bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of DKN-01 (D), an anti-DKK1 monoclonal antibody, in combination with gemcitabine (G) and cisplatin (C) in patients (pts) for first-line therapy with advanced biliary tract cancer (BTC).
Authors: Eads Jennifer Rachel , Stein Stacey , El-Khoueiry Anthony B. , Manji Gulam Abbas , Abrams Thomas Adam , Khorana Alok A. , Miksad Rebecca A. , Mahalingam Devalingam , Sirard Cynthia A. , Zhu Andrew X. , Goyal Lipika
Published: September 2018

4075

Background: DKK1 is a secreted modulator of Wnt signaling often expressed in tumors, including BTC. DKK1 expression in BTC is associated with advanced stage and shorter survival. Depletion of DKK1 has efficacy in BTC xenograft models, inhibits cell invasion, and decreases MMP9 and VEGF-C expression, known promoters of metastasis and angiogenesis. D is a humanized monoclonal antibody against DKK1. This study evaluated the safety and efficacy of D in combination with GC in pts with advanced BTC. Methods: In Part A, pts received D at either 150 or 300 mg (and 300 mg D in Part B expansion) with 1000 mg/m2 G and 25 mg/m2 C on days 1 and 8 of each 21-day cycle. Response assessed every 2 cycles using RECISTv1.1. Results: 27 pts were enrolled; 4 dosed at 150 mg and 23 dosed at 300 mg. Median age: 65; Female: 74%; White: 85%. Gallbladder cancer 37%, intrahepatic cholangiocarcinoma 59%. 3 pts had prior G: 2 pts with adjuvant G; 1 pt with 2 prior regimens. Median number of cycles with D: 8 (range 1, 17). Median duration on study 6.8 mos; 8 pts still on therapy. No dose limiting toxicities or D-related serious adverse events have been observed. 24 pts (89%) had grade 3/4 treatment emergent adverse events (TEAEs); events in ≥ 3 pts include: neutropenia (n = 19), leukopenia (n = 9), thrombocytopenia (n = 9), hyperbilirubinemia (n = 6), anemia (n = 5), AST/ALT elevation (n = 4), and ALP elevation, bacteremia, hypertension, and hyponatremia (n = 3 each). The MTD of D + GC was 300 mg. At the MTD; 7 pts had a confirmed partial response (PR), 14 pts had stable disease > 6 weeks, and 1 pt had progressive disease. Both overall and MTD median PFS were 9.4 mos (95% CI 4.6, NE); median overall survival and duration of response were not reached. Conclusions: The addition of D (300 mg) to GC demonstrated a preliminary PFS of 9.4 mos and disease control rate of 96% with a 32% PR rate in pts with BTC. D + GC is well tolerated with no new emerging safety trends. Clinical trial information: NCT02375880.
Final progression-free survival (PFS) analyses for lanreotide autogel/depot 120 mg in metastatic enteropancreatic neuroendocrine tumors (NETs): The CLARINET extension study.
Authors: Wolin Edward M. , Pavel Marianne , Cwikla Jaroslaw B , Phan Alexandria T. , Raderer Markus , Sedlackova Eva , Cadiot Guillaume , Capdevila Jaume , Wall Lucy , Rindi Guido , Lombard-Bohas Catherine , Liyanage Nilani , Thanh Xuan Mai Truong , Ruszniewski Philippe , Caplin Martyn E. ,   CLARINET Investigators
Published: September 2018

4089

Background: In the CLARINET core study, lanreotide Autogel (LAN) 120 mg deep sc monthly significantly improved PFS vs PBO in metastatic grade-1/2 enteropancreatic NETs. An interim analysis of patients with stable disease (SD) in the core study continuing LAN in the open-label extension (OLE, of which safety was primary objective) showed continued antitumor effects. Here, we report final LAN PFS analyses for subgroups according to tumor origin and prior therapy. Methods: In the core study, patients with metastatic well/moderately differentiated non-functioning (N-F) enteropancreatic NETs, Ki-67 <10%, no prior somatostatin-analog treatment and no other prior medical therapies in the previous 6 months were randomized to LAN 120 mg (n=101) or PBO (n=103) for 96 weeks or until death/progressive disease (PD; RECIST 1.0). Patients with SD receiving LAN and any patient receiving PBO could enter a single-arm (LAN) OLE (NCT00842348). Main efficacy endpoint: PFS (time from core-study randomization to death/PD) for core-study intent-to-treat population from Kaplan–Meier survival analysis. Here, PFS was analyzed in subgroups of LAN–LAN patients. Results: OLE final population comprised 89 patients (LAN–LAN 42 [41 with SD]; PBO–LAN 47 [15 with SD]); 38% had pancreatic and 38% midgut NETs. During the OLE, 40% continuing LAN vs 47% switched to LAN had treatment-related adverse events. No new safety concerns were identified. Overall LAN median PFS from the LAN–LAN group was 38.5 months, and varied with tumor origin and prior therapy (Table). Conclusions: CLARINET OLE suggests sustained antitumor effects with LAN 120 mg in enteropancreatic NETs irrespective of tumor origin, and suggests benefits with LAN as early treatment. Clinical trial information: NCT00842348. [Table: see text]
Efficacy of gemcitabine with erlotinib in rash-positive patients selected according to eligibility for FOLFIRINOX.
Authors: Haas Michael , Boeck Stefan Hubert , Siveke Jens T. , Schenk Michael , Lerch Markus , Caca Karel , Freiberg-Richter Jens , Fischer von Weikersthal Ludwig , Kullmann Frank , Reinacher-Schick Anke C. , Fuchs Martin , Ettrich Thomas Jens , Kanzler Stephan , Kunzmann Volker , Kruger Stephan , Westphalen Benedikt , Held Swantje , Heinemann Volker
Published: September 2018

