bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-free DNA methylation as a predictive biomarker of response to neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer in SWOG S1314.
Authors: Lu Yi-Tsung , Plets Melissa , Morrison Gareth , Cunha Alexander T. , Cen Steven Y. , Rhie Suhn K. , Siegmund Kimberly , Daneshmand Siamak , Quinn David I. , Meeks Joshua J , Lerner Seth P. , Petrylak Daniel P. , McConkey David James , Flaig Thomas W. , Thompson Ian M , Goldkorn Amir
Published: June 2022

4506

Background: Neoadjuvant chemotherapy is the standard of care in muscle-invasive bladder cancer patients. However, treatment is intense, the overall benefit is small, and there is no established marker to identify patients who benefit most. The aim of the study is to characterize cell-free DNA (cfDNA) methylation from patients receiving neoadjuvant chemotherapy in SWOG S1314, a prospective cooperative group trial, and to correlate the methylation signatures with pathologic response. Methods: Blood samples were collected prospectively from 73 patients before and during standard neoadjuvant chemotherapy. At radical cystectomy, pathologic response was documented. Plasma cfDNA was profiled using Infinium MethylationEPIC BeadChip array. Differential methylation between pathologic responders (≤pT1N0M0) and non-responders was analyzed, and a Random Forest model was used to generate a classifier predictive of treatment response. Results: Using pre-chemotherapy plasma cfDNA, we developed a methylation-based response score (mR-score) predictive of pathologic response. The mR-score also could be calculated using plasma samples collected after the first cycle of neoadjuvant chemotherapy, resulting in a similar predictive ability. Furthermore, we used cfDNA methylation data to calculate the circulating bladder DNA fraction, which had a modest but independent predictive ability for treatment response. When we combined the mR-score and circulating bladder DNA fraction, we successfully predicted pathologic response outcomes in 79% of patients based on their plasma collected before chemotherapy and after 1 cycle of chemotherapy. Conclusions: Our study provides proof of concept that cfDNA methylation may be used to predict treatment response in bladder cancer patients receiving neoadjuvant chemotherapy. Clinical trial information: NCT02177695.
TRUCE-02: An open label, single-arm, phase II study of tislelizumab combined with nab-paclitaxel for high-risk non-muscle-invasive urothelial bladder carcinoma.
Authors: Wang HaiTao , Hu Hailong , Niu Yuanjie , Tian Dawei , Shen Chong , Da La , Wu Zhouliang , Zhao Gangjian , Zhou Diansheng , Bai Yiduo , Chen Houyuan
Published: June 2022

4507

Background: Pts with multiple or tumors with large invasion areas which are un-completely-resectable through TURBT would be recommended radical cystectomy in the clinical treatment. The KEYNOTE-057 study has illuminated the efficiency of immune checkpoint inhibitors monotherapy in HR-NMIBC pts, with acceptable adverse events (AEs). However, the role of PD-1/PD-L1 inhibitor in combination with chemotherapy in NMIBC pts remains unclear. We report preliminary treatment efficiency, safety data, and exploratory work of TRUCE-02 trial. Methods: TRUCE-02 is a phase II study for NMIBC pts with uncompletely resectable tumour by TURBT. The primary endpoint was complete response(absence of non-muscle-invasive bladder cancer or progressive disease). Pts that meet the criteria would receive tislelizumab 200mg on days 1 plus paclitaxel 200mg on days 2 every 3 weeks (Q3W) x 3 or 4 cycles followed by a comprehensive assessment including pathology, urine cytology, and imageology. Meanwhile, biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay) and whole transcriptome RNA sequencing of the tumor. Results: Between July 2020 and January 2022, 54 pts were enrolled. 42 pts have completed whole 3 or 4 treatment cycles and reached the primary endpoint. 23 pts achieved CR condition (56%, 95%CI, 43.6% and 74.4%). ORR of 60% (N=25/42, 95%CI, 45.2% and 74.8%). As a secondary endpoint, 33 pts remain cystectomy-free condition (78.6%, 95%CI, 66.2% and 91%). Grade 3-4 AEs were lower than 2%. Urine cytology showed its diagnostic efficiency of 68.42% (95%CI, 61.3% and 75.6%), urine FISH showed a diagnostic efficiency of 45.71% (95%CI, 37.7% and 53.4%) before pathological assessment. As for PD-L1 expression, 47.3% (N = 9/19) of response pts (CR+PR) showed positive, 50% (N = 5/10) of un-response pts (PD+SD) showed positive. We also found out through sequencing results that AR, TCF7L2 might be underlying markers that predict adverse outcomes for pts in this crew. HRR mutation may predict a positive prognosis and mutations in NMIBC which might predict the prognosis of this treatment plan. Conclusions: Tislelizumab with nab-paclitaxel represents a novel treatment option with a satisfactory benefit in treating NMIBC. PD-L1 expression has no obvious correlation with the efficiency of this treatment plan. WGS result also showed that there are mutation markers that may predict whether pts would benefit from this treatment plan. Clinical trial information: NCT04730232. [Table: see text]
Association of DNA damage repair (DDR) mutations (mts) and clinical outcomes in CALGB 90601 (Alliance).
Authors: Iyer Gopa , Halabi Susan , Luo Bin , Rosenberg Jonathan E. , Choi Woonyoung , Al-Ahmadie Hikmat A. , Mountain Jack , Regazzi Ashley Marie , Fong Megan , Mouw Kent William , Van Allen Eliezer Mendel , McConkey David James , Wen Yujia , McCart Linda , Ballman Karla V. , Beltran Himisha , Morris Michael J.
Published: June 2022

