bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore.
Authors: De Bono Johann S. , Morris Michael J. , Sartor Oliver , Wei Xiao X. , Fizazi Karim , Herrmann Ken , Piulats Josep M. , Mahammedi Hakim , Logothetis Christopher , George Daniel J. , Eldjerou Lamis K. , Wong Connie , Barys Louise , Rajagopal Nisha , Rodosthenous Theodoulos , Chi Kim N.
Published: June 2024

5008

Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). In this exploratory analysis, associations between baseline circulating tumor DNA (ctDNA) and outcomes were assessed. Methods: Patients were randomized 1:1 to 177Lu-PSMA-617 (7.4 GBq Q6W; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients known to have actionable mutations (e.g. BRCA) were excluded. The primary endpoint was rPFS. Baseline plasma ctDNA was analyzed using a customized 585-gene sequencing assay. ctDNA fraction was assessed in all samples passing quality control. Alterations in key prostate cancer drivers (prevalent in >10% participants) were assessed in samples with ctDNA fraction >1%. Univariate Cox regression (reference: ARPI change) was used to assess association of ctDNA fraction or alterations with rPFS, prostate-specific antigen response (≥50% decline; PSA50) and RECIST response (RR) at the June 21, 2023 data cutoff. Results: Of 360 samples from 468 patients, 255 passed quality control and 156 had ctDNA fraction >1% (median 5.85%; range 0–85). Detection of ctDNA alterations was comparable between arms and with published data. Median rPFS was shorter for patients with ctDNA fraction > versus ≤1% (HR 2.753; 95% CI 1.957–3.872; p<0.0001) (Table); ctDNA fraction >1% was also associated with worse RR and PSA50 response. Median rPFS was shorter for patients with detected versus undetected AR(HR 1.954; 95% CI 1.333–2.865; p<0.001), TP53(1.655; 1.13–2.426; p<0.01) and PTEN(1.62; 1.018–2.578; p<0.05) alterations. Median rPFS was longer with 177Lu-PSMA-617 versus ARPI change in patients with detected AR, TP53, PTEN(Table) , PI3K pathway and DNA repair pathway alterations. There was no significant association between ctDNA alterations and PSA50 or RR. Conclusions: ctDNA fraction >1% and AR, TP53and PTENalterations were associated with worse outcomes in PSMAfore regardless of treatment. Nonetheless, patients with these negative prognostic biomarkers did better with 177Lu-PSMA-617 than with ARPI change. Clinical trial information: NCT04689828 . [Table: see text]
Prognostic PSMA-PET PROMISE nomograms for patients with prostate cancer.
Authors: Fendler Wolfgang Peter , Karpinski Madeleine J. , Hüsing Johannes , Claassen Kevin , Möller Lennart , Kajüter Hiltraud , Oesterling Florian , Grünwald Viktor , Umutlu Lale , Lanzafame Helena , Telli Tugce , Merkel-Jens Anja , Hüsing Anika , Kesch Claudia , Herrmann Ken , Stang Andreas , Hadaschik Boris A.
Published: June 2024

5016

Background: Prostate Specific Membrane Antigen Positron-Emission-Tomography (PSMA-PET) was introduced for prostate cancer staging in 2012. PSMA-PET reported by standardized PROMISE criteria delivers accurate staging with potential prognostic value. Here we assess the prognostic value of PSMA-PET including tumor volume in a large prostate cancer dataset with overall survival follow-up and compare it head-to-head to clinical risk scores. Methods: Prostate cancer patients, who underwent PSMA-PET between October 2014 and December 2019 at the Essen University Hospital, were analyzed retrospectively. We collected PSMA-PET stage using the molecular imaging TNM system (miTNM), tumor volume, SUVmean and overall survival follow-up. The dataset was split into development and validation cohorts (2:1). We created a visual and quantitative nomogram based on Cox regression models with LASSO penalty using the development cohort. Performance of nomograms in the validation cohort were measured using C-index and calibration plots. Head-to-head comparison to clinical risk scores for each staging group was examined using ROC-curves and C-index. Results: The cohort includes 1612 prostate cancer patients across all disease stages with 567 (35.2%) recorded deaths. PSMA-PET based predictors included into the quantitative PSMA-PET nomogram were locoregional lymph node metastases (miN2), distant metastases (miM1a, miM1b pattern, miM1c), tumor volume and tumor SUVmean (Table). The visual nomogram includes distant metastases and total tumor lesion count. Overall C-indices were 0.81 or 0.78 for the quantitative or visual nomogram, respectively. The quantitative PSMA-PET nomogram was superior to STARCAP at initial staging (AUC: 0.72 vs. 0.53; p=0.02), to EAU risk score at BCR (AUC: 0.69 vs. 0.52; p<0.001), and to NCCN groups at any timepoint (AUC: 0.81 vs. 0.73; p<0.001). The visual PSMA-PET nomogram was superior to EAU risk score (AUC: 0.64 vs. 0.52; p<0.001) and NCCN groups (AUC: 0.79 vs. 0.73 p<0.001). Conclusions: Our prognostic PSMA-PET nomograms based on PROMISE criteria were accurate in early and late stages of prostate cancer. Prediction of overall survival was superior when compared to clinical risk tools. Multi-center validation in the PROMISE registry is ongoing. Development cohort (n=1110 patients) univariate regression findings for PROMISE variables included in the quantitative PSMA-PET nomogram for prediction of overall survival.[Table: see text]
68Ga-PSMA PET/CT response and clinical outcomes in patients treated with enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC): Results of a prospective study.
Authors: Giunta Emilio Francesco , Caroli Paola , Scarpi Emanuela , Altavilla Amelia , Marini Irene , Celli Monica , Casadei Chiara , Lolli Cristian , Schepisi Giuseppe , Bleve Sara , Brighi Nicole , Cursano Maria Concetta , Martinelli Giovanni , Matteucci Federica , De Giorgi Ugo
Published: June 2024

