 months of ADT and ECOG performance status 0-2. Patients were randomized between Arms A (6 cycles of docetaxel 75mg/m2 followed by 6 doses of PROSTVAC) and B (docetaxel concurrent with PROSTVAC). After rapid accrual to the first 2 arms, Arm C was added by protocol amendment (6 doses of PROSTVAC prior to 6 cycles of docetaxel). ADT was continued throughout the treatment period. The primary endpoint was to evaluate antigen-specific responses to the tumor antigens, PSA and MUC1, and brachyury, a transcription factor implicated in the metastatic process, after patients completed their respective sequence of docetaxel and PROSTVAC. This was done using intracellular cytokine staining of 4 established markers in both CD4+ and CD8+ T-cells, for a total of 8 measures of activation per antigen. Results: The study enrolled 73 patients with a median age of 63 years (range 41-86). Gleason scores for patients were 6 (4.1%), 7 (21.6%) and 8-10 (68.9%), with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Per CHAARTED criteria, disease volume was low in 41.1% and high in 58.9% of patients. Numbers of patients evaluable for immune responses in arms A, B, and C were 16, 12 and 18, respectively. Clinical responses have previously been presented (Atiq, MO et al., ASCO 2021), with 22% of all patients having PSA <0.2 at 2 years. Conclusions: This data provides some insights into the potential of immune activating therapies in relation to chemotherapy in patients with prostate cancer. This preliminary analysis suggests the greatest magnitude of immune activation is seen when immunotherapy is followed by chemotherapy. Additional analysis of the breadth of immune responses and associations with clinical outcomes is ongoing and will be presented. Clinical trial information: NCT02649855. [Table: see text]
Blood biomarkers and association with clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC): prespecified longitudinal analysis from the ACIS study of apalutamide (APA) or placebo combined with abiraterone acetate plus prednisone (AAP).
Authors: Efstathiou Eleni , Attard Gerhardt , Lucas Justin , Thomas Shibu , Gormley Michael , Aguilar-Bonavides Clemente , Flaig Thomas W. , Franke Fabio , Goodman Oscar B. , Oudard Stephane , Pieczonka Christopher Michael , Li Susan , Dibaj Shiva , Brookman-May Sabine D. , Yeruva Kesav , McCarthy Sharon Anne , Steuber Thomas , Suzuki Hiroyoshi , Rathkopf Dana E. , Saad Fred
Published: February 2022

142

Background: In ACIS, APA + AAP improved radiographic progression-free survival in mCRPC vs AAP; difference in overall survival (OS) was not statistically significant. We report a prespecified analysis of androgen receptor (AR) or non-AR genomic/transcriptional aberrations, known to be associated with poor prognosis, and their associations with OS in patients (pts) with mCRPC. Methods: Circulating tumor (ct)DNA and aberrations in 17 PC-relevant genes were assessed using next-generation sequencing at baseline (BL; n = 197) and at end of study treatment (EOST; n = 140) (biomarker population). ctDNA was summarized qualitatively; genomic aberrations were normalized by ctDNA detection. AR splice variant version 7 (ARv7) was detected by quantitative RT-PCR. Cox proportional hazards model assessed association of OS with biomarkers in univariate/multivariate analyses overall and in pts receiving subsequent treatment (tx). Results: BL characteristics of biomarker and total study populations were similar. From BL to EOST: ctDNA detection did not differ (123/196 [63%] to 92/140 [66%], p=0.6); significant increases occurred in ARv7, AR mutations, and any AR aberration (Table). Prevalence of aberrations in PI3K and homologous recombination repair (HRR) pathways did not change from BL to EOST (40/123 [33%] to 34/92 [37%], p=0.5 and 18/123 [15%] to 14/92 [15%], p>0.9, respectively). Worse OS was associated with ctDNA detection or HRR pathway inactivation at BL (HR, 2.5 or 2.2; all p < 0.001) or presence of ctDNA, ARv7, AR amplification or inactivation of TP53, RB1, or RB1/TP35 pathway at EOST (2.2, p < 0.001; 2.1, p < 0.001; 2.6, p < 0.001; 1.5, p < 0.05; 1.7, p < 0.05; 2.1, p < 0.001, respectively) in univariate analyses. EOST ARv7, AR amplification, and inactivation of RB1, TP53, or RB1/TP53 pathway was associated with worse OS in pts receiving subsequent tx. Detection of ctDNA and RB1 inactivation at BL and RB1/TP53 pathway inactivation at EOST was strongly associated with worse OS (2.1, 3.3, 2.9, respectively, all p < 0.01) in multivariate analyses. Conclusions: In ACIS, AAP or APA + AAP tx was associated with increased AR mutations and ARv7 expression. Detection of ctDNA and select AR/non-AR aberrations may predict poor survival in mCRPC. These markers may be used to improve tx selection following confirmation of their predictive value. Clinical trial information: NCT02257736. [Table: see text]
Changes in bone turnover markers (BTM) and association with outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) +/- docetaxel (D) in CHAARTED (ECOG-ACRIN E3805).
Authors: McGregor Bradley Alexander , Wang Xin Victoria , Hamnvik Ole-Petter R , Cheung, Yee Ming , Wei Xiao X. , Ravi Praful , Fichorova Raina N. , Sweeney Christopher
Published: February 2022

