tbuckley/cabot-search huggingface dataset:
Cardiovascular medications and overall survival in metastatic hormone-sensitive prostate cancer.
Authors: Kara Ingram, Carley Pickett, Daniel B. Eaton, Steven Tohmasi, Krishny Karunanandaa, Deepika Gopukumar, Varun Puri, Martin W. Schoen
Journal: Journal of Clinical Oncology (2024)

75 Background: The assessment of comorbid cardiovascular disease can predict health outcomes and may risk-stratify patients for adverse events and death. Current methods used to estimate patient risk, such as the Charlson Comorbidity Index (CCI), are based on International Classification of Diseases (ICD) codes, which are a poor indicator of severity and complexity of comorbid disease. Alternatively, the number of cardiovascular drugs could be an efficient tool for estimating patient risk. In this study, we examined the relationship between cardiovascular medications and survival in patients being treated for metastatic hormone-sensitive prostate cancer (mHSPC). Methods: A nationwide retrospective observational study of US Veterans with de novo mHSPC in the Veterans Health Administration between 2011-2021 with at least 1 prescription medicine of any class. We determined the number of cardiovascular drugs from Anatomic Therapeutic Chemical (ATC) drug class C prescribed in the year prior up to 14 days before initiation of treatment. Multivariable logistic regression and Cox proportional hazard modeling was used to assess the association between number of drugs with overall survival (OS) while accounting for important covariates including age, body-mass index (BMI), prostate specific antigen (PSA), CCI, race, and weight change. Results: Among 7,875 veterans, a median (IQR) of 2 (1-4) unique cardiovascular medications were filled in the year prior to treatment. The mean age was 74.3 years (SD 10.0) with a median CCI of 3 (3-6). Age was associated with increased number of cardiac medicines with a mean of 1.6 drugs in &lt;60 years, 2.2 drugs in 60-69, 2.5 drugs in 70-80, and 2.5 drugs in 80+ years (p&lt;0.001). Increased number of medications was associated with decreased OS using the Kaplan-Meier method (p&lt;0.001, see table). After adjusting for age, race, BMI, weight change, PSA, and CCI, the number of medications was independently associated with increased mortality with an adjusted hazard ratio (aHR) of 1.05 (1.03-1.06) for each additional cardiac drug. Increased mortality was observed in patients treated with 2 or more cardiac drugs (see table). Conclusions: The number of cardiovascular medications is associated with decreased survival in veterans undergoing treatment for mHSPC, even after accounting for important covariates including age, BMI, PSA, and CCI. The assessment of cardiovascular medications may provide a simple and reliable tool to estimate comorbid disease and survival in patients with cancer. [Table: see text]
Real-world experience on tolerability and safety of relugolix combined with androgen signaling inhibitors in patients with advanced prostate cancer.
Authors: Jian Guan, Shubham Adroja, Zainub Ajmal, Yuan Gao, Nicholas Spetsieris, Siqi Hu, Raj Satkunasivam, Michael A Brooks, Andrew M. Farach, E. Brian Butler, Brian Miles, Eleni Efstathiou
Journal: Journal of Clinical Oncology (2024)

85 Background: Relugolix is the first oral GNRH antagonist approved by the FDA in 2021 for the treatment of advanced prostate cancer (PCa). Approval was based on HERO study, which showed a rapid and sustained testosterone suppression superior to that of Leuprolide coupled with a significantly shorter time to eugonad state after discontinuation. Relugolix was associated with a 54% lower risk of major adverse cardiovascular events as compared with Leuprolide. There is very little data available regarding the tolerability safety of Relugolix in combination Enhanced Androgen Signaling Inhibitors (ASI). Here we provide real world experience on the combination of Relugolix and ASIs in patients(pts) with advanced PCa, focusing on safety, tolerability and pharmacodynamic outcome measures. Methods: Houston Methodist Genitourinary Oncology records were reviewed for identification of pts treated with combination Relugolix plus ASI for at least 1 month, from 09/21 to 07/23. Data collected included pts’ baseline and tumor characteristics, cardiovascular and metabolic comorbidities concomitant medication. We recorded Adverse Events, potential Drug Drug Interaction (DDI) and Testosterone (T) and PSA decline. Results: We report 152 advanced hormone-naive PCa pts with median age of 71 (range 48-96). 81% were White or/and Hispanic, 17 % black, 2 % Asian. Majority (90%) had at least 1 cardiovascular risk factor; hypertension (72%), hyperlipidemia (52%), obesity (41 %), diabetes mellitus (26%), coronary artery disease (30%) and atrial fibrillation (13%). ASIs combined with Relugolix included: Darolutamide (78%), Abiraterone (14%), Apalutamide (7%) and Enzalutamide (1%). All but one pt were compliant (99%). Median treatment exposure is 8 months (range 1 -21). All pts had baseline Testosterone &gt;150ng/dL. All pts reached castrate T levels and 90% of patients achieved a T &lt; 20 ng/dL. 55% pts reached PSA &lt;0.1 at median of 4ms, 75% PSA decline &gt; 90% and 91% PSA decline ≥50%. 7% pts discontinued Relugolix due to adverse events. Three pts (2%) had a major adverse cardiovascular event, including one sudden death, one with congestive heart failure, and one with myocardial infarction. Two pts (1%) reported grade 3 fatigue. G3 LFT elevations recorded in 2 pts (1%). No clinical signals of DDI reported. Conclusions: This is the first large original report of the combination of Relugolix with ASIs in real world practice. The combination has a favorable safety and tolerability profile with no new safety concerns. No new DDI concerns were raised. These findings in combination with pharmacodynamic outcome measures of T / PSA support the use of Relugolix in combination with ASIs as standard of care in advanced PCa.