5018

Background: 68Ga prostate specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) is a highly sensitive diagnostic tool whose adoption is constantly increasing in prostate cancer patients, also for monitoring response to therapies. We evaluated the impact of 68Ga-PSMA PET/CT response, as compared to prostate-specific antigen (PSA) response, in patients treated with enzalutamide as first-line therapy (1L) for mCRPC. Methods: From Oct 2017 to May 2022, in an observational prospective study, 70 consecutive mCRPC patients were treated with 1L enzalutamide 160 mg QD and underwent 68Ga-PSMA PET/CT within 3 weeks before (baseline) and 12 weeks (SD: ±4 weeks) after treatment initiation. We measured at both the timepoints the sum of metabolic total volume (sMTV), mean and maximum standardized uptake volume (sSUVmean and sSUVmax, respectively) and total lesion activity (sTLA), which is the product of MTV and SUVmean, for a maximum of 20 lesions. On the basis of EAU/EANM criteria, patients were categorized as PSMA responders (PET-R, in case of complete/partial response or stable disease) or PSMA non-responders (PET-NR, in case of progressive disease). Based on prostate-specific antigen (PSA), patients were classified as biochemical responders (PSA-R, in case of PSA decrease ≥ 50%) or non-responders (PSA-NR in all other cases). Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. Results: At the data cut-off (31st Dec 2023), 69 mCRPC patients were considered fully evaluable. The median age was 75 years (range: 47-91), GS was <8 in 24 (35%) and ≥8 in 37 (53%), the median baseline PSA was 2.57 µg/L (range: 0.09-197). We observed a median sSUVmax of 41.6, median SSUVmean of 28.2 and median sTLA of 44.8. The median follow-up was 57 months. In the Table, we reported survival results according to PSA and PET response. Differences between the discordant groups were not statistically significant for both median progression-free survival (mPFS) and median overall survival (mOS) (p=0.09 and 0.41, respectively), even if a positive trend for PET was shown. At multivariate analysis, only sTLA at 12 weeks was significantly associated with both mPFS (p=0.0004) and mOS (p=0.0006). Conclusions: 68Ga-PSMA PET/CT response appeared more accurate than PSA monitoring to predict survival to enzalutamide initiation in mCRPC. Some PET parameters may better predict survival benefit and need future validation. [Table: see text]
Dissecting the significance of ACP1 gene alterations in prostate cancer (PCa).
Authors: Abdallah Nour , Elliott Andrew , Nabhan Chadi , Stanford Stephanie M , Agarwal Neeraj , Bagrodia Aditya , Garje Rohan , Bottini Nunzio Bottini , McKay Rana R.
Published: June 2024

5025

Background: The acid phosphatase 1 ( ACP1) gene encodes low molecular weight protein tyrosine phosphatase (LMPTP), which is overexpressed in PCa. Previous studies demonstrate that LMPTP plays a critical role in PCa growth and metastasis and is evolving as a potential therapeutic target. Thus, we analyzed ACP1 expression in primary and metastatic PCa samples and the association of ACP1 with molecular profiles and clinical outcomes. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed for PCa specimens (n=5028) submitted to Caris Life Sciences. ACP1-High/Low expression was defined as quartile 4 (Q4) and 1 (Q1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for samples stratified by ACP1 expression quartiles. Gene set enrichment analysis was used to assess the Hallmark collection of cancer pathways. Tumor cell PD-L1+ status (≥2+, ≥5%; SP142) was tested by immunohistochemistry. Immune cell fractions in the tumor microenvironment (TME) were estimated by RNA deconvolution using QuanTIseq. Overall survival (OS) was assessed from the time of specimen collection to death or last follow-up, with hazard ratio (HR) calculated using the Cox proportional hazards model, and P values calculated using the log-rank test. Results: Samples included 3058 (60.8%) derived from the prostate, 634 (12.6%) from lymph node metastases (LNM), and 1307 (26.0%) from distant metastases (DM). ACP1 expression was higher in LNM and DM than in the prostate (49.8 and 47.9, respectively, vs 44.1 TPM, p<0.0001 each). TP53 mutations were enriched in the highest ACP1 quartile (37.9% Q4 vs 27.0% Q1, p<0.001) among prostate samples but not LNM or DM. Pathways associated with cell cycle regulation, oxidative phosphorylation, and androgen response were enriched in Q4, while epithelial-mesenchymal transition and TNF-α signaling via NFKB pathways were enriched in Q1. Both neuroendocrine and androgen receptor signaling increased in Q4. M2 macrophages and NK cell fractions were increased, while T cells and M1 macrophages were decreased in Q4. PD-L1 expression did not differ by ACP1 expression. High ACP1 was associated with worse OS among prostate tumors (63.4 vs 86.3 months (mos) in ACP1-high vs low tumors, HR 1.5, 95% CI 1.3-1.7, p<0.0001) and DM (22.0 vs 27.7 mos in ACP1-high vs low tumors, HR 1.2, 95% CI 1.0-1.4, p<0.05) but not LNM (31.9 vs 30.9 mos in ACP1-high vs low tumors, HR 1.0, 95% CI 0.8-1.3, p=0.88). OS from the start of ARSI and taxane chemotherapy was similar in ACP1 high/low groups across prostate, LNM, and DM. Conclusions: In the largest study investigating the significance of ACP1 expression in PCa, we demonstrate that ACP1-high tumors exhibit a distinct molecular profile enriched for TP53 alterations and associated with a ‘cold’ TME. Our findings may provide a rationale for novel therapeutic targeting of ACP1-high tumors.
Metastatic pure seminomas with early relapse: Prognostic roles of high dose chemotherapy and surgery of residual disease.
Authors: Duval Lucile , Allignet Benoît , Chevreau Christine , Gravis Gwenaelle , Mazza Camille , Gross-Goupil Marine , Laguerre Brigitte , Peyrat Patrice , Izarn Floriane , Patrikidou Anna , Flechon Aude
Published: June 2024