145

Background: In the phase 3 CHAARTED trial pts with mHSPC treated with ADT + D had an improved overall survival (OS) and longer time to castrate resistant prostate cancer (TTCRPC) than pts treated with ADT alone. We aimed to define the association of BTM levels with pt outcomes recognizing both ADT and bone metastases impact bone turnover. Methods: Serum samples were collected at baseline (BL) (within 28 days of starting ADT) in 233 (116 in ADT, 117 in ADT+D) pts and at week 24 in 423 (224 ADT+D, 199 ADT) pts. Samples were analyzed for osteocalcin (OC), osteoprotegrin (OPG), sclerostin (SL), RANKL and bone alkaline phosphatase (BALP). Cox proportional hazards models were used to assess the prognostic and predictive effects of the BTM in terms of OS and TTCPRC. Results: Whereas BALP baseline (BL) level < BL median was associated with longer OS independent of therapy (HR 0.44 95% CI 0.31-0.63, p<0.001); BL OPG > BL median and BL RANKL < BL median were associated with longer OS in the ADT+D arm (HR 0.54 95% CI 0.32-0.9, p=0.015 and HR 1.69 95% CI 1,03-2.79, p=0.037) but not in the ADT alone arm (HR 0.75, 95% CI 0.45 − 1.25, p=0.271 and HR 1.06 95% CI 0.65 − 1.73 p=0.827). Changes in markers from BL to week 24 varied based on treatment and volume of disease with statistically significant changes noted (Table). A rise in OC or BALP on therapy from BL to week 24 was associated with improved TTCRPC and OS (OC: HR(TTCRPC) 0.792, p=0.033, HR(OS) 0.78 p=0.047; BALP: HR(TTCRPC) 0.82, p=0.03, HR (OS) 0.79, p=0.013) controlling for week 24 levels. However higher absolute OC and BALP levels at week 24 were associated with worse outcomes. (OC: HR(TTCRPC) 1.37, p=0.003, HR(OS)1.38, p=0.006; BALP: HR(TTCRPC) 1.54, p=0.007, HR(OS) 1.77, p=0.001). Conclusions: The BL finding with BALP are consistent with higher BALP being a poor prognostic marker. The BL OPG and RANKL findings suggest these markers might identify men who benefit from addingf D to ADT. The paradoxical improved survival with a rise in OC and BALP on therapy but worse outcomes with absolute higher levels at week 24 highlights complex dynamics of bone turnover related to varied impact from ADT, bone healing when responding to therapy versus active cancer. Clinical trial information: NCT00309985. [Table: see text]
Genomic classification of clinically advanced major genito-urinary cancers (GUca) based on methylthioadenosine phosphorylase (MTAP) genomic loss.
Authors: Spiess Philippe E. , Necchi Andrea , Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Parini Vamsi , Decker Brennan , Lin Douglas I. , Pavlick Dean C. , Danziger Natalie , Ross Jeffrey S.
Published: February 2022

164

Background: Novel treatments for clinically advanced GUca including castrate resistant prostate ca (PC), bladder urothelial ca (BUC) and clear cell renal ca (ccRCC) are widely needed. Recently, the targeting of cancer cells with arginine accumulation caused by MTAP loss has emerged as a new synthetic lethality-based anti-cancer program. Methods: 8,436 mCRPC, 2,683 BUC and 841 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by IHC (Dako 22C3). Results: 1.3% of PC, 24.2% of BUC and 5.5% of ccRCC featured MTAP loss. There were no significant age or gender differences associated with MTAP loss. CDKN2A/B loss ranged from 94% in ccRCC to > 99% in PC and BUC. The GA/tumor frequencies were similar when CDKN2A/B GA are excluded. In PC, GA in TP53, PTEN and BRCA1 were more frequent, while GA in AR, CDK12, RB1 and BRCA2 were less frequent in cases with MTAP loss. In BUC, GA in TSC1 and FGFR3 were more frequent and GA in RB1and TP53 were less frequent in cases with MTAP loss. In ccRCC, GA in NF2 were more frequent in cases with MTAP loss, while GA in VHL and PBRM1 were less frequent in cases with MTAP loss. “Targetable” kinase GA were rare in all groups, except for FGFR3 GA in MTAP loss BUC. Immunotherapy (IO) putative biomarkers varied among tumors, with MSI-high status less frequent and TMB ≥ 10 mut/Mb more frequent in BUC MTAP-intact than BUC with MTAP loss. PD-L1 expression was similar except for high PD-L1 expression more frequent in MTAP-intact BUC. Conclusions: When compared with PC and ccRCC, the clinical development of novel drugs, such as PRMT5 and MTA2 inhibitors in GUca will likely be focused on BUC given the 24% frequency of MTAP loss in that tumor type. CGP of PC, BUC and ccRCC reveal significant differences in GA in MTAP-intact and tumors with MTAP loss, which may impact future combinatorial clinical trial designs.[Table: see text]
Blood-based tumor mutational burden from circulating tumor DNA and immune checkpoint inhibitors in advanced prostate cancer.
Authors: Rauterkus Grant , Hadadi Agreen , Barnett Reagan , Weipert Caroline , Drusbosky Leylah , Gao Xin , Lilly Michael B. , Bryce Alan Haruo , Naqvi Syed Arsalan Ahmed , Barata Pedro C. , Bilen Mehmet Asim
Published: February 2022

