bluuebunny/crossref_metadata_2025 huggingface dataset:
Hospital Anxiety and Depression Scale (HADS) score trends among testicular cancer survivors: A longitudinal study.
Authors: Alkhatib Khalid Y. , Roberson Daniel , Talwar Ruchika , Jia Hanna , Nathanson Katherine , Malkowicz S. Bruce , Guzzo Thomas J. , Pierorazio Phillip , Jacobs Linda A. , Vaughn David J.
Published: June 2023

5042

Background: The rarity of testicular germ cell tumors, in conjunction with the young age of its patients, makes it challenging to study its long-term adverse effects. We sought to investigate the changes in Hospital Anxiety and Depression Scale (HADS) scores over time in our institutional cohort of testicular cancer (TC) survivors, hypothesizing that anxiety and depression indices will improve over time, and specifically after treatment completion. Methods: A longitudinal analysis of TC survivors at the University of Pennsylvania between 2013 and 2020, quality of life metrics were measured annually during routine clinic visits. A validated HADS score was utilized to calculate indices of anxiety and depression. Multivariable linear mixed-effects regression models adjusted for pathology type, stage, treatment type, age, marital status, education, income, insurance, employment status, living situation, and time from diagnosis to first survey administration were used to calculate the mean predicted HADS, HADS-Anxiety, and HADS-Depression scores. ANOVA was used to test for parallelism and changes between survey scores. Each item is rated on a 4-point scale (ranging from 0 = no not at all, to 3 = yes definitely), for a total score ranging from 0-21 for each sub-scale with a cut-off point of 8/21 for anxiety or depression. Results: A total of 353 patients were included in the study. Baseline mean scores were 7.3, 4.9, and 2.4 for HADS overall, HADS-Anxiety, and HADS-Depression, respectively. Mean scores did not change over time, ANOVA testing of p=0.84, p=0.78, and p=0.0.65 for overall HADS, HADS-Anxiety, and HADS-Depression, respectively. Stratification by pathology, stage, or treatment did not show any significant interaction. Conclusions: Our data demonstrates that there was no significant change over time in HADS scores, thus considering the risks associated with depression and anxiety, such as suicide, it is essential to consider early referrals to psychiatric services. Our results are from a single institution, limited by a small sample size, and data lacks granularity, including mental health history. Nonetheless, our findings serve as a framework for future prospective studies of TC survivors.
Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study.
Authors: Sager Rebecca A , Spiess Philippe E. , Li Roger , Grivas Petros , Kamat Ashish M. , Necchi Andrea , Pavlick Dean C. , Huang Richard S.P. , Lin Douglas I. , Ross Jeffrey S. , Danziger Natalie , Jacob Joseph M , Bratslavsky Gennady
Published: June 2023

5044

Background: TMB has emerged as a novel biomarker of immune checkpoint inhibitor (ICPI) response in a wide variety of malignancies, but not yet in PSCC. Methods: 397 clinically advanced PSCC underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). TMB was determined on up to 1.1 Mb of sequenced DNA and categorized into three groups: <10 mutations/Megabase [muts/Mb] (low), 10-19 muts/Mb (high), and >20 muts/Mb (very high). MSI was determined on 114 loci. Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and PD-L1 expression by IHC (TPS and Dako 22C3). Statistical comparisons utilized the Bonferonni correction method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases. The mean age of PSCC with very high TMB at 70.1 yrs was older than TMB low at 63.4 yrs (p=.08). The GA per tumor frequencies ranged from 5.4 to 5.5 in the 3 groups. There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% in the TMB 10-19 and 11.8% in the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than TMB low (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. In total, 6.5% of all GA were predicted to be of germline nature. The highest proportions of germline GA were seen for HRR genes ATM and CHEK2 (both 40%) and BRCA2 (37.5%) and PMS2 (40%) linked to Lynch syndrome. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for TMB low, 50.0% for TMB high and 58.8% for TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels reveals significant differences in biomarkers for the near 15% of cases that have TMB ≥10 muts/Mb. TMB and MSI status can also serve as biomarkers of response to SOC anti-PD1 based on the current FDA indications. These data may be useful to provide rationale for inclusion of PSCC in basket or umbrella trials testing novel monotherapies or combination therapies. [Table: see text]
Effects of [177Lu] Lu-PSMA-617 on overall survival in TheraP versus VISION randomized trials: An exploratory analysis.
Authors: Soon Yu Yang , Marschner Ian , Hofman Michael S , Emmett Louise , Davis Ian D. , Stockler Martin R. , Martin Andrew James
Published: June 2023

