bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic validation of a digital pathology-based multi-modal artificial intelligence (MMAI) biomarker in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the CHAARTED trial (ECOG-ACRIN EA3805).
Authors: Markowski Mark Christopher , Ren Yi , Croucher Danielle , Royce Trevor Joseph , Yamashita Rikiya , Tierney Meghan , Huang Huei-Chung , Todorovic Tamara , Chen Emmalyn , Carducci Michael Anthony , Chen Yu-Hui , Liu Glenn , Parker Charles , Esteva Andre , Feng Felix Y , Attard Gerhardt , Sweeney Christopher 
Published: June 2024

5077 Background: The ArteraAI MMAI prognostic biomarker leverages histopathology images and clinical data to risk stratify patients (pts) with localized prostate cancer. This study aimed to validate the MMAI biomarker in mHSPC. Methods: The validation cohort included a subset of pts from the CHAARTED phase III randomized trial with known age at diagnosis, baseline PSA, T-stage, and available histopathology images. Baseline characteristics were compared to examine the balance between included and excluded patients. Using the existing MMAI model, scores were generated, and prognostic ability was evaluated for overall survival (OS) in Cox proportional hazard model. Four defined prognostic groups based on tumor volume (high (HV) vs. low (LV)) and metastatic stage at diagnosis (M1 vs. M0) were included: 1. M0LV, 2. M0HV, 3. M1LV, 4. M1HV. These clinical groups were evaluated using multivariable analysis (MVA) which included MMAI risk group and treatment. Results: A subset of the CHAARTED patient population had evaluable digital histopathological images, allowing inclusion in this study (N=456/790, 57.7%), of which 370 (81.1%) were classified as MMAI-high and 86 (18.9%) as MMAI-intermediate/low risk. Data were available from 394/456 pts for classification into M0LV (N=57), M0HV (N=29), M1LV (N=66), or M1HV (N=242). MMAI-high proportion among groups were 56.1%, 69.0%, 86.4% and 92.6%, respectively. Median follow-up of the censored patients was 4.1 (IQR: 3.3-5.0) yrs. The estimated 5-yr OS across MMAI high, intermediate, and low groups was 39%, 58%, 83%, respectively (log rank p=<0.001). On MVA, the MMAI-high risk group model associated with OS (HR: 1.77 (95% CI: 1.10-2.84) p=0.02) adjusting for treatment arm, volume status, and stage at diagnosis (Table 1). When compared to M0LV, HV subgroups were also associated with OS on MVA. Conclusions: The ArteraAI MMAI model was found to be prognostic for OS among men with mHSPC in CHAARTED. This effect persisted when controlling for treatment, metastatic burden, and metastatic status at diagnosis. On MVA, M0HV and M1HV also maintained prognostic value. This analysis is exploratory in nature, to be followed by development of a model optimized for advanced prostate cancer.[Table: see text]
Long-term survival outcomes for hormonal therapy in premenopausal patients with clinical stage I endometrial cancer.