165

Background: A prior study of patients with advanced cancers treated with immune checkpoint inhibitors (ICI) associated improved overall survival with tissue tumor mutational burden above the 80th percentile in each histology (tTMB-H). TMB can also reliably be calculated via liquid biopsy (bTMB), and trends higher than tTMB in analogous tumors. Here, we generate a plasma-informed benchmark for bTMB-H in advanced prostate cancer and report preliminary data from an ongoing multi-institutional case series of patients treated with ICI. Methods: Circulating tumor DNA (ctDNA) next generation sequencing (NGS) results from 3,504 patients with advanced prostate cancer who received a Guardant360 liquid biopsy within a 12-month period were analyzed. The 80th percentile of TMB was defined as the benchmark for bTMB-H in this cohort, and prevalence of microsatellite instability (MSI-H) was determined. Subsequently, clinical data were collected from patients across five institutions who received pembrolizumab based on bTMB scores or other tumor characteristics (i.e. CDK12 mutation). Results: Overall, mean and median bTMB were calculated as 12.34 mut/Mb and 8.61 mut/Mb, respectively (range: 0 – 1164.75 mut/Mb). The 80th percentile of bTMB was 13.4 mut/Mb and the 90th percentile was 16.6 mut/Mb. 2.6% of patients were both MSI-H and bTMB-H. No patients with bTMB < 13.4 mut/Mb (TMB-L) were found to be MSI-H. Ten patients from five institutions received pembrolizumab (8 monotherapy) after a median of 4.5 lines of prior therapy (Table). Four patients were MSI-H. The 3 patients in the cohort with PSA decreases > 50% had both MSI-H and bTMB ≥ 13.4 mut/Mb. Per RECIST criteria, disease was controlled (CR, PR, SD) in 6 of 7 (86%) patients with bTMB scores ≥ 13.4 mut/Mb. Conclusions: These data continue to affirm that ctDNA NGS is a practical and cost-effective means of assessing potential predictors of ICI activity in patients with advanced prostate cancer. Preliminary data from this growing cohort of patients who have received ICI guided by bTMB scores and other molecular parameters identified via ctDNA NGS, including MSI-H, demonstrate a clinical benefit from therapy. Further studies are warranted for contextualizing individual tumor bTMB scores with established, pathology-specific benchmarks.[Table: see text]
ADAM: A multicenter, non-interventional, prospective cohort study for determination of prevalence of homologous recombination repair genes mutations (HRRm) in metastatic castrate-resistant prostate cancer (mCRPC)—Interim analysis.
Authors: Alexeev Boris , Lyubchenko Liudmila , Gordiev Marat , Filipenko Maxim , Anzhiganova Yulia , Sultanbaev Alexander , Bystrov Alexander , Orlov Alexander , Gopp Galina , Kopyltsov Evgeny , Lykov Alexander , Atduev Vagif , Alekseeva Galina , Mailyan Ovsep , Semenov Vladislav , Vedrova Olga , Perevoschikov Alexander , Andreev Sergei , Evgenia Logacheva
Published: February 2022

169

Background: The HRRm detection is used to prescribe PARP inhibitors in mCRPC patients. The frequency of HRR alterations has been investigated in several clinical studies, but the prevalence of HRRm in real clinical practice remains unclear. We conducted the first study to evaluate prevalence of HRRm in mCRPC patients in Russia. This interim analysis is aimed to provide HRRm rate in real practice in Russian population. Methods: Patients with mCRPC and available tumor tissue samples (FFPEs) were enrolled from October 2020 till May 2021. Samples were analyzed in 3 labs. Target enrichment using multiplex PCR and library preparation of genes involved in HRR (BRCA2, BRCA1, RAD54L, FANCL, BARD1, ATM, CHEK1, RAD51B, PALB2, RAD51D, CDK12, RAD51C, BRIP1, CHEK2) was performed using three different techniques: GeneReader NGS System (QIAGEN), KAPA HyperPlus and SeqCap EZ Choice (Roche) and in-house targeted NGS-panel. For last 2 sequencing was performed using MiSeq (Illumina). Results: In this interim analysis we included 331 mCRPC patients from 20 sites with median age 67 years, 86,7% caucasian. Family or personal history of oncological diseases had 66 (20%) of pts 300 FFPEs were analyzed by NGS, 31 (9%) were not valid (poor quality/not enough DNA). HRRm rate is 19,7% (59/300). Most frequently mutated genes ( > 1%) listed in the table below. Other mutations (RAD51B, RAD51C, BARD1, FANCL, RAD51D, RAD54L) were detected in 1-2 cases per gene. Conclusions: This first systematic analysis of HRRm in Russian population of mCRPC patients showed general consistency with previously reported HRRm data (19,7% in our trial in comparison with 27.9% in PROfound trial). Lab approach using different techniques in real practice has to be established.[Table: see text]
Frequencies of actionable alterations found by somatic tumor sequencing in veterans with metastatic prostate cancer.
Authors: Nickols Nicholas George , Maxwell Kara Noelle , Lee Kyung Min , Hausler Ryan , Anglin-Foote Tori , Garraway Isla , Lynch Julie Ann
Published: February 2022