4521

Background: Platinum-based chemotherapy is the standard 1st-line therapy for metastatic urothelial cancer (mUC). C90601 was a randomized phase III trial testing gemcitabine and cisplatin (GC) with bevacizumab (B) or placebo (P) in patients (pts) with untreated mUC. Median overall survival (OS) for GCB vs GCP was 14.5 months (mo) vs 14.3 mo (p=0.14) and median progression-free survival (PFS) was 8 vs 6.7 mo, respectively. DDR mts have been implicated in response and survival in mUC and were investigated in this negative trial. Methods: C90601 enrolled 506 pts randomized 1:1 to GCB or GCP from 7/15/09-12/2/14, with stratification for prior chemotherapy and visceral metastases. Consenting pts submitted archival FFPE tumor specimens and blood for matched germline (g)DNA. Tumor and gDNA were sequenced by MSK-IMPACT, a 468-gene exon capture assay, to detect mts in select DDR genes. The proportional hazards model was used to correlate mts in the DNA helicase ERCC2 (pre-specified hypothesis) and additional DDR gene panels being explored in prospective trials in muscle-invasive disease with OS and PFS, adjusting for tumor mt burden and stratification factors. Mts were categorized as deleterious (del) or non-del using pre-defined published criteria. Results: 208 pts underwent DNA sequencing. Clinical features and PFS/OS were comparable to the 506-pt cohort. Median sequencing coverage was 497X. Median mutation count was 13.2 and 8.8 for DDR mt and wild-type tumors, respectively. A non-significant improvement in OS and PFS was seen in pts with ERCC2 mts (HR 0.70), but the 5.3% frequency of ERCC2 mts was lower than in historical series. Neither del mts (table) nor any mts in DDR genes were associated with PFS/OS. Conclusions: DDR mts were not associated with improved outcomes in C90601. The reliance on archival specimens, lower-than-expected ERCC2 mt frequency, small sample sizes, and tumor genomic heterogeneity may have influenced the predictive capacity of DDR mts in this cohort. Similar analyses are underway in pts who received neoadjuvant chemotherapy prior to cystectomy from completed prospective trials. Support: U10CA180821, U10CA180882, Genentech.[Table: see text]
Progression-free survival after second line of therapy (PFS-2) for metastatic clear cell renal cell carcinoma (ccRCC) in patients treated with first-line immunotherapy combinations.
Authors: Fitzgerald Kelly N. , Duzgol Cihan , Knezevic Andrea , Shapnik Natalie , Kotecha Ritesh , Aggen David Henry , Carlo Maria Isabel , Shah Neil J. , Voss Martin H , Feldman Darren R. , Motzer Robert J. , Lee Chung-Han
Published: June 2022

4536

Background: Front-line therapy with immunotherapy combinations is standard of care for metastatic ccRCC, with ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted tyrosine kinase inhibitor with a PD-1 inhibitor (TKI/IO) showing superior efficacy to TKI monotherapy. PFS-2 evaluates the ability to be salvaged by 2nd line therapy and is a surrogate for overall survival (OS). PFS-2 was compared in patients receiving 1st line IO/IO vs TKI/IO for metastatic ccRCC. Methods: A retrospective analysis was performed on patients with ccRCC treated at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020, in cohorts defined by 1st line: IO/IO or TKI/IO. PFS-2 is defined as time from start of 1st line to progression on next therapy, or death. Patients without a PFS-2 event were censored at a prespecified cutoff date. Objective response rate to 1st (ORR1st) and 2nd (ORR2nd) line are compared with the Fisher’s exact test. OS, PFS-2, and time on therapy are estimated with the Kaplan-Meier method and compared with the log-rank test. Results: One hundred seventy-three patients received 1st line IO/IO (N = 90) or 1st line TKI/IO (N = 83); respectively, 52 and 40 patients had a PFS-2 event. 1st line TKI/IO regimens included: 34% axitinib/pembrolizumab, 29% lenvatinib/pembrolizumab, 25% axitinib/avelumab, 11% other. More IO/IO patients had brain metastases and intermediate/poor MSKCC risk category (respectively p = 0.007, p < 0.001). ORR1st and median months on 1st line were higher with TKI/IO vs IO/IO (65% vs 39%, p < 0.001; 16.1 vs 5.1, p < 0.001). ORR2nd was higher with IO/IO vs TKI/IO (47% vs 13%, p < 0.001), and median months on 2nd line was not significantly different (7.7 vs 7.1, p = 0.30). Median PFS-2 for TKI/IO was 44 months (95% CI: 27, 53) vs 23 months (95% CI: 16, 47) for IO/IO, p = 0.13. For TKI/IO and IO/IO groups, respective PFS-2 at 12 months was 86% (95% CI 77, 92) and 74% (95% CI 63, 82); PFS-2 at 36 months was 51% (95% CI 39, 63) and 42% (95% CI 30, 53). OS was not significantly different (p = 0.32; 3 year OS: IO/IO 60%, 95% CI 47, 71; TKI/IO 62%, 95% CI 49, 73). (Table) Conclusions: In patients receiving 1st line IO/IO or TKI/IO, ORR2nd was higher with IO/IO and median PFS-2 was numerically higher with TKI/IO, but no statistically significant difference in PFS-2 or OS was seen. These findings suggest that IO/IO and TKI/O are both acceptable 1st line treatment strategies in ccRCC. [Table: see text]
Prognostic factors for patients with advanced renal cell carcinoma (aRCC) in the era of first-line (1L) treatment with immune checkpoint inhibitors (ICIs).
Authors: Mantia Charlene , Jegede Opeyemi , Regan Meredith M. , Atkins Michael B. , McDermott David F.
Published: June 2022