4108

Background: The efficacy and safety of gemcitabine + erlotinib has not yet been defined prospectively in patients (pts) with metastatic pancreatic cancer (mPC) selected according to the inclusion criteria defined by Conroy et al. for FOLFIRINOX (e. g. ECOG 0-1, age < 75, bilirubin < 1.5xULN). Methods: In this German phase II trial, 150 pts with histologically confirmed mPC were recruited between July 2012 and July 2015 in 20 centers. If pts showed skin rash of any grade within 4 weeks after start of treatment with gemcitabine (1000 mg/m2 weekly) and erlotinib (100 mg daily), this regimen was continued; rash-negative pts were switched to FOLFIRINOX. The primary study endpoint was the 1-year survival rate in rash-positive pts (hypothesis: ≥40%). Results: Ninety pts who were under treatment with gemcitabine + erlotinib for 4 weeks developed skin rash of any grade: the 1-year survival rate in those pts positive for skin rash was 40.0% (95%CI 29.8-50.9); median overall survival (OS) counted from day of first treatment was 10.1 months (mo) (95%CI 9.0-12.5), progression-free survival (PFS) 3.9 mo (95%CI 3.5-4.9), objective response rate (ORR) and disease control rate (DCR) were 21% and 64%, respectively. Median treatment duration with gemcitabine+erlotinib was 3.7 mo (Range 0.7-17.5). In rash-negative pts who were switched to FOLFIRINOX after 4 weeks of gemcitabine + erlotinib (n = 28) the 1-year survival rate was 46.4% (95%CI 27.5-66.1), median OS 10.6 mo (95%CI 6.6-13.6), median PFS 5.2 mo (95%CI 2.3-7.9) and the corresponding ORR and DCR rates were 29 and 54%, respectively. The rate of salvage therapy was 53% after gemcitabine+erlotinib, mostly consisting of 5-FU-based schemas (42 % 5-FU/folinic acid + irinotecan or oxaliplatin, 38% FOLFIRINOX) and 43% after FOLFIRINOX (all pts received gemcitabine, 67% in combination with nab-paclitaxel). In the Intention To Treat (ITT) population (n = 145) OS was 9.7 mon (95%CI 7.8-10.9). Conclusions: In rash-positive pts deemed fit for FOLFIRINOX first-line treatment with gemcitabine + erlotinib appears effective achieving a one-year-survival rate of 40%. Early switch to FOLFIRINOX was an effective strategy in rash-negative patients. Clinical trial information: NCT01729481.
Nomogram for predicting overall survival (OS) in patients (pts) treated with nab-paclitaxel (nab-P) plus gemcitabine (Gem) or Gem alone for metastatic pancreatic cancer (MPC).
Authors: Goldstein David , Von Hoff Daniel D. , Chiorean E. Gabriela , Reni Michele , Tabernero Josep , Ramanathan Ramesh K. , Aly Abdalla , Botteman Marc , Wilkersen Julia , Margunato-Debay Sandra , Lu Brian , Louis Chrystal Ursula , Renschler Markus Frederic , McGovern Desmond Micahel Thomas , Lee Chee Khoon
Published: September 2018

4109

Background: Prognostic nomograms have been developed in various cancers, including ovarian, breast, and gastrointestinal; however, there is limited information on nomograms in MPC. The large, phase 3 MPACT study of nab-P + Gem vs Gem alone for the treatment of MPC provides a robust database for the development of a nomogram to predict OS using baseline patient variables. Methods: A multivariable Cox model was created from MPACT data using factors that were significantly predictive of OS in univariable analysis or considered clinically important (stepwise selection to remain in model). From the Cox model, a nomogram was derived that assigned points equal to the weighted sum of relative significance of each variable. The nomogram was internally validated using bootstrapping, a concordance index (c-index), and calibration plots. Results: Data from all 861 pts were used. Seven of the 34 considered variables were retained in the multivariable analysis (Table; all factors significant at the P < 0.01 level, except for analgesic use [ P = 0.07]). The resulting nomogram was able to distinguish low (n = 216), medium (n = 430), and high (n = 215) risk groups (c-index: 0.69; CI: 0.67-0.71) with median OS values of 12.9, 8.2, and 3.7 months, respectively. Calibration curves showed that the nomogram’s predicted probabilities were mostly consistent with observed probabilities for 6-, 9-, and 12-month OS. Conclusions: Treatment arm, Karnofsky performance status (KPS), neutrophil-to-lymphocyte ratio (NLR), albumin level, sum of longest tumor diameters (SLD), and presence of liver metastasis were the key predictors of OS. This nomogram, which will be presented in visual format in the final presentation, may help physicians and pts make informed treatment decisions. Clinical trial information: NCT00844649. [Table: see text]
Single agent HuMab-5B1 (MVT-5873), a monoclonal antibody targeting sLea, in patients with pancreatic cancer and other CA19-9 positive malignancies.
Authors: O'Reilly Eileen Mary , Wang Judy Sing-Zan , Yu Kenneth H. , Lowery Maeve Aine , Varghese Anna M. , Bendell Johanna C. , Borazanci Erkut Hasan , Estrella Hayley , Fowler Kimberly , Hoskin Mariella , Jun H. Toni , Melink Teresa J. , Maffuid Paul , Klein Pamela , Gutheil John , Bauer Todd Michael
Published: September 2018

4110

Background: MVT-5873, a fully human IgG1 monoclonal antibody (mAb), targets sialyl Lewis A (sLea), an epitope on CA19-9. CA19-9 is expressed in pancreatic (PDAC) and other GI cancers, plays a role in tumor adhesion and metastasis, and is a marker of an aggressive tumor phenotype. MVT-5873 is active as a single agent and with chemotherapy in murine xenografts. Methods: MVT-5873 was given IV every other week (Group 1) or weekly (Group 2). Eligible patients had progressive, locally-advanced or metastatic PDAC or other CA19-9+ malignancy and ECOG PS ≤1. Dose escalation followed a 3+3 design with a 10 patient expansion at MTD. Endpoints include safety, MTD, pharmacokinetics (PK) and efficacy. Exploratory endpoints include changes in serum CA19-9 levels. Results: As of 2-Feb 2017, data are available from N = 25 in Groups 1 (N = 9) and 2 (N = 16) at doses ranging from 1 to 3 mg/kg. Dose limiting toxicities of transient grade 3 elevations in AST, ALT, and total bilirubin were encountered at 3 mg/kg in both groups. Liver function laboratory abnormalities typically emerged and resolved within a week of dosing without significant clinical sequelae. Of toxicities deemed possibly related, most were low grade and included GI toxicity (abdominal pain/cramps/diarrhea/nausea) and infusion reactions. Infusion reactions were mitigated by using pre-medications and decreasing the infusion rate. Initial PK data demonstrate initial (20 hours) and terminal (211 hours) half-lives, comparable to other mAbs. Stable disease of > 4 months was observed in 24% of patients. CA19-9 levels were measured pre- and post-dose with each treatment. Immediate reductions showed dose-dependent reductions of up to 97% from baseline at 3 mg/kg. Downward trends of CA19-9 with successive doses were seen, with 48% and 22% of patients exhibiting ≥50% and ≥90% reductions in CA19-9 levels, respectively. Conclusions: Single agent MVT-5873 appears safe and tolerable at biologically active doses. DLTs included reversible serologic liver toxicity. The safety profile, efficacy, and reductions in serum CA19-9 levels over time support further development of MVT-5873 in this indication both as a single agent and in combination. Clinical trial information: NCT02672917.
Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) plus FOLFOX in metastatic pancreatic adenocarcinoma (PDAC).
Authors: Hecht J. Randolph , Falchook Gerald Steven , Patel Manish R. , Aljumaily Raid , Infante Jeffrey R. , Naing Aung , Wong Deborah Jean Lee , Autio Karen A. , Ratti Navneet , Wainberg Zev A. , Bendell Johanna C. , Pant Shubham , Brown Gail Linda , Van Vlasselaer Peter , Oft Martin , Papadopoulos Kyriakos P.
Published: September 2018

