bluuebunny/crossref_metadata_2025 huggingface dataset:
Geographic variation of decipher genomic classifier in patients with early prostate cancer.
Authors: Keizman Daniel , Davicioni Elai , Peer Avivit , Dresler Hadas , Sella Avishay , Sarid David Leonid , Rouvinov Keren , Manaster Yoav
Published: March 2023

376

Background: External factors such as environmental or lifestyle-related exposure may influence genomic composition of cancer, and therefore its progression and outcome. Thus geographic data is of importance. Decipher is a gene expression classifier used in risk stratification of early non metastatic prostate cancer. Currently, there are no data reporting geographic variation of the test. We aimed to analyze Decipher genomic score results among Israeli patients, in comparison to American patients. Methods: The Decioher database (Decipher Biosciences Inc) contains data from patients who have given consent for broad data-sharing. We identified and analyzed Decipher test results ordered among Israeli patients with localized prostate cancer. Matched analysis to the US population was done. Results: 144 patients (median age 69.5, range 64-74) were included in the present analysis. The clinical NCCN risk grouping was low in 42.4% (n=61), favorable intermediate in 38.9% (n=56), unfavorable intermediate in 17.4% (n=25), and high risk in 1.4% (n=2). Physicians primarily obtained Decipher for low-intermediate NCCN risk. Median Decipher score was 0.57 (Q1 0.385, Q3 0.823). Decipher risk grouping was low in 38.1% (n=61), intermediate in 16.9% (n=27), and high in 45% (n=72). Median Decipher score increased with Grade Group. 46% of NCCN low risk patients had a higher risk as per Decipher. 82% of NCCN favorable intermediate and unfavorable intermediate risk were reclassified to lower or higher risk. 9% of NCCN high risk patients had a lower risk as per Decipher. The present study cohort had a higher proportion of higher Decipher scores than observed in similar grade US population (n=43065) in the Decipher database (Median 0.43, Q1 0.27, Q3 0.66; 52%/18%/30% with low/intermediate/high risk). Conclusions: The preliminary results of the present study suggest a higher proportion of high risk Decipher among Israeli patients with early prostate cancer. These results should be interpreted cautiously. The study and further data collection are ongoing.
CDK12 pathogenic mutations in African American and White patients with prostate cancer.
Authors: Ledet Elisa M. , Mitsiades Nicholas , Jaeger Ellen B. , Chao Calvin Y. , Sartor A. Oliver
Published: March 2023

38

Background: African American (AA) men are underrepresented in prostate cancer (PC) trials but have a greater probability of both developing and dying from prostate cancer (PC) than other populations. CDK12 mutations in PC are associated with aggressive disease, increased metastasis, and decreased overall survival. Some preliminary data has suggested that CDK12 mutations may be more common in AA men. This study reports data from next-generation sequencing (NGS) of tissue from a large population of patients with PC in the real-world setting to investigate frequency of pathogenic CDK12 mutations in AA men and White men. Methods: De-identified records from patients with primary PC who underwent NGS with Tempus xT (solid tumor, 648 genes, 500× coverage, full transcriptome RNAseq for a subset of patients) were analyzed to characterize the frequency and types of pathogenic CDK12 mutations, and co-mutation in other assessed genes. Results were compared between patients identified as AA and White. Patients were excluded if they were Microsatellite Instability high (MSI-H), Tumor Mutational Burden (TMB) ≥10, or Mismatch Repair deficient (MMR-d). Results: Genomic profiles were analyzed from tissue samples of 6121 unique patients; of 3,555 patients with known race, 646 (18%) were AA, 2657 (75%) were White, and 252 (7%) were of other races. Of these patients, 3026 were AA or White after excluding 277 patients with known MSI-H, TMB≥10, or MMR-d status. AA were younger at diagnosis than Whites (median 63 vs 66 years; p<0.001). Tissue samples from AA men were significantly more likely than those from Whites to express a pathogenic CDK12 mutation (42 [7.2%] vs 93 [3.8%], p<0.001). The majority of the variants identified were truncating mutations. There were no differences in truncating vs. non-truncating alterations between White and AA men, nor were there differences in the prevalence or distribution of co-mutations between the two populations. Conclusions: AA men with PC show a higher frequency of pathogenic CDK12 mutations than Whites in a large real-world population. Co-mutations did not vary by race, and the alterations were most likely to be truncating mutations in both races.
Germline testing for men with prostate cancer: Need to broaden the indications in Europe?
Authors: Trevisi Elena , Koster Kira-Lee , Heinimann Karl , Zuerrer Ursina , Turco Fabio , Bosetti Davide Giovanni , Colombo Ilaria , Maitz Silvia , Nerone Marta , Omlin Aurelius Gabriel , Vogl Ursula , Gillessen Silke , Graffeo Rossella
Published: March 2023