4544

Background: The most commonly used prognostic models in aRCC, the Memorial Sloan-Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, were developed when cytokines and VEGF targeted monotherapies were standard of care, respectively. aRCC 1L treatment now includes combination therapy with 2 ICIs or ICI+VEGF receptor inhibitor. Re-evaluation of the MSKCC and IMDC prognostic models in the era of ICI therapy and identification of additional prognostic factors are overdue. Methods: Data from 1052 patients with aRCC treated on the CheckMate-214 (CM214) clinical trial with 1L nivolumab/ipilimumab (NIVO/IPI) or sunitinib (SUN) were analyzed retrospectively at median follow-up 5 yrs. For each treatment group, multivariable Cox model hazard ratios (HR) were compared to the published MSKCC and IMDC model HRs. Discrimination (c index) was assessed based upon the continuous scores obtained as the weighted combination of regression parameters from the published MSKCC & IMDC models. Results: KPS < 80% remained highly prognostic in both treatment groups (HRs > 2.5). With the exception of high calcium, the other factors of time from dx to treatment < 1 yr, hemoglobin < lower limit of normal (LLN), neutrophils > upper limit of normal (ULN), platelets > ULN and LDH > 1.5xULN consistently retained prognostic value for SUN (HRs ≥ published model HRs) but had diminished prognostic value for NIVO/IPI (each HR < published model HR). High calcium had diminished prognostic value for SUN and retained prognostic value for NIVO/IPI. The c-indices for discrimination were 0.61 and 0.64 for the MSKCC model in the NIVO/IPI and SUN treatment groups, respectively, and were 0.63 and 0.67 for the IMDC model in the NIVO/IPI and SUN treatment groups compared to reported IMDC c-index of 0.73 (Heng 2009). (Table) Conclusions: The prognostic ability of the MSKCC and IMDC risk models is reduced with combination ICI treatment. Evaluation of additional prognostic factors and development of new risk scores are needed and this work is ongoing. [Table: see text]
Artificial intelligence algorithms for the diagnosis of urothelial carcinoma based on urine cytology: A noninvasive and efficient diagnostic approach.
Authors: Shen Chong , Wang HaiTao , Hu Hailong , Niu Yuanjie , Tian Dawei , Huang Shiwang , Zhao Gangjian , Huang Chuanyi , Wu Zhouliang , Zhang Zhe
Published: June 2022

4590

Background: Urine cytology is a noninvasive and relatively inexpensive approach that plays an important role in both screening/initial diagnosis of urothelial carcinoma, and surveillance of tumor recurrence; However, interpretation of urine cytology is labor-intensive and time-consuming. Artificial intelligence (AI) has been widely used in the field of medically assisted diagnosis, but it is almost blank in the field of urothelial carcinoma diagnosis based on urine cytology. In this study, artificial intelligence (AI) algorithms have been developed to efficiently and automatically analyze urinary cytological specimens stained with Acridine orange fluorescence for screening and diagnosis of urothelial carcinoma with a good clinical application prospect. Methods: To develop the algorithms, images of urinary cytological specimens with Acridine orange Fluorescence staining were collected from patients who underwent examination, surgery, or both at the Second Hospital of Tianjin Medical University from August 2015 to August 2021. To standardize the urine cytological determination, the images were determined by 3 certified and experienced cytopathologists in this hospital. Images were collected to establish a dataset containing two major categories: Malignant (Defined as images containing malignant cells) and Benign (Defined as images containing malignant cells). From the acquired database, 2794 malignant and 2787 benign eligible images were selected for AI training/validation/testing. Inception V3, a specific type of neural network optimized for image classification called a deep convolutional neural network was trained based on the database. To prevent the model from over-fitting during training, data augmentation methods, such as rotation and flipping were adopted. The diagnosing performance of the binary classification model was analyzed using accuracy, F1 score, operating characteristic (ROC), and the area under the curve (AUC) generated from the sensitivity and specificity to evaluate. Results: A total of 21022 slides of urine cytological specimens with Acridine orange Fluorescence staining were collected. The AI algorithms achieved excellent performance, which showed the best prediction with an accuracy of 92.25%, a sensitivity of 98.50% along with a specificity of 86.00%, the F1score was 0.9271, and the area under the ROC curve was 0.96. Conclusions: Our novel artificial intelligence algorithms could accurately classify urine specimens as malignant or benign efficiently and automatically. The use of AI during cytopathology screening provides a new strategy and technical support for the diagnosis and screen of urothelial carcinoma. [Table: see text]
Prognostic factors and clinical outcomes in patients with upper tract urothelial carcinoma undergoing surgery: The Cleveland Clinic experience.
Authors: Ahmed Ramsha , Sheu Michael , Wei Wei , Ornstein Moshe Chaim , Gilligan Timothy D. , Dima Danai , Campbell Steven , Lee Byron H , Weight Christopher , Wee Christopher Eing , Mian Omar Y. , Kaouk Jihad , Haber Georges-Pascal , Gupta Shilpa
Published: June 2022