Novel dual inhibitors of AR/AR variants and AKR1C3: Preclinical activities for advanced prostate cancer therapy.
Authors: Allen Gao, Shu Ning, Cameron Armstrong, Enming Xing, Wei Lou, Pui-Kai Li, Christopher P. Evans
Journal: Journal of Clinical Oncology (2024)

169 Background: AR/AR-variants and AKR1C3 play critical roles in prostate cancer progression and driving resistance to antiandrogens, and are attractive targets for therapeutic intervention for advanced prostate cancer. However, there are currently no clinically available therapies that simultaneously target both AR/AR variants and AKR1C3. We have developed the novel small molecule inhibitors, LX-1 and its analog LX-1S, which target both the AR-V7 splice variant and the enzyme AKR1C3. Methods: A library of the LX compounds was designed and synthesized according to structure based computer modeling. The effects of the lead LXs on the expression and activity of AR/AR-variants and AKR1C3 were evaluated. RNA-seq was performed on the lead LXs. Resistant cell sublines generated from C4-2B cells resistant to enzalutamide (MDVR), apalutamide (ApalR), darolutamide (DaroR), or abiraterone (AbiR) were treated with LX-1 or their respective antiandrogen. Mice bearing VCaP xenograft tumors and LuCaP35CR PDX tumors were treated with LX-1/LX-1s and effects on tumor growth were assessed. Results: Molecular docking studies and in vitro experiments demonstrated that LX compounds effectively bind to the AKR1C3 active site and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and inhibit their target gene signaling, induce G0/G1 arrest in anti-androgen resistant cell lines. LX-1/LX-1S treatment resulted in reduced tumor volumes and decreased intratumoral testosterone in both xenograft tumor and PDX models. LX-1 effectively inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. Moreover, LX-1 synergized with enzalutamide and abiraterone as well as docetaxel, suggesting its potential to enhance the anti-tumor activity of these standard therapies in resistant prostate cancer. Furthermore, LX-1/LX-1S improved enzalutamide treatment in resistant prostate cancer tumor models. Notably, LX-1S demonstrates significantly better bioavailability and efficacy than LX-1 in reducing resistant cell growth in both in vitro and in vivo animal models. Conclusions: Our study unveils the potential of LX compounds, especially LX-1 and its analog LX-1S, as promising therapeutic agents for advanced prostate cancer. These compounds not only inhibit AR and AKR1C3 signaling but also suppress resistant tumor growth and synergize with antiandrogens to enhance their therapeutic efficacy.
Burnout among GU oncologists and associated factors: BUCARE survey.