Authors: Suzuki Yukio , Huang Yongmei , Havrilesky Laura J , Blank Stephanie V. , Elkin Elena B. , Melamed Alexander , Ferris Jennifer S. , Saji Haruya , Miyagi Etsuko , Kong Chung Yin , Myers Evan R. , Wright Jason Dennis 
Published: June 2024

5508 Background: As the number of young women with early-stage endometrial cancer is increasing, there is growing interest in use of progesterone-based therapy to allow fertility preservation. To date, there is a paucity of data on the safety and long-term outcomes of progesterone therapy. The objective of our study was to determine the safety and long-term outcomes of hormonal therapy for clinical stage I endometrial cancer in premenopausal women. Methods: The National Cancer Database was used to identify patients 18-49 years of age with clinical stage I, grade 1-2, endometrioid endometrial cancer diagnosed from 2004-2020. Primary treatment was defined as hysterectomy or hormonal therapy. Trends in the use of hormonal therapy were examined. A multivariable regression model was developed to examine the association between hormonal therapy and demographic factors. After propensity score matching, survival was compared between patients treated primarily with hormonal therapy and with primary hysterectomy. Results: A total of 15,849 patients, including 14,662 (92.5%) treated with primary hysterectomy and 1,187 (7.5%) who received primary hormonal therapy were identified. The use of hormonal treatment increased from 5.2% in 2004 to 13.8% in 2020 (P<0.0001). In a multivariable model, younger age, more recent year of diagnosis, non-White race, lower tumor grade, and earlier stage were associated with use of hormonal therapy (P<0.05 for all). After propensity score balancing, 5-year survival was 98.5% (95% CI, 97.3-99.2%) for hysterectomy and 96.8% (95% CI, 95.3-97.8%) for hormonal therapy (HR=1.84; 95% CI 1.06-3.21). Among patients <40 years of age, there was no difference in survival between hysterectomy and hormonal therapy (HR=1.00; 95% CI, 0.50-2.00). However, for patients age 40-49, hormonal therapy was associated with a significantly increased risk of death (HR=4.94; 95% CI, 1.89-12.91). There was no statistically significant difference in outcomes for hormonal therapy compared to hysterectomy in sub-set analyses stratified by grade (1 or 2) or stage (1A or 1B). Conclusions: The use of fertility-preserving hormonal therapy among reproductive age patients with early-stage endometrial cancer has increased over time. Among women age 40-49, hormonal therapy is associated with decreased survival. [Table: see text]
Final safety results from ATHENA–MONO (GOG-3020/ENGOT-ov45), a randomized, placebo-controlled, double-blind, phase 3 trial evaluating rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer.
Authors: O'Malley David M. , Monk Bradley J. , Lim Myong Cheol , Fuentes Pradera Jose , Buscema Joseph , Wilson Michelle K. , De Vivo Rocco , Herzog Thomas J. , Zagouri Flora , Oza Amit M. , Mikheeva Olga N. , Diaz John Paul , Lisyanskaya Alla Sergeevna , Morris Robert , Bruchim Ilan , Craib Marcia , Connor Christy , Shih Danny , Fujiwara Keiichi , Kristeleit Rebecca 
Published: June 2024

5554 Background: Rucaparib provided a sustained progression-free survival benefit in patients (pts) with newly diagnosed advanced ovarian cancer after first-line treatment in the phase 3 ATHENA-MONO study (NCT03522246). We report final safety analyses (data cutoff 09 Mar 2023). Methods: Rucaparib was administered in 28-day cycles. Eligible pts were randomized 4:1 to oral rucaparib 600 mg BID (N=427) or placebo (N=111), with a treatment cap defined as 24 months. The safety population included randomized pts who received at least 1 dose of study drug (rucaparib, n=425; placebo, n=110). Results: All ATHENA-MONO pts discontinued treatment as of 24 Nov 2022 with a median treatment duration of 15 months and 35% of pts reaching the 24-month treatment cap. The median (range) relative dose intensity was 89% (30-110) for rucaparib. The rate of treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, TEAEs leading to interruption, dose reduction, or discontinuation with rucaparib remained consistent with the primary endpoint analysis with some minor changes (see Table below). Most common grade ≥3 TEAEs were anemia/decreased hemoglobin (28.7%), neutropenia/decreased neutrophils (14.6%), increased ALT/AST (10.6%), and thrombocytopenia/decreased platelets (7.3%). The most common TEAEs leading to discontinuation were anemia/decreased hemoglobin (3.5%), asthenia/fatigue (4.9%), and nausea (2.1%). Hypertension continued to be the most common TEAE observed in the placebo group (3.6%) compared with 1.6% in the rucaparib group. There were no changes in the incidence of serious adverse events or TEAEs leading to death since the primary endpoint analysis. Myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) were reported in a total of 3 pts in the rucaparib group (1 MDS during treatment [0.2%] and 1 AML and 1 MDS during long-term follow-up [0.5%]), of which the latter occurred since the primary readout. The initial MDS event that occurred during treatment, included in these incidence numbers, was considered resolved by the investigator since the initial analysis. Conclusions: Long-term maintenance treatment with rucaparib demonstrates a consistent and manageable safety profile in a broad population of pts with newly diagnosed ovarian cancer. No new safety signals were identified. Adverse events were generally manageable and led to discontinuation in a low proportion of pts. Clinical trial information: NCT03522246 . [Table: see text]
Consistent data about the predictive factors of the success of interval debulking surgery (CC0-IDS) in patients with advanced ovarian cancers in two large independent datasets.
