bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using artificial intelligence-powered evidence-based molecular decision-making for improved outcomes in ovarian cancer.
Authors: Orr Brian Christopher , Uihlein Arlette Harper , Montgomery Robert , Radolec Mackenzy , Edwards Robert P. 
Published: June 2024

5555 Background: High grade serous ovarian cancer (HGSC) is a complex deadly disease. Due to the lack of symptoms at early stages, vast majority patients present at stage III/IV. Frontline chemotherapy and surgery is effective with nearly all patients experiencing a remission, though over 80% patients will recur in the first 1-2 years and ultimately die of the disease in the next few years. Approximately 20% will be long-term survivors, but no current clinical data can predict who may be a short- or long-term survivor. Clinical management, monitoring, and systemic treatment decisions could be optimally individualized to patients if able to better define the prognosis. The goal of this study is to employ artificial intelligence multi-omic machine learning models to predict survival outcomes. Methods: Clinical data and tumor specimens from University of Pittsburgh Center from 2010-2016 were analyzed. Patient data, whole exome sequencing (WES), whole transcriptome sequencing (WTS), drug response profile, and digital pathology profile were used as input feature sets for training the multi-omic machine learning (ML) models. Hypothesis-free training of the ML models was utilized to classify patient survival at 2yr and 5yr threshold. Model performance was estimated using AUROC (area under the receiver operating characteristic curve) metric, scores >0.5 having higher prediction potential. Validation of the prediction results of each ML model with top performing models meeting statistical significance threshold of α=0.01. Results: 160 HGSC model builds were completed. ML models achieved high prediction accuracy for both short-term (2y) and long-term (5y) patient cohorts, identifying 7 models with ≥ 0.7 AUROC model performance for 2yr OS threshold and 13 models with ≥ 0.7 AUROC model performance for 5yr OS threshold. Addition of multi-omic feature sets to clinical profile improved the model’s ability to predict OS for both short-term and long-term thresholds. Multi-omic feature set inputs led to superior prediction and improved performance over clinical profile information alone, and top performing multi-omic models predicted better than any feature set in isolation. Comparison of top features identified by 2y and 5y OS threshold models, we found that molecular features (WTS followed by WES feature sets) predominantly drove 2y cohort while digital pathology imaging features were the driver the 5y cohort top performing models. Conclusions: Current clinical data does not accurately predict prognosis. Utilizing multi-omic machine learning models, superior prediction of short- and long-term survivors was achieved. The specific drivers of the top performing models were different for the short- and long-term cohorts, identifying future research opportunities as well as development potential of a clinical decision tool.
Systematic review of frailty assessment in ovarian cancer studies.
Authors: Madariaga Ainhoa , Alqaisi Husam , Castelo Alicia , Fazelzad Rouhi , Lheureux Stephanie , Oza Amit M. 
Published: June 2024

5564 Background: Frailty is a state of vulnerability to poor resolution of homeostasis following a stressor event, such as chemotherapy or surgery. Better knowledge of frailty assessments (FA) in ovarian cancer could help drive a global and individualized care strategy. Methods: A search was performed in 10 databases including Medline, Embase and Cochrane (up to March 2022). The search strategy utilized a combination of keywords and controlled vocabulary related to ovarian cancer, frailty/geriatric assessment. Studies performing FA in patients with ovarian cancer on systemic therapy, surgery and surveillance were included. The 2020 PRISMA checklists were followed, and the study was registered in PROSPERO (CRD42022323409). Primary objective was to identify frailty scales used in ovarian cancer studies. Secondary objectives were to describe impact of results on decision making and outcomes, adherence to ASCO Vulnerability Assessment (VA) guidelines. Results: 2,259 articles were screened, and 48 included in the final analysis. Studies were published between 2004-2022 and included 84,575 patients. 23 studies (48%) had an age limit for inclusion (≥65 to ≥80 years). Six studies were interventional (1 phase 3 clinical trial [CT], rest phase 2) and 42 were observational (45% retrospective). FA were highly variable. Median number of tests to assess frailty were 3 (range 1-13). Most studies used a combination of tests (several may apply): validated frailty scales (21 studies, 43.7%), nutritional/sarcopenia status (20 studies, 41.7%), functionality/physical performance (19 studies, 39.6%), geriatric assessment (7 studies, 14.6%). Global measures with all the comprehensive assessment items of the ASCO VA guideline were included in 14.6% of studies. FA was not used for decision making in any study. One FA designed for ovarian cancer was identified, the GINECO Geriatric Vulnerability score. Frailty was the primary objective in 26 studies (54%), out of which 12 were retrospective. Among them, study objectives were highly variable including survival, complications, or cost of surgery (13 studies) and systemic therapy (7 studies), prognosis (4 studies), treatment compliance and dependence (1 each). All but one (a prognostic study) met its primary outcome demonstrating worse outcomes in frail patients. Conclusions: Frailty assessments are heterogeneous in ovarian cancer studies. Most studies do not adhere to the ASCO vulnerability assessment guidelines. An association between frailty and poor outcomes was detected in surgical and systemic therapy studies. There is room for improvement, as none of the assessed studies used the frailty for decision making.[Table: see text]
Phase Ib INEOV neoadjuvant trial of durvalumab +/- tremelimumab with platinum chemotherapy for patients (pts) with unresectable ovarian cancer (OC): Survival outcomes and immune correlates.