178

Background: Prostate cancer comprises one third of male Veteran cancers and is their second leading cause of cancer death. Metastatic prostate cancer is lethal. Next Generation Sequencing (NGS) of somatic tumors is recommended for metastatic prostate to identify actionable alterations targeted with approved therapies. Veterans with prostate cancers harboring alterations in genes involved in the DNA damage response (e.g. BRCA1/2) or high microsatellite instability (MSI-High) may be eligible for PARP inhibitors or checkpoint blockade immunotherapy, respectively. Potential candidates may be identified for ongoing clinical trials of novel precision oncology approaches. Methods: This is a retrospective analysis of clinical, genomic, demographic data from Veterans with metastatic prostate cancer who underwent somatic NGS using the Foundation Medicine NGS platform from 2019-February 2021. To be included, prostate cancer was submitted diagnosis for the NGS testing and metastatic disease determined by the VINCI natural language processing tool. Variables included demographic, clinical, and pathological characteristics (self-identified race/ethnicity, age, rurality of residence, Gleason score, specimen site, other cancer diagnosis, mutation frequency). Primary outcome was mutation rates in homologous recombination (HR) genes under current FDA approval for olaparib (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L) or MSI-High. Raw variant data, submitted diagnosis, and clinical data were extracted from the NGS reports and harmonized for further variant annotation. Variant data included chromosome, position, reference and alternate allele, total depth, variant allele depth, and quality scores. Variants were annotated using ANNOVAR. Likely oncogenic and oncogenic mutations were identified using OncoKB. Results: 1,597 Veterans with metastatic prostate cancer underwent FMI NGS testing (63% White, 33% African American, 4% other). Median age was 66 years, 78.6% of cases from >60 years. Of the 1,597 who underwent blood or tumor testing, at least one likely oncogenic mutation in an HR gene under FDA approval for olaparib was found in 369 (23.1%) of Veterans (19% of tissue-based tests, 32.9% of blood-based tests). Of 651 liquid biopsy tests with at least one HR gene mutation, 125 of 214 (52%) had mutations at a variant allele frequency (VAF) <0.5% or were found in an MSI-High sample that could indicate a spurious mutation due to clonal hematopoiesis. 33 patients (2.1%) were MSI-High, (21 tissue-based and 12 blood-based). Frequencies of alterations in ATM (3.6%), CDK12 (5.6%), and BRCA2 (4%) in tissue-based tests were not significantly different from those reported in other series. Conclusions: NGS of somatic tumors from Veterans with metastatic prostate cancer identifies alterations that impact management and clinical outcomes.
Putative germline findings in tumor-only and liquid biopsy sequencing in veterans with aggressive prostate cancer.
Authors: Maxwell Kara Noelle , Hausler Ryan , Garraway Isla , Nickols Nicholas George , Lee Kyung Min , Lynch Julie Ann
Published: February 2022

179

Background: Tumor-only and/or liquid-biopsy based Next Generation Sequencing (NGS)-based tests, which are routinely performed in metastatic prostate cancer patients, may identify putative germline mutations. The European Society of Medical Oncology (ESMO) made recommendations on findings which should be referred for germline genetic testing; however, it is unknown the burden of genetic testing referrals that may result from implementation of these recommendations. We therefore determined the frequency of putative germline findings in Veterans with metastatic prostate cancer who have undergone NGS-based sequencing of tumor and/or cell-free DNA (cfDNA) on the Foundation Medicine (FMI) platform. Methods: This is a retrospective analysis of Veterans with FMI NGS testing results reported from January 2019-February 2021 who had prostate cancer as the submitted diagnosis and metastatic diagnosis according to a VINCI natural language processing tool. Raw variant data were extracted from FMI reports and harmonized for variant annotation. Variants were annotated using ANNOVAR. Putative germline mutations were defined as 1) likely pathogenic or pathogenic (LP/P) by Clinvar annotation and VAF> 30%. Mutation rates are reported in genes recommended by ESMO to trigger referral for germline testing in all tumor types and all ages of diagnosis and proposed prostate cancer susceptibility genes ( ATM, BARD1, CHEK2). Results: 1,597 Veterans with metastatic prostate cancer underwent FMI NGS testing (63% White, 33% African American, 4% other). Median age was 66 years, with 78.6% of cases from men >60 years. Of 1,597 prostate cancer patients who underwent blood or tumor testing, n=85 (5.3%) had an LP/P mutation in an ESMO-guideline gene. When mutations in ATM, BARD1 and CHEK2 were added, n=133 (8.3%) of patients had an LP/P mutation. The most commonly identified putative germline findings were in BRCA2 (n=49 patients, 3.1%). 18 patients (1.1%) had mutations in other prostate cancer risk genes on the ESMO list ( BRCA1, MLH1, MSH2, MSH6, PMS2). 18 (1.1%) of patients had putative incidental germline findings, which included mutations in PALB2, BRIP1, RAD51C, RAD51D, SDHC. No putative incidental germline mutations were identified in RET, SDHA, SDHB, SDHD, TSC2, VHL. Comparing self-identified White versus self-identified Black patients, putative germline mutation rates were nearly the same in all ESMO-referral genes combined (8.2% vs 8.5%), BRCA2 (2.9% vs 3.0%), and ATM (2.4% vs 2.1%). Conclusions: While guidelines recommend that all veterans with metastatic prostate cancer undergo germline genetic testing, significant patient and system-level barriers continue to limit access to germline genetic testing for many Veterans. Tumor-only NGS testing, with a low rate of putative incidental findings, can help to prioritize which Veterans should be referred for germline genetic testing.
3JC48-3: Novel MYC inhibition in advanced prostate cancer.
Authors: Chalfant Victor , Riveros Carlos , Shukla Sanjeev , Osumi Teruko , Balaji KC
Published: February 2022