4111

Background: Oxaliplatin or nal-irinotecan plus 5-FU are used as 2nd-line PDAC therapy (mOS 5-6 months (m)). PDAC also has been largely refractory to immune therapies which may depend on the expansion of activated, intratumoral, tumor specific cytotoxic CD8+ T cells that are low in most PDACs. AM0010 stimulates survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune activation, durable stable disease and a 1yr survival of 22.5% was seen in salvage PDAC patients (pts) receiving AM0010 alone. Platins or 5-FU may activate immune responses to cancer and AM0010 has shown synergistic anti-tumor results with FOLFOX in preclinical models. In this phase 1b clinical study, the safety and efficacy of AM0010 +FOLFOX was studied in PDAC pts. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated with AM0010 (5ug/kg SQ, qd) + FOLFOX (n = 21), an additional 4 pts with prior oxaliplatin and 5-FU were included in the safety population (n = 25). Tumor responses were assessed using irRC. Serum cytokines, activation of blood derived T cells and peripheral T cell clonality were analyzed. Pretreatment archival tissue samples were evaluated by IHC for tumor infiltration by CD8+ T cells. Results: On AM0010 + FOLFOX, G3/4 TrAEs included thrombocytopenia (52%), anemia (36%) and neutropenia (36%). A modified AM0010 dose schedule (5 days on 2 days off) avoided G3/4 thrombocytopenia. As of 01/31/2017, 2 patients remained on treatment for > 1 year. 19 pts had objective tumor response assessment; 2 had irCR, 1 irPR, 11 irSD. ORR is 15.8%, DCR is 73.7%. With median follow-up of 11.0 m (range 5.8-16.3), mPFS was 3.5 m and mOS 10.0 m. Pts with more intra-tumoral CD8+ T cells had longer OS. AM0010 + FOLFOX increased serum Th1 cytokines and reduced mediators of chronic inflammation and TGFb. AM0010 induced de-novo oligoclonal expansion of T cell clones in patients with prolonged survival. Conclusions: AM0010 plus FOLFOX is well tolerated in patients with PDAC. The observed immune activation including clonal T cell expansion and prolonged objective tumor responses are encouraging in this advanced PDAC population. This regimen is currently being studied in a phase 3 trial. Clinical trial information: NCT02009449.
Adjuvant chemotherapy and outcome in patients (pts) with nodal (N-) and resection margin negative (R0) pancreatic adenocarcinoma (PC): A systematic review and meta-analysis.
Authors: Flaum Nicola , Hubner Richard , Valle Juan W. , Amir Eitan , McNamara Mairead G
Published: September 2018

4114

Background: Adjuvant chemotherapy following PC resection improves overall survival (OS). It is uncertain whether benefit is influenced by nodal and resection status or other factors. Methods: A systematic review of electronic databases identified published phase 2/3 studies investigating use of adjuvant chemotherapy in pts with resected PC. Efficacy (disease-free survival [DFS], OS, 5 yr OS) was explored using meta-analysis. Subgroup analysis explored effects based on nodal/resection status. Meta-regression also explored influence of age, gender, performance status [PS] and proportion of pts with head of pancreas (HOP) tumors on benefit of adjuvant chemotherapy. Results: Ten studies comprising 3644 pts were included. Two prospective phase 2 studies; 8 phase 3 trials. Median age was 63 yrs (range 24-84), 46% male. In 2268 pts with PS reported; 42% were PS 0, 51% PS 1. Tumor location was reported in 719 pts; 82% had HOP tumors. Of 3524 pts with available data; 33% N- and 67% R0. Overall, in studies of experimental vs control, adjuvant therapy significantly improved DFS (HR 0.67, CI 0.48-0.93, P = 0.02), OS (HR 0.77, 95% CI 0.68-0.87, P < 0.001) and odds of death risk at 5 yrs (OR 0.53, 95% CI 0.41-0.70, P < 0.001). In studies comparing chemotherapy to surgery only, adjuvant therapy also significantly improved DFS (HR 0.57, 95% CI 0.49-0.76, P < 0.001) and OS (HR 0.74, 95% CI 0.64-0.87, P < 0.001). There was a numerical but non-significant greater effect of adjuvant therapy in N- vs N+ pts (HR 0.58 vs 0.71, P for difference = 0.29). There was no difference in effect between pts with R0 or R1 disease (HR 0.70 vs 0.69, P for difference = 0.95). There was greater OS benefit from adjuvant therapy in pts with PS 0 (P = 0.04) and significantly less benefit on 5 yr OS in pts with HOP tumors (P = 0.04). Conclusions: The relative benefit of adjuvant chemotherapy seems similar in N-/N+ and in R0/R1 pts. This will translate into greater absolute benefit in the N+ and R1 pts due to their greater absolute risk of recurrence/death. Adjuvant chemotherapy is recommended for all pts with resected PC, where clinically appropriate, and greater benefit was seen in pts with PS 0 and body/tail tumors.
Effect of inflammatory and nutritional (IN) status on induction chemotherapy (CT) followed by chemoradiotherapy (CRT) for locally advanced pancreatic cancer (LAPC): An exploratory subgroup analysis of JCOG1106.
Authors: Mizuno Nobumasa , Fukutomi Akira , Mizusawa Junki , Katayama Hiroshi , Nakamura Satoaki , Ito Yoshinori , Hiraoka Nobuyoshi , Ioka Tatsuya , Ueno Makoto , Ikeda Masafumi , Sugimori Kazuya , Shimizu Kyoko , Okusaka Takuji , Ozaka Masato , Yanagimoto Hiroaki , Nakamori Shoji , Azuma Takeshi , Hosokawa Ayumu , Ishii Hiroshi , Furuse Junji ,   Japan Clinical Oncology Group (JCOG)
Published: September 2018