Authors: Leary Alexandra , Chardin Laure , Lortholary Alain , Asselain Bernard , Alexandre Jerome , Lebreton Coriolan , Savoye Aude-Marie , Oudard Stephane , Gavoille Céline , You Benoit , D'hondt Veronique , Grenier Julien , Yaniz-Galende Elisa , Roussel-Simonin Cyril , De La Motte Rouge Thibault , Pujade-Lauraine Eric 
Published: June 2024

5569 Background: Ineov was a phase Ib randomized trial of neoadjuvant carboplatin/paclitaxel (NACT) + durvalumab (D) +/- tremelimumab (T) in unresectable OC. We previously reported safety and encouraging complete resection rates (CC0=70%) and complete pathological response rates (pCR=18%) at interval debulking surgery (IDS). However there were no significant differences with the addition of T to D+NACT. Here we report survival outcomes and immune correlates with a focus on long-term responders. Methods: Pts with unresectable stage IIIC/IV OC were randomized to NACT + D (1125mg) alone (arm A) or with T (75mg once at C2) (arm B). IDS was planned after C3, or delayed after C6. Pts in arm A not operable after C3 crossed over to arm B, pts in arm B crossed over to standard of care (SOC) and assessed for delayed IDS after C6. PFS was assessed by Kaplan-Meier and PFS compared between arms A and B by Log-Rank test. Intra-epithalial CD8+ lymphocytes were scored as nb/mm2 and HLA-I expression was scored by H-score. Results: 70 patients were randomized to Arm A (N=36) or Arm B (N=34). 4 pts were replaced for early toxicity and one early death attributed to COVID. Median PFS in all pts was encouraging at 18mo but not different between arms. CCO at IDS was associated with significantly improved PFS (mPFS 25mo vs 14mo; p 0.0008). NACT+D+/-T significantly increased intra-epithelial CD8+ infiltration (p<0.0001) and HLA-I levels (p=0.007), but the changes were no different in arm A vs B. While high ieCD8 predicted improved pathological response (p=0.0014), neither ieCD8 nor HLA-1 levels at baseline or IDS predicted improved PFS. 8 (12.5%) pts were disease free at >40months. When compared to the other patients in the trial, this subset of long-responders was characterized by higher pCR (38% vs 11%), higher CC0 rates (100% vs 66% ) but showed no differences in immune profile. Among pts with known BRCA status, 43% of long-responders had a BRCAm (vs 20%). Conclusions: NACT combined with immunotherapy resulted in encouraging CC0, pCR and PFS in pts with unresectable OC, however the addition of T to D did not improve immune infiltration or outcomes. Features associated with long response were pCR, CC0 and BRCAm, not immune features. Clinical trial information: NCT03249142 .
Molecular and immune characterization of squamous cell ovarian cancers for identification of therapeutic targets.