181

Background: The proto-oncogene c-Myc is a transcription factor that is upregulated in several human cancers. Despite its key role, therapeutic targeting of c-Myc remains a challenge because of a disordered protein tertiary structure. The basic helical structure and zipper protein of c-Myc forms an obligate heterodimer with its partner MAX to function as a transcription factor. An attractive strategy is to inhibit MYC/MAX dimerization to decrease c-Myc transcriptional function. Several methods have been described to inhibit MYC/MAX dimerization including small molecular inhibitors and proteomimetics. Methods: We used NOD SCID gamma mice (NGS mice) that are immunodeficient, non-obese diabetic laboratory mice (Jackson Laboratories, Cat #J000077451) carrying patient-derived xenograft (PDX) following implantation of grade IV adenocarcinoma of the prostate from a patient into the flanks of each mouse. For maximum tolerable dose studies, we used C57BL/6 wild type mice (Jackson Laboratories, Cat #J000664). We performed a maximum dose tolerability study with the drug 3JC48-3 up to 100 mg/kg to determine limiting toxicity. We monitored the rate of growth for 2 weeks and measured the final volume of the tumors. Immunoprecipitation studies were performed using the prostate cancer cell line, PC-3, that were treated with the drug 3JC48-3 at different doses (0, 5, 10, and 20uM) for 24 hours and subsequently lysed. Results: We found 3JC48-3 decreases prostate cancer growth and viability in a dose-dependent fashion in vitro. We confirmed the inhibition of MYC/MAX dimerization by 3JC48-3 using immunoprecipitation experiments. Normal mice and mice with patient-derived prostate cancer xenografts (PDX) tolerated intraperitoneal injections of 3JC48-3 up to 100 mg/kg body weight without dose-limiting toxicity. Preliminary results in these PDX mouse models suggest that 3JC48-3 may be effective in decreasing the rate of tumor growth. Conclusions: Our study demonstrates that 3JC48-3 is a potent MYC/MAX heterodimerization inhibitor that decreases prostate cancer growth and viability in association with upregulation of both PrKD1 expression and kinase activity. In addition, 3JC48-3 is well tolerated in prostate cancer PDX mice models and may be a candidate drug for further preclinical development.
Extracellular vesicle-based assay for detecting metastases and dynamic monitoring of prostate cancer.
Authors: Wang Jasmine Jiemei , Sun Na , Lee Yi-Te , Kim Minhyung , You Sungyong , Tseng Hsian-Rong , Zhu Yazhen , Posadas Edwin Melencio
Published: February 2022

182

Background: There is an unmet need to develop a noninvasive assay to detect the metastatic progression of prostate cancer (PCa) patients for timely treatment. We aim to optimize an extracellular vesicle (EV)-based Digital Scoring Assay to reflect the disease status of PCa. Methods: PCa EV Digital Scoring Assay integrated a PCa-derived EV purification device (i.e., EV Click Chip) and downstream reverse-transcription droplet digital PCR for transcriptomic profiling of PCa-derived EVs. The performance of the Assay for purifying PCa-derived EVs was assessed using artificial plasma samples with spiked EVs. In parallel, a panel of 11 PCa-relevant mRNA markers were selected and validated. PCa EV Digital Scoring Assay in conjugation with the 11-gene panel was tested using plasma from 20 localized, 20 metastatic PCa patients, and serial plasma from three PCa patients. mRNA expressions were computed using weighted Z score method. ROC analysis was utilized to distinguish localized from metastatic PCa. Results: After optimization, the capability of purifying PCa-derived EVs from artificial plasma samples by EV Click Chips (92.5 ± 5.4%) outperformed ultracentrifugation or precipitation methods (41.0 ± 3.2%; 34.9± 2.2%; P < 0.001). Eleven genes, i.e., ACP3, FOLH1, HOXB13, KLK2, KLK3, KLK4, MSMB, RLN1, SLC45A3, STEAP2, and TMPRSS, were selected using The Tissue Atlas and a gene set from a blood-based study as our panel. Strong signals of the panel were detected from three PCa cells (LNCaP, C4-2B, and 22Rv1) and their derived EVs, while rare signals were detected in either WBCs or EVs purified from male healthy donor. In the clinical study, the Z scores calculated from the selected 11-gene panel, were significantly higher in 20 metastatic PCa than 20 localized PCa with an area under the ROC curve of 0.88 (95% CI = 0.78-0.98). Lastly, longitudinal analyses of three PCa patients showed that the Z scores can reflect the clinical progression, response, and stable status, even when disease is undetectable by imaging. Conclusions: We develop a sensitive PCa EV Digital Scoring Assay to distinguish metastatic PCa and reveal the dynamic disease states in a noninvasive manner. This assay holds the potential to augment current imaging tools and tests for timely detection of PCa progression and improve care for patients.
Low-value prostate cancer screening among young men with private insurance.
Authors: Vehawn Jeffrey , Lange Suzanne , Choudry Mouneeb , Ambrose Jacob P. , Haaland Benjamin , Paudel Niraj , Hanson Heidi A. , O Neil Brock
Published: February 2022