383

Background: The clinical role of germline testing (GT) for prostate cancer (PC) is rapidly increasing due to the growing implications of precision medicine in metastatic disease, where genetic results can address eligibility for novel targeted treatments. Thus, ESMO and NCCN guidelines recommend GT for all metastatic PC individuals, whereas American testing criteria are more broad and include family history and other tumor features, such as high-risk disease, or intraductal or cribriform histology. Methods: We have retrospectively collected and analyzed clinical and genetic features of men with PC who underwent single-gene or multi-gene GT at some Swiss Institutions with expertise in hereditary cancers from July 2018 until October 2022. All patients (pts) have given written informed consent for research. Results: 109 men with PC underwent GT and received pre- and post-test counseling. Of these, 54 (50%) were metastatic, 34 (31%) had high-risk localized disease according to NCCN criteria, 7 (6%) presented cribriform or intraductal histology. A significant family history, as defined by current NCCN guidelines, was found in 79 (72%). 67 (61%) had no pathogenic (P) or likely pathogenic (LP) variants; 25 (23%) had a variant of unknown significance (VUS); 17 (16%) were found to have a P/LP variant in the following genes: BRCA2 (8), ATM (4), BRIP1 (1), FANCA (1), NBN (1), POT1 (1), TP53 (1). Among these 17 pts, the median age at diagnosis was 66 (45-80), 10 had metastatic disease, 5 had high-risk localized disease, 14 had a family history and 5 had a personal history of another cancer. Only 6 pts were <60 years old at the time of diagnosis. Cascade screening was offered to 16 families (94%). Conclusions: Our preliminary data support the increasing role of GT in PC and suggest the need to expand its indications. In this cohort, 7/17 (41%) of men with localized PC were found to carry P/LP variants and would not have met the criteria to undergo GT according to current European guidelines. GT may have treatment implications for metastatic PC pts whereas in early stage disease can inform cancer risk and screening for pts and their male and female relatives.
Diagnosis of prostate cancer using cell-free DNA methylation profiles from expressed prostatic secretions.
Authors: Shen Wenhao , Dong Hang , Tang Haoran , Zhang Yue , Jia Shidong , Luo Yang
Published: March 2023

389

Background: Urinary and seminal cell-free DNA (cfDNA) have been recognized as promising biomarkers of prostate cancer. DNA methylation signal in tumor is increasingly used as tumor diagnosis and longitudinal monitoring indicator. However, the clinical utility of cfDNA from expressed prostatic secretions (EPS) remains unknown. Methods: The prospective study includes 50 prostate cancer (PC) patients and equivalent benign prostatic hyperplasia (BPH) patients, where EPS samples were collected after the prostatic massage of each patient. Cell-free DNA from EPS was extracted and treated by PredicineEPIC, a liquid biopsy comprehensive DNA methylation assay. The study developed integrated bioinformatic algorithms to profile the genome-wide epigenomic characteristics and investigate tumor-specific methylation patterns. Results: The initial exploratory cohort included 5 PC and 11 BPH cases. PredicineEPIC whole-genome DNA methylation of EPS identified over 300 differentially methylated regions (DMRs). Prostate cancers were distinguished from the BPH group by an unsupervised clustering method, suggesting that the identified DMRs embody the specific profiles of malignant tumors. Additionally, this study detected genome-wide copy number variation burden (CNB) in parallel. A risk model was built for cancer risk assessment based on methylation and CNB characteristics. Conclusions: This study demonstrated the feasibility of methylation profiling of cfDNA in EPS in prostate cancer. This non-invasive liquid biopsy approach could sensitively navigate prostate cancer from benign prostatic hyperplasia, suggesting future direction of methylation-based liquid biopsy in detecting prostate cancer.
Long-term rates of biochemical recurrence after primary external beam radiation therapy (EBRT) for prostate cancer.
Authors: Escobar Domenique , Wang Lufan , Banton Jasmin , Cowan Janet E. , Washington Samuel L. , Mohamad Osama , Menon Mani , Carroll Peter
Published: March 2023

393

Background: Radiation therapy is a common form of treatment for men with prostate cancer. Biochemical recurrence (BCR) is most commonly defined using the Phoenix definition of PSA nadir + 2. We sought to characterize long term rates of biochemical recurrence in a large, well-characterized and well-followed cohort of men treated with primary EBRT. Methods: Patients enrolled in CaPSURE, a national registry of men diagnosed with prostate cancer, from 1995 - 2017 with clinically localized prostate cancer (cN0M0/X, PSA<=50) treated with primary EBRT were included. Cancer risk was defined by NCCN criteria. Cox proportional hazards regressions were used to assess associations between patient characteristics and BCR as defined by PSA nadir + 2. Results: 1193 patients were included. Mean age at diagnosis was 70 (SD 6.82), median PSA at diagnosis was 7.6 and mean number of follow up PSA tests was 5. Overall rates of BCR were 17.4% at 5 years and 39.4% at 10 years. Rates of BCR were significantly associated with NCCN risk with high-risk patients having the highest rates of recurrence, followed by intermediate- and low-risk groups (61.5%, 36.4% and 28.5% respectively at 10 years). NCCN high vs low clinical risk was significantly associated with likelihood of BCR (HR 4.8, CI 2.5 – 9.2). Rates of salvage treatment, usually ADT, were 16% at 5 years and 19% at 10 years and these were also significantly associated with NCCN high vs low clinical risk (HR 3.7, CI 2.3 – 6) and concurrent ADT (HR 1.83, CI 1.2 – 2.7). Overall rates of bone metastases were 2.6% at 5 years and 4% at 10 years. Overall prostate cancer specific mortality was 3% at 5 years and 7% at 10 years. Conclusions: In this analysis, rates of BCR were fairly high and consistent with published RTOG studies, but rates of salvage treatment were relatively low in comparison, indicating that not all patients who recur need, are offered or want treatment. The limitations of this analysis include incomplete information on radiation dose and field size. The strengths of this analysis include the size of the cohort and the length of follow-up. Furthermore, as this cohort largely represents treatment in community settings, the results may be broadly applicable.
National population-based survival estimates after definitive radiation therapy for prostate cancer.
Authors: Herr Daniel , Elliott David , Stensland Kristian , Caram Megan Veresh , Burns Jennifer , Hollenbeck Brent , Sparks Jordan , Shin Chris , Zaslavsky Alexander , Tsodikov Alexander , Skolarus Ted
Published: March 2023