Authors: Alisher Kahharov, Ilya Tsimafeyeu, Oxana Shatkovskaya, Dilyara Kaidarova, Jamila Polatova, Fuad Guliyev, Bakytzhan Ongarbayev, Timur Mitin
Journal: Journal of Clinical Oncology (2024)

293 Background: The growing number of patients with genitourinary (GU) cancers coupled with complexity of their treatments could create an increasing burden on GU oncologists. The Bureau for Cancer Research (BUCARE) assessed the prevalence of burnout among GU oncologists. Methods: This is a cross-sectional survey study conducted online among practicing surgical, medical and radiation oncologists from Kazakhstan, Russia, Uzbekistan, Azerbaijan, Georgia, Kyrgyzstan, Tajikistan, and Israel. The primary outcome is burnout experience assessed through the Maslach Burnout Inventory. Association between respondents’ characteristics and presence of burnout was tested using X-test. Results: From April to August 2023,a total of 674 GU oncologists completed the questionnaire. The characteristics of respondents are 50% female, 45% medical oncologists, 35% surgeons, 15% radiation oncologists, working in outpatient (35%) and inpatient (65%) departments. Ninety-two percent of responders are interested in their daily work and 83.7% have a great interest in further professional development. However, 71.5% (482 of 674) had symptoms of burnout (high emotional exhaustion and/or depersonalization scores) and 60.8% of respondents describe readiness to seek psychological support. 172 (25.5%) and 401 (59.5%) participants reported that they do not have enough time to communicate with their family at all or partially, respectively. Significant drivers of burnout identified in multivariable regression modeling include ≥20 patients per day (odds ratio [OR] = 15.1; P&lt;0.001) and ≥10 working hours per day (OR=10.4; P&lt;0.001). Male gender (OR=0.1; P&lt;0.001) and specialization in radiation oncology (OR=0.19; P&lt;0.01) are associated with lower odds of burnout. Conclusions: Two-thirds of surveyed GU oncologists met predefined standardized criteria for burnout. Expanding the staff of GU oncologists and reducing the daily workload may improve the emotional state of these physicians. Special attention must be paid to the work environment of female providers as well as surgical and medical oncologists to decrease the rate of burnout.
Health-related quality of life (HrQoL) of first-line treatments in metastatic renal cell carcinoma (mRCC): A network meta-analysis.
Authors: Oluseyi Abidoye, Syed Arsalan Ahmed Naqvi, Kunwer Sufyan Faisal, Manal Imran, Kaneez Zahra Rubab Khakwani, Ammad Raina, Nikita Tripathi, Haidar Abdul-Muhsin, Brian Addis Costello, Parminder Singh, Alan Haruo Bryce, Irbaz Bin Riaz
Journal: Journal of Clinical Oncology (2024)

412 Background: Previously we have reported comparative effectiveness data regarding survival of first line (1L) treatment options in mRCC. However, it is not known how the life-prolonging frontline combinations compare to patient-reported outcomes. Methods: Electronic databases including MEDLINE and EMBASE were searched from each database’s inception through July 1 st 2023. Phase III randomized controlled trials (RCTs) assessing 1L immune-checkpoint inhibitor (ICI) combination therapies for mRCC and reporting HrQoL were included. Small sample size adjusted standardized mean differences (SMD; Hedges’ g) with 95% confidence intervals (CI) were computed for global, physical, functional, and emotional QoL. Positive SMD indicated an improvement. A network meta-analysis was conducted to assess the comparative HrQoL across different treatment options. P-scores were computed to assess relative treatment rankings. Results: Of 5770 citations identified, five trials (nine references) were included in this analysis. Patient-reported outcomes have not been reported in the JAVELIN Renal 101 or COSMIC-313 trials yet. Global QoL was significantly improved with cabozantinib-nivolumab (CaboNivo) as compared to Nivo-ipilimumab (SMD 2.74, 95% CI 2.54; 2.93), lenvatinib-pembrolizumab (LenPem; 2.79, 2.53; 3.06), sunitinib (2.87, 2.72; 3.03), Pem-axitinib (PemAxi; 3.09, 2.89; 3.30) and atezolizumab-bevacizumab (AteBev; 3.24, 3.04; 3.45). Global QoL improvement was also observed with NivoIpi compared to sunitinib (0.14, 0.02; 0.25), PemAxi (0.36, 0.18; 0.54) and AteBev (0.51, 0.33; 0.68). Physical QoL improvement were consistent with CaboNivo. Likewise, LenPem significantly improved QoL compared to sunitinib (0.26, 0.04; 0.47), PemAxi (0.38, 0.13; 0.64) and NivoIpi (0.51, 0.27; 0.76). Significant functional QoL benefits were only observed with CaboNivo (0.32, 0.17; 0.48) and NivoIpi (0.19, 0.08; 0.31) compared to sunitinib. No significant mixed treatment comparisons were observed for emotional QoL, however, currently available data suggests that LenPem (rank 1) may potentially improve QoL (Table). Conclusions: CaboNivo and NivoIpi as 1L therapy may offer an improved overall HrQoL compared to other contemporary treatment options in mRCC. [Table: see text]
Outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma and histology variants: Analysis of the UNITE study.