5045

Background: Observed effects on overall survival (OS) differed in the first two randomized trials (RCTs) of [177Lu] Lu-PSMA-617 (LuPSMA) in metastatic, castration-resistant prostate cancer. TheraP randomized participants to LuPSMA or Cabazitaxel (CBZ). In TheraP, the CBZ group (n = 101) included 20 participants who crossed over to LuPSMA, and the LuPSMA group (n = 99) included 32 who crossed over to CBZ. VISION randomized participants to treatment with or without LuPSMA, plus physicians’ choice among protocol-defined treatments, excluding CBZ. Thirty-eight percent of control group participants in VISION had received CBZ prior to randomization. This study investigated explanations for differences in these RCTs in the observed effects of LuPSMA on OS. Methods: Individual participant data (IPD) on survival time from VISION was extracted from published survival curves for comparison with IPD from TheraP. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighting (IPCW) were used in TheraP to estimate treatment effects on OS in counterfactual analyses assuming crossover had not occurred in either group, or in both groups. Results: OS was longer in the comparator group of TheraP than the comparator group of VISION (HR: 0.57, 95% CI 0.43 - 0.75) while OS was similar in the LuPSMA groups of VISION and TheraP (HR: 0.92, 95% CI 0.70 - 1.19). No significant differences in OS between the LuPSMA and CBZ groups of TheraP were apparent using counterfactual analyses assuming crossovers had not occurred (No crossover from CBZ: RPSFT HR 0.97, 95% CI 0.62 –1.52, IPCW HR 0.92, 95% CI 0.65-1.32; No crossover from LuPSMA: RPSFT HR 0.97, 95% CI 0.60–1.58, IPCW HR 0.82, 95% CI 0.55–1.24; No crossover from LuPSMA or CBZ: RPSFT HR 0.97, 95% CI 0.53-1.74, IPCW HR 0.82, 95% CI 0.53–1.27). Conclusions: The difference in observed effects of LuPSMA on overall survival in TheraP and VISION are better explained by the use of different comparator treatments in their control groups than by crossovers in TheraP from Cabazitaxel to LuPSMA, or LuPMSA to Cabazitaxel. Clinical trial information: NCT03392428 , NCT03511664 .
Concurrent chemo-hormonal therapy of enzalutamide (ENZ) and cabazitaxel (CAB) in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC): Final analysis of objective response rate (ORR), radiographic progression-free survival (rPFS), and overall survival (OS).
Authors: Sokolova Alexandra , Graff Julie N. , Smith Claire E , Beer Tomasz M. , Latour Emile , Grivas Petros , Schweizer Michael Thomas , Higano Celestia S. , Alumkal Joshi J. , Vuky Jacqueline , Yu Evan Y. , Cheng Heather H.
Published: June 2023

5047

Background: We previously reported the PSA response rate and toxicity data of a phase 1/2 single-arm, multi-institutional trial to examine the efficacy and safety of co-administration of ENZ + CAB in mCRPC without prior chemotherapy given in the mCRPC setting. We found that full doses of ENZ (160 mg daily) and CAB (25 mg/m2) were tolerable and that 80% of pts had PSA decline ≥50%. Here, we report the final analysis of ORR, rPFS and OS. Methods: We calculated the ORR (CR/PR) and 95% confidence intervals using the Clopper-Pearson Exact Method. We determined response according to RECIST 1.1 for measurable disease and Prostate Cancer Working Group 2 criteria for non-measurable (bone) disease. We estimated median rPFS (time from the study entry to the time of confirmed progression (radiographic or clinical) or death) and OS (time from the study entry to death) with 95% confidence intervals using the Kaplan-Meier method; data cutoff was 6/1/22. Statistical analysis was performed using R: A language and environment for statistical computing. Results: 37 pts consented and 35 were included in the efficacy analyses (1 withdrew consent, 1 was lost to follow up before efficacy assessment); 7/35 (20%) had prior exposure to chemotherapy given for mHSPC and 9/35 (25%) had prior exposure to abiraterone (ABI), including 2/35 (25.7%) with prior exposure to chemotherapy and ABI. 28 pts had at least one on-study trial imaging study and were evaluable for ORR. After a median follow-up of 23.7 (range: 4.9 to 62.4) months (mo), median OS was 25.1 mo (95%CI 19.4 - 37.6 mo). Median PSA PFS was 11.9 mo (95%CI 9.2 - 15.4), and median rPFS was 22.2 mo (95%CI 13.6 - 25.2). PK assessments revealed that ENZ decreased CAB levels: CAB (monotherapy) Cmax 178.9ng*h/ml vs CAB (in the presence of ENZ) Cmax 85.5 ng*h/ml (p<0.05). Conclusions: The combination of ENZ+CAB in this heterogeneous mCRPC population, which included about a quarter of pts with prior chemotherapy and ABI exposure, resulted in an OS of 22.5 mo comparing favorably with the OS of 25.2 mo seen in the FIRSTANA trial of single agent CAB in docetaxel naïve men, 15.1 mo post chemotherapy in the TROPIC trial, and 13.6 mo in the post-docetaxel, post-ABI in the CARD trial. Of note, the rPFS in this trial was 22.2 months compared to 5.1 months in FIRSTANA suggesting improved efficacy; however cross-trial comparisons are discouraged due to several confounders. Chemo-hormonal therapies and prognostic/predictive biomarkers warrant further study in mCRPC. Clinical trial information: NCT02522715 . [Table: see text]
Real-world safety and effectiveness of radium-223 (223Ra) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated in the US: The non-interventional REASSURE study.
Authors: Song Daniel Y. , George Saby , Zimberg Shawn , Nordquist Luke T. , Tomaszewski Jeffrey , Conti Peter S , Meltzer Jeffrey , Verholen Frank , Schmall Anja , Higano Celestia S. , Sartor A. Oliver
Published: June 2023