240

Background: Debate remains about the value of Prostate-specific antigen (PSA) based prostate cancer screening among men aged 55-69 (USPSTF Grade C). However, no professional society or guideline recommends PSA based prostate cancer screening in men younger than age 40. This study aims to understand the risk of PSA testing exposure in young men, and we hypothesize that substantial low-value testing occurs in this population. Methods: We performed a retrospective analysis of claims data from the MarketScan database to identify men aged 18 to 39 without prostate cancer who received a PSA test from 2008 to 2017. For the primary analysis, men were required to be continuously in the database for least 5 years. Age groups were stratified to include: men less than 25, 25-29, 30-34, and 35-39 years. Secondary analysis did not limit subjects to those with 5 years of continuous data and explored the association of Charlson Comorbidity Index (CCI), lower urinary tract symptoms, erectile dysfunction, depression/anxiety, prostate cancer screening, infertility, and hypogonadism with PSA testing in young men. We used logistic regression to determine which of the factors were associated with PSA testing in young men. Results: We identified claims for 40,164,773 adult men who met study criteria. Of these men, 3,230,748 were continuously in the Marketscan database for at least 5 years. The cumulative risk for receiving a PSA over 5 years for men under 40 is 2.5%. Stratified by age, men aged 35-39 are at highest risk (Table). Logistic multivariable regression showed that, relative to all men between 18 and 40, patients in this age group who received a PSA were more likely to be diagnosed with hypogonadism (OR 20.55, 95% CI 20.39-20.71) or lower urinary tract symptoms (OR 9.34, 95% CI 9.26-9.41). Higher CCIs appeared to correlate with a decreased rate of PSA testing. This population was not significantly more likely to be diagnosed with infertility, depression, or anxiety. Conclusions: PSA screening for men under 40 is not uncommon, especially when associated with concomitant genitourinary symptoms. At a population level, this represents substantial low-value testing. Interventions aimed at clarifying the relationship between common urologic conditions and prostate cancer, the extremely low incidence of prostate cancer in this age group, and the lack of guidelines supporting this practice may help decrease low-value PSA testing. Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number K08CA234431. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.[Table: see text]
Immunotherapy to prevent progression on active surveillance study (IPASS): A phase II, randomized, double-blind, controlled trial of PROSTVAC in prostate cancer patients who are candidates for active surveillance.
Authors: Parsons J Kellogg , Pinto Peter A. , Parnes Howard L. , Pavlovich Christian P. , Uchio Edward M. , Nguyen Mike Minh , Kim Hyung Lae , Gulley James L. , Sater Houssein Abdul , Jamieson Christina , Hsu Chiu-Hsieh , Wojtowicz Malgorzata E. , Schlom Jeffrey , Donahue Renee Nicole , Centuori Sara , Bailey Shania , Bauman Julie E. , Chow H H
Published: February 2022

249

Background: Immunotherapy could potentially prevent disease progression for early-stage prostate cancer. In this randomized Phase 2 clinical trial, we evaluated the clinical effects of PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy that contains PSA and three T-cell costimulatory molecules, in patients with localized prostate cancer. Methods:154 patients with clinically localized, low- or favorable intermediate-risk prostate cancer active surveillance were randomized (2:1) to receive 7 doses of subcutaneous PROSTVAC or placebo (empty fowlpox vector) over 140 days. Post-intervention prostate biopsy was performed 7-14 days after the last dose. Participants were followed for 6 months post-treatment. The primary outcome was change from baseline to post-vaccination in CD4 and CD8 T cell infiltration in biopsy tumor tissue. Secondary outcomes included changes in prostate biopsy Gleason grade (Grade Group) and serum PSA. Results: There were no differences in CD4 and CD8 densities (count of cells/mm2) in post-treatment biopsy tumor tissue between groups ( p = 0.63 and p = 0.75, respectively). Compared to placebo, patients who received PROSTVAC were less likely to demonstrate upgrading at follow-up biopsy, but this difference did not attain significance (22% vs. 40%, p= 0.08). There was no difference in the change of PSA from baseline to 6 months post-treatment between arms ( p= 0.30). Conclusions: In this first-of-kind trial of immunotherapy for localized prostate cancer, PROSTVAC was well tolerated but did not elicit significant prostate tissue T-cell responses compared to placebo. The favorable post-treatment biopsy grade findings in PROSTVAC patients merit further evaluation and longer-term clinical follow-up. Clinical trial information: NCT02326805.
The effect of postoperative pathological findings related to the eligibility of adjuvant immunotherapy on oncologic outcomes in patients with locally advanced urothelial cancer.
Authors: Hatakeyama Shingo , Tanaka Toshikazu , Hamaya Tomoko , Togashi Kyo , Iwamura Hiromichi , Okamoto Teppei , Yoneyama Takahiro , Ohyama Chikara , Miura Yuki
Published: February 2022