Authors: Tanya Jindal, Cindy Y. Jiang, Omar Alhalabi, Charles B Nguyen, Amanda Nizam, Arnab Basu, Mehmet Asim Bilen, Yousef Zakharia, Matthew I. Milowsky, Jason R Brown, Deepak Kilari, Hamid Emamekhoo, Christopher J. Hoimes, Ali Raza Khaki, Shilpa Gupta, Petros Grivas, Joaquim Bellmunt, Matthew T Campbell, Ajjai Shivaram Alva, Vadim S Koshkin
Journal: Journal of Clinical Oncology (2024)

652 Background: Enfortumab vedotin (EV) is approved for patients (pts) with advanced urothelial carcinoma (aUC) but outcomes in pts with histology variants (HV) have not been well described. We hypothesized that presence of HV would impact EV treatment outcomes. Methods: UNITE is a multi-site retrospective study of pts with aUC treated with targeted agents, including 650 pts treated with EV regimens. We compared outcomes to EV monotherapy in pts with pure UC (pUC) relative to pts with any HV and with specific HVs. In pts with scans after &gt; 1 cycle of EV, observed response rate (ORR) was assessed using χ 2 test and logistic regression. Median progression-free survival (PFS) and overall survival (OS) from EV start were measured using the Kaplan Meier method and Cox proportional hazard test. Results: A total of 566 pts (366 with pUC; 200 with HV) from 17 US sites were treated with EV monotherapy. Median age was 70 years, 71% men, 87% Caucasian, 74% with ECOG PS 0/1 and 28% with liver mets. Median follow up was 21 mos from EV start, ORR was 49%, mPFS and mOS were 5.8 mos (95% CI: 5.29-6.67) and 12.2 mos (95% CI: 11.5 – 13.8), respectively. Pts with pUC had more visceral mets (69% vs 60%, p = 0.04) and liver mets (32% vs 21%, p =0.003) than pts with HV. No significant difference in outcomes were seen between pUC and pts with HV component (1-100%). Pts with predominant HV (50-99%; N=35), had numerically lower ORR relative to pUC pts (36% vs 52% OR 0.31, p &lt;0.09), but no difference in mPFS or mOS. Pts with pure HV (pHV) (100%: N=14) had inferior outcomes relative to pts with pUC (ORR 0% vs 52%, p&lt;0.001; mOS HR: 2.96 (95% CI: 1.60 – 5.46), p &lt;0.001; mPFS HR: 1.9 (95% CI: 1.06 – 3.39), p=0.03). ORRs for specific HV are listed in the table. No significant difference in treatment outcomes were seen in pts with pUC vs any specific HV, except for NE HV which had inferior ORR (0% vs 52%; p=0.003). Conclusions: Responses to EV are noted in some aUC pts with HV, except for NE (any component) and pHV. Certain HV notable for poor outcomes, such as sarcomatoid and plasmacytoid, demonstrated responses to EV. These hypothesis-generating findings require further validation in studies with adequate sample size for specific HV, and in particular pHV. Evaluation of biomarkers, including Nectin4 expression, in HV is paramount. [Table: see text]
Association of ARID1A deficiency with invasive transformation in metastatic bladder cancer.