4593

Background: Upper tract urothelial carcinoma (UTUC) is a rare and heterogeneous disease accounting for approximately 5-10% of UC. While tumor grade and stage are known prognostic factors, data on other factors affecting outcomes in UTUC patients (pts) undergoing surgery is scant. We studied effect of various clinical factors and treatment on outcomes in UTUC. Methods: This is a single-institution retrospective study of 607 pts with UTUC undergoing surgery (nephroureterectomy (NU) or ureterectomy (U)) between Jan 2000 and Dec 2020. We studied effect of demographics, clinicopathological features, tumor location, preoperative Neutrophil-to-Lymphocyte ratio (NLR) and Albumin-to-Globulin ratio (AGR) and use of neoadjuvant or adjuvant chemotherapy on overall survival (OS) and recurrence free survival (RFS). Results: Of the 607 pts 401 (66.06%) were males and 355 (58.48%) were > 70 yrs; 232 pts (38.22%) had UTUC of renal pelvis, 242 (39.87%) of ureter and 133 (21.91%) of both. 542 pts (89.29%) underwent radical NU and 65 (10.71%) segmental U; 328 patients (54.04%) were diagnosed with muscle invasive UC (MIUC) ( > / = pT2) and 276 (45.47%) with non-MIUC ( < / = pT2). Only 51 (8.4%) pts had lymph node positive (N+) disease. Lymphovascular invasion (LVI) was identified in 163 (26.85%) and carcinoma- in-situ (CIS) in 163 (26.85%) pts. Surgical margins were positive in 92 pts (15.16%). Median NLR cutoff was 3.25 and AGR cutoff was 1.25 (dichotomized based on literature). 44 pts (7.2%) received Neoadjuvant chemotherapy and 49 pts (8%) received adjuvant chemotherapy. Tumor recurrence occurred in 216 pts (35.58%) of which 65% were at urothelial and 35% at non-urothelial sites. With median follow up of 35.2 mos, median OS was 82.69 mos and 5-yr OS rate was 60%; median RFS was 29.47 mos and 5-yr RFS rate was 40%. High grade, age > / = 70 yrs, high NLR, low AGR, presence of LVI, positive margins, CIS, MIUC, N+ disease were associated with worse outcomes. Pts with only renal pelvis involvement had better OS. Conclusions: In this large, long term follow-up series of UTUC pts, we identified several prognostic factors besides grade and stage that impact outcomes. These findings warrant further validation for use in clinical practice. [Table: see text]
Assessing intermediate clinical endpoints (ICE) as potential surrogates for overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Halabi Susan , Roy Akash , Rydzewska Larysa , Godolphin Peter , Parmar Mahesh K. B. , Hussain Maha H. A. , Tangen Catherine , Thompson Ian , Xie Wanling , Carducci Michael Anthony , Smith Matthew Raymond , Morris Michael J. , Gravis Gwenaelle , Dearnaley David P. , Verhagen Paul , Goto Takayuki , James Nicholas D. , Buyse Marc E. , Tierney Jayne F. , Sweeney Christopher
Published: June 2022

5006

Background: We hypothesized that radiographic progression free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration. Methods: We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of rPFS and cPFS as potential ICEs. rPFS was defined as time from randomization to radiographic progression (defined per protocol) or death from any cause whichever occurred first; cPFS was defined as time from randomization to date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. OS was defined as time from randomization to death from any cause, if patients had not died they were censored at the date of last follow-up. We implemented a two-stage meta-analytic validation model where conditions of trial level and patient level surrogacy had to be met. We computed the surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS. Results: IPD from 8592 patients randomized from 1994-2012 from 13 trials were pooled for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 75.6 months. In addition, there were 6227 rPFS and 6314 cPFS events. The median OS, rPFS and cPFS were 49.4, 26.8 and 25.2 months, respectively. The STE was 0.82 for rPFS and 0.84 for cPFS. Conclusions: Both rPFS and cPFS appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary endpoint as a surrogate for OS in phase 3 mHSPC trials and would expedite trial conduct. Validation of these ICEs in trials with drugs having other mechanisms of action is planned. Clinical trial information: Several. [Table: see text]
Biomarker-directed therapy in black and white men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hwang Clara , Henderson Nicholas , Cackowski Frank Cameron , Pilling Amanda , Jang Albert , Rothstein Shoshana , Labriola Matthew , Park Joseph J. , Ghose Alyssa , Bilen Mehmet Asim , Kilari Deepak , Tripathi Abhishek , Garje Rohan , Koshkin Vadim S , Schweizer Michael Thomas , Armstrong Andrew J. , McKay Rana R. , Dorff Tanya B. , Alva Ajjai Shivaram , Barata Pedro C.
Published: June 2022

5013

Background: Black men have been underrepresented in large-scale molecular prostate cancer (PC) surveys, despite having higher PC incidence and mortality. Since molecular profiling to guide the use of targeted agents is increasingly important in mCRPC, we compared precision medicine data and utilization in a cohort of black and white men with mCRPC. Methods: The PROMISE precision medicine database is an academic collaboration to compile clinical and genomic data from men with PC. All patients have had germline and/or somatic genetic testing performed. Eligibility criteria for this analysis included a diagnosis of mCRPC with available race and biomarker data. The primary outcome was the proportion of non-Hispanic black (NHB) and non-Hispanic white (NHW) men with actionable molecular data, defined as the presence of mismatch repair deficiency (MMRd/MSI-H), homologous recombination repair deficiency (HRRd), tumor mutational burden (TMB) ≥ 10 mut/MB, or AR-V7. Secondary outcomes included the proportion of NHB and NHW men with other alterations, the type and timing of genomic testing performed, and the use of targeted therapy. Results: A total of 962 mCRPC patients (21.2% NHB; 78.8% NHW) met inclusion criteria of 1619 in the overall database. Median age (NHB/NHW) was 61/63; 77.5/68.8% had Gleason 8-10; 52.5/56.7% presented with de novo metastatic disease (33.8/29.9% LN, 36.2/32.2% bone and 8.3/6.1% viscera). The median time from diagnosis to first molecular result was 56.3 mo for NHB v 58.7 mo for NHW (p = 0.45). Use of blood-based molecular testing was more common in NHB men (48.7% v 36.4%, p < 0.001). Overall, 32.8% of NHB men harbored actionable molecular data compared to 30.3% of NHW men (Table). MMRd/MSI-H was more common in NHB men (9.1 v 4.9%, p = 0.04). Other than PTEN (12.7/23.8% NHB/NHW, p = 0.0001), no significant differences were seen in the 15 most frequently mutated genes, including TP53, AR, CDK12, RB1, and PIK3CA. Tumor suppressor co-mutations (PTEN/TP53/RB1) were found in 13.1% of NHB and 18.0% NHW (p = 0.13). Delivery of targeted therapy was reported in 19.6% of NHB and 23.7% of NHW men (p = 0.25) after a median of 2 CRPC lines. Median OS from development of mCRPC was 41.5 mo (95% CI, 34.7-51.3) and 44.7 mo (95% CI, 41.1-51.5) for NHB and NHW men, respectively (p = 0.14). Conclusions: In a real-world mCRPC molecular profiling cohort, we found similar overall rates of actionable molecular alterations in NHB and NHW men, but higher rates of MMRd/MSI-H and lower frequency of PTEN alterations in NHB men. We did not find differences in delivery of targeted therapy. [Table: see text]
Long-term predictive value of serum PSA values obtained in clinical practice: Results from the Norwegian Prostate Cancer Consortium (NPCC).
Authors: Oldenburg Jan , Bjerner Johan Lars , Lilja Hans , Aas Kirsti , Fossa Sophie D. , Mueller Christoph , Mueller Stig , Thomas Owen , Stensvold Andreas , Walz Jochen , Røe Oluf D. , Bratt Ola , Carlsson Sigrid V.
Published: June 2022