5031

Background: Metastatic seminomatous germ cell tumors (mSGCT) are a rare form of cancer. Few studies focused on early relapse (< 12 months) after first-line chemotherapy (ChT). We aimed to evaluate the impact of salvage retroperitoneal lymph node dissection (RPLND), and high-dose ChT with hematopoietic stem cell transplantation (HDCT-HSCT) in mSGCT patients in a situation of early relapse. Methods: Ninety-one mSGCT patients treated between 2005 and 2022 in 7 French expert centers for an early recurrence after an initial favorable response to 1st-line ChT were retrospectively included. Patient clinical characteristics, progression-free survival after first relapse (PFS) and overall survival (OS) were evaluated. We also assessed the role of HDCT-HSCT as first salvage treatment, and the impact of complementary RPLND after salvage ChT. Results: After a median follow-up of 56 months, 3-year PFS and OS rates were 77.6% (95%CI, 68.3-88.1) and 88.4% (95%CI, 81.0-96.4), respectively. HDCT-HSCT was not associated with longer PFS or OS compared to standard-dose 2nd-line ChT. In contrast, patients who underwent RPLND after salvage ChT demonstrated significantly longer PFS (at 3-years: 97.1% vs 63%; HR 0.15; 95%CI 0.03-0.65; p=0.012) and a notable trend towards improved OS (at 3-years: 97.0% vs 81.8%; HR 0.15; 95%CI 0.02-1.23; p=0.078). Conclusions: In mSGCT patients with first-year relapse, RPLND after salvage treatment is correlated with longer PFS and tends to be associated with longer OS. Identification of a subpopulation that might benefit from HDCT-HSCT ought to be performed since it did not confer survival benefits in the overall population.
Prognostic reclassification and survival outcomes in intermediate- and poor-risk nonseminomatous germ cell tumors (NSGCT).
Authors: Jobanputra Kunal Naishadh , Prakash Gagan , Arora Amandeep , Jadhav Bhagyashri , Pal Mahendra , Pawar Akash , Dey Sayak , Bakshi Ganesh , Murthy Vedang , Maitre Priyamvada , Menon Nandini Sharrel , Shah Minit Jalan , Menon Santosh , Popat Palak , Ringe-Katdare Aparna , Sable Nilesh , Agrawal Archi , Noronha Vanita , Prabhash Kumar , Joshi Amit
Published: June 2024

5033

Background: Intermediate and poor-risk nonseminomatous germ cell tumors (NSGCT) form a large group of patients with varying prognosis. There is a need to revisit the existing International Germ Cell Cancer Collaborative Group (IGCCCG) classification to identify the ‘poorest subset’ of patients. Methods: We retrospectively analysed the outcomes of consecutive patients with intermediate and poor-risk NSGCT who were diagnosed between 2015 to 2021 at our centre and had received first-line chemotherapy. Overall survival (OS) and relapse-free survival (RFS) were calculated by Kaplan-Meier analysis. A multivariate risk factor model was constructed out of the prognostic factors for OS and RFS. Concordance statistic (c-statistic) was computed and compared between the proposed model and IGCCCG classification and boot-strap sampling was used to evaluate this comparison. Results: A total of 360 patients were included, having a median age of 29 (IQR: 24-34) years, with 149 in the intermediate-risk and 211 in the poor-risk according to the IGCCCG classification. Most of the patients had testis as the primary site of the tumor (336 patients, 93.3%). Median follow-up was 58.0 months (95%CI 50.7-65.3). The 5-year OS was 84.4% (95%CI 78.5-90.8) in the intermediate-risk versus 55.3% (95%CI 48.4-63.1) in the poor-risk (p < 0.001). RFS at 5 years was 76.8% (95%CI 70.0-84.3) in the intermediate-risk and 46.2% (95%CI 39.7-53.9) in the poor-risk (p < 0.001). Age above 35 years, baseline alpha-fetoprotein (AFP) >10,000 ng/mL, presence of liver and brain metastasis were identified to be poor prognostic risk factors for OS, while lung metastasis in addition to the above factors was prognostic for RFS by multivariate analysis. The multivariate model using the above four risk factors for OS had a higher c-statistic (0.668) than the existing IGCCCG classification (0.632) with an improvement of 0.036 (Table). This model also showed a similar improvement in c-statistic over IGCCCG classification for RFS (0.659 vs 0.625). Conclusions: The proposed model showed better discriminatory ability than the existing IGCCCG classification. This emphasizes the need to revise the risk stratification to identify the ‘very-high risk’ subset of patients for potential treatment intensification.[Table: see text]
Association of tumor genetics with outcomes in patients (pts) with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA-617.
Authors: Panian Justine , Henderson Nicholas , Barata Pedro C. , Bilen Mehmet Asim , Graham Laura , Heath Elisabeth I. , Herchenhorn Daniel , Hwang Clara , Kilari Deepak , Koshkin Vadim S , Nauseef Jones T. , Sokolova Alexandra , Zakharia Yousef , Schweizer Michael Thomas , Dorff Tanya B. , Armstrong Andrew J. , Alva Ajjai Shivaram , McKay Rana R.
Published: June 2024