395

Background: Understanding contemporary radiation therapy outcomes for prostate cancer (i.e., metastasis, death) is important for shared decision-making and setting expectations for patients and providers. Unfortunately, long-term outcome estimates are often derived from meta-analyses of outdated prospective clinical trials or population-based data lacking reliable clinical details (e.g., incident metastatic disease). For these reasons, we used a recently validated, natural language processing algorithm to identify incident metastatic prostate cancer within the electronic medical records of men treated with radiation therapy for localized prostate cancer in order to conduct an innovative and contemporary population-based survival outcomes study. Methods: We used national administrative, cancer registry, and electronic health record data for patients undergoing definitive radiation therapy with or without concurrent androgen deprivation therapy (ADT) within the Veterans Health Administration from 2005 to 2015. We used National Death Index data through 2019 for overall and prostate cancer-specific survival, and identified the date of incident metastatic prostate cancer using a validated natural language processing algorithm. We estimated metastasis-free, prostate cancer-specific, and overall survival using Kaplan-Meier methods. Results: We identified 41,876 patients treated with definitive radiation therapy for prostate cancer from 2005 through 2015, and followed them for over 8 years (follow up, median, 8.7 years, age at diagnosis, median, 65 years). Most patients had intermediate (42%) and high risk (33%) disease, with nearly half treated with ADT as part of initial therapy (44%). Unadjusted 10-year metastasis-free survival was 96%, 92%, and 80% for low, intermediate, and high risk disease. Similarly, unadjusted 10-year prostate cancer-specific survival was 98%, 97%, and 90% for low, intermediate, and high risk disease. Unadjusted overall survival was lower across disease risk categories at 77%, 71%, and 62% for low, intermediate, and high risk disease. Conclusions: These data provide population-based benchmarks for clinically relevant endpoints, including metastasis-free survival, among patients with low, intermediate, and high risk prostate cancer undergoing radiation therapy using contemporary techniques. The survival rates for high risk disease, in particular, compare favorably with historical outcomes.
Source of funding and enrollment disparity in prostate cancer (PCa) clinical trials.
Authors: Riaz Irbaz Bin , Naqvi Syed Arsalan Ahmed , Islam Mahnoor , Ikram Waleed , Khakwani Kaneez Zahra Rubab , Ijaz Hafsah , Ayaz Ahsan , Singh Parminder , Bryce Alan Haruo
Published: March 2023

40

Background: Previously we have reported enrollment disparities in PCa clinical trials. Funding source can influence minority representation in clinical trials. Hence, we aimed to evaluate the impact of source of funding on enrollment disparities in PCa clinical trials. Methods: MEDLINE and EMBASE were searched to identify phase II/III PCa trials. All relevant trials reporting age by 65 years were considered eligible for inclusion. Trials recruiting from the United States (US) were considered eligible for analysis by race and ethnicity. The trial proportions of age, or racial/ethnic subgroup category and the global incidence in the corresponding age subgroup (from the global burden of disease database), or the US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 21 database) were used to compute enrollment incidence ratio (EIR) at each trial. EIRs with corresponding 95% confidence intervals (CI) were then meta-analyzed using a random-effects model and stratified by sources of funding (industry, US-government, and others [academic and non-US govt]). A univariate meta-regression was conducted to assess the temporal changes in EIR by each funding category. Results: Of 127 trials recruiting from the US, 89 (70%) reported race, and 35 (27%) reported ethnicity. Among those, 57 (64%), 14 (16%), and 18 (20%) trials reported industry, US-government, and other sources of funding, respectively. Of those reporting ethnicity, 23 (66%), 4 (11%), and 8 (23%) trials reported industry, US-government, and other sources of funding, respectively. Among the 287 eligible trials, 49 trials (17%) reported age by 65 years. Of those, 36 (73%), 6 (12%), and 7 (13%) reported industry, US-government, and other sources of funding, respectively. In terms of racial/ethnic enrollment, Black patients were significantly under-represented in industry funded trials (0.33; 0.27-0.41). No significant disparity was observed in US-government funded trials (0.75: 0.57-1.00). The P-value of interaction was <0.0001. Hispanics were significantly under-represented in industry funded clinical trials (0.56; 0.43-0.74). The number of US-government funded trials reporting Hispanics were small (<10) which precluded any meaningful statistics. No significant disparity was observed in terms of older adults (EIR: 1.00; 95% CI: 0.95; 1.05) overall and by funding sources. Black patients’ representation in industry funded PCa trials has significantly decreased over the last three decades. No significant change was observed in US-government funded PCa trials over the last three decades (P:0.004). Conclusions: Black and Hispanic men with PCa are likely to be under-represented in industry sponsored clinical trials. Black patients’ representation in industry sponsored trials has declined over time, thus widening the cancer-care inequities in these patients.
Longitudinal evaluation of plasma miR371 to detect minimal residual disease and early relapse of germ cell tumors.
Authors: Nappi Lucia , Saxena Neetu , Pautasso Sara , Mazurek Sylwia , Ozgun Guliz , Kollmannsberger Catarina , Trottier Chi Max , Morin Coulombe Antoine , Soleimani Maryam , Chi Kim N. , Eigl Bernhard J. , Black Peter C. , So Alan , Gleave Martin , Kern Sean , Daneshmand Siamak , Adra Nabil , Einhorn Lawrence H. , Nichols Craig R. , Kollmannsberger Christian K.
Published: March 2023