5021

Background: A baseline prostate-specific antigen (PSA) level in midlife is strongly associated with risk of lethal prostate cancer several decades later. In most prior studies, PSA was measured in archived blood from men participating in cohort studies unrelated to prostate cancer. In clinical practice, however, men commonly obtain a PSA test because of lower urinary tract symptoms. Here, we study the association between PSA values when a first PSA test was obtained as part of clinical care – and subsequent risks of prostate cancer diagnosis and death. Methods: The NPCC database contained laboratory results from 1995-2006 of the first (“baseline”) PSA test below 4.0 ng/mL in 157,836 men aged 40-69 years without prior prostate cancer (PCa) diagnosis. PSA strata were pre-defined: < 1, 1-1.99, 2-2.99, 3-3.99 ng/ml and analyses were split in two age groups based on a prior risk: 40-54 (“younger”) and 55-69 (“older”). Predictive accuracy was assessed with Harrell’s concordance (C) index. The Kaplan-Meier method was used to visualize risk of PCa death as reported on the death certificate by PSA strata for the two age groups. Results: Among 157,836 men with a PSA below 4.0 ng/mL, 83% had < 2.0 ng/mL. Risk of prostate cancer and death from prostate cancer were strongly associated with PSA-levels and age: Harrell’s C-index 0.75 and 0.72 for diagnosis of younger and older group, respectively and 0.72 for PCa death for both age groups. In the younger age group 196 deaths among 75,446 men (0.26%) were registered, in the older 943 deaths among 82,390 men (1.14%). The risk of PCa death in lowest (< 1) and highest (3-3.99) strata were 0.23% and 3.22%, respectively (189 deaths among 81,982 vs. 274 deaths among 8517 men). Conclusions: This population-based NPCC study shows as strong predictive impact of the different strata of the initial PSA measurement in routine clinical care as prior studies based on cryopreserved blood samples. [Table: see text]
Genomic alterations and evolution in patients with prostate cancer with histologic evidence of neuroendocrine differentiation.
Authors: Barnett Ethan , Carbone Emily , Keegan Niamh M. , Vasselman Samantha E , Nweji Barbara , Zaidi Samir , Scher Howard I.
Published: June 2022

5029

Background: The incidence of transformation to neuroendocrine prostate cancer (NEPC) has increased in castration resistant prostate cancer (CRPC) in parallel with treatment advances inhibiting androgen receptor signaling. The current understanding is that this occurs in ̃10-20% of CRPC cases. Missing is a determination of the timing of molecular events that drive the process. Methods: Under an IRB-approved protocol, retrospective annotation of all MSK-reviewed pathology reports was conducted for 1447 prostate cancer patients with MSK-IMPACT sequencing data. For patients with pathologically confirmed NEPC, the date of the first sample with unequivocally reported NEPC (described as “neuroendocrine carcinoma” or as having “neuroendocrine differentiation” or “neuroendocrine features”) was recorded. Patients with early signs of histologic transformation not specifically reported as NEPC (double negative prostate cancer or rare/focal staining for NE markers) were analyzed separately. Sequencing results were described by castration-status at collection (CRPC vs castration-sensitive) and, if applicable, the relationship to NEPC diagnosis (i.e. pre- vs post-NEPC). Genomic enrichment analysis was used to identify differentially altered genes between groups. Results: In total, 95 (6.6%) patients had pathologically confirmed NEPC during their disease course, from whom 150 samples with sequencing results were available: including 18 patients with matched pre- and post-NEPC samples. CRPC samples from patients with NEPC (n = 70) were significantly enriched for RB1 alterations (50% vs 12%, p < 10-10, q < 10-10). AR alterations were significantly enriched in CRPC samples from patients without NEPC (n = 380) (63% vs 21%, p < 10-10, q < 1.27*10-8). Further, alterations in numerous genes including TP53, AMER1, ARID5B, YAP1, SOX2, and NKX2.1 were enriched in NEPC patients at the 95% confidence interval (CI) without correction for repeat testing. Matched pre- and post-NEPC samples demonstrated that TP53 alterations in post-NEPC samples are detected in the majority of pre-NEPC samples (8 of 10 patients), but RB1 alterations in post-NEPC samples are detected in a minority of pre-NEPC samples (1 of 8 patients). 54 (3.7%) patients had evidence of early histologic transformation. CRPC samples from these patients (n = 29) were enriched for mutations in RB1, MAP2K2, MUTYH, and CTNNB1 at the 95% CI without correction. FOXA1 mutations were enriched in patients without transformation. Conclusions: RB1, consistent with previous findings, is enriched in NEPC. The inability to detect RB1 alterations in pre-NEPC samples supports divergent evolution, although technical limits of tissue panel sequencing make it difficult to rule out the presence of sub-clonal alterations. Further study of additional genes which contribute to histologic transformation and the development of NEPC is warranted.
Salvage high-dose chemotherapy (HDCT) for relapsed primary mediastinal nonseminomatous germ-cell tumors (PMNSGCT).
Authors: Taza Fadi , Abonour Rafat , Althouse Sandra K. , Ashkar Ryan , Abu Zaid Mohammad Issam , Hanna Nasser H. , Kessler Kenneth A. , Adra Nabil , Einhorn Lawrence H.
Published: June 2022

