bluuebunny/crossref_metadata_2025_split huggingface dataset:
The correlation of homologous recombination deficiency status with and Olaparib efficacy in Chinese ovarian cancer patients.
Authors: Peng Yongpai , Xie Qingsheng , Xu Guocai , Zhang Bingzhong 
Published: June 2022

e17556 Background: Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2, results in homologous recombination deficiency (HRD) can be a target for therapeutic strategies of ovarian cancer (OC) including poly (ADP-ribose) polymerase inhibitors (PARPi). Here, we proposed an emerging method based on ADx-GSS algorithm to predict HRD status and explore the correlation between HRD status and first-line maintenance therapy of Olaparib in OC patients or Olaparib maintenance therapy in platinum-sensitive relapsed (PSR) OC patients. Methods: Formalin-fixed, paraffin-embedded tissues of 38 consented OC patients between January 2016 and March 2021 were retrospectively collected. Genomic DNA was extracted and subjected to AmoyDx HRD Focus Panel (Amoy Diagnostics Co., Ltd) covering HRD score and BRCA1/2. The HRD score was calculated as the weighted sum of different types of copy number variation (CNV) trained through BRCAness events. Tumors were defined as genomic instability with an HRD score of ≥ 50 (i.e. HRD-positive). The primary endpoint was progression-free survival (PFS), and was assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: Histology of collected samples were mostly serous OC (84.2%). All samples were at stage III-IV (80.84%). The fractions of HRD-positive (n = 26) and HRD-negative (n = 12) group were 68.4%, and 31.6%, respectively. 65.8% (n = 25) of the OC patients had received Olaparib first-line maintenance therapy and 34.2% (n = 13) of PSR patients had received Olaparib maintenance therapy. In December 2021, 34.2% (n = 13) of the whole patients had relapsed. A significant PFS benefit was seen in HRD-positive patients compared with HRD-negative ones (P = 0.0017) or in the first-line maintenance treated population (P = 0.0068). In patients with HRD-positive tumors that did not have BRCA mutations, the PFS benefit was improved versus HRD-negative patients without BRCA mutations. However, Olaparib showed no efficacy difference between HRD-positive and HRD-negative tumor in PSR OC patients. Conclusions: HRD status tested by AmoyDx HRD Focus Panel is significantly correlated with the efficacy of Olaparib, and our results demonstrated a significant PFS benefit for HRD-positive patients compared with HRD-negative patients, especially for patients received Olaparib first-line maintenance therapy.
Relationship between BRCA mutation status and adverse effects of PARP inhibitors.
Authors: Gao Yuewen , Li Hongqi , Li Changzhong , Wang Fei , Li Chunyan , Zou Yonghui , Zhang Tiange , Gai Minxue , Zhang Hongyang 
Published: June 2022

e17566 Background: PARP inhibitors exert their anti-tumor effects by targeting BRCA-deficient cancer cells through a mechanism of synthetic lethality and PARP trapping. However, as a drug in the systemic route of administration, it has the same killing effect on BRCA-deficient normal cells in vivo, especially those with faster proliferation, such as those in the bone marrow hematopoietic cells and cells in the digestive tract. We, therefore, hypothesize that BRCA mutant patients are more likely than BRCA wild-type patients to have severe adverse effects that result in dose reduction, interruption, or discontinuation of the drug, thus affecting the patient's prognosis. Methods: Information was retrospectively collected on 46 patients diagnosed with ovarian cancer who had been treated with PARP inhibitors between August 2018 and October 2021. The patients were divided into BRCA mutation group (n = 24), BRCA wild-type group (n = 16), and BRCA unknown group (n = 6) according to the genetic test results. Results: The most common adverse effects in all three groups were gastrointestinal reactions, mostly grade 1 and 2. Hematologic reactions were the next common adverse effects, the most common of which was anemia. No extremely serious adverse effects such as myelodysplastic syndrome occurred in our patients. The most serious adverse effects in our patients were grade 3, 75% of which were anemia. In BRCA mutant patients, the incidence of gastrointestinal reactions and hematologic effects was 75% and 50%, respectively, while these two rates were 50% and 25% in BRCA wild-type patients. The incidence of adverse effects was significantly higher in BRCA mutant patients than in BRCA wild-type patients. The incidence of grade 3 adverse events was 37.5% in BRCA mutant patients and 12.5% in BRCA wild-type patients. The incidence of grade 3 adverse events was significantly higher in BRCA mutant patients than in BRCA wild-type patients. Overall, adverse events were higher and more severe in the BRCA mutant than in the BRCA wild type (P＜0.05). Conclusions: Patients with BRCA mutations are more likely than patients with BRCA wild-type to have serious adverse effects that result in dose reduction, interruption, or discontinuation of the drug. Therefore, we should pay more attention to the monitoring of BRCA mutant patients and take more measures to prevent or mitigate their adverse effects, so that they can always take PARP inhibitors according to the recommended dose as much as possible, which may lead to a better prognosis for more patients.[Table: see text]
Cancer stem cell assay for identification of effective treatments for platinum-resistant recurrent ovarian cancer.
Authors: Claudio Pier Paolo , Howard Candace M. , Valluri Anisha P , Lawrence Logan , Bush Stephen , Bou Zgheib Nadim , Lirette Seth T. , Denning Krista L , Valluri Jagan 
Published: June 2022