5050

Background: 223Ra improved overall survival (OS) and quality of life and demonstrated a favorable safety profile in pts with mCRPC in the phase 3 ALSYMPCA trial. REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of 223Ra use in pts with mCRPC and bone metastases in routine clinical practice. Here, we present clinical outcomes from the second planned interim analysis of REASSURE for pts treated in the US. Methods: This analysis included pts with confirmed mCRPC with bone metastases scheduled to receive 223Ra in the US. All pts received ≥1 dose of 223Ra. Primary endpoints are short- and long-term safety, including incidence of bone marrow suppression and second primary malignancies (SPM). Secondary endpoints included OS and pt-reported pain (Brief Pain Inventory – Short Form [BPI–SF] scores). A clinically meaningful pain response was defined as a decrease from baseline of ≥2 points in BPI-SF worst pain item. Results: Pts were enrolled from 2014–2017. Overall, 498 pts were included in this analysis. At the data cut-off (20 March 2019), the median duration of observation was 11.9 months (0.4–41.3). Most pts (81%) had bone metastases only; 69% of pts received 5–6 223Ra injections. Overall, 77% of pts had received ≥1 prior life-prolonging therapies: abiraterone (45%), enzalutamide (48%), docetaxel (25%), cabazitaxel (6%), or sipuleucel-T (24%). Concomitant enzalutamide was received by 31% of pts, and 47% received concomitant bone health agents. After 223Ra, 31% of pts received ≥1 life prolonging therapies. During treatment, 208/358 (58%) pts with a baseline BPI-SF ≥2 had a clinically meaningful pain response. Any-grade and grade ≥3 drug-related treatment-emergent adverse events (TEAEs) occurred in 32% and 10% of pts, respectively. Drug-related TEAEs resulted in 223Ra discontinuation in 4% of pts. Treatment-emergent and drug-related serious AEs (SAEs) occurred in 21% and 6% of pts, respectively. The most common (>5% of pts) any-grade drug-related TEAEs were diarrhea (10%), fatigue (9%), anemia (8%) and nausea (7%). Overall, 4% of pts had fractures; 2% of pts developed bone disorders. Eleven SPMs occurred in 10 pts (2%). In total, 60% of pts died during study follow-up. Median OS was 17.8 months (95% CI 15.6–19.4). Conclusions: Within the current treatment landscape in routine clinical practice in the US, median OS after 223Ra treatment was close to 18 months. A majority of pts completed 5–6 223Ra injections. The known safety profile of 223Ra was confirmed with no new safety signals. Over half of pts with pain at baseline had a clinically meaningful pain response during 223Ra treatment. Clinical trial information: NCT02141438 .
The effect of a reduced dose of enzalutamide on fatigue and cognition.
Authors: Overbeek Joanneke , Boerrigter Emmy , Benoist Guillemette Emma , Somford Diederik Meindert , Hamberg Paul , Tol Jolien , Scholtes Brian , Willemsen Annelieke E.C.A.B. , Buffart Laurien M , Kessels Roy P.C. , Mehra Niven , van Oort Inge M. , Van Erp Nielka P.
Published: June 2023

5051

Background: Enzalutamide (ENZA) is a highly effective treatment for patients (pts) with metastatic prostate cancer, but central nervous system (CNS)-associated side effects occur frequently and may hamper the quality of life. These side effects are addressed with dose reductions, while they potentially can be prevented by starting at a reduced dose, since androgen receptor saturation is already observed at dose levels above 60 mg once daily (OD) and ENZA plasma concentrations > 5 mg/L. We hypothesized that a lower starting dose of ENZA can reduce the risk of CNS side effects in frail pts while preserving efficacy. In this study (NCT03927391) the effect of a reduced dose of ENZA on fatigue and cognitive side effects is determined. Methods: This randomized multi-center trial compared the ENZA standard dose of 160 mg OD to the reduced dose of 120 mg OD in frail prostate cancer pts. At baseline, and 6, 12, and 24 weeks after start of ENZA, fatigue and cognitive side effects were measured by the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) and Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) questionnaires. A change in scores of 3.0 for the FACIT-F and 7.0 for the FACT-Cog was considered clinically relevant. Linear mixed effects models were used to study within and between-group differences in fatigue and cognitive side effects over time. Furthermore, ENZA plasma concentrations were measured after 6, 12, and 24 weeks of treatment and PSA response (>50% PSA decline) was compared between the two dosing regimens. Results: A total of 51 pts were included (25 reduced dose, 26 standard dose). Completion rates for the questionnaires were high throughout the study (>90%). Pts treated at the reduced dose showed no significant changes in FACIT-F and FACT-Cog scores over time. Pts treated at the standard dose showed increasingly worse FACIT-F and FACT-Cog scores. This resulted in clinically relevant and statistically significant better FACIT-F and FACT-Cog scores for pts treated at the reduced dose compared to pts treated at the standard dose after 24 weeks (table). All pts had therapeutic ENZA concentrations (>5 mg/L) throughout the study. PSA response did not differ between both groups (87% for 120mg OD vs 80% for 160mg OD, p=0.796). Conclusions: By starting with a reduced dose of ENZA of 120mg OD CNS side effects can be prevented, which might beneficially affect the quality of life of frail prostate cancer pts, without any indication of interference with efficacy endpoints. Clinical trial information: NCT03927391 . [Table: see text]
Final results of a pilot study of docetaxel and carboplatin for treatment of patients with mCRPC containing biallelic inactivation of genes in the homologous recombination DNA repair pathway.
Authors: Raychaudhuri Ruben , DeJong Makayla , Yu Evan Y. , Gulati Roman , Rettig Matthew , Nelson Peter , Pritchard Colin C. , Montgomery Robert Bruce , Cheng Heather H.
Published: June 2023