5032

Background: Patients with PMNSGCT have high relapse rates after first-line therapy. Historical outcomes in this subset with standard-dose salvage chemotherapy or HDCT+bone marrow transplant (BMT) have been poor. The use of peripheral-blood stem-cell transplant (PBSCT) has allowed for more rapid engraftment and the ability to start the 2nd course 3-4 weeks after the 1st course of HDCT. We report survival outcomes of salvage HDCT+PBSCT in relapsed PMNSGCT. Methods: Between 2004-January 2021, 32 pts with relapsed PMNSGCT were treated with HDCT+PBSCTx2 utilizing our institutional regimen: carboplatin 700 mg/m2 + etoposide 750 mg/m2, for 3 consecutive days, followed by PBSCT. Median time between cycle1 day1 to cycle2 day1 was 3.2 wks (range, 2.6-4.6). Kaplan-Meier methods were used for progression-free (PFS) and overall survival (OS) analysis. Results: Median age was 30. At the start of HDCT, median AFP was 192 (range, 4-17130) and hCG 1.5 (range, 0.6-15711). First-line therapy was standard germ cell tumor chemotherapy such as bleomycin-etoposide-cisplatin (BEP) or etoposide-ifosfamide-cisplatin (VIP). HDCT was 2nd line in (26, 81.3%) and 3rd line in (6, 18.8%). Eighteen (56.3%) pts had platinum-refractory disease defined as progression within 4 weeks of 1st line chemo. Twenty-three (72%) patients had extra mediastinal metastases (mets) at the start of HDCT. Metastatic sites included pulmonary (17), lymph nodes (2), liver (3), bone (2), brain (1). Median follow-up time from start of HDCT was 1 yr (range, 0.02-14.1). Twenty-six (81%) pts completed both cycles, while 6 (19%) completed only one cycle due to toxicity or progression. The estimated 2-yr PFS was 30.7 (95% CI, 15.8-46.9) and 2-yr OS was 35.2 (95% CI, 18.9-51.9). At the most recent follow-up, 9 (28%) pts were continuously no evidence of disease (NED), including 2 pts who had surgical resection of teratoma following HDCT. Median follow-up from the start of HDCT for the NED pts was 4.6 yrs (range, 1-14.1). Five of the NED pts had extra mediastinal mets, and 2 had platinum-refractory disease. Among the 9 NED pts, HDCT was 2nd line in 7 (77.8%) and 3rd line in 2 (22.2%). These results compare favorably to historical data with standard-dose chemotherapy or HDCT+BMT in relapsed primary mediastinal GCT with salvage rates < 10% (Hartmann et al., JCO 19:1641-1648, 2001). Grade ≥3 toxicity, as previously described in our study (Adra et al., JCO 35:1096-1102, 2017), occurred in 8 (25%) pts. There were two treatment-related deaths. Conclusions: HDCT+PBSCT is a safe and effective salvage therapy in pts with relapsed PMNSGCT with curative potential. In our opinion, these complicated patients are best managed at tertiary centers with expertise in medical oncology, stem cell transplantation, and thoracic surgical oncology.
Final analysis of the phase 1b/2 study of sabizabulin in men with metastatic castration-resistant prostate cancer who progressed on an androgen receptor targeting agent.
Authors: Markowski Mark Christopher , Eisenberger Mario A. , Pieczonka Christopher Michael , Getzenberg Robert H. , Rodriguez Domingo , Barnette K. Gary , Steiner Mitchell S. , Saltzstein Daniel R. , Antonarakis Emmanuel S. , Tutrone Ronald F.
Published: June 2022

5049

Background: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents. Methods: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose of 63 mg daily. Efficacy was assessed by bone/CT scans. A final analysis of the safety and efficacy data including the primary endpoint, the median progression-free survival was conducted. Results: Although the MTD was not reached in the Phase 1b, the recommended Phase 2 dose was set at 63 mg/day to maximize GI tolerability. The most common adverse events (> 10% frequency) at the 63 mg oral daily dosing (combined Phase 1b/2 data) were predominantly Grade 1-2. Grade ³3 events included diarrhea (7.4%), fatigue (5.6%) and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle (21 days) of 63 mg or higher (n = 55) included an objective response rate of 6/29 (20.7%) in patients with measurable disease (1 complete, 5 partial). 14/48 (29.2%) of the patients had PSA declines. The Kaplan-Meier median radiographic progression-free survival was estimated to be 11.4 months (95% C.I. 29.63-65.79) (n = 55). Durable responses lasting > 2.75 years were observed with 14.5% (8/55) demonstrating a response greater than 12 months. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent. Clinical trial information: NCT03752099.
Activation of the AKT pathway and outcomes in patients (pts) treated with or without ipatasertib (ipat) in metastatic castration-resistant prostate cancer (mCRPC): Next-generation sequencing (NGS) data from the phase III IPATential150 trial.
Authors: Sweeney Christopher , Chi Kim N. , Bracarda Sergio , Sternberg Cora N. , Olmos David , Sandhu Shahneen , Massard Christophe , Matsubara Nobuaki , Nowicka Malgorzata , Selak Bienz Nives , Schenkel Fanny , Chen Geng , Wongchenko Matthew J. , Garcia Josep , De Bono Johann S.
Published: June 2022