e17584 Background: Disease recurrence and progression of ovarian cancer is a common event, which is accompanied by the development of platinum-resistant or refractory disease. The presence of chemo-resistant cancer stem cells (CSCs) contributes to tumor propagation, maintenance, and treatment resistance of this difficult to treat disease. The choice of appropriate chemotherapy is critical to the management of advanced epithelial ovarian cancer. We developed a CSCs assay (ChemoID) that identifies the most effective chemotherapy for individual patients from a panel of FDA-approved chemotherapies. Methods: Ascites or interventional radiology biopsies were collected under physician order from 85 consecutive patients affected by 3rd relapsed ovarian cancer. Test results from the assay were used to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, if needed. Our study assessed the correlation of the ChemoID test results to treatment outcomes independently of other biomarkers. A retrospective chart analysis and review of CT and PET scans were performed to determine patients’ outcomes for tumor response, progression-free survival (PFS), and overall survival (OS). Results: We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the ChemoID drug response assay had an improvement in their median PFS and OS when compared to historical median PFS and OS and/or when compared to patients who could not receive high cell kill chemotherapies (PFS low cell kill 3.5 months vs. high cell kill 12.0 months; OS low cell kill 6.0 months vs. high cell kill 15.0 months). Conclusions: The current evidence strongly suggests that the ChemoID assay predicted the effectiveness of specific therapies, as well as improved outcomes for patients treated with assay-sensitive therapies.
Therapeutic implications of mutations in high grade serous ovarian carcinoma when evaluated by race.
Authors: Garg Ruchi , Schink Julian C. , Buttin Barbara , Elvin Julia Andrea , Godbee Natalie , Moran Amber , Doctor Vicki , Tan Bradford A. , Sequeria Judy , Farley John H. , Markman Maurie 
Published: June 2022

e17590 Background: Individualizing oncologic treatment by using precision oncology techniques that allow for detection of genomic alterations (GA) has become critical. We present an analysis of comprehensive genomic profiling (CGP) of a large series of high grade serous ovarian carcinoma (HGSOC) patients assayed in a nationwide cancer network. Racial disparities in genomic alterations may assist in better targeting therapies, predicting drug resistance, and potential germline mutations. Methods: 312 patients with HGSOC underwent CGP with hybrid capture on tumor tissue for treatment decision-making between 01-2013 to 06-2021. Clinically relevant genomic alterations (CRGA) were reported as targetable marker. Statistical analysis performed with Fisher Exact test. Results: Median age was 55 years (range, 23-81), 71.2% were White, 16.4% were Black, 3.9% were Hispanic, and 1.3% were Asian. GA were identified in 98.7% (308/312) of these patients. TP53 mutations were present in 286 of 312 patients (91.7%) and interestingly, while not statistically significant (p = 0.06) was present in 98% of black women and 89.2% of white women. BRCA1 mutation was present in 14.4% of white women and in 17.6% of black women. BRCA2 mutation was present in 9.9% of white women and 9.8% of black women. Several interesting mutations were identified, see table below. Conclusions: In this 312-patient series of women with HGSOC, we note several prominent mutations in the tumors. While not statistically significant, there is a trend of larger number of poorer prognostic mutations in black women including p53, KRAS and CCNE1. Some studies have found the amplification of CCNE1 and mutation of homologous recombination repair genes to be mutually exclusive in HGSOC which may compel us to find other therapeutic interventions than the PARP inhibitors for these patients.[Table: see text]
Efficacy and safety of apatinib in the treatment of advanced platinum-resistant recurrent epithelial ovarian cancer: A retrospective study.
Authors: Pan Zhongmian , Luo Zhongbin , He Hongying , Chen Yujie , Zhao Bingbing , Yang Zhijun , Li Li 
Published: June 2022