407

Background: Active surveillance is routinely recommended to manage patients (pts) with clinical stage I (CSI) germ cell testicular tumors (GCT), the most common presentation of newly diagnosed GCT. Circulating plasma miR371a-3p (miR371) has shown high sensitivity and specificity in pts with metastatic non teratoma GCT or in pts with clinically detectable testicular GCT prior to orchiectomy. However, limited data are available about this biomarker accuracy to detect minimal residual disease post-orchiectomy in pts on active surveillance for early stage disease. Methods: CSI GCT pts with available plasma samples after radical orchiectomy enrolled in the British Columbia provincial biobank research program were selected for this study. RT-PCR was used for qualitative miR371 analysis. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC in predicting tumor recurrence were evaluated for miR371 and compared to the same operating characteristics of current gold standard diagnostic tests. Relapse free survival (RFS) was correlated to post-orchiectomy miR371 (positive or negative) status. Fisher’s exact test was used to evaluate the sensitivity and specificity, unpaired t-test for comparison of miR371 expression. RFS was calculated using the Kaplan-Meier method, and differences between groups were estimated using the log rank test, 2-sided and with 5% significance threshold. Results: With a median follow-up of 41 months, 101 pts with CSI GTCwere included, of whom 35 (34.6%) experienced a disease relapse during the follow-up. miR371 was positive in 22/35 (62.8%) of the relapsed pts. miR371 positivity preceded clinical evident disease by a median of 3 months (range: 1-12 months).The specificity and PPV were 100% (95% CI: 94.5 - 100 for both), sensitivity 62.8% (95% CI: 44.9 - 78.5), NPV 83.5% (95% CI: 76.7 - 88.6) and AUC 0.81 (95% CI: 0.71 - 0.91). No false positive results were observed. The RFS of the pts with positive post-orchiectomy miR371 was significantly shorter (median: 3.5 months vs. not reached; p<0.0001) compared to the pts with a negative post-orchiectomy miR371 (HR: 16.9; 95% CI: 2.1 - 135.7; p<0.0001). miR371 sensitivity correlated with tumor burden, time between tumor relapse and miRNA testing and histology (nonseminoma > seminoma). Conclusions: miR371 has high specificity and PPV in detecting GCT at an early stage and could be used to guide treatment selection after orchiectomy. Further studies, including the SWOG S1823 clinical trial, are ongoing or have been planned in this setting for validation of clinical utility.
European Association of Urology (EAU) Testicular Cancer Guidelines Panel: A new prognostic factor risk group classification for patients with clinical stage 1 seminoma in active surveillance.
Authors: Boormans Joost , Sylvester Richard J , Anson-Cartwright Lynn , Glicksman Rachel , Hamilton Robert James , Daugaard Gedske , Lauritsen Jakob , Wagner Thomas , Avuzzi Barbara , Nicolai Nicola , Aparicio Jorge , Garcia del Muro Xavier , Laguna Pilar
Published: March 2023

410

Background: Between 4%- 30% of patients with clinical stage 1 (CS I) seminoma testis (ST) in active surveillance (AS) relapse depending on pathological risk factors tumor size (TS) and rete testis invasion (RTI). The level of evidence supporting these pathological risk factors in clinical decision-making is low due to heterogeneous study design and reporting and the difficulty to analyze patient subgroups according to combination of these factors. The objectives of the present study were to identify the most important pathological prognostic factors predicting relapse in CS I seminoma patients with normal post-orchidectomy serum tumor marker (STM) levels in AS and to construct risk-groups for guiding treatment decision-making and follow-up. Methods: Individual patient data from 1016 CS I-ST patients diagnosed between February 1994 and January 2019 in AS were collected from 9 institutions. Central pathology review was not routinely performed in all institutions; therefore, pagetoid and stromal RTI were not differentiated explicitly in most cases. Assessing patient age, pre-orchidectomy STM b-human chorionic gonadotropin and lactate dehydrogenase, pathological TS, RTI, lympho-vascular invasion (LVI), multi-focality, and GCNIS, multivariable Cox proportional hazards regression models were fit to identify the most important prognostic factors for the time to first relapse by imaging and/or markers (primary endpoint). Probabilities of relapse were estimated using Kaplan-Meier curves. Results: After median follow-up of 7.7 years, 149 (14.7%) patients relapsed, 104 identified by imaging alone, 44 by imaging with elevated STMs and 1 by elevated STMs alone. Excluding 18 patients with unknown LVI from the multivariable analyses, TS (≤ 2 cm, between 2 and 5 cm, > 5 cm), presence of RTI and presence of LVI were used to form three risk groups: very low, low and high-risk (Table). Five-years probability of relapse varied from 8% in the very low risk-group to 44% in the high risk-group. The new model outperformed the current model with TS < 4cm vs ≥ 4 and RTI (Harrell's C index 0.65 vs 0.61) and identifies a subgroup of patients with a higher risk of relapse. Conclusions: The new risk-group stratification for CS I -ST patients in AS outperforms the histopathological model based on TS and RTI. It will serve to better inform patients on the risk of relapse during follow-up after orchidectomy but requires an independent validation. [Table: see text]
Peripheral blood immune cell profiling in survivors of testicular germ cell tumors.
Authors: Chovanec Michal , Mlcakova Andrea , Sestakova Zuzana , Kalavska Katarina , Obertova Jana , Palacka Patrik , Rejlekova Katarina , Sycova Zuzana , De Angelis Valentina , Orszaghova Zuzana , Lesko Peter , Sekaninova Kristina , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Mego Michal
Published: March 2023