4123

Background: JCOG1106 is a randomized selection phase 2 trial to evaluate the efficacy and safety of CRT (S-1 concurrent RT) with (Arm B) or without (Arm A) induction CT of gemcitabine (GEM) for LAPC. In the final analysis, we selected Arm A as a promising regimen due to a poorer 2-year overall survival (OS) of Arm B, in spite of a favorable 1-year OS with crossing of the survival curves around 1-year (Ioka, ESMO2016). Therefore, this study aimed to explore subgroups benefit more from either treatment. IN statuses defined by such as serum C-reactive protein (CRP) and serum albumin (Alb) are recognized as prognostic and predictive factors in patients (pts) with various cancers receiving CT or CRT. We hypothesized that IN status may modify the effect of induction CT. Methods: Subjects were all eligible pts who were enrolled in JCOG1106 (n = 51/49 in Arm A/B). Glasgow Prognostic Score (GPS) was classified by baseline CRP and Alb. Pts with a CRP ≤ 10 mg/L and Alb ≥ 35 g/L were allocated to GPS 0, with a CRP > 10 mg/L or Alb < 35 g/L to GPS 1, and with a CRP > 10 mg/L and Alb < 35 g/L to GPS 2. This exploratory subgroup analysis was performed by Cox regression analysis to investigate the impact of IN status at baseline on OS. Less than 0.1 of P-value for interaction was regarded as significant. Results: GPS, CRP and Alb showed significant treatment interactions in terms of OS. HRs of Arm B to Arm A were 1.35 (0.82–2.23) and 0.59 (0.24–1.50) in the GPS 0 (n = 44/34 in Arm A/B) and GPS 1/2 group (n = 7/15) ( P-interaction = 0.06). HRs were 2.57 (1.36–4.86) and 0.70 (0.37–1.32) in the low CRP group (≤ 1.35 mg/L, n = 25/25) and high CRP ( > 1.35 mg/L, n = 26/24) ( P= 0.01). HRs were 1.62 (0.77–3.40), 2.70 (1.17–6.23) and 0.52 (0.24–1.13) in the 1st (≤ 0.7 mg/L, n = 16/16), 2nd ( > 0.7, ≤ 3.0 mg/L, n = 20/16), and 3rd tertiary CRP group ( > 3.0 mg/L, n = 15/17) ( P= 0.01). HRs were 2.29 (1.11–4.69) and 0.89 (0.51–1.54) in the high Alb group ( > 40 g/L, n = 23/17) and low Alb (≤ 40 g/L, n = 28/32) ( P= 0.04). Arm B showed better survival in subgroups of GPS 1/2, higher CRP or lower Alb compared to Arm A. Conclusions: Pts with poor IN status may have treatment benefit of induction CT followed by CRT for LAPC. Clinical trial information: UMIN000006811.
Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma (RCC): Validation of the 16-gene Recurrence Score in stage III patients.
Authors: Escudier Bernard J. , Rini Brian I. , Martini Jean-Francois , Chang Wayne Yen-Hwa , Breza Jan , Magheli Ahmed , Svedman Christer , Lopatin Margarita , Knezevic Dejan , Goddard Audrey D. , English Patricia A , Li Rachel , Lin Xun , Valota Olga , Cartenì Giacomo , Staehler Michael D. , Motzer Robert J. , Ravaud Alain
Published: September 2018

4508

Background: Adjuvant therapy with sunitinib (SU) compared with placebo (PBO) prolonged disease-free survival (DFS) in 615 patients (pts) with high-risk RCC (hazard ratio [HR] 0.76; P= 0.03) in the S-TRAC trial. The 16-gene Recurrence Score (RS) was developed and validated to predict risk of recurrence of RCC after nephrectomy in 2 cohorts of stage I–III pts (Rini et al., Lancet Oncol 2015;16:676-85). We present further validation of RS results in high-risk stage III pts from S-TRAC. Methods: The study was prospectively designed with prespecified genes, algorithm, endpoints, analytical methods, and analysis plan using primary RCC tissues from 212 evaluable pts with informed consent. Gene expression was quantitated by RT-PCR; primary analysis focused on stage III (n = 193 pts). Time to recurrence (TTR) and DFS were analyzed using Cox proportional hazard regression. Results: Baseline characteristics were similar in SU and PBO arms and in pts with and without gene expression data; effect of SU was numerically similar to that in the entire trial (DFS HR 0.78, 95% CI 0.48–1.24; P= 0.29). RS predicted TTR and DFS in both treatment arms with the strongest results observed in PBO arm where high RS group had significantly higher risk (Table). Interaction of RS with treatment was not significant (TTR P= 0.192; DFS P= 0.219); however, the number of events was relatively low. Conclusions: The prognostic value of the 16-gene assay was confirmed in S-TRAC. RS is now validated with consistent results in 2 separate studies (level IB evidence). RS results may help identify patients at high risk who could derive higher absolute benefit from adjuvant treatment. The predictive value of RS to select patients for adjuvant SU requires further investigation in independent adjuvant trials. [Table: see text]
Mismatch repair (MMR) detection in urothelial carcinoma (UC) and correlation with immune checkpoint blockade (ICB) response.
Authors: Iyer Gopa , Audenet Francois , Middha Sumit , Carlo Maria Isabel , Regazzi Ashley Marie , Funt Samuel , Al-Ahmadie Hikmat , Solit David B. , Rosenberg Jonathan E. , Bajorin Dean F.
Published: September 2018