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Background: The CheckMate 274 trial demonstrated a benefit in disease-free survival (DFS) with adjuvant nivolumab therapy in patients at high risk of muscle-invasive UC and may become a standard of care in the future. In that study, postoperative pT3-4/ypT2-4 or pN+ was used as an inclusion criterion for the high-risk group, but the validity of this criterion in clinical practice remains unclear. Also, there is an urgent need for the proportion of patients who are eligible for adjuvant immunotherapy in clinical practice. We aimed to evaluate the effect of postoperative pathological findings related to the eligibility of adjuvant immunotherapy on oncologic outcomes in patients with localized and locally advanced muscle-invasive bladder carcinoma (MIBC) and upper tract urothelial carcinoma (UTUC). Methods: We retrospectively evaluated 1082 patients treated with radical cystectomy (n = 597) and nephroureterectomy (n = 485) between January 2000 and April 2021. Patients were divided into two groups: pT3-4 or pN+ without neoadjuvant chemotherapy and ypT2-4 or pN+ treated with neoadjuvant chemotherapy (trial-eligible group) or others (trial-ineligible group). The primary outcome was the effect of trial eligibility for adjuvant immunotherapy on disease-free survival (DFS) and overall survival (OS). Secondary outcomes included the additional effect of lymphovascular invasion (LVI) status to the clinical trial criteria on prognosis and a risk model development. Results: The median age of the patients was 69 and 72 years in the MIBC and UTUC groups, respectively. Fifty-two percent of patients met the trial inclusion criteria. Trial eligibility was significantly associated with poor DFS and OS among patients with MIBC and UTUC. LVI-positive status was significantly associated with poor prognosis among patients in the trial-eligible group. A very high risk (LVI+ or pN+ among the pT3-4 or ypT2-4) was significantly associated with poor prognosis. Conclusions: A total of 52% of patients were eligible for adjuvant immunotherapy. Trial eligibility was significantly associated with a poor prognosis. LVI+ and pN+ may play a key role in candidate selection for adjuvant immunotherapy.
Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx).
Authors: Bex Axel , Abu-Ghanem Yasmin , Van Thienen Johannes V. , Graafland Niels , Lagerveld Brunolf , Zondervan Patricia , Beerlage Harrie , van Moorselaar Jeroen , Kockx Mark , Van Dam Pieter-Jan , Szabados Bernadett , Blank Christian U. , Powles Thomas , Haanen John B. A. G.
Published: February 2022

289

Background: Antibodies targeting PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors are a first-line standard of care for metastatic RCC. Neoadjuvant use of these combinations may lead to downstaging and reduce the risk of recurrence. In addition, sequential tissue may allow identification of key immune biomarkers associated with outcome. Methods: Neoavax is a single arm phase II trial of 12 weeks neoadjuvant avelumab/axitinib prior to nephrectomy in 40 pts with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4cN0-1M0, Grades 3-4). Primary endpoint is RECIST 1.1 partial response (PR) in the primary tumour (PT) in ≥25%. Secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. Biomarker analysis on sequential tissue is an exploratory endpoint. Expression of PD-L1 (SP263), CD8+, CD8-granzyme-B (CD8/GZMB)+, Foxp3+ cells, CD8/CD39+ and MHC-I were compared on pre-treatment biopsy and nephrectomy samples from 34 pts (NCT03341845). Results: Pts/tumour characteristics are shown in table. Twelve pts (30%) had a PR of the PT from a baseline mean diameter of 10.3 (range 5.6-16.4) cm. Median PT downsizing was 20 (0-43.5) % and median post-treatment vital tumour presence was 50 (1-100) %. At a median follow-up of 23.5 months, recurrence occurred in 13 (32%) pts at a median of 8 (2-23) months and 3 died of disease. Of the 12 pts with PT PR, 11 (92%) are disease-free. Median DFS and OS are not reached. Postoperative adverse events occurred in 8 pts (2 Clavien Dindo grade 3a). There were no treatment-related surgery delays and no PT progression. Post-treatment samples showed upregulation of PD-L1 expression (p <0.0001) and total CD8+ densities (p < 0.01) when compared to pre-treatment biopsies. Comparing samples of pts with PR vs no PR in the PT, no clear immune marker differences were observed. Post-treatment samples from pts that recurred were characterized by lower densities of total, intra-epithelial and stromal CD8+, intra-epithelial CD8+CD39+ (p<0.05) and total CD8+GZMB+ (p=0.1). Pre-treatment biopsies showed no clear differences. Conclusions: Neoadjuvant avelumab/axitinib for non-metastatic high-risk RCC leads to PR of the PT in 30% which is associated with DFS. Pts without recurrence had a significant increase in CD8+ densities compared to pts with recurrence suggesting expansion of a pre-existing immune response. Clinical trial information: NCT03341845. [Table: see text]
Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with clear cell RCC (ccRCC): Impact of FLCN genomic alteration (GA) status.
Authors: Bratslavsky Gennady , Necchi Andrea , Spiess Philippe E. , Grivas Petros , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Parini Vamsi , Decker Brennan , Lin Douglas I. , Pavlick Dean C. , Danziger Natalie , Ross Jeffrey S.
Published: February 2022