417

Background: Testicular germ cell tumors (GCT) achieve exceptional cure rate with cisplatin-based chemotherapy. Survivors of GCTs represent a unique population to study post-cancer treatment physiology and late toxicities. The impact of cancer treatment on the immune-cell profile in long-term GCT survivors is unknown. In this study, we performed an immune-phenotyping in survivors of GCTs. Methods: Whole peripheral blood was obtained from GCT survivors (N = 202) at National Cancer Institute of Slovakia within the protocol of the ongoing survivorship study on a day of their annual follow-up visit. The median follow-up was 11 years (2-25). GCT survivors were distributed into treatment groups: RT – radiotherapy to the retroperitoneum (N = 18), CT - chemotherapy (N = 143), CTRT - chemotherapy + radiotherapy (N=9); and a control group: AS - active surveillance/orchiectomy only (N=32). Immuno-phenotyping of peripheral blood leukocyte populations was performed with flow-cytometry. Immune cell subpopulations were statistically assessed for associations with received treatment. Results: Survivors treated with RT vs AS had higher no of classical dendritic cells (DCs) (mean ± SEM = 82.0 ± 1.9 vs 76.5 ±1.5, p = 0.03) and non-significantly lower no of plasmacytoid DCs and CD16+ DCs (0.11 ± 0.01 vs 0.15 ± 0.01, p = 0.06 and 54.4 ± 4.1 vs 64.8 ± 3.2, p = 0.07, respectively). Survivors treated with CT vs AS had higher no of CD19+ B cells (11.9 ± 0.3 vs 10.4 ± 0.7, p = 0.04)and lower no of CD8+ T cells (26.0 ± 1.3 vs 23.7 ± 0.6, p = 0.04). Similarly, survivors treated with CTRT vs AS had higher no of CD19+ B cells (13.6 ± 1.4 vs 10.4 ± 0.7, p = 0.04) and lower no of CD8+ T cells (20.7 ± 2.4 vs 26.0 ± 1.3, p = 0.04). Survivors treated with ≥ 400mg/m2 of cisplatin-based chemotherapy vs AS had no of CD19+ B cells (12.2 ± 0.5 vs 10.4 ± 0.7, p = 0.04) and lower no of CD8+ T cells (23.4 ± 0.9 vs 26.3 ±1.3, p = 0.04). The immunoregulatory index CD4/CD8 was higher in CTRT vs AS (2.5 ± 0.3 vs 1.8 ± 0.1, p = 0.04). Conclusions: Certain subpopulations of leukocytes differ according to received treatment in survivors of GCTs. Our results may suggest that chemotherapy and/or radiotherapy may produce long-term immunomodulatory effects. Interplay between B and T cells may be a contributing mechanism of late toxicities. Further research is needed to uncover the causal relationship to the long-term health of GCT survivors.
Prognostic value of circulating cell-free DNA in association with choriocarcinoma syndrome development in patients with germ cell tumors.
Authors: Rejlekova Katarina , Celec Peter , Vlkova Barbora , Kalavska Katarina , Hapakova Nikola , Makovnik Marek , Chovanec Michal , De Angelis Valentina , Obertova Jana , Palacka Patrik , Sycova-Mila Zuzana , Mardiak Jozef , Mego Michal
Published: March 2023

424

Background: Germ cell tumors (GCTs) represent a highly curable malignancy; however, a small portion of patients can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS) with high mortality rate shortly after the chemotherapy start. The aim of this study was to assess the prognostic value of circulating cell-free – extracellular DNA (ecDNA) in patients with GCTs and its association with CS development and outcome. Methods: This study included 23 patients with poor-prognosis GCTs treated from November 2002 to May 2018 at the National Cancer Institute in Slovakia. Pre-treatment total ecDNA, nuclear (ncDNA) and mitochondrial DNA (mtDNA) were quantified in plasma using fluorometry and real-time PCR and analyzed in association with CS development and survival. Results: Four (17%) patients developed CS and all of them died due to ARDS shortly after the chemotherapy start. Total ecDNA, but not ncDNA or mtDNA were associated with CS development. Four out of 11 (37%) patients with high plasma ecDNA developed CS compared to 0 out of 12 (0%) patients with low plasma ecDNA (p = 0.037). In univariate analysis, higher concentration of ecDNA also positively correlated with ECOG PS ≥2, metastatic lung involvement ≥50%, weight loss ≥10%, hemoglobin ≤100 g/l, and neutrophil to lymphocyte ratio ≥ 3.3 at the time of presentation. Patients with low ecDNA had significantly better PFS (HR = 0.35, 95% CI 0.11-1.17, p = 0.043) and OS (HR = 0.26, 95% CI 0.06-1.20, p = 0.032) compared to patients with high pretreatment concentration of ecDNA. Conclusions: In this study we have proved that quantitative analysis of plasma ecDNA has prognostic value for CS development in patients treated due to GCTs. Further research focused on the biology of ecDNA may help us to understand its role as a biomarker, but also a potentially treatable pathogenic factor for choriocarcinoma syndrome development.
Association of plasma vitamin D with outcomes in patients with germ cell tumour.
Authors: Lesko Peter , Vlkova Barbora , Kalavska Katarina , De Angelis Valentina , Obertova Jana , Orszaghova Zuzana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , Mardiak Jozef , Chovanec Michal , Celec Peter , Miskovska Vera , Mego Michal
Published: March 2023