5056

Background: Ipat + abiraterone (abi) significantly reduced the risk of radiographic disease progression vs placebo (pbo) + abi in pts with mCRPC and PTEN loss tumors by immunohistochemistry (IHC; HR, 0.77; 95% CI: 0.61, 0.98; P=0.034) but not in ITT pts (HR, 0.84; 95% CI: 0.71, 0.99; P=0.043; Sweeney Lancet 2021). A greater risk reduction was seen in pts with PTEN loss by NGS (HR, 0.65; 95% CI: 0.45, 0.95). We describe the efficacy and safety of pbo + abi vs ipat + abi at the second interim analysis (IA) of overall survival (OS) and explore the impact of AKT pathway alterations. Methods: Pts with mCRPC were randomized 1:1 to ipat (400 mg/d) + abi (1000 mg/d) + prednisone (5 mg bid) or pbo + abi + prednisone. Coprimary endpoints were investigator-assessed radiographic progression-free survival by Prostate Cancer Working Group 3 (PCWG3) criteria in pts with PTEN loss tumors by IHC (PTEN loss in ≥50% of tumor cells) and in ITT pts. Secondary endpoints in both populations included OS, objective response rate (ORR) per RECIST 1.1 and PCWG3 and time to pain progression (TPP). Ad hoc analyses assessed pts with PIK3CA/ AKT1/ PTEN alterations by NGS vs wildtype (WT). Results: Median follow-up was 31 mo (cutoff: 2021 Sept 30). In PTEN loss by IHC pts, median OS was 35.8 mo (n=261) with pbo + abi and 36.8 mo (n=260) with ipat + abi (HR: 0.95; 95% CI: 0.74, 1.21; P=0.665); in ITT pts, median OS was 36.7 mo (n=554) with pbo + abi and 40.3 mo (n=547) with ipat + abi (HR: 0.90; 95% CI: 0.76, 1.07). With longer follow-up, the safety profile was consistent with that of the primary analysis. In the full NGS evaluable population (n=743), ipat + abi was associated with better outcomes in pts with PIK3CA/ AKT1/ PTEN alterations (Table). Among pts with PTEN loss tumors by NGS (205 of the evaluable 518 pts), median OS was 29.8 mo (n=102) with pbo + abi and 35.8 mo (n=103) with ipat + abi (unstratified HR: 0.82; 95% CI: 0.56, 1.19). Conclusions: At the second IA, no significant improvement in OS was observed with ipat + abi in pts with PTEN loss by IHC. Exploratory analyses in pts with PIK3CA/ AKT1/ PTEN alterations by NGS suggest that these patients have poorer prognosis but may derive greater benefit from ipat + abi. Clinical trial information: NCT03072238. [Table: see text]
Efficacy and safety of relugolix in men with advanced prostate cancer based on baseline body mass index (BMI): A subgroup analysis from the randomized, phase 3 HERO study versus leuprolide (LEU).
Authors: Saad Fred , George Daniel J. , Cookson Michael , Saltzstein Daniel , Tutrone Ronald F. , Garnick Marc B. , Brown Bruce , Lu Sophia , Fallick Mark , Hanson Sarah , Crawford E. David , Shore Neal D.
Published: June 2022

5073

Background: BMI has been correlated with adverse prostate cancer outcomes, such as risk of biochemical failure, mortality and androgen deprivation therapy complications. Relugolix is a FDA-approved, once-daily oral GnRH receptor antagonist that has demonstrated superior continuous suppression of testosterone (T) to castrate levels through Week 48 compared to LEU (96.7% vs 88.8%, respectively; Shore N, NEJM 2020;382:2187) in men with advanced prostate cancer (APC). This HERO subgroup analysis looks at the impact of baseline BMI on efficacy and safety. Methods: HERO was a phase 3 randomized, open-label study to evaluate relugolix vs LEU in 930 men with APC. This analysis looked at all men enrolled and treated in the HERO study divided by baseline BMI (BMI subgroups: <25.0 [underweight and healthy weight]; 25.0 – 29.9 [overweight]; and >29.9 [obese]). Assessments included sustained T suppression to castrate levels (<50 ng/dL) from Day 29 through 48 weeks, early T suppression to castrate levels (Day 4 and Day 15), prostate specific antigen (PSA) response (>50% decrease from baseline) at Day 15 with confirmation at Day 29, and profound castration rate (<20 ng/dL) at Day 15. T recovery subset analysis was not included due to low patient numbers. All analyses performed were descriptive. Results: Of the 930 men (relugolix:622; LEU:308) treated in HERO, 287 (30.9%) men had BMI <25, 424 (45.6%) were 25 – 29.9, 219 (23.5%) were >29.9. Sustained castration rates through 48 weeks were higher for the relugolix group than the LEU group and results for select key secondary endpoints were generally consistent across BMI categories, although PSA response proportions were lower in obese patients (table). No differences were noted in the incidence or types of adverse events within treatment groups in the subgroups analyzed. Conclusions: In this HERO study subgroup analysis, relugolix demonstrated greater continuous T suppression than LEU regardless of baseline BMI. Although higher BMI has been associated with poorer outcomes, we did not observe a similar trend with T responses. A numerically lower PSA response was seen in obese patients. Additional research with longer follow-up is warranted. Clinical trial information: NCT03085095. [Table: see text]
Effect of docetaxel (D) use on survival outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with novel hormonal therapies (NHTs): A meta-analysis.
Authors: Guven Deniz Can , Sayegh Nicolas , Tripathi Nishita , Erman Mustafa , Agarwal Neeraj , Swami Umang
Published: June 2022