Authors: You Benoit , Fagotti Anna , Colomban Olivier , Giannarelli Diana , Blanc-Durand Felix , Scambia Giovanni , Carrot Aurore , Lorusso Domenica , Pujade-Lauraine Eric , Ergasti Raffaella , De Rauglaudre Gaetan , Sassu Carolina Maria , Ray-Coquard Isabelle Laure , Capomacchia Filippo Maria , Combe Pierre , Apostol Adriana Ionela , Ferron Gwenael , Malapelle Umberto , Leary Alexandra , Marchetti Claudia 
Published: June 2024

5560 Background: More than 50% of patients with FIGO stage III-IV epithelial ovarian cancers are treated with neoadjuvant chemotherapy (NACT) to achieve a complete interval debulking surgery (IDS), in the case of tumor response. Therefore, understanding the determinants of IDS success is crucial. The French GINECO and the Gemelli (Italy) groups analyzed 2 independent datasets to identify the predictive factors associated with low peritoneal carcinomatosis index (PCI) after 3or4 NACT cycles; complete IDS with no macroscopic residual lesion (CC0); high pathological chemotherapy response score (CRS3). Methods: The French dataset was built with the CHIVA (C) randomized phase II trial in 133 patients (NCT01583322). The Italian dataset was built with the Policlinico GEMELLI (G) real-life registry with 357 patients (ID5936–ProtN45). Univariate/multivariate logistic regression models were used to identify the clinical and biological covariates associated with: 1) low PCI after NACT (Sugarbaker PCI ≤ 10, or Fagotti score at IDS ≤ 2); 2) CC0 IDS; and 3) pathological CRS3. The tested predictors were the modeled CA-125 longitudinal kinetics parameter KELIM; the best radiological response according to RECIST 1.1; and BRCA mutation/ homologous recombination deficiency (HRD) status (C: ShallowHRD; G: Myriad&AmoyDx). The analyses were led independently in the 2 datasets. Results: Odds-ratios (OR) outcomes [95%CI] are presented in Table (*significant variables at multivariate). In both datasets, higher KELIM was the only predictor reproducibly associated with lower PCI after NACT (OR 4.08-4.44); higher probability of complete IDS (OR 4.66-7.29); and higher probability of pathology CRS3 (OR 2.97-12.43). The radiological response was inconsistently significant. The BRCA/HRD status was not predictive of IDS success elements. Conclusions: In 2 independent international datasets, the tumor primary chemosensitivity (assessed by CA-125 KELIM) was the only consistent predictor of IDS success after NACT in both datasets. Clinical trial information: NCT01583322 . [Table: see text]
The BEV1L study: Do real-world outcomes associated with the addition of bevacizumab to first-line chemotherapy in patients with ovarian cancer reinforce clinical trial findings?
Authors: Duska Linda R. , Lim Jonathan , Boyle Tirza Areli Calderón , Guinter Mark , Halloran Siobhan , Hartman John , Schilder Jeanne M. , Hurteau Jean A. , Golembesky Amanda 
Published: June 2024

5563 Background: Data from the GOG-0218 (NCT00262847) and ICON7 (NCT00483782) trials suggest that adding bevacizumab (bev) to first-line (1L) chemotherapy (CT) for treatment of stage III/IV ovarian cancer (OC) improves progression-free survival (PFS) among the overall population, but an improvement in overall survival (OS) may be limited to patients (pts) with high-risk clinical factors. Real-world (rw) evidence assessing the impact of adding bev to 1L CT may help identify subgroups of pts who may benefit from 1L CT alone vs CT + bev. Methods: This retrospective study included pts from the US nationwide Flatiron Health electronic health record–derived deidentified database who were diagnosed with stage III/IV epithelial OC on/after 1/1/2016 and initiated 1L CT ± bev on/after 1/1/2017. Pts with high-risk clinical factors were defined as those with stage IV disease or stage III disease with either visible residual disease or no evidence of surgery. Rw endpoints included time to next treatment (rwTTNT), rwPFS, and rwOS. Kaplan-Meier methods were used to estimate unadjusted median outcomes, indexed to 1L start date. Results: Among 1752 pts, median age was 68 years (IQR, 60–75 years), and median follow-up time was 18.5 months (IQR, 8.0–36.6 months). Among pts with high-risk clinical factors, median rwTTNT was significantly longer with 1L CT + bev than with CT alone; no differences were seen with median rwPFS, although a trend toward longer rwOS was observed with 1L CT + bev vs with CT alone (Table). Among pts without high-risk clinical factors, no significant differences were observed in median estimates of rwTTNT, rwPFS, or rwOS between pts receiving 1L CT + bev and pts receiving CT alone. Conclusions: This rw study provides support for findings from ICON7 and GOG-0218, suggesting that the benefit of adding bev to 1L CT may be limited to pts with high-risk clinical factors. [Table: see text]
Artificial intelligence to predict homologous recombination deficiency in ovarian cancer from whole-slide histopathological images.