5050

Background: 177Lu-PSMA-617 is approved for the treatment (tx) of mCRPC. Though tx is associated with improved survival, not all pts experience a benefit. Acquired resistance is common and some pts have intrinsic resistance. There is a lack of data on genomic markers that could aid in selecting pts for tx. In this study, we aim to characterize molecular predictors of benefit to 177Lu-PSMA-617. Methods: We used the retrospective Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database (n=2100). The primary endpoint was to investigate the association of genomic alterations with a ≥50% PSA decline (PSA50) from baseline following 177Lu-PSMA-617. Associations were assessed using Wald-chi square test and Cox regression in multivariable analysis. Secondary endpoints included clinical progression-free survival (PFS) and overall survival (OS). Results: We identified 115 pts with PSMA PET+ mCRPC treated with 177Lu-PSMA-617 who had commercial genetic sequencing prior to tx (median age 72 yrs, 25% non-white). Median number of prior lines for mCRPC was 3 with 71 pts (62%) receiving >1 androgen receptor signaling inhibitor (ARSI) and 55 pts (48%) receiving >1 taxane; 11 pts (9%) received ARSI with 177Lu-PSMA-617. Overall, the PSA50 was 49% with median OS and PFS of 14.0 and 7.6 months (mos), respectively. In pts with a PSA50, median OS and PFS were 22.6 and 11.6 mos, respectively, vs 11.2 and 5.6 mos for those without a PSA50. Genetic alterations associated with PSA50 are in the table. PSA50 was 48% in pts with (n=32) vs 49% in pts without DDR alterations (n=83). PSA50 was 44% in pts with tumor suppressor gene alterations (TSGa) ( PTEN, p53, RB1) (n=68) vs 56% in pts without (n=47). Median PFS was 7.6 vs 7.3 mos for pts with and without any TSGa (p=0.90), and median OS was 12.2 mos vs 22.6 mos for pts with and without TSGa (p=0.004). Of the 43 pts with AR alterations, 8/15 (53%) with LBD mutations, 10/27 (37%) with AR amplification, and 0/1 with AR-V7 had a PSA50. FGFR, CDK12 and MYC alterations were enriched in individuals without a PSA50 (75-83%). Conclusions: We demonstrate that CDK12, MYC and FGFR alterations were associated with a lower PSA50 with 177Lu-PSMA-617. Larger cohorts should be investigated for confirmation, as biomarkers to inform relative benefit of tx could be useful in prioritizing options for mCRPC. [Table: see text]
Real-world comparative effectiveness and cardiovascular safety of enzalutamide versus abiraterone amongst older men diagnosed with metastatic castration-resistant prostate cancer.
Authors: Gaber Charles , Okpara Ebere , Abdelaziz Abdullah , Sarker Jyotirmoy , Hanson Kent , Hassan Lubna , Lin Fang-Ju , Lee Todd , Reizine Natalie Marie
Published: June 2024

5053

Background: Abiraterone and enzalutamide are frequently used in treating metastatic castration-resistant prostate cancer (mCRPC), and their use has expanded to castration-sensitive and non-metastatic settings. The objective of this study was to compare real-world overall survival and risk of major adverse cardiovascular events (MACE) between initiators of abiraterone and enzalutamide in a cohort of older adult men with mCRPC. Methods: The Surveillance Epidemiology and End Results-Medicare database was leveraged to design a comparative observational study. Initiators of abiraterone or enzalutamide between 2011-2017 were identified, a period when both drugs were only approved for mCRPC. Propensity scores and inverse-probability-of-treatment weighting were used to balance measured confounders. MACE was defined as a hospitalization for myocardial infarction, heart failure, or ischemic stroke or transient ischemic attack. Hazard ratios were obtained from weighted Cox proportional hazards (mortality) and Fine-and-Gray models (MACE). Results: The study population consisted of 5,633 men 66 years of age and older diagnosed with mCRPC, of which 3,720 initiated abiraterone and 1,913 enzalutamide. The median age at initiation was 77. Compared to enzalutamide initiators, the overall survival was similar in patients initiating abiraterone at both one-year (mortality hazard ratio (HR) = 1.05; 95% CI: 0.95 – 1.17) and five-years of follow up (HR= 1.01; 95% CI: 0.95 – 1.08). The one-year risk of MACE was higher in abiraterone initiators (HR = 1.30; 95% CI: 1.01 – 1.67). The agents displayed similar effects on MACE when considering a five-year follow-up period after therapy initiation (Table). Conclusions: The long-term comparative effectiveness and cardiovascular safety of abiraterone and enzalutamide were similar, though a short-term increase in MACE was seen in abiraterone initiators, highlighting the importance of considering cardiovascular risk and cancer prognosis during therapy selection.[Table: see text]
Matching-adjusted indirect comparisons (MAICs) of talazoparib plus enzalutamide (TALA+ENZA) versus olaparib plus abiraterone and prednisone/prednisolone (OLAP+AAP) for first-line (1L) therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair mutations (HRRm)/BRCAm.
Authors: Castro Elena , Wang Di , Haltner Anja , Paganelli Stefanie , Niyazov Alexander , Kirker Melissa , Thompson Allison , Samjoo Imtiaz
Published: June 2024