429

Background: Testicular cancer is the most common malignancy among young men. Vitamin D has pluripotent effects on cancer pathogenesis and plays a role in the metastatic cascade. The aim of this study is to analyze plasma vitamin D in association with clinico-pathological findings and prognosis in patients with testicular germ-cell tumours (GCTs). Methods: This study included 120 newly diagnosed and/or relapsed GCTs patients treated from April 2013 to July 2020. Blood samples were drawn at the time before 1st chemotherapy cycle as well as before the 2nd cycle. Plasma vitamin D was measured using ELISA and matched with disease characteristics and correlated with the patient outcome. For survival analysis the cohort was dichotomized to “low” and “high” based on median vitamin D. Results: Mean ± standard error of mean plasma vitamin D in GCTs patients was 15.87±0.68 mg/ml. Patients with brain metastases had significantly lower D vitamin compared to patients without brain metastases (10.9 ± 3.05 vs 15.99 ± 0.7, p=0.034). Vitamin D was not associated with other patient characteristics. Low vitamin D was associated with an unfavorable response compared to favorable responses (11.26 ± 1.84 vs 16.47± 0.74, p=0.016), with disease recurrence (16.19 vs 13.71, p=0.011) and with inferior progression-free survival but not with overall survival (HR= 3.02, 95%CI (1.36-6.71), p=0.014 for PFS and HR= 2.06, 95%CI (0.84 – 5.06), p=0.135 for OS, respectively). Conclusions: Our study suggests a prognostic value of pretreatment vitamin D concentrations in GCTs patients. Low plasma vitamin D was associated with unfavorable response to therapy and disease recurrence. However, it remains to elucidated whether the biology of the disease confirms a causative role of low vitamin D and if its supplementation affects the outcome.
Prostate cancer screening: Have we tipped the seesaw?
Authors: Hobbs Matthew David , Norori Natalia , Harding Thomas , Rylance Amy
Published: March 2023

43

Background: Screening for prostate cancer has been and remains contentious with evidence of harms and benefits finely balanced and inadequate to tip the see saw one way or another in order to give men clear, understandable guidance on PSA testing. In recent years the diagnostic pathway has changed significantly delivering a modern pathway that is likely to do far less harm and possibly more benefit. Our work quantifies the levels of harm and benefit at each stage of the entire pathway currently used in the UK from initial PSA through to biopsy-confirmed diagnosis of prostate cancer. Methods: Combining the full results of the most recent high quality diagnosis clinical trials, as well as real world evidence and practice patterns we have mapped each stage of the UK diagnostic pathway. Through this research we are able to quantify the number of men benefitting (i.e. those who move through the pathway correctly with an eventual diagnosis of clinically significant prostate cancer) and the number of men suffering harm (those who suffer biopsy side effects or who are subjected to unnecessary testing as they move through the pathway with no clinically significant cancer). Results: Initial results using clinical trial data and current practice patterns in the UK indicate that 10,000 men entering the diagnostic pathway with a PSA test would generate the following results. Diagnostic outcomes: 463 men would be diagnosed with a clinically significant (Gleason 3+4 or above) localised prostate cancer; 110 men would be diagnosed with a clinically insignificant (Gleason 3+3) prostate cancer; and 646 men would be taken through the entire diagnostic pathway with no diagnosis of prostate cancer. Harm: a maximum of 38 men would suffer clinical side effects from their biopsy. Healthcare costs: 10,000 PSA tests, 1,449 multiparametric MRI scans, and 1,207 biopsies would yield 463 significant cancers diagnosed. An estimated 1,258 clinically insignificant and 168 clinically significant cancers would remain undiagnosed using the current diagnostic pathway due to initial PSA below 3ng/ml. Conclusions: Rates of biopsy-related harm in modern practice are encouragingly low and likely to reduce further. A PSA-initiated diagnostic pathway misses a significant proportion of clinically important cancers. It is interesting to note the high conversion from MRI to biopsy in the data underpinning this model. Next steps will include analysis of the same outcomes in several centres in the UK to determine if actual practice matches expected outcomes (harms and benefits) from previous clinical trials.
Randomised phase II trial of adaptive image guided radiotherapy in muscle invasive bladder cancer: Late toxicity and cancer outcomes.
Authors: Huddart Robert A , Hafeez Shaista , Omar Abdullahi , Birtle Alison Jane , Cheung Ka Ching , Choudhury Ananya , Foroudi Farshad , Gribble Hannah , Griffin Clare , Henry Ann , Hindson Ben , Lewis Rebecca , McLaren Duncan , McNair Helen , Nikapota Ashok , Parikh Omi , Syndikus Isabel , Varughese Mohini Anna , Webster Amanda , Hall Emma
Published: March 2023