Authors: Hollingsworth Jessie , Wu Sharon , Adkoli Anusha , Farrell Alex Patrick , Hodges Kurt , Oberley Matthew James , Karnezis Anthony , Thaker Premal H. , Girda Eugenia 
Published: June 2024

5584 Background: Squamous cell carcinoma (SCC) represents <1% of all Ovarian cancers (OC) and is associated with poor prognosis. This study seeks to identify prognostic factors and molecular markers associated with OSCC compared to Endometrioid OC (EOC), Clear Cell OC (CCOC), HPV16/18-negative vulvar SCC (VSCC) and HPV16/18-negative cervical SCC (CSCC). Methods: 812 EOC, 846 CCOC, 32 OSCC, 15 malignant BT, 500 HPV16/18- CSCC, and 472 HPV16/18- VSC were analyzed using next-generation sequencing of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq, WTS) (Caris Life Sciences, Phx, AZ). Tumor mutational burden (TMB) was measured by totaling all somatic mutations (mt) per tumor (TMB-H: > 10 mt/MB). PD-L1 IHC positivity was determined by a cut-off of >1% CPS (22c3, Agilent) and >2|5% (SP142, Spring Biosciences). HPV status determined by WES for HPV16 and 18. Statistical significance determined using chi-square and Mann-Whitney U test and adjusted for multiple comparisons (q<0.05). UMAP was used to visualize differences or similarities in transcriptomic profiles. Real-world overall survival (rwOS) obtained from insurance claims data and calculated from first treatment to last contact. Hazard ratio (HR) was calculated by Cox proportional hazards, with p-value calculated using log-rank test. Results: OSCC had the highest rate of TP53-mt and CDKN2A-mt compared to BT, EOC, CCOC, and CSCC (TP53-mt: 71.9%, 33.3%, 25.1%, 11.6% and 27.1%, CDKN2A-mt: 25%, 0%, 1.49%, 0.48%, and 4.45%) but lower than VSCC (TP53-mt: 80%, CDKN2A-mt: 38.9%). OSCC had lower mt of Chromatin Remodeling (CR) genes ARID1A (3.13%) compared to EOC (39.3%) and CCOC (58.2%) but higher mt of CR gene KMT2D (19.4%) compared to CCOC (3.62%) (q<0.05). OSCC had increased TMB-H than EOC, CCOC and VSCC (41.9% vs 13.6% vs 5.7% vs 8.84%) and PD-L1 IHC (all q<0.05). There was no ER/PR staining in OSCC. Median interferon (IFN) score was higher in OSCC compared to EOC, CCOC and BT (-0.24 vs -0.44 vs -0.46 vs -0.51, q<0.05) but similar to CSCC (-0.29) and VSCC (-0.17). Pathway analysis showed enrichment of IFNγ Response, Inflammatory Response, EMT and TNFα Signaling (NES: 1.53-2.05, FDR<0.25) in OSCC compared to EOC and CCOC. UMAP showed OSCC clustering more closely with CSCC and VSCC compared to EOC and CCOC. OSCC had worse post-Carboplatin survival (19.6 mo) compared to EOC (71.6 mo, p<0.01) and CCOC (46.9 mo, p<0.01), similar post-Carbo survival to TP53-mt CSCC (22.5 mo; p=0.80) but improved post-Carbo survival compared to TP53-mt VSCC (9.05 mo; p=0.01). Conclusions: The molecular and transcriptomic profile of OSCC is distinct from EOC, CCOC, and BT but similar to CSCC and VSCC. OSCC demonstrated a more immune hot phenotype. Further studies are needed to investigate the potential use of immunotherapy in OSCC.
Durvalumab + carboplatin/paclitaxel (CP) followed by durvalumab ± olaparib as first-line treatment for newly diagnosed advanced or recurrent endometrial cancer (EC) in DUO-E: Results by BRCA1/BRCA2 mutation (BRCAm) status.