5063

Background: Poly-ADP ribose polymerase inhibitors (PARPi) in combination with a novel hormonal therapy (NHT) have shown benefit for the 1L treatment of mCRPC in an all-comers population as well as HRRm and BRCAm subpopulations (TALA+ENZA [TALAPRO-2; NCT03395197] and OLAP+AAP [PROpel; NCT03732820]). In the absence of head-to-head studies, their comparative efficacy is unknown. The relative efficacy of TALA+ENZA (n=200 HRRm; n=71 BRCAm) vs OLAP+AAP (n=111 HRRm; n=47 BRCAm) in these subpopulations were estimated using MAICs for radiographic progression-free survival (rPFS) based on blinded independent central review and overall survival (OS). Methods: Unanchored MAICs were conducted using individual patient data from TALAPRO-2 Cohort 2 (data cutoff [DCO]: 03/10/22 [rPFS/OS]) and published summary level data from PROpel (DCO: 30/07/21 [rPFS]; 12/10/22 [OS]). To align across the two trials, patients from TALAPRO-2 with specific HRRm/BRCAm (co-occurring or standalone) that were not assessed in PROpel were removed from the dataset for each analysis. TALAPRO-2 patients were also matched based on PROpel’s eligibility criteria and characteristics were adjusted for key prognostic factors identified in the literature and clinical expertise including prior taxane chemotherapy in castration sensitive prostate cancer (CSPC), visceral metastasis, bone only metastasis, Eastern Cooperative Oncology Group score, prostate-specific antigen levels, Gleason score, BRCA1 and BRCA2. Results: After the removal of patients with specific gene mutations not assessed in PROpel and those who received prior NHT in CSPC, 157 and 64 patients remained in the TALA+ENZA arm for HRRm and BRCAm, respectively. The comparative effect estimates for rPFS and OS are presented in the Table. None of the results were statistically significant. Conclusions: These analyses demonstrate numerically favorable results for TALA+ENZA compared to OLAP+AAP highlighting its therapeutic potential in 1L mCRPC for patients with HRRm and BRCAm. Limitations include inability to adjust for all characteristics and biases due to unobserved trial differences. [Table: see text]
Treatment outcomes for patients with Ga68-PSMA-PET prostate cancer (PC) with or without conventional imaging correlates.
Authors: Issa Wadih , Aliru Maureen , Gunenc Damla , Zhang Song , Zhou Qinhan , Qin Qian , Wang Jue , Arafat Waddah , Courtney Kevin Dale , Yang Daniel X. , Desai Neil B , Garant Aurelie , Hannan Raquibul , Cadeddu Jeffrey A. , Gaston Kris , Woldu Solomon L. , Margulis Vitaly , Lotan Yair , Wang Andrew Zhuang , Zhang Tian
Published: June 2024

5078

Background: The high sensitivity of PSMA PET/CT in pts with PC has created a new advanced disease space (PSMA+/CT-) with stage migration. Treatment outcomes and optimal management remain largely unstudied for these pts. Methods: Pts with metastatic castration sensitive PC identified during standard of care PMSA PET/CT imaging (Ga68 gozetotide/PSMA-11) were reviewed retrospectively at UTSW and stratified by whether a CT lesion correlates to a PSMA avid lesion (SUVmax >2.5): PSMA+/CT- vs PSMA+/CT+ groups. The primary objective was PSA Progression Free Survival (PFS) and time to castration resistance (TTCR) between cohorts. The secondary objective was TTCR in pts with PSMA+/CT- disease based on exposure to androgen deprivation therapy (ADT) alone or with AR-targeted therapy (ARTT intensification). Cohorts were compared using a two-sample t-test or a chi-square test; survival analysis was conducted using Kaplan-Meier and Cox proportional hazards regression. Results: Overall,135 pts were included; of whom 122 received ADT (PSMA+/CT- [n=73] vs PSMA+/CT+ [n=49]) and 13 PMSA+/CT- pts received localized treatment only. PSMA+/CT- and PSMA+/CT+ pts had comparable median age at diagnosis and similar racial distribution. The median follow-up was 19 months. In pts who received ADT, the PSMA+/CT- group had a lower median PSA (1.3 vs 14 ng/ml, P=0.0002), a lower rate of de-novo metastatic disease (30% vs 55%, p=0.0082) and ADT+ ARTT use (59% vs 88%, p=0.0006) compared to the PMSA+/CT+ group. Median therapy duration was similar. In pts receiving ADT, the median PSA PFS in the PSMA+/CT- group was not reached (NR) versus 37 months in the PSMA+/CT+ group. After adjusting for known prognostic factors, PSMA+/CT- lesions were significantly associated with a better PSA PFS and TTCR (Table). In pts with PMSA+/CT- receiving ADT alone (n=30) vs ADT+ARTT (n=43), only 1 patient progressed to castration resistance. After adjusting for prognostic factors, pts with PSMA+CT- disease who received ADT had a better PSA PFS [HR 0.1 (0.02-0.45)] compared to those who received localized therapy only (n=13). Conclusions: Pts with PSMA+CT- PC vs pts with PSMA+/CT+ PC have better prognosis and outcomes, with low rates of PSA progression and castration resistance. Localized therapy alone is likely insufficient for these pts, and ARTT intensification to improve longer term outcomes needs prospective studies through ongoing trials. [Table: see text]
Mutational burden among patients with metastatic prostate cancer differs by race in 3 key genes: An analysis of genomic and clinical data from the AACR Project GENIE biopharma collaborative in cBioPortal.
Authors: Arigbede Olumide M. , Gbogbo David , Buxbaum Sarah
Published: June 2024