446

Background: The bladder is a mobile, deformable structure which makes radiotherapy (RT) delivery challenging. Plan of the day (POD) adaptive image guided RT and tumour boost dose escalation can optimise treatment. We aimed to define a feasible, safe schedule for muscle invasive bladder cancer (BC) using these techniques. Methods: RAIDER (ISRCTN 26779187) is a 3-arm, international phase II trial. Participants (pts) had unifocal T2-T4a urothelial BC and were randomized (1:1:2) to: standard whole bladder RT (WBRT), standard dose adaptive tumour focused RT (SART) or dose escalated adaptive tumour boost RT (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 64Gy/32f or 55Gy/20f and DART was 70Gy/32f or 60Gy/20f. For SART and DART, POD (small, medium, large) was chosen daily. Neoadjuvant chemotherapy (NAC) and concomitant radiosensitising therapy (CTh) were permitted. Primary endpoint is proportion of pts with RT related CTCAE grade≥3 (G≥3) toxicity 6-18 months (m) after RT. A non-comparative design to rule out >20% G≥3 toxicity in DART pts required 57 evaluable DART pts in each fractionation cohort (90% power, 5% 1-sided alpha). Adverse events (AE) are treatment emergent with RT relatedness assessed blind to treatment allocation. In each fractionation cohort, toxicity analysis is by treatment received in the evaluable population (pts with at ≥1 toxicity assessment between 6-18m). 3m local control was assessed by cystoscopic biopsy. Cancer outcomes are analysed by intention-to-treat with fractionation cohorts combined. Results: 345 pts were randomised (Oct 2015 - Apr 2020): 46/41 WBRT, 46/41 SART and 90/81 DART pts in 32f/20f cohorts respectively. Baseline characteristics for 32f/20f were median age 73 years (IQR 67, 79)/ 72 (67, 79); 83%/ 78% T2; 46%/ 52% had NAC and 71%/ 70% CTh. Median follow-up was 32f: 38.2m (IQR 26.2, 50.2), 20f: 42.1m (35.6, 50.1). 3588/6222 (58%) fractions delivered to SART and DART pts used small or large POD. Late toxicity outcomes are shown in table. RT related G≥3 in 20f DART was 1/58 (90% CI 0.1, 7.9) and in 32f DART was 0/57. 3m local control was achieved in 44/51 (86%) WBRT, 45/53 (85%) SART and 82/92(89%) DART. 2 year survival was 79% (95% CI: 69, 86) WBRT, 74% (63, 82) SART and 80% (73, 85) DART. Conclusions: Late G≥3 toxicity was low in all treatment groups. 20f and 32f DART was safe and feasible to deliver with toxicity rates below predefined thresholds. Local control for image guided (chemo)RT was good. CTCAE G≥3 and G≥2 treatment emergent toxicity 6-18m after RT. Clinical trial information: 26779187 . [Table: see text]
Patterns of failure after radiotherapy (RT) in patients with prostate cancer re-staged with 18F-DCFPyL PSMA-PET: A regional cohort analysis.
Authors: Mesci Aruz , Mukherjee Sneha , Gouran-Savadkoohi Mohammad , Kapoor Anil , Bauman Glenn , Lukka Himu , Dayes Ian S. , Schnarr Kara , Goldberg Mira , Quan Kimmen , Zukotynski Katherine A. , Tsakiridis Theodoros
Published: March 2023

45

Background: In Ontario, PSMA-PET is available to patients with prostate cancer who experience biochemical failure after definitive primary RT (pRT) or salvage/adjuvant RT (sRT) through a provincial registry study (PREP protocol). Here we review patterns of PSMA-PET-detected failure after primary (pRT) or salvage/adjuvant RT (sRT) radiotherapy (RT) in cohorts of PREP-registry patients from the Local Health Integration Network (LHIN) 4 region. Methods: With ethics approval, we retrospectively analyzed patients imaged with PSMA-PET in Hamilton, Ontario, Canada, after biochemical failure, following pRT or sRT. Demographic, clinical and treatment parameters as well as PSMA-PET results were collected. Results: Between April 2019 and December 2021, 104 pRT and 91 sRT patients were imaged with 18F-DCFPyL PSMA-PET. Median PSA (ng/mL) before PSMA-PET for the two groups was 5.0 (IQR:3.1-8.9) and 1.3 (IQR:0.6-3.4). The percentages of Prostate or Prostatic bed RT alone (Pr-RT) and Pr + pelvic Lymph Node RT (Pr+LN-RT) RT treatments, were Pr-RT:76% vs Pr+LN-RT:24% for the pRT group and Pr-RT:49.4% vs Pr+LN-RT:50.6% for the sRT group, respectively. Rates of PSMA-PET detected local, pelvic lymph node and distant recurrence are shown. In the pRT group, increasing D’Amico risk category (low to high risk) was associated with lower risk for local and increased risk for pelvic and distant metastasis. Pelvic RT was associated with reduce risk for local recurrence in the pRT but not in the sRT group. Conclusions: In this cohort of patients PSMA-PET detected a considerable risk for local recurrence in patient treated with pRT. A high number of patients are detected with pelvic-only disease recurrence, but pelvic RT seems to be associated with reduction in this risk only in the pRT population. Studies with PSMA-PET at baseline, before pRT or sRT, may help discern better patients that would benefit from pelvic RT and systemic therapy.[Table: see text]
Clinical significance of squamous differentiation in upper tract urothelial carcinoma treated with radical nephroureterectomy.
Authors: Minato Akinori , Noguchi Hirotsugu , Kimuro Rieko , Tomisaki Ikko , Harada Kenichi , Fujimoto Naohiro
Published: March 2023