Authors: Van Nieuwenhuysen Els , Baurain Jean-Francois , Chon Hye Sook , Thomes Pepin Jessica , Sundborg Michael J. , Gold Michael A. , Kim Byoung-Gie , Blank Stephanie V. , Liu Ji-Hong , McCollum Michael , Mori Masahiko , Jonuškienė Goda , Moore Kathleen N. , Novák Zoltán , Ramos Pedro , de Padua Charles Andreé Joseph , Gil-Martin Marta , Kowgier Matthew , del Rosario Paula Michelle , Westin Shannon Neville 
Published: June 2024

5595 Background: DUO-E (NCT04269200) showed statistically significant, clinically meaningful improvement in progression-free survival (PFS) with addition of durvalumab to CP, followed by durvalumab ± the PARP inhibitor olaparib, vs CP alone for patients (pts) with EC (Westin SN et al. J Clin Oncol 2024;42:283–99). PARP inhibitors are an established approach to targeting tumors with homologous recombination deficiency, so we performed post hoc exploratory analyses of PFS by BRCAm status. Methods: Pts with newly diagnosed FIGO Stage III/IV or recurrent EC and naïve to first-line systemic treatment were randomized 1:1:1 to CP (CP + durvalumab placebo [pbo; 6 cycles] followed by durvalumab pbo + olaparib pbo), CP+D (CP + durvalumab [1120 mg q3w; 6 cycles] followed by durvalumab [1500 mg q4w] + olaparib pbo) or CP+D+O (CP + durvalumab [6 cycles] followed by durvalumab + olaparib [300 mg bid]). Tissue BRCAm status was determined retrospectively (FoundationOneCDx assay, Foundation Medicine). Results: Of 718 pts randomized, 19.9% were mismatch repair deficient (dMMR) and 80.1% MMR proficient (pMMR). At primary analysis (April 12, 2023), PFS improvement was observed for CP+D and CP+D+O vs CP irrespective of BRCAm status (Table). BRCAm prevalence was low overall (dMMR: 12.6% BRCAm, 61.5% non-BRCAm, 25.9% unknown; pMMR: 4.0% BRCAm, 65.9% non-BRCAm, 30.1% unknown). PFS outcomes for CP+D+O vs CP in pMMR non-BRCAm pts (HR 0.57, 95% CI 0.42–0.78) were consistent with the overall pMMR subgroup (HR 0.57, 95% CI 0.44–0.73); BRCAm subgroup analyses were descriptive due to small sample size. Conclusions: Clinical benefit with addition of durvalumab to CP, followed by durvalumab + olaparib, vs CP alone was observed in the ITT and pMMR populations irrespective of BRCAm status. Clinical trial information: NCT04269200 . [Table: see text]
Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: A multicenter, single-arm, phase II trial.
Authors: Lan Chunyan , Yang Xielan , Zhao Jing , Zheng Min , Yang Fan , Xie Zhiwen , Wu Xiaoliu , Yang Hongying , Wang Wenyan , Huang Xin 
Published: June 2024

5600 Background: Lenvatinib plus pembrolizumab is the standard treatment for patients with advanced endometrial cancer with mismatch repair-proficient (pMMR) disease who had disease progression after the receipt of prior systemic platinum-based therapy. Cadonilimab is a PD-1/CTLA-4 bi-specific antibody. We aimed to assess the combination of cadonilimab and lenvatinib in patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy. Methods: In this phase II study with a safety-run in, eligible patients were aged 18 years or older with advanced endometrial cancer of any histologic subtype, except sarcoma, progressed after at least one prior platinum-based chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1. In the safety run-in period, a 3+3 dose de-escalation design was used to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of lenvatinib (16 mg or 12 mg once daily) combined with cadonilimab 10 mg/kg every 3 weeks. After the completion of safety run-in period, the phase II cohort at the RP2D will open. Approximately 29 patients are planned to receive treatment at the RP2D. The primary endpoint was objective response rate (ORR) at the RP2D. Key secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between 8 May 2023 and 18 December 2023, 24 patients were enrolled. As of 31 December 2023, enrollment was ongoing. No DLTs were observed during the safety run-in period. The RP2D of lenvatinib is 16 mg once daily. Among 21 efficacy-evaluable patients, the ORR was 52.4% (95% CI: 29.1–75.7), and the DCR was 90.5% (95% CI: 69.6–98.8). The Medians for DOR, PFS, and OS were not reached. Grade 3–4 treatment-related adverse events included increased ALT (2 [8.3%]), increased AST (1 [4.2%]), increased creatine phosphokinase (1 [4.2%]), hypertension (1 [4.2%]), and intestinal perforation (1 [4.2%]). Conclusions: Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy. The combination therapy had a favorable and manageable safety profile. Clinical trial information: NCT05824481 . [Table: see text]
Endometrial carcinoma in Black vs Asian women: Racial disparities and opportunities to improve survival in 219,301 patients in the USA.
Authors: Becerra Henry Alberto , Ilerhunmwuwa Nosakhare Paul , Wasifuddin Mustafa , Uche Ifeanyi , Osorio Juan C. , Wang Jen Chin C. 