4511

Background: High mutation burden correlates with response to ICB in UC. Loss of function alterations or epigenetic silencing of MMR genes results in MMR deficient (MMR-D) UC, leading to a microsatellite instability (MSI) mutation signature. We used a CLIA-certified pipeline (MSISensor) to interrogate Next Generation sequencing (NGS) data from UC tumors to identify MMR-D patients (pts). We correlated MMR-D with mutation load and response to ICB. Methods: 447 tumors from 424 UC pts underwent prospective NGS using the MSK-IMPACT exon capture assay and genomic interrogation of microsatellite (MS) sites using MSIsensor, which assesses the number/length of MS within the targeted regions of tumor-normal sample pairs. Loci are considered unstable (somatic) if k-mer distributions are significantly different between tumor and matched normal using a standard multiple testing correction of χ2 p-values. The fraction of unstable sites is reported as an MSIsensor score. MSI high tumors have scores >10 while <3 are denoted MS stable. Scores from 3-10 were categorized as MS intermediate. Results: Thirteen pts (3%) had an MSI score >10 and a median mutation count of 52 (36.5-73.5) vs 8 (5-13) in 410 non-MMR-D pts (p<0.01). Ten pts (71%) had upper tract UC. Of 9 pts with germline sequencing performed, 8 (89%) had heritable loss of function mutations in MMR proteins (Lynch syndrome, LS). One pt had a somatic MSH2 mutation. Fifteen pts had MS scores from 3-10: 3 had LS, one a BRCA1 germline alteration, and 9 did not have germline testing available. Two pts with MSI scores <3 had extremely high mutation loads (213 and 414) and both had POLE mutations. Five pts received ICB therapy for metastatic and all achieved near-complete or complete responses. No MMR-D pt has died at 27 months follow-up vs 125 non-MMR-D pts (p=0.014). Conclusions: The MSI Sensor assay can discriminate MSI high from MMR proficient UC. While rare, MMR-D UC is characterized by a high mutation load, strong association with Lynch syndrome, and durable responses to ICB, similar to data in colon cancer. An MMR-D signature should trigger genetic testing for Lynch syndrome. ICB should be considered early in the treatment course of patients with MMR-D metastatic UC.
FDG PET scan (PET) positive residual lesions after chemotherapy (chemo) for metastatic seminoma: Results of an International Global Germ Cell Cancer Group (G3) registry.
Authors: Cathomas Richard , Klingbiel Dirk , Bernard Brandon David , Lorch Anja , Garcia del Muro Xavier , Morelli Franco , De Giorgi Ugo , Fedyanin Mikhail , Oing Christoph , Haugnes Hege Sagstuen , Hentrich Marcus , Fankhauser Christian Daniel , Goncalves Margarida Brito , Cohn-Cedermark Gabriella Elisabeth , Daugaard Gedske , Fornarini Giuseppe , Aurilio Gaetano , Mayer Frank , Huss Katharina , Beyer Joerg
Published: September 2018

4521

Background: Residual disease is a frequent finding after chemo for metastatic seminoma. Watchful waiting is recommended for residual lesions < 3 cm or lesions ≥3 cm with negative PET. Data on the optimal management of PET positive residual lesions is lacking. Methods: A retrospective analysis within the G3 Group identified 91 patients (pts) from 9 countries with metastatic seminoma and residual PET positive lesions after chemo. Pts with elevated AFP ( > 2xULN) or non-seminomatous components at diagnosis were excluded. We analyzed the post PET management chosen and its impact on relapse and survival. Results: Median follow-up was 29 (IQR 10 – 64) months. Median age at diagnosis was 41 (range 19 – 69) years. The primary tumor was gonadal in 68 pts (76%), retroperitoneal in 12 pts (13%) and mediastinal in 10 pts (11%). Prior to chemo the median size of the largest metastasis was 10 (range 1.4 – 23) cm, 67 pts (74%) had elevated LDH and 51 pts (57%) elevated HCG. Median diameter of the largest residual mass was 4.8 (range 1.1 – 14) cm mainly located in the retroperitoneum (77%), pelvis (15%), mediastinum (16%) or lung (4%). Median time from last day of chemo to PET was 7 (IQR 4 – 10) weeks. Post PET management was repeated imaging in 46 pts (51%), resection in 32 pts (35%), biopsy in 9 pts (10%) and radiotherapy in 4 pts (4%). Histology of the resected specimen was necrosis only in 25 (78%) and vital seminoma in 7 cases (22%). No biopsy revealed vital seminoma. Relapses occurred after a median of 3.7 (IQR 2.5 – 4.9) months in 16 pts (18%): 2/9 (22%) after biopsy, 12/46 (26%) on repeated imaging and 2/32 (6%) after resection (one necrosis, one < 10% vital seminoma). Site of relapse was the area of residual disease in 14 pts (88%) and additional distant relapse (one bone, one lung) in 2 pts (12%). All relapsed pts received successful salvage chemo apart from one who died from treatment and two pts who are alive with ongoing treatment. Conclusions: PET positive post chemo residual lesions in seminoma pts are false positive in about 75%. Relapses in PET positive pts occur early and can be salvaged with chemo. Further analysis is needed to identify risk factors for relapse.
Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC).
Authors: Hahn Noah M. , Powles Thomas , Massard Christophe , Arkenau Hendrik-Tobias , Friedlander Terence W. , Hoimes Christopher J. , Lee Jae-Lyun , Ong Michael , Sridhar Srikala S. , Vogelzang Nicholas J. , Fishman Mayer N. , Zhang Jingsong , Srinivas Sandy , Parikh Jigar , Antal Joyce , Jin Xiaoping , Ben Yong , Gupta Ashok Kumar , O'Donnell Peter H.
Published: September 2018