Authors: Vincent D'Andrea, Timothy Hanlon, Rea Chroneos, Raie Bekele, Timothy Clinton, Filipe L.F. Carvalho, Kent William Mouw
Journal: Journal of Clinical Oncology (2024)

656 Background: ARID1A is an essential component of the BAF complex, a large SWI/SNF chromatin-remodeling complex which is implicated in bladder cancer (BC) pathogenesis. While ARID1A mutations are more highly represented in metastatic rather than localized tumors, the biological consequences of ARID1A loss in BC remain to be elucidated. We hypothesize that ARID1A deficiency primes an invasive transformation in BC, thus increasing the likelihood of disease progression and metastases. We used CRISPR/Cas9-mediated gene editing to knockout (KO) the ARID1A gene in several BC cell lines, thus providing a platform for cellular function assays. We show that ARIDA1 loss potentiates an invasive phenotype in these cell lines, giving evidence for its transformative role in the development of higher stage and metastatic BC. Methods: A CRISPR-Cas9 KO was performed with three cell lines with wild-type (WT) ARID1A (T24, SW1710, and 5637). This was accomplished by developing sgRNAs against ARID1A with a GFP marker and carrying out single-cell fluorescence-activated cell sorting (FACS) following nucleofection to identify ARID1A-deficient clones. Western blot analysis was performed on the resulting clones to confirm complete loss of ARID1A. Baseline proliferation studies were performed on the KO and WT cell lines. Finally, invasion studies were performed on the KO and WT cells with a scratch assay. Results: CRISPR-Cas9 directed KO of ARID1A yielded ARID1A-deficient clones for SW1710, T24, and 5637. The proliferation rates for each cell line were analyzed and compared which showed no significant differences. A scratch assay was performed with the cell lines in triplicate, with each ARID1A-deficient cell line showing a trend towards more rapid wound closure than its matched WT cell line (WT=31.5% vs. KO=53.5% for SW1710, p=0.15; WT=17.2% vs. KO=52.0% for T24, p=0.07; WT=10.4% vs. KO=13.9% for 5637, p=0.59). Conclusions: To explore the increased frequency of ARID1A alterations in metastatic BC compared to non-invasive tumors, we developed a model of ARID1A-deficient BC using CRISPR-Cas9. We compared the relative invasiveness of the lines using a scratch assay. All lines trended towards a more invasive phenotype following ARID1A KO, which was especially pronounced in T24. Taken together, these data suggest that ARID1A deficiency in BC may prime tumors for a more invasive phenotype, which may help to explain the higher frequency of ARID1A alterations in higher stage and metastatic samples.
Association of BTN2A1+ microvesicles with overall survival and the role of γδ T cells as a potential therapeutic target in patients with hormone-sensitive metastatic prostate cancer.
Authors: Emilien Billon, Caroline Imbert, Laurent Gorvel, Manon Richaud, Rania Ghossoub, Virginie Girault, Thierry Fest, Gwenaelle Gravis, Daniel Olive
Journal: Journal of Clinical Oncology (2024)

194 Background: Despite the recent progress in cancer management, metastatic prostate cancer remains incurable. In the context of immunotherapy failure, we need to identify new immune biomarkers, to improve patient therapy, and explore their potential as therapeutic target. To this end, we screened the prognostic value of soluble immune checkpoints in the plasma of metastatic prostate cancer patients at diagnosis, and depicted their role in anti-tumor activities. Methods: Patients with hormone naive metastatic prostate cancer were prospectively included in the NK-Prostate study (NCT02963155). Blood collection was performed before treatment and patients were followed for 5 years. We determined by ELISA assay plasma levels the soluble form of PD-L1, Pan-BTN3A, BTN3A1, BTN2A1 and BTLA. Large extracellular vesicles (MVs) were pelleted at 10 000g by sequential ultracentrifugation. Results: 66 patients were included in the NK-Prostate with a median follow-up of 42.6 months. Only plasma levels of BTN2A1 were associated with overall survival &gt; 50 months. Patients with enriched sBTN2A1 (soluble form of BTN2A1) presented poorer overall survival (HR for death 2.91 95%CI 1.33 – 6.33, p=0.0072) and progression-free survival than low-level patients (HR for progression 2.73 95%CI 1.48 – 5.05, p=0.0012). Prostate cancer cell line produced sBTN2A1, with 40% associated with extracellular vesicles. High level of BTN2A1+ microvesicles (MVs) were identified by spectral cytometry in patient’ plasma but not in healthy volunteer plasma, and deep phenotyping revealed that B cell-derived BTN2A1+ MVs were associated with shorter overall survival (HR 4.22 95%CI 1.68 – 10.57, p=0.0021). To evaluate the impact of BTN2A1+ MVs on γδ T cells, we generated BTN2A1 KO MVs, BTN2A1 overexpressed MVs, and BTN2A1 mutant overexpressed MVs (that do not interact with γδ TCR). We demonstrated that BTN2A1 overexpressed MVs could specifically interact with γδ T cell; and impaired their proliferation and cytotoxicity against prostate cancer cell lines (LNCaP, DU145 and PC3). Conclusions: Our study shows the negative impact of B cell derived BTN2A1+ MVs in hormone naïve metastatic prostate cancer. Plasma MVs phenotyping is an easy-to-perform test, accessible for all patients. Our results highlight the role of γδ T cell in the anti-tumor immunity in prostate cancer, making them an interesting target for immunotherapy in this pathology. Clinical trial information: NCT02963155 .