5054

Background: Inactivating mutations in genes important in homologous recombination DNA repair (HRD) are present in the tumors of ~25% of patients with metastatic castration resistant prostate cancer (mCRPC). These alterations are associated with more aggressive disease but may also predict vulnerability to DNA damaging agents. We previously reported promising interim results from a single arm, Phase 1/2 trial studying the combination of the DNA damaging agent carboplatin with docetaxel for patients with mCRPC containing HRD mutations. Here we report final results after completing accrual and two additional years of follow up. Methods: We assessed response to the combination of docetaxel 60mg/m2 and carboplatin AUC 5 IV q21 days in patients with mCRPC whose tumors had evidence of biallelic inactivation of genes involved in HRD and who had progressed on any prior treatment, including docetaxel and/or PARP inhibitor (PARPi). The primary endpoint was the proportion of patients who achieved ≥50% PSA decline from baseline (PSA50). With H0 of PSA50 of 26%, 14 patients provided 80% power to conclude H1 of PSA50 of 60% based on Simon's 2-stage design with 1-sided α = 5%. The secondary endpoints included PSA30, response duration, progression-free survival (PFS), and overall survival (OS). Results: The trial opened in Jan 2016 and completed in Sep 2021. A total of 16 patients were treated on study, including 6 who had previously received PARPi and 5 who had received docetaxel. 11/16 patients (69%) achieved PSA50. 7/9 patients (78%) with biallelic inactivation of BRCA2 (7), BRCA1 (1), or PALB2 (1) achieved PSA50. Other biallelic inactivated HRD-related genes were ATM (1), CHD1 (1), CDK12 (3), MRE11A (1), and NBN (1). Of these patients, 4/7 (57%) achieved PSA50. Notably, 3/6 patients (50%) previously treated with PARPi therapy achieved PSA50. The median PFS was 8.4 months, and the median OS was 2 years. 6/16 patients (38%) had grade 3 AEs, most commonly thrombocytopenia (25%) and anemia (13%). One patient (6%) had a grade 4 AE (thrombocytopenia). Conclusions: The addition of carboplatin to docetaxel significantly improved response rates in patients with mCRPC with biallelic inactivation in genes involved in the HRD pathway. Responses were also seen in patients who had previously received PARPi. The combination was relatively safe and well-tolerated. The encouraging activity and favorable toxicity profile observed here merits further investigation. Additional work is ongoing to further refine biomarkers predictive of treatment response and resistance. Clinical trial information: NCT02598895 .
Tumor heterogeneity and treatment response assessment using next generation imaging and liquid biopsy in patients with metastatic castration resistant prostate cancer receiving abiraterone (ANGELA): A single-center prospective observational trial.
Authors: Zhu Yao , Wu Junlong , Pan Jian , Wang Beihe , Wei Yu , Ye Ding-Wei
Published: June 2023

5057

Background: Metastatic castration resistant prostate cancer (mCRPC) is a disease of intra-patient tumor heterogeneity which poses obstacles in treatment and response evaluation. With the development of next generation imaging (NGI) and liquid biopsy, precise assessment of heterogeneity has entered a new era. In this study, we used longitudinal NGI (68Ga-PSMA and 18F-FDG PET/CT) and circulating tumor DNA (ctDNA) testing to assess tumor heterogeneity and treatment response in mCRPC patients receiving abiraterone. Methods: ANGELA is a single-center prospective observational trial (NCT05188911). We recruited mCRPC patients who received abiraterone as initial hormonal treatment. Eligible patients should have a life expectancy >12 months. CtDNA testing and NGI were performed at baseline and after 12 weeks of abiraterone (Week 13). Conventional imaging and PSA testing were performed at Week 1 and every 12 weeks. Primary end-point of this study is intra-patient lesion heterogeneity evaluated by 3 dimensions: (1) Imaging heterogeneity: defined as at least 1 lesion with FDG+/PSMA- phenotype at baseline and/or Week 13; (2) Genomic heterogeneity: quantified by ctDNA fraction increase and mutational changes per gene between baseline and Week 13; (3) Response heterogeneity: defined as at least 1 new tumoral lesion with either PSMA or FDG abnormal uptake at Week 13. Secondary end-points are correlations of heterogeneity with conventional-evaluated progression-free survival (PFS) and 2-year overall survival (OS). Results: Between May 20, 2020 and Feb 02, 2021, we included 33 eligible patients in our study. FDG+/PSMA- tumoral lesion was observed in 7/33 (21.2%) and 8/33 (24.2%) of patients at baseline and Week 13, respectively. Notably, 5 of 8 patients with imaging heterogeneity at Week 13 had no FDG+/PSMA- lesion at baseline. For genomic heterogeneity, we detected ctDNA fraction increase in 4/33 patients (12.1%). In addition, we found new gene mutations detected in Week 13 ctDNA testing in 5/33 patients (15.2%), 2 of 5 had ctDNA fraction increase. For response heterogeneity, we observed 15/33 patients (45.5%) patients developed at least 1 new tumoral lesion (FDG+ or PSMA+) at Week 13. We correlated heterogeneity factors with prognosis, and found that detection of new mutated genes (P=0.005 and P<0.001), new PSMA+ lesion (P<0.001 and P<0.001), and new FDG+ lesion (P=0.008 and P<0.0001) at Week 13 were significant predictors of shorter PFS and decreased 2-year OS. Detailed biomarker study for response analysis is still in process. Conclusions: Intra-patient tumor heterogeneity was common among mCRPC patients receiving abiraterone. Combining liquid biopsy with NGI can monitor changes in tumor heterogeneity and indicate early combination therapy. Clinical trial information: NCT05188911 .
Early changes of PSMA PET signal after initiation of androgen receptor signaling inhibitors in mCRPC: An international multicenter retrospective study.
Authors: Unterrainer Lena , Farolfi Andrea , Rosar Florian , Denis Chloé Santina , Emmett Louise , de Kouchkovsky Ivan , Hope Thomas A. , Hotta Masatoshi , Gafita Andrei , Djaileb Loic , Czernin Johannes , Calais Jeremie
Published: June 2023