5106

Background: Prostate cancer exhibits a range of aggressive oncological traits due to its genomic heterogeneity. The extent to which clinical and demographic variables affect cancer behaviors and increase disparities is a complex and open question. Objective: We aim to comprehensively explore the genomic and epigenetic characteristics of metastatic prostate cancer (PCa) across different racial groups to elucidate potential molecular and immune mechanisms underlying disparities in disease progression and treatment response. Methods: Data from the Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR-GENIE) registry to study men diagnosed with PCa was queried. Patients with metastatic disease (n = 1,684) were stratified into three racial groups: White (80.5%), Black (8.1%), and Asian (3.1%). cBioPortal was used to analyze the differences in genetic mutation frequencies by race and to determine the importance of these mutations. The relationships between mutation frequencies and race were examined using chi-squared test. Results: In our study, among patients with metastatic prostate cancer, the following three genes demonstrated the highest differences in frequencies of mutation: TP53, ATR, and PTEN. The most significant differences in mutation frequencies by race in metastatic PCa patients were found in TP53 (White: 3.1%; Black: 16.7%; Asian: 11.8%; P <0.005) and ATR (White: 2.39%; Black: 3.58%; Asian: 4.87%; P = 0.035). PTEN has a metastatic tumor frequency of 6.5% in Asians, 4.2% in Black men, and 7.1% in White men (P = 0.0434). Conclusions: Consistent with previous literature, our study provides new insight into the complex interplay between PCa pathogenesis and progression, paving the way for precision. In the TP53 gene, Black men were more likely than their counterparts to have a higher mutational burden. This research has significant implications for improving health equity in PCa.
Oral cyclophosphamide plus bevacizumab in recurrent ovarian, fallopian tube and primary peritoneal cancer.
Authors: Eyada Mostafa , Michael Victoria , Fellman Bryan M. , Patel Shrina , Soliman Pamela T. , How Jeffrey Andrew , Jazaeri Amir A. , Fleming Nicole D. , Sood Anil K , Westin Shannon Neville , Sims Travis T.
Published: June 2024

5517

Background: The combination of bevacizumab, cyclophosphamide and pembrolizumab is NCCN compendium listed based on a phase 2 trial that lacked a comparison arm. The objective of this study was to assess safety and efficacy of bevacizumab plus oral cyclophosphamide in patients with recurrent high-grade ovarian, fallopian tube and primary peritoneal cancer. Methods: This retrospective analysis included patients with recurrent platinum sensitive or resistant high-grade ovarian cancer treated with oral cyclophosphamide plus bevacizumab at a single institution. Treatment consisted of bevacizumab 15 mg/kg intravenously every 3 weeks in combination with oral cyclophosphamide 50 mg daily. Patients with platinum free interval of 6 months or longer were considered to have a platinum sensitive disease. Objective response rate to chemotherapy (ORR = complete response (CR) + partial response (PR)) was calculated with 95% confidence interval (95% CI). Progression free survival (PFS) was calculated from initiation of chemotherapy to earliest date of progression or death and estimated using the methods of Kaplan and Meier. Adverse events were collected and graded using CTCAE v. 5.0. Results: One hundred patients were identified; 14 (14%) were platinum sensitive and 86 (86%) were platinum resistant. Median age was 58 (38-80). The majority of patients had high-grade serous histology (95%) and stage III or IV at diagnosis (95%). The median number of previous treatments was 3 (range 1-9). Thirty-three patients (33%) received bevacizumab in a prior regimen. A median of 5 (range 2-34) cycles of bevacizumab with daily oral cyclophosphamide were administered. ORR was 40.4% (95% CI: 30.7-50.7) with 4% CR, 36% PR, 20% SD, 39% PD. ORR among patients who received bevacizumab in a prior regimen was 12 (36%) compared to ORR of 24 (42%) among patient who never received bevacizumab in a prior regimen (P = 0.59). The median PFS was 4.6 months (95% CI: 3.42-5.9). There was no relationship between platinum status or platinum free interval and response to this regimen, although the population was predominantly platinum resistant. Seventy-six (76%) of patients had documented adverse events. Most common grade 3-4 toxicities included hypertension (3%), thrombocytopenia (3%), and hemorrhagic cystitis (1%). Conclusions: Bevacizumab in combination with oral cyclophosphamide was well tolerated and active, with a response rate of 40% in patients with recurrent platinum resistant high-grade ovarian cancer.
Value of ctDNA-based molecular residual disease (MRD) in evaluating the adjuvant therapy effect in ovarian cancer.
Authors: Wang Jingjing , Chen Keyao , Guo Yu , He Ying , Cheng Shaochen , Sun Li , Teng Jiaman
Published: June 2024

5525

Background: Ovarian carcinoma (OC) is the fifth leading cause of cancer-related mortality in women worldwide. Circulating tumor DNA (ctDNA) is a promising biomarker for ovarian cancer and can be detected using a noninvasive liquid biopsy. It reflects the status of molecular residual disease and post-surgery therapy effect in real-time. In this study, we examined the concordance of mutations detected in ctDNA samples with those identified in the corresponding tumor specimens of different types of OC. Additionally, investigated whether mutations in plasma ctDNA can provide predictive insight into OC and provide a new perspective on the efficacy of postoperative adjuvant therapy. Methods: Stage I-IV ovarian cancer patients were recruited from 2022.11 to 2023.12. Tumor tissues were collected at excision and then subjected to whole exome sequencing(WES) for comprehensive somatic variant detection in 1000x depth. Personalized tumor-informed molecular residual disease (MRD) panel was designed for up to 40 loci including SNVs and InDELS. Plasma samples were collected at baseline and post-operation adjuvant therapy. Plasma samples performed on ctDNA-based MRD assay underwent 100,000x ultra-deep sequencing. Results: The cohort included 20 patients with high-grade serous carcinomas (HGSC), 5 with borderline tumors, 2 with clear cell carcinoma, 2 with mucinous carcinomas, 2 with endometrioid carcinoma, 1 with low-grade serous carcinomas, and 2 with other types. WES identified 2542 variants in 1906 genes, encompassing 2297 single nucleotide variants (SNVs) and 245 insertions/deletions (InDels), with missense mutations accounting for 84.5% of the major mutations. The most frequently mutated gene was TP53 (76.47%), followed by ZNF285 (44.12%), TTN (29.41%), TOPAZ1 (29.41%), THADA (23.53%), and UBE4A (20.59%). The mutation landscape showed no significant differences among subtypes. The baseline ctDNA detection rate is 88.23% for the entire cohort and 90% for HGSC patients. The consistency between plasma and tissue was verified by Pearson (p=2.7e-6) and Spearman (p=3.7e-7) correlation analyses. All HGSC patients underwent adjuvant therapy post-surgery (up to 8 cycles). 75% (15/20) of HGSC patients achieved complete response (CR), 20% (4/20) achieved partial response (PR), and 5% (1/20) showed progressive disease (PD). MRD monitoring showed a continuous decrease in postoperative ctDNA concentration, with 60% (9/15) of patients achieving MRD negativity. Among the patients with CR, 4 became MRD negative for the first time after surgery and maintained negativity after up to 6 cycles of adjuvant therapy. Conclusions: The results of this real-world study indicate that tumor-informed MRD can serve as a prognostic biomarker for OC, and would provide information about postoperative MRD status and long-term monitoring of adjuvant therapy for further precise treatment.
Molecular characterization of cervical cancer histological subtypes: The VENUS study.
Authors: Braik Dina , Alqaisi Husam , Garg Vikas , Soberanis Pina Pamela , Valente Lage Liana , Veneziani Ana , Grant Brooke , Pannu Anmol Kaur , Lajkosz Katherine , Msan Anthony , Hodgson Anjelica , Rouzbahman Marjan , Stockley Tracy , Bowering Valerie , Grant Robert C , Dhani Neesha C. , Lheureux Stephanie , Oza Amit M.
Published: June 2024