292

Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with ccRCC. Methods: 108 chrRCC and 2110 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female and younger than pts with ccRCC p <.0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in only 2.3% of the ccRCC cases with 37% of the GA predicted to be germline. chrRCC did not reveal somatic or germline FLCN GA. GA/tumor were slightly higher in ccRCC vs chrRCC (3.6 vs 2.4; NS). GA more frequent in chrRCC included TP53, RB1 and PTEN. GA more frequent in the ccRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Putative biomarkers of immune checkpoint inhibitor (ICPI) response were infrequent in both groups with only a slightly higher, but still low, mean TMB in ccRCC vs chrRCC cases. IHC revealed moderate PD-L1 expression at low and minimal PD-L1 expression at high staining level, which was slightly increased in the chrRCC group. Conclusions: FLCN mutations that are associated with the familial incidence of chrRCC were not associated with sporadic chrRCC. Sporadic chrRCC has substantially different genomic profile from ccRCC and may harbor a few ‘targetable’ GA. The prediction of response to ICPI in RCC remains challenging with chrRCC featuring slightly higher PD-L1 expression and ccRCC featuring higher PBRM1 GA and higher TMB.[Table: see text]
Predictors of objective response to first-line immuno-oncology combination therapies in metastatic renal cell carcinoma: Results from the international metastatic renal cell database consortium (IMDC).
Authors: Navani Vishal , Ernst Matthew Scott , Wells Connor , Yuasa Takeshi , Takemura Kosuke , Donskov Frede , Basappa Naveen S. , Schmidt Andrew Lachlan , Pal Sumanta K. , Meza Luis A , Wood Lori , Ernst D. Scott , Szabados Bernadett , McKay Rana R. , Weickhardt Andrew James , Suárez Cristina , Kapoor Anil , Lee Jae-Lyun , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2022

310

Background: Predictors of objective response to first-line (1L) immuno-oncology (IO) combination therapies remain elusive. We sought to characterise clinical variables and their association with investigator assessed best overall response. Methods: Using the IMDC, we retrospectively identified patients treated with 1L ipilimumab nivolumab (IPI-NIVO) or approved IO/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE). Patients were classified, per RECIST v1.1, as responders (complete or partial response (CR or PR)) or non-responders (stable or progressive disease (SD or PD)). Logistic regression was used to adjust for IMDC criteria. Results: Out of 1084 patients, 794 (73%) received IPI-NIVO and 290 (27%) received IOVE (axitinib+pembrolizumab, cabozantinib+nivolumab, axitinib+avelumab, lenvatinib+pembrolizumab). Favourable, intermediate and poor IMDC risk comprised 147 (16%), 517 (55%) and 272 (29%) respectively. Of the 898 patients with evaluable responses, 37 (4%) achieved a best response of CR, 343 (38%) PR, 315 (35%) SD and 203 (23%) PD. Corresponding median overall survival from time of 1L initiation was: not reached, 55.9, 48.1, and 13 months respectively (logrank p < 0.0001). In a multivariable model, lung metastases and cytoreductive nephrectomy (CN) (performed after diagnosis of metastatic disease and before 1L therapy) retained independent association with response, after adjustment for IMDC criteria. Factors not associated with response included (with univariable p values): gender (p = 0.58), age (p = 0.06), sarcomatoid histology (p = 0.99), smoking status (p = 0.39), liver (p = 0.63) and brain (p = 0.12) metastases. As in the VEGF monotherapy era, improved IMDC prognostic risk was associated with response. Results were similar when restricted to the IPI-NIVO cohort. Conclusions: Presence of lung metastases, CN and better IMDC risk group are associated with a higher probability of response to 1L immunotherapy combination regimens. Further work to identify reliable predictors of response to guide treatment selection and patient counselling is warranted.[Table: see text]
Mixed methods assessment of providers’ needs in the management of advanced renal cell carcinoma.
Authors: Campbell Matthew T , Lazure Patrice , Augustyniak Monica , Jaimes Edgar A. , Bilen Mehmet Asim , Lemke Emily , Jacobs Ginny , McFadden Pamela
Published: February 2022

313

Background: There is a paucity of data regarding the challenges associated with the timely and accurate diagnosis of Renal Cell Carcinoma (RCC) and its effective multidisciplinary management. This study aimed to assess the knowledge and skills of healthcare providers (HCPs) managing and coordinating the care of patients with advanced RCC (aRCC) across multidisciplinary teams. Methods: A sequential mixed methods needs assessment was conducted across the United States with medical oncologists (ONCs), nephrologists (NEPHs), physician assistants (PAs), nurse practitioners (NPs), and registered nurses (RNs). Interviews, transcribed and thematically analyzed, and online surveys, statistically analyzed, were triangulated. Results: A total of 305 HCPs completed an interview (n=40) or the survey (n=265): 78 ONCs, 62 NEPHs, 57 PAs, 55 NPs, 53 RNs. One third (33%) of HCPs reported suboptimal skills in adjusting the dose of a treatment for aRCC in the event of adverse reactions. Interviews underscored a lack of clarity for HCPs on when to reduce the dose or when to discontinue and/or switch to other drugs. Suboptimal knowledge and skills related to toxicities were found (Table). Breakdowns in communication across multidisciplinary teams were identified by 46% of HCPs. Of those, 61% occurred when monitoring side effects and 48% when referring to ONCs. Some NEPHs reported never, rarely, or sometimes being involved with ONCs in the management of nephritis (25%), chronic kidney disease (19%), or acute renal failure (24%). Interviews suggested the role of NEPHs in the care of aRCC is poorly recognized and that NEPHs are perceived to have limited time to spend in the care of cancer patients. Few NEPHs reported gaps in knowledge/skills managing key renal complications such as nephritis (13%/15%), chronic kidney disease (6%/15%), and acute renal failure (9%/9%). Conclusions: This study identified a need to improve HCPs’ knowledge of the signs/symptoms of treatment side effects, skills in identifying/referring patients to appropriate specialists, and skills in managing adverse events. Barriers to involving NEPHs in the co-management of aRCC included a lack of recognition of their role in managing treatment-induced renal complications.These results should inform educational interventions for professionals caring for aRCC patients.[Table: see text]