5063

Background: Androgen receptor signaling inhibitors (ARSi) play a relevant role in the treatment of prostate cancer. A potential influence of ARSi on PSMA expression has been described. We evaluated early changes of PSMA-expression by PET in mCRPC patients. Methods: This retrospective study included 5 international sites. Patients with mCRPC undergoing 68Ga-PSMA-11 PET/CT prior to (PET1) and early after ARSi (PET2 within 29 days maximum) were included. Whole-body (WB) PSMA-positive tumor volume (PSMA-TV) was evaluated using a liver-specific semi-automatically threshold (Affinity 3.0.2, Hermes Medical Solutions). WB PSMA-TV, SUVmean and SUVmax and their respective changes (%) were analyzed. PSA changes between PET 1 and PET2 were evaluated. Median values and ranges are provided. Results: 54 patients were included in the analysis. ARSi was initiated 1 day (range 0 – 28) after PET1 while PET2 was performed 14 days (range 7 – 29) after ARSi initiation. PSA at PET1 and PET2 was 9.5 ng/ml (range 0.2 – 490.0) and 8.7 ng/ml (range 0.1 – 732.0), respectively (p = 0.035): -33.0% (range -98% – +496%). The WB PSMA-TV at PET1 and PET2 was 89.9 ml (0.0 – 3097.0) and 112.2 ml (0.0 – 3133.0) ml, respectively (p = 0.016; change of +6.0% (range -88% – +260%). WB PSMA SUVmean and SUVmax at PET1 and PET2 was 9.0 (range 5.0 – 43.7) and 9.3 (range 0.0 – 42.5) and 26.5 (range 0.0 – 125.0) and 28.5 (range 0.0 – 212.0), respectively (p = 0.194 and p = 0.353): % change of +3 % (-85% – +71%) and 0% (-55% – +232%). Four of 7 patients with PSA increases at PET2 had an increasing PSMA-TV, 6/7 showed an increasing SUVmean and 5/7 presented with an increased SUVmax. Decreasing WB-PSMA-TV in 18/54 (33%) patients was accompanied by decreasing SUVs in 10 of them (56%). Percent PSA change was unrelated to changes in PSMA-TV, SUVmean and SUVmax. Conclusions: PSMA-PET performed early after ARSI revealed slight increases in the WB-PSMA-TV, stable WB-PSMA SUVs while serum PSA decreased in most of the patients. We conclude that ARSi does not have a strong effect on PSMA expression within 30 days after treatment initiation. [Table: see text]
Genomic alterations and self-reported Agent Orange exposure in United States veterans with metastatic prostate cancer.
Authors: Zhang JJ Haijing , Wadhwa Ananta , Weiner Adam B , Kwan Lorna , Kelley Michael J. , Chamie Karim , Maxwell Kara Noelle , Garraway Isla
Published: June 2023

5068

Background: Agent Orange has been posited as an environmental risk factor for prostate cancer among United States Veterans. Prior studies have shown that Veterans with Agent Orange exposure are diagnosed at a younger age and at more advanced clinical stages. It is unknown if there are differences in somatic alterations among Veterans exposed to Agent Orange. Methods: Genomic alterations were identified from clinical tumor testing conducted from 2019 – 2022 in a large cohort of Veterans with metastatic prostate cancer diagnosed from 2001 – 2022. Primary prostate and metastatic carcinoma tissue specimens were submitted for Foundation Medicine tumor-only sequencing. Baseline demographics, clinical, and genomic alterations data were stratified by Veteran self-reported exposure to Agent Orange in accordance with an institutional review board approved protocol. Results: Of the 2673 Veterans with metastatic prostate cancer who underwent tumor-only genomic testing, 629 reported exposure to Agent Orange and 2044 were not exposed. After verification of military service records of Veterans with self-reported Agent Orange exposure to include only Veterans who served in the Vietnam War between 1962 – 1975 and Korean War between 1967 – 1971, 603 patients with self-reported Agent Orange exposure (22.8%) and 2044 without exposure (77.2%) were included in the analysis. On univariate analysis, TMPRSS2-ERG fusions were significantly more frequent in men who reported exposure to Agent Orange (35.3% vs 28.8%, p<0.01) after multiple hypothesis testing with Benjamini-Hochberg. Agent Orange exposure also correlated to higher rates of androgen receptor ( AR) alterations (12.4% vs 9.5%, p=0.04) and FGFR1/2/3/4 alterations (3.2% vs 1.7%, p=0.02). There were no significant differences in alterations by Agent Orange exposure in TP53, CDK12, ERBB2, EGFR, BRCA, and genes implicated in the DNA damage response and repair (DDR), mismatch repair (MMR), and PTEN/PI3K/AKT pathways. On multivariable analysis controlling for race, age at diagnosis, smoking, secondary malignancies, and environment, only alterations in AR (OR 1.43, p=0.02) remained more frequent in Veterans exposed to Agent Orange. As expected, age at diagnosis (OR 0.98, p <0.001) and Black/African-American race (OR 0.33, p<0.001) were associated with decreased odds of TMPRSS2-ERG alterations. Conclusions: Agent Orange exposure may contribute to tumor somatic alterations in Veterans with prostate cancer. These findings hold potential prognostic and therapeutic implications for U.S. Veterans with metastatic prostate cancer. [Table: see text]
Differential tumor gene expression profiling of obese and non-obese patients (pts) with prostatic adenocarcinoma (PC).
Authors: Mathew Thomas Vinay , Chigarira Beverly , Gebrael Georges , Sayegh Nicolas , Tripathi Nishita , Nussenzveig Roberto , Sahu Kamal Kant , Li Haoran , Fortuna Gliceida Galarza , Tandar Clara , Goel Divyam , Brundage James , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj
Published: June 2023