Published: June 2024

5608 Background: Endometrial Carcinoma (EC) is the most prevalent gynecological malignancy in the USA (1,2). Incidence and mortality has been increasing, making it a growing public health problem (2-4). While hysterectomy-corrected studies have revealed racial differences for EC (5,6), factors that influence the poor prognosis among black women with EC in the USA remain. The objective of this study is to describe sociodemographic characteristics, survival outcomes and prognostic factors based on race in EC patients. Methods: Cases of EC from the Surveillance, Epidemiology, and End Results (SEER) Research Plus Data, 17 Registries, from 2000 to 2020, were analyzed in SPSS v25. Variables were compared with Chi-squared test. Median Overall Survival (OS) was done using Kaplan-Meier method. Cox Regression analysis was done to identify independent prognostic factors influencing survival. A two-sided p-value ≤0.05 was considered statistically significant. Results: 219,301 patients with EC were included. Median follow up: 64 months. Median age of diagnosis: 62 years. 69.5% were whites, 8.6% blacks and 8.4% asians. Treatments were surgery (91.8%), radiotherapy (26.1%) and chemotherapy (18.1%). The median OS was 209 months (95%CI:207.1-210.9). Notably, the shortest median OS was observed in blacks (118 months), followed by 205 months for whites, while it was not reached for asians. Multivariate analysis showed that, compared to whites, blacks exhibit the poorest prognosis (HR=1.39, 95%CI:1.35-1.43), whereas asians demonstrated the most favorable prognosis across all races (HR=0.88, 95%CI:0.85-0.91). Independent poor prognostic factors found for EC included older age, low income and advanced stage. Differences in the distribution of these factors were observed among races. When comparing to asians, there was a higher proportion of blacks ≥60 years-old (66.9% vs 44%, p<0.001), with incomes <$60,000 (31.3% vs 3.6%, p<0.001) and diagnosed at more advanced stage (37.4% vs 28.9%, p<0.001). Surgery-based treatments showed the best prognosis (HR<0.3 independent of race, p<0.01). However, the distribution of these treatments stratified by race and stage showed that asians were more prone to receive surgical treatment independent of stage compared to blacks (p<0.001). Conclusions: Our findings contribute novel information on distribution of prognostic factors across races and their impact on survival. Notably, compared to asians, blacks appear to face delayed diagnosis, lower income, and less frequent use of surgery-based treatments. This highlights the importance of early access to diagnosis and treatment as potential avenues to improve survival. Limitations include the lack of other potential prognostic factors such as obesity in the database. References (PMID):1. 37147968; 2. 33127429; 3. 34277441; 4. 27741565; 5. 35511145; 6. 31116674.
Prognostic utility of YBX1-mediated genes in clear cell renal cell carcinoma outcomes.
Authors: Ali Waleed , Tawagi Karine , Balla Andre 
Published: June 2024

e16510 Background: The Y-box-binding protein1 (YBX1) transcription factor has been linked to a variety of biological processes such as mRNA stabilization and localization and cell-cycle progression. YBX1 has been shown to have pro-oncogenic effects in some cancers, possibly also modulating cisplatin’s effects in others. However, comparatively less regarding YBX1 has been explored in kidney renal clear cell carcinoma (ccRCC), the most common kind of kidney cancer. This in silico study explores the relationship between YBX1 and associated regulatory targets in ccRCC cases. Methods: The MSig database was utilized to generate a list of genes which contained one or more YBX1 binding sites in their promoter region based on ChIP-seq data. Kaplan-Meier plots of overall survival in ccRCC cases based on YBX1 and YBX1-regulated gene expression were generated using TCGA data on the KMPlot platform with “high” and “low” expression cutoffs based on quartiles. Multiple hypothesis testing was corrected by adjusting the significant p-value cutoff to a FDR >0.05 (adjusted p-value cutoff is 0.023). Enrichment and network analysis was then conducted on genes shown to be differentially expressed in respect to outcome through the Cytoscape and Metascape platform to see which over-represented biological pathways may mediate outcome (p<0.01 for significance). Results: Out of 76 initial genes, 33 showed differential expression in regards to survival, including YBX1 itself. Enrichment analysis highlighted biological processes such as negative regulation of mRNA metabolic processes and Nop56p-associated rRNA complex formation as possible ways YBX1 and its related targets can affect outcomes. A variety of genes were highlighted by the network analysis, such as the membrane trafficking gene YIF1A and acetyltransferase KAT8 among others. Conclusions: Similar to what has been shown in other types of cancers, YBX1 and its regulatory constituents have been linked to ccRCC outcomes, possibly due to its role regarding mRNA regulation as highlighted by our enrichment analysis. Other interactions mediated by genes such as the cell cycle regulator CCAR2 offer other pathways through which YBX1 can mediate outcome. Previously being linked with cisplatin resistance in other cancers such as breast, YBX1 offers a suitable target for further wet-lab research regarding its role in ccRCC.