5537

Background: While the landscape of cervical cancer treatment has undergone considerable advances, systemic treatment options following recurrence remain limited. There is paucity of data on predictive and prognostic molecular alterations within distinct histologic subtypes. Methods: In this prospective, translational, single-institution study (NCT03420118), patients diagnosed with cervical cancer were enrolled. Tumor tissue samples (biopsy or archival) were obtained at different time points from initial histological diagnosis to each progression, when feasible. Genomic DNA was extracted and analyzed, using the UHN Hi5 Panel and the Illumina TruSight Oncology 500 assays, to detect molecular alterations. Variant annotations were obtained from OncoKB database. In addition, clinical data for each patient, including histopathologic subtype, stage at diagnosis, and lines of treatment were collected. Results: 124 patients (median age 48 years; range 24-80) with a pathologic diagnosis of cervical cancer were enrolled. Clinical characteristics of patients with available tumor tissue samples (n=112) are detailed in the table. In 99 of the 112 (88.4%) available tumor tissue samples, 243 validated molecular alterations were identified across 88 different genes. Seven tumors had ≥ 5 alterations detected per sample; one squamous cell carcinoma (SCC) and one poorly differentiated adenocarcinoma (AC) had 14 alterations each. PIK3CA, the most frequently detected alteration (41/243; 16.8%), was identified in 22 of 58 (37.9%) SCC samples vs 8 of 38 (21.1%) AC samples (p-value 0.11). Other commonly detected alterations included TP53 (18/243; 7.4%) and KRAS (13/243; 5.3%), both identified more frequently in AC compared to SCC tumor samples (28.9% vs 3.4%; p-value < 0.001, and 23.7% vs 3.4%; p-value 0.006, respectively). KRAS alterations were predominantly G12D or G12V. No G12C variants were detected. All tumors were MSI-stable. Among rare histologic subtypes, unique alterations were detected. Adenosquamous subtypes had alterations of TET2, BARD1, BRAF, in addition to CCND3 and CCNE1amplifications, while neuroendocrine subtypes showed alterations of ATM, MYC, SDHB, TSC1, FANCE, and FGFR1. Overall survival did not show a significant correlation with molecular alterations among different subtypes. Conclusions: Genomic analysis of histologic subtypes of cervical cancer reveals distinctive molecular features which may allow the development of genomic biomarkers of resistance and sensitivity. [Table: see text]
Differences in physical and emotional distress amongst patients undergoing neoadjuvant chemotherapy versus surgery for advanced ovarian cancer: Patient-reported outcomes at diagnosis.
Authors: Mokshagundam Shilpa , McGree Michaela E , Fought Angela J , Ishitani Karen P , Lee Minji K , Kumar Amanika
Published: June 2024

5546

Background: Advanced ovarian cancer (OC) is managed with cytoreductive surgery and platinum-based chemotherapy. Prehabilitation is a multimodal intervention to improve physical and mental health prior to oncologic surgery. This study evaluates baseline differences in clinical characteristics, functional status, and patient-reported outcomes (PROs) between patients undergoing primary cytoreductive surgery (PCS) versus neoadjuvant chemotherapy (NACT) who enrolled in a prospective prehabilitation trial. Methods: This was a single-institution, non-randomized prospective behavioral intervention trial of patients with suspected advanced stage (IIIC/IV) OC. Baseline functional testing included the Short Physical Performance Battery (SPPB), Fried Frailty Index (FFI), gait speed, and grip strength. Patient-Reported Outcomes Measurement Information System (PROMIS) metrics, the Mindfulness Attention Awareness Scale (MAAS), and the Perceived Stress Scale (PSS-10) were used to evaluate PROs. Comparisons between cohorts utilized two-sample t-test or Kruskal Wallis test for continuous variables and chi-square or Fisher’s exact test for categorical variables. T-scores were obtained for PROMIS data using the HealthMeasures Scoring Service; validated cut points for PROMIS, MAAS, and PSS-10 were used for categorization. Results: Amongst the 53 enrolled patients, physical and emotional distress was higher amongst OC patients compared to population means. When compared to PCS patients, NACT patients were more likely to report “severe” in at least one PROMIS domain (emotional distress and anxiety, pain interference, physical function, and fatigue, p<0.01). NACT patients reported significantly higher levels of perceived stress (p<0.01). NACT patients were more likely to have stage IV disease, albumin <3.5 g/dL, and lower gait speed and grip strength (all p<0.01). Despite differences in clinical variables and PROs including physical function, there were no measurable differences in physical function based on SPPB and FFI. Conclusions: Advanced OC patients have high psychosocial needs, with NACT patients reporting severe perceived symptoms on PRO measures. The PSS-10 may be a valuable screening tool for patients undergoing NACT to prioritize supportive care services. Clinical trial information: NCT05047926 . [Table: see text]
First-in-human, phase I study of CBP-1008, a first-in-class bispecific ligand drug conjugate (Bi-XDC), in patients with advanced solid tumors.
Authors: Li Ning , Gong Jifang , Zhang Jian , Liu Dan , Chen Yaqing , Zhang Youzhong , Huang Yi , Wang Jing , Tang Jie , Li Guiling , Wang Ying , Wu Junyan , Luo Suxia , Lou Ge , Duan Wei , Huang Robert , Xu Mo , Hu Xichun , Wu Lingying , Shen Lin
Published: June 2024