5075

Background: Increased baseline body mass index (BMI) has been linked to poorer prostate cancer outcomes, including recurrence, reduced quality of life, and mortality (PMID: 21325564, 17211863). Herein, we sought to interrogate and validate the corresponding differences in tumor gene expression profiles of obese (Ob) vs. non-obese (N-Ob) pts with PC. Methods: In this IRB-approved retrospective study, eligibility criteria included histologically confirmed PC and available RNA sequencing results from treatment naïve primary prostate tissue from a CLIA-certified lab (either Tempus or Caris Life Sciences). Tempus cohort was used for interrogation and Caris for validation. Pts in each cohort were categorized into two groups: obese (BMI≥30) and non-obese (BMI<30). BMI at the time of diagnosis of PC was used for analysis. 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) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: Tempus cohort: n=60 (Ob =22, N-Ob=38); Caris cohort: n=50 (Ob=17, N-Ob=33). Both Tempus and Caris showed that Ob pts had an increased expression of the heme metabolism, androgen response, protein secretion, fatty acid, and bile metabolism pathways. N-Ob pts had a significantly higher expression of genes involved in the inflammation pathways (interferon-alpha & TNF alpha pathways). Normalized enrichment scores are reported in the table. Differential gene set expression analysis in Ob vs. N-Ob pts with PC. Conclusions: Our study showed an upregulation of distinct genomic pathways in Ob pts with prostate cancer. For example, Ob pts with PC have tumors that depend more on androgen signaling, and N-Ob pts' tumors express increased inflammatory pathway genes that promote PC growth, invasiveness, and metastasis. After external validation, these hypothesis-generating data may provide the rationale for personalized therapy in men with PC. [Table: see text]
Baseline circulating tumor cell (CTC) count as a prognostic marker of overall survival (OS) in metastatic hormone sensitive prostate cancer (mHSPC): Results from SWOG S1216, a phase III randomized trial of androgen deprivation plus orteronel (cyp17 inhibitor) or bicalutamide.
Authors: Goldkorn Amir , Tangen Catherine , Plets Melissa , Bsteh Daniel , Xu Tong , Pinski Jacek K. , Ingles Sue , Triche Timothy Junius , MacVicar Gary R. , Vaena Daniel A. , Crispino Anthony W. , McConkey David James , Lara Primo N , Hussain Maha H. A. , Quinn David I. , Dorff Tanya B. , Thompson Ian , Agarwal Neeraj ,   SWOG GU Committee
Published: June 2023

5080

Background: Biomarkers are needed to predict clinical outcomes in mHSPC. We previously reported that baseline CTC counts in S1216 were prognostic of PSA response and disease progression ( ASCO 2020; CCR 2021). However, the trial’s primary overall survival (OS) endpoint was not yet mature at that time. Here we present the final results of S1216 using all available samples to assess the prognostic value of CTC counts for response, progression, OS, and treatment arm interactions. Methods: In S1216, peripheral blood was drawn with informed consent at registration (baseline) and at progression to metastatic castrate resistant prostate cancer (mCRPC). CTCs were enumerated on the FDA-cleared CellSearch platform (Menarini). CTC counts were evaluated for associations with 3 pre-specified trial endpoints: 7-month PSA (7mPSA) ≤ 0.2 ng/ml vs. 0.2–4.0 vs. > 4.0 using a generalized logit model; and progression-free survival (PFS) and OS using Cox regression. Results: From 2014 to 2021, 503 evaluable samples were collected at baseline and 93 at progression. Baseline CTC count was ≥5 in 11.9% of samples, 1-4 in 19.3%, and 0 in 66.8%. Comparing men with 0 vs. ≥5 CTCs at baseline, those with 0 CTCs were significantly more likely to attain a complete PSA response and had significantly lower risk of a PFS event and death after adjusting for clinical covariates (disease burden, bone metastases, age, race, alkaline phosphatase, hemoglobin, PSA, treatment arm). These associations were not modified by treatment arm. Progression CTCs <5 vs. ≥5 also were prognostic of OS (logrank p=0.001), consistent with prior findings in mCRPC. Same-patient CTC counts in matched baseline-progression pairs (n=61) were highly correlated (Spearman p<0.001). Conclusions: CTC count at the start of treatment for mHSPC was highly prognostic of PSA response, PFS, and OS; associations that held in both treatment arms. Moreover, baseline CTC count strongly correlated with progression count, suggesting that mild vs. aggressive disease phenotypes may persist from mHSPC to mCRPC. This evidence from a large prospective phase 3 trial suggests that baseline CTC count is a valuable prognostic marker in men initiating therapy for mHSPC, discriminating those likely to experience favorable vs. unfavorable response and OS. [Table: see text]
Cost-effectiveness analysis (CEA) of seven treatment regimens in metastatic hormone-sensitive prostate cancer (mHSPC): A public payer perspective using network meta-analysis.
Authors: Kohli Manish , Dougherty Maura , Cutshall Zachary , Beckstead Rylee , Kohli Rhea , Haaland Benjamin , Nelson Richard , Yoo Minkyoung
Published: June 2023

5081

Background: Recently several new drug treatment regimens have been approved in mHSPC state, building on using androgen deprivation therapy (ADT) alone. These include docetaxel + ADT (DA), Abiraterone Acetate + Prednisone + ADT (AAP), Apalutamide + ADT (AAT), Enzalutamide + ADT (ET), Darolutamide + Docetaxel + ADT (DAD) and AAP + ADT + Docetaxel (AAD). At present, there are no predictive biomarkers for choosing a specific drug regimen over the other. The goal of this study was to conduct an economic evaluation of FDA-approved standard of care drug regimens in the current management of mHSPC state to determine a cost-effective optimal treatment from the US public sector (Veterans Affairs-VA) perspective with a 10-year time horizon. Methods: We developed a partitioned survival model in which mHSPC patients (pts) transitioned between three health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a network meta-analysis. A Bayesian network meta-analysis of seven randomized clinical trials included 7,208 mHSPC pts. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values obtained from published literature. Costs in our model included those associated with treatment regimens, subsequent therapies, terminal care, and for managing grade 3-4 drug related adverse events. Costs were obtained from the Federal Supply Schedule and published literature. Incremental cost-effectiveness ratios (ICERs) were calculated for nondominated treatments. Results: Average 10-year costs ranged from $32,697 (ADT) to $649,622 (DAD). Mean QALYs ranged from 3.25 (ADT) to 4.57 (ET). Treatment with DAT, EAD, and DAD were eliminated due to dominance (i.e. they were more costly and less effective than other treatments). AAT was the most cost-effective strategy at a willingness-to-pay threshold of $100,000/QALY (ICER = $70,150/QALY). Results from our analysis for all regimens are shown. Conclusions: Our CEA simulation model found AAT is an optimal cost-effective first-line treatment strategy in mHSPC state from a public (VA) payer perspective. [Table: see text]
Landscape and impact of germline pathogenic variants (PVs) in metastatic hormone sensitive prostate cancer (mHSPC): Ancillary study of E3805 CHAARTED.
Authors: Hamid Anis , Chinsky Tyler M , Vergara Matias , Grist Emily , Attard Gerhardt , Van Allen Eliezer Mendel , Aldubayan Saud , Sweeney Christopher
Published: June 2023