451

Background: Upper tract urothelial carcinoma (UTUC) involving the renal pelvis/ureter is histologically similar to bladder cancer in morphological diversity. Although squamous differentiation (SD) is the most common variant in UTUC, the clinical significance of SD in UC has yet to be comprehensively elucidated given the rarity of the disease compared to bladder cancer. To assess the impact of SD on the prognosis of patients with UTUC undergoing radical nephroureterectomy (RNU). Methods: Among the 244 consecutive patients who underwent RNU at our single institution from May 2005 to October 2019, only patients who had histologically confirmed pure UC or UC with SD (UCSD) were included. SD required the presence of intercellular bridges or keratinization for diagnosis. Metastasis-free survival (MFS) and overall survival (OS) rates were retrospectively evaluated using Kaplan–Meier analysis and Cox regression analysis. Results: We identified 197 (87.9%) and 27 (12.1%) patients with pure UC and UCSD, respectively. No significant differences in age, sex, concomitant carcinoma in situ and tumour grade were observed between the groups. UCSD was significantly associated with an advanced tumour stage and a higher rate of lymphovascular invasion. With a median follow-up time of 58 months, the pure UC and UCSD groups had a 5-year MFS rate of 65.2% and 40.9% ( p=0.005) and a 5-year OS rate of 74.4% and 49.0% ( p=0.002), respectively. Multivariate analyses revealed that the presence of SD was significantly associated with MFS [hazard ratio (HR), 1.88; p=0.027] and OS (HR, 1.70; p=0.048). Conclusions: The patients with UCSD are at high risk for disease metastasis and short-term survival. SD in UC could be an independent predictor of poor prognosis after RNU for UTUC.
Racial and geographical disparities in pivotal bladder cancer clinical trials.
Authors: Padua Tiago Costa de , Marandino Laura , Patanè Damiano Alfio , Raggi Daniele , Necchi Andrea
Published: March 2023

454

Background: According to population-based studies, there is a significant racial difference in patient characteristics, incidence, and survival among bladder cancer patients. Non-Hispanic whites have the highest incidence rate, followed by blacks. However, racial clinical trial disparities in clinical research are a critical problem around the world, with an underrepresentation of the black population. In the last years, multiple phase 2/3 trials have introduced the use of immunotherapy and targeted therapy in the treatment of bladder cancer. We aimed to assess the enrollment disparities in pivotal BC clinical trials. Methods: Published clinical trials were identified from the Bladder Cancer European Society of Medical Oncology (ESMO) guideline, considering the approved drugs and availability in clinical practice. The characteristics of participants, including race and geographic location, were collected. Results: A total of 1 phase 2 or 3 trials were identified, evaluating pembrolizumab, atezolizumab, avelumab, erdafitinib, durvalumab +/- tremelimumab and enfortumab vedotin, with a total of 7748 patients. The table summarizes the findings. Race information is available only in 8 of them, 4 in the original report and 4 in the results section of clinicaltrials.gov, with a pooled sample of 6573 patients. White, Asian and Black patients comprised 71.74% (4716 pts), 19.9% (1313 pts), and 0.66% (44 pts) of all patients, respectively. The percentage of white patients ranged from 51.6% to 88.6%, whereas the black population varied from 0.3% to 2.2%. Geographical location information is available only for 2 clinical trials, with a predominance of patients from the United States and Europe and an under-representation of patients from other continents. Conclusions: We observed a low rate of race reporting in bladder cancer published trials and a very significant under-representation of non-white participants in the pivotal trials for bladder cancer, with just 0.66% of black patients. Based on these finding, there are insufficient data to confirm the effectiveness or safety of new drugs in minority groups, especially blacks. To provide generalizable results, race reporting should be always included in licensing trials, and recruitment of black and other minority population to trials should be stimulated.[Table: see text]
Whole-body diffusion-weighted magnetic resonance imaging to assess bone response in patients with hormone-sensitive metastatic prostate cancer randomly assigned to receive androgen deprivation + enzalutamide ± zoledronic acid.
Authors: Dalla Volta Alberto , Valcamonico Francesca , Zivi Andrea , Procopio Giuseppe , Sepe Pierangela , Del Conte Gianluca , Di Meo Nunzia , Foti Silvia , Zamboni Stefania , Messina Caterina , Lucchini Eleonora , Rizzi Anna , Ravanelli Marco , Milella Michele , Calza Stefano , Simeone Claudio , Maroldi Roberto , Farina Davide , Berruti Alfredo
Published: March 2023

46

Background: Bone is frequently involved in metastatic hormone sensitive prostate cancer (mHSPC). Whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) is a promising imaging technique for the assessment of bone response in prostate cancer. It is not known whether the addition of antiresorptive agents can improve disease response in bone in mHSPC patients undergoing next generation hormonal agents. Methods: In this multicenter phase II study patients with de novo or relapsed mHSPC and bone metastases at bone scan were randomly allocated with a 1:1 ratio to receive either androgen deprivation therapy (ADT) plus Enzalutamide (E arm) or the same combination with the addition of Zoledronic Acid (EZ arm). The study was designed to observe a significant increase in bone response rate in the experimental arm after 12 months of treatment, as assessed through WB-DW-MRI. WB-DW-MRI was performed centrally at baseline and after 6 and 12 months and images were evaluated by the same radiologist. Results: From February 2018 to June 2021, 126 mHSPC patients were randomized, 64 in EZ arm and 62 in E arm. A total of 111 patients, 54 from E arm and 57 from EZ arm, were eligible for WB-DW-MRI assessment (15 patients were excluded because of the absence of bone target lesions at MRI or specific contraindications to MRI). Bone response at 6 months was observed in 41 patients (76%) in E arm and 41 patients (72%) in EZ arm; the corresponding bone response at 12 months were 44 (82%) and 44 (77%), respectively (OR 0.77; 95%IC 0.30-1.93; p = 0.6). Complete response was the best overall bone response after 12 months in 9 patients (17%) from E arm and in 11 patients (19%) from EZ arm. In the same period, treatment was interrupted due to disease progression in 7 (13%) and 7 (12%) patients in E and EZ arm, respectively. Conclusions: The addition of Zoledronic Acid to Enzalutamide and ADT did not improve bone disease response in patients with mHSPC. WB-DW-MRI was able to detect bone responses in a great proportion of patients. Clinical trial information: NCT03336983 .