Authors: Frenel Jean-Sebastien , Bossard Céline , Rynkiewicz Joseph , Thomas Florian , Salhi Yahia , Salhi Sanae , Chetritt Jérôme 
Published: June 2024

5578 Background: In the field of ovarian cancer diagnosis, predicting Homologous Recombination Deficiency (HRD) holds paramount importance for personalized treatment strategies. Histopathology tissue analysis is considered as the gold standard in cancer diagnosis, prognosis, and theranostic. Whole Slide Imaging, i.e the scanning and digitization of entire histology slide, is now being adopted in numerous pathology labs, allowing development of deep-learning analysis of the large amount of morphological features contained in these WSI. The aim of this study is the development of a cutting-edge deep learning model designed to predict HRD status directly from WSIs of ovarian cancer tissue samples. Methods: We introduce a DNN designed to predict the HRD status for patients with ovarian cancer from whole slide images (WSI), using a fusion-like model using both cellular information and tissue-level morphological features. The algorithm has been trained and evaluated using a cross-testing and cross-validation technique on 151 patients with at least one WSI from a discovery dataset using a 5-fold stratified framework. We then externally validated the model onto The Cancer Genome Atlas (TCGA) from which the HRD status is available (n=93). Results: The performance of HRD status prediction was assessed on the basis of area under curve (AUC).The proposed architecture achieved an AUC of 0.74 on the discovery cohort and 0.67 on the TCGA. Results to the pathologist could be provided immediately and integrated into the pathologist report. External validation on the PAOLA cohort dataset is ongoing. Conclusions: By harnessing the power of deep neural networks (DNN), we provide a rapid and scalable solution for HRD prediction, circumventing the limitations of traditional molecular assays. Successful integration of this deep learning model into routine pathology workflows could significantly enhance diagnostic efficiency, reduce the turnaround time and financial cost compared with molecular assay. It could finally inform clinicians in tailoring targeted therapeutic interventions for ovarian cancer patients, thereby advancing precision medicine in the context of HRD-associated ovarian cancers.
Phase II study of pembrolizumab and lenvatinib in platinum sensitive recurrent ovarian cancer.