5079

Background: ARASENS and PEACE-1 trials have shown that the addition of NHTs to D + androgen deprivation therapy (ADT) improves overall survival (OS) outcomes in mCSPC. However, whether a true synergism is present with using NHT+ADT+D is unknown due to the lack of a trial testing the efficacy of adding D to the NHT+ADT backbone. Our objective was to evaluate the survival outcomes with NHTs according to D use in mCSPC. Methods: The literature search was done from PubMed and Embase databases to identify published studies until February 12th, 2022 for meta-analysis. The MeSH search terms were “castration-sensitive prostate cancer” OR “hormone-sensitive prostate cancer” OR “hormone-naïve prostate cancer” AND “abiraterone” OR “apalutamide” OR “enzalutamide” OR “darolutamide”. The target outcome measures were progression-free survival (PFS) and OS. Generic inverse-variance method with a fixed-effects model was used, with hazard ratios with 95% two-sided confidence intervals (CI) as the principal summary measure (Review Manager software, version 5.3, The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). P values below 0.05 were considered statistically significant. Results: The literature search retrieved a total of 2565 records. Six phase III studies encompassing 6701 patients evaluating survival outcomes with NHTs in mCSPC (TITAN, ARCHES, ENZAMET, LATITUDE, STAMPEDE Abi- M1, and PEACE-1) were included after filtering of the available records. Results summarized in below table. In the combined analysis, the addition of NHTs to standard of care (SOC) improved PFS and OS. PFS benefit with NHTs was similar in studies (or study subgroups) with or without D use. However the relative OS benefit with a NHT was higher in studies (or study subgroups) without D than studies permitting D (concurrent or sequential). Conclusions: In this meta-analysis, the PFS and OS benefit with NHT in mCSPC was observed independent of D use. A randomized phase III study comparing D+NHT+ADT with NHT+ADT is needed to evaluate the contribution of D to survival outcomes in patients with mCSPC receiving treatment with NHT+ADT. [Table: see text]
Transcriptomic profiling of patients (pts) with de-novo metastatic castration-sensitive prostate cancer (DN-mCSPC) versus those with mCSPC that have relapsed from prior localized therapy (PLT-mCSPC).
Authors: Sayegh Nicolas , Chigarira Beverly , Hernandez Edgar Javier , McFarland Taylor Ryan , Li Haoran , Sahu Kamal Kant , Tripathi Nishita , Kumar Shruti Adidam , Nordblad Blake , Goel Divyam , Tandar Clara , Yandell Mark , Nussenzveig Roberto , Sirohi Deepika , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj
Published: June 2022

5080

Background: Pts with DN-mCSPC have been reported to experience worse prognosis and outcomes compared to those with PLT-mCSPC. We hypothesized that gene expression profiling of pre-treatment primary prostate tumors from PLT-mCSPC pts would be distinct from those with DN-mCSPC. Methods: Eligibility criteria: histologically confirmed mCSPC and available RNAseq profiling performed by a CLIA certified lab using primary prostate biopsies collected prior to start of treatment. Pts were categorized into two cohorts: PLT-mCSPC versus DN-mCSPC. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) in order to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: Ninety-seven (97) patients met eligibility (52 PLT, 45 de novo). Characteristics of the overall eligible pts: median age = 65, median baseline PSA = 12.6, Gleason score ≥8 = 71%, and high volume of disease = ̃30%. Differential expression and pathway enrichment between cohorts: upregulation of cell-cycle signaling pathways (G2-M checkpoint, E2F) in pts with DN-mCSPC, and upregulation of androgen signaling and immune pathways (inflammatory response, NFKB-mediated TNF-alfa signaling) in pts with PLT-mCSPC (Table). Conclusions: These hypothesis-generating data, upon external validation, may provide the rationale for personalized therapy in men with mCSPC, such as the use of CDK4/6 inhibitors in addition to standard of care intensified ADT in men with DN-mCSPC. [Table: see text]
Diagnosed with advanced prostate cancer: A population-based cohort from national oncology practices.
Authors: Kim Simon P. , Kiani Kayvon , Konety Badrinath , Bronsert Michael , Candelario Nellowe , Kessler Elizabeth R , Gershman Boris , Tyler Robin , Flaig Thomas W.
Published: June 2022

5087

Background: Clinical trials can provide access to novel systemic agents and possible improved survival for men diagnosed with regional and metastatic prostate cancer. Although clinical trials should be accessible to all patient populations, racial disparities to enrollment of clinical trials and its outcomes remain an important unknown outcome. Herein, we sought to elucidate the racial disparities in clinical trial enrollment and survival amongst advanced prostate cancer patients from a large community-based medical oncology consortium. Methods: Using CancerLinQ, we identified all patients who were diagnosed with regional (N1+) and/or metastatic (M1) prostate cancer from 2011 – 2021. Enrollment into a clinical trial and overall survival constituted the primary outcomes in this study. Multivariable logistic regression and Cox proportional hazard regression were used to identify covariates associated with each outcome. Results: Amongst the 160,888 patients with regional/metastatic prostate cancer, only 1.5% patients were enrolled in a clinical trial (n = 2,368). On multivariable analysis, patients with worse ECOG performance status were associated with lowers odds of clinical trial enrollment (p < 0.001). Relative to white patients, African-American men (AAM) also had lower odds of clinical trial enrollment (OR: 0.67; p < 0.001). For the entire cohort, clinical trial enrollment correlated with higher survival (HR: 1.19; p < 001) and lower survival for AAM men (HR: 0.85; p < 0.001) compared to white men after adjusting for other covariates. In the subgroup analysis of patients enrolled in clinical trials, AAM demonstrated similar survival to white patients (HR: 0.96, p = 0.95). Conclusions: Although African-American men with regional/metastatic prostate cancer face barriers to clinical trial enrollment, racial disparities in survival appear to resolve for patients who enroll in clinical trials. Increased attention is needed to address barriers to communication and access to clinical trials.