5082

Background: Enrichment of germline PVs in metastatic castration resistant prostate cancer (mCRPC), compared to localized disease, has directly informed genetic testing guidelines. The prevalence and prognostic/predictive associations of such variants are not well characterized in the mHSPC state, in particular the effect of susceptibility mutations related to DNA damage and repair (DDR) pathways. Methods: We performed whole exome sequencing of germline DNA derived from whole blood available from patients (pts) in the phase III CHAARTED trial (NCT00309985) of androgen deprivation therapy (ADT) versus ADT plus docetaxel (ADT+D). After filtering for low coverage, variant annotation and effect prediction, PVs from a curated list of 588 prostate cancer-associated genes were reviewed. The prognostic effect of PVs was evaluated within each treatment arm. Endpoints of time to CRPC (ttCRPC), time to clinical progression (ttClinPD), and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models evaluating association of endpoints with biomarkers/arm. Multivariable analysis adjusted for metastatic timing and volume. Results: Of 137 pts, 135 had unique germline exomes that passed downstream analysis. Most pts had synchronous (66.7%) and high-volume (62.2%) disease. This biomarker cohort showed benefit of adding docetaxel to ADT (ttCRPC: HR 0.55, 95% CI 0.37-0.82; OS: HR 0.68, 95% CI 0.44-1.07). In total, 61 PVs were detected; 49 pts (36.3%) harbored at least 1 PV in 41 different genes. The most frequently-mutated gene was BRCA2 (6.67%). In addition, PVs were found in DDR-associated genes including PALB2 (1.48%), CHEK2 (1.48%), BRCA1 (0.74%) and PMS2 (0.74%) for an overall prevalence of 11.1% (15/135). Pts with BRCA2 PV on ADT alone had shorter ttCRPC compared with men without the PV (UVA: HR 2.67, 95% CI 0.93-7.63, log rank p=0.057; MVA: HR 2.59, 95% CI 0.91-7.39, p=0.074). There was no evidence of a difference in the ADT+D arm (UVA: HR 1.00, 95% CI 0.31-3.25, log rank p=0.1). Supportive data was observed for ttClinPD in ADT arm (HR 2.85, 95% CI 1.01-8.08, log rank p=0.04). Metastatic volume and timing were not significantly associated with germline BRCA1/2 or DDR PVs. Conclusions: The prevalence of germline BRCA1/2 and DDR PVs in mHSPC is similar to mCRPC and BRCA2 PV may confer worse outcomes on ADT alone. This supports the need for genetic testing at diagnosis of mHSPC. [Table: see text]
The role of volume of disease for treatment selection in patients with metastatic castration sensitive prostate cancer (mCSPC): A living meta-analysis.
Authors: Naqvi Syed Arsalan Ahmed , Riaz Irbaz Bin , He Huan , Imran Manal , Orme Jacob , Childs Daniel S , Ravi Praful , Hussain Syed A. , Singh Parminder , Bryce Alan Haruo
Published: June 2023

5088

Background: Previous evidence suggests that there may be no additional benefit of triplet therapy in low volume disease based on limited data. Therefore, we investigated the efficacy of triplet therapy as compared to docetaxel (D) and androgen pathway inhibitor (API) doublets by volume of disease using the most up to date results from the ARASENS trial. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with API, and/or D in patients with mCSPC were included. Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for OS were pooled using an inverse-variance approach. A DerSimonian-Laird random-effects meta-analysis was conducted to assess the efficacy of triplet therapy compared to D doublet therapy. P-value of interaction was computed to assess difference between high (HV) and low volume (LV) disease subgroups (Pint <0.1 - statistical significance). Additionally mixed treatment comparisons were computed using network meta-analysis (NMA) to assess the comparative effectiveness of triplet therapy compared to API doublets by volume of disease. Results: Pairwise meta-analysis included a total of 3 RCTs (ARASENS, PEACE-1, ENZAMET) with 2518 patients (HV: 1820; LV: 698) as shown. In patients with HV disease, 385 (43%) and 484 (53%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in HV (HR: 0.73; 95% CI: 0.64-0.84). In patients with LV disease, 73 (20%) and 94 (28%) deaths were observed with triplet therapy, and D doublet, respectively. Triplet therapy significantly improved OS as compared to D doublet in LV (HR: 0.71; 95% CI: 0.52-0.97). There was no statistically significant interaction by volume of disease for triplet therapy vs. D doublet (Pint: 0.86). NMA including 10 clinical trials and over 11500 patients updated as of 13th Feb 2023 showed that in HV mCSPC, triplet therapy was ranked as potentially the most efficacious treatment option and may improve OS compared to API doublet therapy (HR: 0.83; 95% CI: 0.66-1.03). In LV mCSPC, API doublet therapy was ranked as potentially the most efficacious treatment followed by triplet therapy. There was no significant difference between triplet therapy and API doublet therapy (HR: 1.12; 95% CI: 0.74-1.12). Conclusions: These results underscore that triplet therapy may be preferred in mCSPC patients with HV disease whereas API doublet therapy may be preferred in LV disease. [Table: see text]
Socio-demographic, clinical, and genetic predictors of low versus high Gleason score among men with prostate cancer in the Detroit Research on Cancer Survivorship (ROCS) cohort.
Authors: Goodenow Samantha , Cackowski Frank Cameron , Heath Elisabeth I. , Ruterbusch Julie J. , Dyson Greg , Beebe-Dimmer Jennifer Lynn , Simon Michael S.
Published: June 2023