4525

Background: Anti-PD-L1 immunotherapy shows promising clinical activity in UC. We report a planned update of the safety and efficacy of durvalumab in patients (pts) with locally advanced/metastatic UC from a multicenter, phase 1/2 open-label study. Methods: Pts received durvalumab 10 mg/kg every 2 weeks (Q2W) up to 12 months (mo) or until unacceptable toxicity, progression, or starting another anticancer therapy. Primary endpoints were safety and confirmed objective response rate (ORR) by blinded independent central review (RECIST v1.1). Duration of response (DoR), progression-free survival (PFS) and overall survival (OS) were key secondary endpoints. Tumor PD-L1 expression was assessed by Ventana SP263 assay (PD-L1 high = ≥25% PD-L1 expression on tumor or immune cells). Results: As of Oct 24, 2016 (data cutoff [DCO]), 191 pts had received treatment. Median follow-up was 5.78 mo (range, 0.4–25.9). All pts had Stage 4 disease and 99.5% had prior anticancer therapy (95.3% post-platinum). As of DCO, ORR was 17.8% (34/191), including 7 CRs, with responses observed regardless of PD-L1 status (Table). Responses occurred early (median time to response, 1.41 mo) and were durable (median DoR not reached [NR]). Median PFS and OS were 1.5 mo (95% CI, 1.4, 1.9) and 18.2 mo (95% CI, 8.1, not estimable [NE]), respectively; the 1-year OS rate was 55.0% (95% CI, 43.9%, 64.7%). Grade 3/4 treatment-related AEs occurred in 6.8% of pts; grade 3/4 immune-mediated (im)AEs occurred in 4 pts; 2 pts discontinued due to imAEs (acute kidney injury and autoimmune hepatitis). Conclusions: Durvalumab 10 mg/kg Q2W shows favorable clinical activity and an excellent safety profile in locally advanced/metastatic UC pts. Table. Antitumor activity in UC pts, including second-line or greater (≥2L) post-platinum pts Clinical trial information: NCT01693562. [Table: see text]
Safety and efficacy of docetaxel + b-701, a selective inhibitor of FGFR3, in subjects with advanced or metastatic urothelial carcinoma.
Authors: Bellmunt Joaquim , Pal Sumanta K. , Picus Joel , Kohli Manish , Arriaga Yull Edwin , Milowsky Matthew I. , Holash Jocelyn , Ramies David Albert , McGreivy Jesse S.
Published: September 2018

4540

Background: Patients w/ locally advanced or metastatic urothelial carcinoma (UCC) have a poor prognosis. Prior to atezolizumab’s approval, there were no approved treatments (txs) for pts who progressed after chemotherapy. Even w/ immune checkpoint inhibitors, most pts require additional txs. FGFR3 is frequently overexpressed in UCC and 15-20% of pts w/ advanced disease have tumors w/ FGFR3 gene mutations or fusions. B-701 (formerly R3Mab) is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. NCT02401542 is a phase (ph) 1b/2 study designed to evaluate the safety and efficacy of B-701 plus docetaxel (D) in advanced UCC pts. Methods: The study has a lead-in (n=20 pts) and a randomized ph (n=201). Eligible pts: Stage IV UCC, relapsed/refractory to 1 or 2 prior chemotherapy regimens not including taxanes with ECOG 0-1. Txs: B-701 at 25 mg/kg q3w (+ loading dose on C1D8) and D at 75 mg/m2 q3w. Efficacy assessed by RECIST 1.1. Primary obj: PFS and safety. Secondary obj: overall response rate (ORR); duration of response (DOR); disease control rate (DCR); overall survival (OS). Exploratory obj: association of FGFR3 status w/ efficacy and AEs. Results: As of 20 Jan 2017, 19 pts enrolled to lead-in ph w/median age 66 yrs, ECOG 1 58%, Hgb <10 gm/dL 5%, liver mets 26% and ≥ 2 prior regimens 63%. 17 evaluable for PFS/ORR. 5 pts w/ FGFR3 mut or TACC3-fus. Gr ≥3 AEs occurring in ≥2 pts: decreased neutrophils (26.3%), neutropenia (10.5%), decreased WBCs (10.5%). 2 pts had D dose reductions and 1 pt discontinued tx due to AE (disseminated intravascular coagulation). Conclusions: Preliminary results show that B-701 combines safely and effectively with D in UCC, with the combination being well tolerated and showing promising ORR and PFS in pts w/ FGFR3 mut/fus. The protocol has been amended to add Cohorts 2 (B-701+D) and 3 (B-701) (n=20 pts/cohort) for pts w/ FGFR3 mut/fus+ tumors only. Clinical trial information: NCT02401542. [Table: see text]
Prognostic role of circulating tumor cells-CTCs in metastatic renal cell carcinoma.
Authors: Basso Umberto , Facchinetti Antonella , Rossi Elisabetta , Maruzzo Marco , Conteduca Vincenza , Aieta Michele , Massari Francesco , Fraccon Anna Paola , Mucciarini Claudia , Sava Teodoro , Santoni Matteo , Pegoraro Maria Cristina , Durante Emilia , Nicodemo Maurizio , Perin Alessandra , Bearz Alessandra , Pasini Felice , Gatti Carlo , Zamarchi Rita , Zagonel Vittorina ,   CTC in mRCC Investigator Group
Published: September 2018

4568

Background: CTCs can be isolated in peripheral blood of cancer pts and have demonstrated to have prognostic role in several metastatic tumors such as breast, colorectal and prostate cancer. Few data are available for Renal Cell Carcinoma-RCC. Methods: We designed a multicenter prospective observational trial aiming to assess the association between CTC counts and PFS of RCC pts treated with an antiangiogenic tyrosine-kinase inhibitors as a first-line regimen for metastatic disease. OS and response rate were secondary objectives. Both basal and sequential counts were enumerated by Cellsearch system at 4 time points: day 0 of treatment, +1 mo, +3 mo, at progression or 12 mo in the absence of progression. Ethics Committee approval was obtained. Results: Among 246 pts, 195 are eligible for the present analysis, 71.4% males, median age 69 yrs (range, 27 to 91), 81% with previous partial/total nephrectomy. Treatment was sunitinib (77.5%), pazopanib (21%) or sorafenib (1.5%). According to Heng criteria there were 24.6% good, 62.6% intermediate and 24.6% poor prognosis pts. After a median follow-up of 31.5 mo, median PFS is 13.6 mo (23% censored), 49.2% of pts are still alive. Investigator-assessed best response was 3.8% complete, 37.3% partial response, 33% stable, 25.9% progression. At baseline 91 pts had 1 or more CTCs, median 2, range 1 to 263. Pts with at least 1 CTC had a significantly shorter PFS compared to negative pts (8.8 vs 16.6 mo, p = 0.03), HR = 1.41 (95%CI 1.02-1.9). Thirty pts had > = 3 CTCs, with a median PFS of 5.8 vs 15 mo in the remaining pts (p = 0.002), HR = 1.99 (CI 1.28-3.03). Percentage of pts with > = 3 CTCs increased from 6.6% of good, 18.4% intermediate and 38.9% poor Heng score pts (p = 0.042). Pts with > = 3 CTCs had a shorter estimated OS of 13.8 mo vs 52.8 mo (p = 0.003), HR = 1.99 (CI 1,17-3.2). Correlation between CTC positivity and response rate was not significant. Conclusions: In this robust multicenter prospective cohort of first-line metastatic RCC pts, the presence of 3 or more CTCs predicts a significantly shorter PFS and OS. Further analyses are ongoing on apoptotic markers of CTCs and concomitant counts of endothelial cells collected in the same cohort.
Integrative analysis of sarcomatoid clear-cell renal cell carcinomas reveals an immune subgroup.
Authors: Malouf Gabriel G. , Flippot Ronan , Mouawad Roger , Yao Hui , Comperat Eva , Roupret Morgan , Khayat David , Spano Jean-Philippe , Su Xiaoping , Tannir Nizar M.
Published: September 2018