Authors: Bauer Smadar , Saad Akram , Greenhouse Inbal , Rapoport Anna Ruth , Shahar Shir , Barnatan Tania , Satchi-Fainaro Ronit , Shapira-Frommer Ronnie 
Published: June 2024

5581 Background: Ovarian cancer (OC) is characterized by a high recurrence rate following primary surgical and systemic therapy with decreasing efficacy of subsequent treatment lines and accumulating toxicity. Immunotherapy had shown limited efficacy in recurrent OC with 8% response rate in a notable cohort study (Keynote 100).The combination of Pembrolizumab (P) with Lenvatinib (L) was evaluated in a small cohort of platinum resistant OC (LEEP 005) with a 32% response rate. This study assessed the P+L combination’s effectiveness in the platinum sensitive recurrence setting. Methods: In this investigator initiated phase 2 study (NCT04519151), we enrolled patients with platinum sensitive recurrent OC. Inclusion criteria were high grade serous or endometrioid histology, maximum of two previous treatment lines, measurable disease per RECIST 1.1, reserved organ function, and ECOG of 0 or 1. Patients received P (200mg every three weeks) and L (20mg daily) until disease progression or unacceptable toxicity or up to 35 cycles of P. L treatment could be maintained beyond 35 courses of P per investigator decision. Study's primary end point is response rate (RR), and secondary end points encompass progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and quality of life. Correlative study explored archival/fresh tumor tissue and blood biomarkers for response as well as fecal and vaginal microbiome. Results: Between May 2021 and July 2023 24 patients were treated. Median age was 65 years (range 43-77). 11(46%) received 1 prior treatment line and 11(46%) received prior bevacizumab. At a median follow up of 30 months, 12/24 (50%) had RECIST 1.1 response, 2 (8%) with CR and 10 (42%) with PR. Median PFS was 8 months. Median OS and DOR were not reached. At 6 and 12 months, response persisted in 10 and 3 patients, respectively. Treatment-related adverse events were noted in all patients, predominantly hypertension and fatigue. Dose reduction of L occurred in 19 (79%) patients mainly due to hypertension 8(33%), fatigue in 7(30%) and arthralgia in 5(21%). Discontinuation due to adverse event occurred in three patients (hepatitis, nephrotic range proteinuria, diabetic keto-acidosis). There was no treatment-related death. Data on the QOL analysis and biomarker study will be presented later. Conclusions: L+P combination showed meaningful responses and manageable toxicity in platinum sensitive recurrent OC patients thus potentially provides a non chemotherapy alternative. Effect on survival and response to subsequent therapies is yet to be evaluated. Further research is essential to pinpoint the patient subset that can benefit the most from this combination. Clinical trial information: NCT04519151 .
Phase 2, single arm clinical trial to evaluate the safety and activity of oregovomab and niraparib as a combinatorial immune priming strategy in subjects with platinum sensitive recurrent ovarian cancer: FLORA-4 study.
Authors: Duska Linda R. , Secord Angeles Alvarez , Richardson Debra L. , Jada Srinivas Rao , Gupta Sunil 
Published: June 2024

5586 Background: Oregovomab, a murine IgGκ1 MAb, with high affinity binding (1.16 x 1010/M−1) to the tumor associated antigen CA125 acts as a therapeutic vaccine inducing indirect immunization by cellular and humoral immune responses directed against CA125. We hypothesize that T cells which have been immune sensitized by oregovomab may be further activated in the presence of niraparib mediated induction of STING (STimulator of INterferon Genes). The primary objective was to assess the safety and activity of combination oregovomab and niraparib in platinum sensitive EOC. Methods: An open-label single arm Phase 2 evaluation of the combination of oregovomab and niraparib in subjects previously treated with 1 to 3 lines of platinum-based chemotherapy. All subjects received the niraparib and oregovomab. The daily dose of niraparib was weight based (200-300 mg) taken orally from Day 1 Week 1 to at least the end of Week 12. Oregovomab (2 mg) was administered at Day 1 of Weeks 1, 4, 7, 12, and 20. This study endpoints were disease control rate (DCR) defined as patients that achieved CR, PR and SD; early humoral response; and safety. Results: Between July 2022 and June 2023, 10 eligible patients with a median age was 67.5 years were enrolled, and all patients were included in this analysis. 6 patients had received 2 prior lines and 4 patients had received 1 prior line of chemotherapy. Five patients received prior PARP inhibitors, 1 patient with HRD, and 1 patient with gBRCA mutation. The median number of oregovomab doses administered were 5 (range, 2.0 to 5.0) and median niraparib doses were 118.5 (range, 28.0 to 168.0). Of the 10 patients enrolled, 1 patient (10%) achieved an objective partial response (PR) and 5 patients had disease stabilization (SD), for an overall DCR of 60% at 12 weeks assessment. Of the 5 patients with SD, 2 maintained SD until week 24 assessment while the remaining patients progressed. The duration of response in the 1 patient with objective response was 2.9 months and the median duration of DCR is not evaluable (range 2.9 months - NE). Treatment related all grades adverse events (AEs) to niraparib included anemia (30%), thrombocytopenia (30.0%) and hypertension (30.0%), and oregovomab related all grades AEs included urticaria in 1 patient (10%). Conclusions: Combination oregovomab and niraparib in patients with platinum sensitive EOC was well tolerated with no new safety signals. Translational research is ongoing to assess biomarkers of early humoral response. Clinical trial information: NCT04498117 .