5092

Background: Black men with prostate cancer typically present with a higher Gleason Score (GS) and more aggressive disease than White men. The purpose of this project is to describe the relationship between socio-demographic, clinical and genomic variability with GS categories among 599 men with prostate cancer in the Detroit Research on Cancer Survivorship (ROCS) cohort. Methods: Detroit ROCS is a cohort of Black cancer survivors based in the Detroit Metropolitan area. Patient data was obtained from a self-administered questionnaire, cancer registry and biologic samples were collected through at home phlebotomy or mailed saliva kits. The primary analysis focused on clinical and genetic differences between men with GS ≤ 6 vs. ≥ 7. Germline data was compiled into the multi-ethnic genotyping array (MEGA) data panel and 21 genes were chosen for analysis (2,393 SNPS) based on their clinical applicability. Eight tools were used in ANNOtate VARiation (ANNOVAR) to determine whether a genetic variant was pathogenic. The determination of pathogenicity was defined by at least seven of the tools indicating variant pathogenicity. We assessed the rate of pathogenic variants for each GS category. Multivariable models of predictors of GS categories were conducted using logistic regression. Results: The categories across GS in the ROCS cohort included: ≤ 6 (21.2%), 3+4 (40.4%), 4+3 (20.2%) and ≥ 8 (18.2%). Variables associated with increased GS (≥ 7 vs. ≤ 6) included age (for each 10-year increase the OR was 1.71, 95% CI 1.26-2.34) and body mass index (for each 5 unit increase the OR was 1.27, 95% 1.06-1.54). Higher vs. lower education (some college education or higher vs less than or equal to a high school education) was associated with lower GS, OR 0.58, 95% CI 0.37-0.96. Out of a total of 2,393 SNPs analyzed, 880 (36.8%) were polymorphic, of which 684 had a minor allele frequency (MAF) >0.001, and 282 had a MAF >0.05. Overall, 16.2% of the men were carriers of a pathogenic variant, the most common of which were ATR (9.3%), FANCL (3.5%), and ATM (1.7). Men with GS 6 had a lower rate of pathogenic variants (8.7%), than those with GS 3+4 (18.2%), GS 4+3 (16.5%), and GS 8 (20.2%). Men with a pathogenic variant in ATR were 2.87 (95% CI 1.08- 7.65) times more likely to have GS ≥ 7 vs. ≤ 6. Higher GS was specifically associated with SNP rs33972295 in the ATR gene. Conclusions: The relationship between older age, higher BMI, and less educational background suggests that sociodemographic risk factors should be accounted for when assessing risk for higher grade prostate cancer. Identification of genomic differences associated with aggressive prostate cancer may provide insight into new targeted therapy options.
Prognosis and trends in chemotherapy use for patients with stage IA triple-negative breast cancer (TNBC): A population-based study.
Authors: Tarantino Paolo , Leone Julieta , Vallejo Carlos Teodoro , Freedman Rachel A. , Waks Adrienne Gropper , Martínez-Sáez Olga , Garrido-Castro Ana Christina , Lynce Filipa , Tayob Nabihah , Lin Nancy U. , Tolaney Sara M. , Leone Jose Pablo
Published: June 2023

510

Background: Outcomes for patients with stage IA TNBC in the modern era remain poorly characterized, and the benefit and utilization of adjuvant chemotherapy (chemo) in this setting remains controversial. Methods: We analyzed data from women diagnosed with pathological stage IA TNBC in the Surveillance, Epidemiology, and End Results (SEER) database during 2010 to 2019. We evaluated the associations of adjuvant chemo with breast-cancer specific survival (BCSS) stratified by tumor size, using multivariate cox models adjusted for tumor size (overall cohort only), age at diagnosis, race, tumor grade, histology, radiation, marital status, income, and rurality. Frequency of chemo use over time was examined by tumor size. Multivariate logistic regression assessed variables associated with chemo administration. Results: In total, we examined data from 8,601 women with stage IA TNBC. Median age at diagnosis was 62 years. Most patients had high-grade tumors (70.1%), ductal histology (92.8%), and received adjuvant chemo (61.6%). Median follow up was 48 months (IQR: 20 – 83). The use of chemo significantly increased during 2010-2019 for both T1b tumors (p for trend = 0.001) and T1c tumors (p for trend < 0.001), with 52.5% and 63% of the patients with T1b and T1c TNBCs receiving chemo in 2010, respectively, compared with 60.5% and 71.1% in 2019. No significant differences were observed in the use of chemo for T1mic (p for trend = 0.567) and T1a (p for trend = 0.637) tumors, with low utilization seen in both cohorts (9.5% overall in T1mic, 22.5% overall in T1a). Variables associated with chemo use included younger age, white race, married status, higher income, more recent diagnosis, higher tumor grade, ductal histology, and larger tumor size (all p < 0.02). Overall, 5-year BCSS was high across T groups ( > 90%; Table). Receiving chemo (vs. none/unknown) was associated with an improved 5-year BCSS (adjusted HR for BCSS = 0.70, p = 0.006). For T1c tumors specifically, adjuvant chemo (vs. none/unknown) was also associated with BCSS (adjusted HR 0.64, p = 0.002). The small number of BCSS events precluded comparisons for other tumor size subgroups. Table shows sample sizes and 5-year BCSS rate by chemo receipt for each T group. Conclusions: In a large population-based cohort of patients with stage IA TNBC, we observed excellent 5-year BCSS outcomes, supporting the good prognosis of this patient population. The use of adjuvant chemo increased over time for T1b and T1c TNBCs, and was associated with improved BCSS for T1c tumors, although evaluation of benefit is limited by the inherent treatment bias in registry data. [Table: see text]