4571

Background: Integrative analysis of clear-cell renal cell carcinomas (ccRCC) has revealed four transcriptomic subgroups associated with distinct patients outcomes. Integrative analysis of sarcomatoid ccRCC which represent the most agressive forms of ccRCC remains unknown. Methods: We performed integrative analysis of sarcomatoid (n = 28) and Fuhrman grade IV ccRCC (n = 9) using whole-exome sequencing (n = 37), RNA-sequencing (n = 32), and DNA methylation profiling by Infinium 450K arrays (n = 31). Correlation with clinico-pathlogical tumor features and patients outcomes were performed. Results: The most frequent somatic mutations in sarcomatoid ccRCC were VHL (71%), PBRM1 (50%), SETD2 (21%), BAP1 (11%), and TP53 (11%). Hierarchical unsupervised clustering of gene expression revealed two transcriptomic subgroups C1 and C2 which do not differ in term of clinical features, presence of sarcomatoid dedifferentiation and patients outcomes. Furthermore, these clusters do not differ according to their genomic features ( VHL, PBRM1 and SETD2 mutations) or their mutational loads. Strikingly, C1 cluster was highly enriched for genes related to T cell receptor signaling pathway (p = 2.6x10-6) and adapative immunity (p = 8.5x10-5); in addition, the C1 « immune » subgroup was characterized by up-regulation of genes related to cell cycle. Conversely, C2 cluster revealed down-regulation of metabolic pathways (p = 7. 5x10-5). At the epigenetic level, methylome clustering revealed two distinct epi-clusters, epi-C1 (n = 10) and epi-C2 (n = 21); patients with tumors belonging to C2 epi-cluster displayed 9p loss and harbored inferior progression-free survival as compared to those in C1 epi-cluster (11 months versus NR ; P = 0.02); of note, this was independent of clinico-pathological tumor features and transcriptomic classification. Conclusions: Our data suggest that genetic and epigenetic landscapes of sarcomatoid ccRCC might not differ from grade IV ccRCC. In addition, we discovered an immune sarcomatoid ccRCC cluster. This finding provides a rationale for use of immune checkpoint inhibitors in sarcomatoid ccRCC.
Safety and efficacy of nivolumab for metastatic renal cell carcinoma (mRCC): Real world data from an Italian expanded access program (EAP).
Authors: De Giorgi Ugo , Scagliarini Sarah , Basso Umberto , Galli Luca , Mosillo Claudia , Caserta Claudia , Rossetti Sabrina , Guida Annalisa , Bearz Alessandra , Buti Sebastiano , Lo Re Giovanni , Valcamonico Francesca , Hamzaj Alketa , Cognetti Francesco , Rastelli Francesca , Fornarini Giuseppe , Porta Camillo , Del Bene Gabriella , Turci Daniele , Procopio Giuseppe ,   Italian EAP RCC Group
Published: September 2018

4577

Background: Nivolumab showed a survival benefit in a randomised phase III trial in pre-treated mRCC. The EAP provided the opportunity to treat patients (pts) in real world clinical practice before market availability of the drug clinical practice. The aim of this analysis was to evaluate the safety and activity of nivolumab in a real world setting. Methods: Nivolumab was available upon physician request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for mRCC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks. Pts included in the analysis had received ≥ 1 dose of nivolumab and were monitored for adverse events using CTCAE v.4.0. Results: Totally, 389 pts were enrolled in the EAP across 95 Italian sites, median age was 65 years (range, 34-85) with 70 (18%) aged ≥ 75 yrs. Pts had a clear-cell RCC in 92% of cases, bone metastases in 50% and brain metastases in 8%, and received more than one previous line in 79% of cases. At the time of this analysis, median number of doses received was 10 (1-31) and 82 (21%) pts were treated beyond progression. Among 389 pts, 18 pts (5%) discontinued treatment due to AE. The best overall response rate was 17% including one complete and 66 partial responses, whereas 121 (31%) had stable disease. With a median follow-up of 7 months (range, 1 to 16), 6-month and 9-month survival rates were 83% and 77%, respectively. Response and survival rates were comparable among pts regardless age, presence of brain or bone metastases and number of prior therapies. Conclusions: This EAP represents the most extensive reported real-world experience with nivolumab in pre-treated RCC pts. These first data seem to confirm efficacy and safety data of the pivotal trial in a real world setting. Results in patient populations poorly (elderly or bone metastases) or not represented at all (brain metastases) in the pivotal trial encourage the use of nivolumab in these subgroups of RCC pts.
Evaluation of disease-free survival as an intermediate metric for overall survival in localized renal cell carcinoma: A trial-level meta-analysis.
Authors: Harshman Lauren Christine , Xie Wanling , Moreira Raphael Brandao , Bosse Dominick , Ruiz Ares Gustavo , Sweeney Christopher , Choueiri Toni K.
Published: September 2018