5556

Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload and is administered by intravenous infusion Q2W. Methods: This phase 1 study includes the dose-escalation of Ia and the dose-expansion of Ib. The phase Ia started with accelerated titration (0.015, 0.03mg/kg) and then switched to 3+3 design (0.12, 0.15, 0.17, 0.18, 0.20mg/kg). Phase Ib dose-expansion study includes 4 cohorts, platinum-resistant high-grade serous ovarian cancer (HGSOC), other sub-types of ovarian cancer such as clear cell ovarian cancer (OCCC) and low-grade serous ovarian cancer, metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective is to assess the safety and preliminary efficacy. Results: As of December 8, 2023, 240 patients (phase Ia: n=40; phase Ib: n=200) have been enrolled including 136 HGSOC,17 OCCC, 24 TNBC and 63 other tumor types. Majority of adverse events were mild to moderate. Common (≥50%) treatment-related AEs (TRAEs) were neutropenia, WBC decreased, AST increased, pyrexia, ALT increased and nausea. Grade 3/4 TRAEs (≥5%) were neutropenia (49%), WBC decreased (26.8%), AST increased (5.9%), ALT increased (5.9%), anaemia (5.4%). 41 HGSOC patients at dose of 0.15mg/kg with ≤3 prior treatment regimens, regardless of FRα expression levels were evaluable for efficacy assessment. 13 patients achieved partial response (PR) and 29 patients achieved stable disease (SD). The objective response rate (ORR) and the disease control rate (DCR) were 31.7% and 70.7%, respectively. For 19 patients with FRα expression level 0 to 49%, 6 patients achieved PR and ORR was 31.6%. The longest treatment duration exceeds 13 months. Conclusions: The current result showed that CBP-1008 demonstrated manageable safety profile. Promising antitumor activity was observed in ovarian cancer patients at dose of 0.15mg/kg, especially in platinum-resistant HGSOC patients with ≤3 prior treatment regimens. CBP-1008 has the potential to provide a better treatment option for ovarian cancer patients regardless of FRα expression levels. Clinical trial information: NCT04740398 .
Association of physical activity with self-reported quality of life after primary chemotherapy for ovarian cancer.
Authors: Meyer Larissa Alejandra , Schneider Amy K. , Aghajani Haleh , Basabe Maria del Sol , Martinez Leidy Huie , Estrada Gladys M , Iniesta-Donate Maria , Liao Yue , Sun Charlotte C.
Published: June 2024

5574

Background: Patients (pts) with advanced stage ovarian cancer may proceed to maintenance therapy or routine surveillance following primary treatment. As part of a larger research study to assess real world experiences of pts, we explored whether physical activity was associated with self-reported quality of life (QOL). Methods: Pts were asked to wear a wrist health tracker and complete the FACT-Ovarian (FACT-O) survey at baseline and every 3 months for up to 24 months. Total FACT-O score, including well-being subscales for physical (PWB), social (SWB), emotional (EWB), functional (FWB), and ovarian cancer-specific QOL were calculated. Health tracker data corresponding to each FACT-O 7-day recall period were analyzed. Multilevel linear regression analysis examined the relationship between FACT-O and 7-day health tracker data. The potential moderating effect by age (<60 vs. ≥ 60 yrs) was examined. Results: Data were analyzed for 77 pts with 250 total observations. Median age was 59 yrs (range 31, 82); 69% were White (6/53 pts self-identified as Hispanic), 4% Black, 9% Asian, 17% Other (13/14 pts self-identified as Hispanic). Of the 77 pts, 73% were married/partnered; median BMI 25.5; the majority had some college education. Pts completed a mean of 3 FACT-O surveys beyond baseline. Younger pts had better PWB (p<.01) and FWB (p<.01) than older pts, while older pts had better SWB (p<.01). Compared to older pts, younger pts had more daily activity minutes (19.9 vs 10.2, p<.01) and higher step counts (7035 vs 4689.8, p<.01). Apart from SWB and FWB with activity minutes, activity minutes and step counts were positively associated with FACT-O overall and subscale scores (Table). Older pts had stronger positive associations between physical activity minutes and PWB (p<.001), step counts and PWB (p<.001); step counts and FWB (p=.004), while younger pts had stronger positive associations between step counts and ovarian cancer-specific QOL (p=.03). Positive associations between physical activity minutes and SWB (p<.001) and EWB (p=.03), and ovarian cancer-specific QOL with activity minutes (p<.001) were observed only in younger patients. Conclusions: We observed positive associations between health tracker physical activity data and pt-reported QOL. Stronger associations were observed in younger pts. Interventions aimed at increasing physical activity may have broader quality of life benefits for individuals with ovarian cancer. [Table: see text]