4585

Background: Adjuvant trials aim to integrate systemic therapy earlier to increase cure rates over surgery alone. Overall survival (OS) is a critical endpoint for these studies but requires long durations to events and significant patient resources. We explored the potential use of disease-free survival (DFS) as an intermediate readout for OS in the adjuvant setting for localized renal cell carcinoma (RCC). Methods: We performed a systematic literature review following the PRISMA guidelines. Inclusion criteria required randomized controlled trials (RCT) for adjuvant systemic therapy in localized RCC, which reported on both DFS and OS. Data on hazard ratio (HR) and 5-year event-free rate from Kaplan-Meier estimates were extracted. We performed a trial level meta-analysis and correlated these estimates for OS and DFS, weighted by the number of DFS events. R-square > 0.7 would indicate a strong correlation and potential for surrogacy. Results: Thirteen RCTs encompassing 6,473 patients treated with various forms of systemic therapy were eligible for the analyses. Minimum follow-up was 40 months. There was a moderate correlation between 5-year DFS and 5-year OS rates (R-square = 0.49, 95% CI:0.15-0.68) and between treatment effects as measured by DFS and OS hazard ratios (R-square = 0.44, 95% CI:0.00-0.69). Conclusions: Across trials of adjuvant systemic therapy for localized RCC, we observed a moderate correlation between 5-year DFS and OS rates and between treatment effects (HRs) on these endpoints. Further granularity may be achieved using individual patient data to assess different and earlier time points for surrogacy than are commonly reported. [Table: see text]
Next-generation sequencing (NGS) of tissue and cell free DNA (cfDNA) to identify somatic and germline alterations in advanced prostate cancer.
Authors: Cheng Michael L. , Abida Wassim , Rathkopf Dana E. , Arcila Maria E. , Barron David , Autio Karen A. , Zehir Ahmet , Danila Daniel Costin , Morris Michael J. , Gopalan Anuradha , Reuter Victor E. , Kantoff Philip W. , Slovin Susan F. , Robson Mark E. , Zhang Liying , Mandelker Diana , Tsui Dana , Taylor Barry S. , Solit David B. , Scher Howard I.
Published: September 2018

5010

Background: With the goal of accelerating enrollment onto appropriate clinical trials, we performed prospective genomic characterization of pts with advanced prostate cancer. Given the long natural history and osseous disease predominance, we also analyzed plasma cfDNA to assess the feasibility of identifying targetable alterations in pts for whom adequate tumor tissue was unavailable. Methods: 1038 tumors from 896 pts along with matched normal DNA were analyzed with a capture-based NGS assay (MSK-IMPACT) targeting 341–468 genes. In 5/2015, the protocol was amended to allow pts to opt-in for a formal germline analysis of 76 genes associated with heritable cancer risk. In select pts, plasma cfDNA was collected and analyzed using the same assay. Results: Between 2/2014 and 2/2017, 576 primary tumors and 462 metastases were sequenced. The most notable finding was the high frequency of known or likely pathogenic germline and somatic mutations in genes that regulate DNA damage response (DDR). In the subset with both tumor and germline analysis, 28.84% (169/586) had a DDR mutation identified compared to only 10.65% (33/310) of pts with somatic only analysis. In the subset with tumor and germline analysis, 9.39% (55/586) had somatic only DDR mutations and 16.38% (96/586) had germline only DDR mutations, including 8 pts with two germline mutations. 3.07% (18/586) had co-occurring somatic and germline DDR mutations, with only 0.68% (4/586) involving the same DDR gene (all BRCA2). Prostate cancer had the highest tissue failure rate among the overall MSK-IMPACT solid tumor cohort, and bone biopsy-derived tissue was successfully sequenced in only 42% of pts. Profiling of cfDNA did identify somatic DDR or AR mutations in 12.5% (4/32) of pts without adequate tumor for analysis. Conclusions: This prospective genomic profiling effort identified frequent somatic and germline DDR mutations that may guide PARPi or platinum therapy. Both somatic and germline analyses were required to identify all pts with likely pathogenic DDR alterations. NGS-based cfDNA analysis is feasible in advanced prostate cancer and may identify mutations missed by tumor only sequencing.
Time to metastasis or death in non-metastatic castrate resistant prostate cancer (nmCRPC) patients by National Comprehensive Cancer Network (NCCN) risk groups.
Authors: Macomson Brian , Lin Jennifer H , Tunceli Ozgur , Behl Ajay S. , Pericone Chris , Deshmukh Siddhant , Shore Neal D.
Published: September 2018

5027

Background: Interventions in nmCRPC are the last defense against metastasis, which drives health care cost and mortality. To assess the value of such interventions we must analyze risk factors for metastasis and death. Methods: This was a retrospective study of data (Optum electronic health record database, 2007 – 2016) from men with a prostate cancer diagnosis, 2 rising PSA levels ≥1 week apart, castrate level ( < 50 ng/dL) testosterone (T) and no ICD-9/10 code or therapy indicating metastasis. Gleason grade (G) and PSA data up to and including nmCRPC index date (ie, date of 2nd PSA rise) were used to assign NCCN risk groups: Low (G ≤6 and PSA < 10 ng/mL), Intermediate (IM) (G = 7 or 10 ≤ PSA ≤ 20 ng/mL) or High (G ≥ 8 or PSA > 20 ng/mL). The LP/NG group comprised men with PSA < 10 ng/mL (LP) and missing G (NG). A Cox proportional hazard model, adjusted for age, race, comorbidity index score, T level, therapy type and bone scans was used to compare LP/NG, IM and High with the Low risk group. Results: Among 1008 men with nmCRPC (mean age 76 years; 12% African American), 553 developed metastases and 430 died during follow-up. Mean time to metastasis was 28, 22, 15, 13 months in the Low, LP/NG, IM, and High groups, respectively. In the Low group, 9 of 29 (31%) men developed metastases, vs 131/285 (46%) in the LP/NG group (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 0.86-3.35), 175/320 (55%) in the IM group (HR = 2.52, 95% CI: 1.28-4.91) and 238/374 (64%) in the High group (HR = 3.63, 95% CI: 1.85-7.10). Mean time to death was 32, 30, 24, 21 months in the Low, LP/NG, IM, High groups, respectively. There were 8 deaths in the Low group (27.6%), vs 101 (35.4%) (HR = 1.35, 95% CI: 0.65-2.79) in the LP/NG group, 124 (38.8%) (HR = 1.79, 95% CI: 0.87-3.70) in the IM group and 197 (52.7%) (HR = 2.96, 95% CI: 1.45-6.05) in the High group. The High risk group was more likely to develop metastasis during the first year and die within the first 2 years. Conclusions: Metastasis and death occurred earlier and more frequently in the Intermediate and High groups relative to the Low risk group. These findings may further inform diagnostic and management strategies for combating disease progression.