e17594 Background: Apatinib is an oral anti-angiogenic drug that mainly targets vascular endothelial growth factor receptor 2 (VEGFR-2) and is widely used in a variety of solid tumours. The purpose of this study is to evaluate the clinical efficacy and safety of apatinib in patients with advanced platinum-resistant relapsed epithelial ovarian cancer (EOC). Methods: This study retrospectively analyzed the clinical data of patients with stage IIIC-IV platinum-resistant relapsed EOC between January 2014 and May 2018. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were reviewed and evaluated. The propensity score matching (PSM) method was used to determine the data included in this study of the final case. Results: This study included 36 patients in the apatinib group and 72 patients in the control group, according to the 1:2 propensity matching. The follow-up ended in January 2019, and the median follow-up time was 28 months. The ORR was 30.56% in the apatinib group and 16.67% in the control group. The DCR in both cohorts was 66.67% and 44.44%, respectively. The median PFS (6.0 vs. 3.3 months) and OS (15.8 vs. 9.2 months) in the apatinib group were significantly longer than that in the control group. In addition, apatinib was more effective than conventional chemotherapy in reducing the risk of PFS [HR 0.40 (95% CI 0.22-0.76), P = 0.0017] and OS [HR 0.40 (95% CI 0.21-0.73), P = 0.002]. Multivariate Cox analysis showed that the course of treatment and decrease in serum CA125 levels are independent risk factors for PFS in patients, while for apatinib, the length of treatment course and the location of the lesion are independent risk factors for recurrence that affects the OS of patients. The most common grade 3/4 toxicities in the apatinib group were hypertension, hand-foot syndrome, and oral mucosal ulcers. Conclusions: Apatinib therapy was an effective treatment for patients with advanced platinum-resistant relapsed EOC. The toxicities were tolerable and manageable.
Associations between genomic instability score (GIS), molecular characterization, and clinical outcomes in high grade serous ovarian cancers (HGSOC).
Authors: Watson Catherine , Paradis Jessie , Thomas Samantha M. , Timms Kirsten , Perry Michael , Perry TC , Secord Angeles Alvarez 
Published: June 2022

e17596 Background: To describe the molecular profiles of tumors with a positive GIS status (GI+) in patients with newly diagnosed BRCA wild-type HGSOC and to examine possible associations between genomic mutations and survival outcomes in these patients. Methods: Genetic testing results of patients who underwent both somatic BRCA1/BRCA2 and germline multigene panel testing between 1/1/2015 and 12/1/2020 were prospectively collected. Patients had multigene panel germline testing in tandem with Myriad somatic BRCA1/2 testing and GIS assay. Expanded somatic NGS testing (108 gene panel) was then performed on GIS+ (GIS ≥42) tumor samples from women without somatic or germline BRCA mutations. The primary outcomes were the type and frequency of genomic mutations, which were grouped according to the following pathways: DNA-repair related (separated into homologous recombination (HR), Fanconi anemia (FA), other DNA repair related pathway) or non-DNA repair related. GIS and molecular profiles of tumors from patients who recurred versus those who did not recur were compared. Results: 143 women with HGSOC underwent both germline and somatic testing. 18/143 (12.5%) tumors with negative germline multigene panel and negative somatic BRCA1/2 testing were GIS+. 17/18 (94.4%) GIS+ tumors had pathogenic TP53 mutations. While all samples had at least one DNA repair related variant, only 22.2% had an HR-associated variant, and 16.7% had an FA variant. At time of analysis, 10 patients had recurred and 8 patients had not recurred. Median PFS of those who recurred was 15.8 months (range 4.8-30.1 months). Patients who recurred had lower GIS (median 47.5 vs. 69.5, p = 0.04), but they had no appreciable differences in gene or pathway alterations when compared to those who did not recur. Conclusions: Known pathogenic alterations in DNA repair pathways commonly associated with HR were rare in this cohort of BRCA negative HGSOC patients with GIS+ tumors. However, there was a high frequency of other DNA repair pathway alterations. Further investigation of the molecular signatures associated with recurrence are needed to identify potential novel targets. Lower GIS in this cohort were associated with higher risk of recurrence, although this finding must be validated in the setting of larger studies. [Table: see text]
A deep learning solution for detection of homologous recombination deficiency in ovarian cancer using low pass whole-genome sequencing: Evaluation of the analytical performance.
Authors: Buisson Adrien , Saintigny Pierre , Pujade-Lauraine Eric , Montoto-Grillot Christine , Vacirca Davide , Barberis Massimo , Colombo Nicoletta , Harle Alexandre , Gilson Pauline , Roma Cristin , Bergantino Francesca , Harter Philipp , Pignata Sandro , Gonzalez Martin Antonio , Schauer Christian , Fujiwara Keiichi , Vergote Ignace , Nøttrup Trine Jakobi , Just Pierre-Alexandre , Ray-Coquard Isabelle Laure 
Published: June 2022

e17599 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) induce synthetic lethality in cells with homologous recombination deficiency (HRD). PARPi treatment revolutionized management of patients with cancer, particularly in types where HRD is common, such as ovarian and breast cancer. However, challenges in the implementation of available methods currently limit adoption of HRD testing in the clinics. Here we present the analytical performance evaluation of the Genomic Integrity Index (GII) (SOPHiA GENETICs SA). Methods: GII is a deep-learning based solution for identification of HRD positive tumors from low-pass whole genome sequencing (lpWGS) data (X1 fold coverage). The analytical performance of the GII was evaluated as positive (PPA), negative (NPA) and overall (OPA) percentage of agreement with the HRD status determined by Myriad myChoice CDx (Myriad Genetic Laboratories, Inc.; US FDA-approved). We generated whole genome sequencing libraries for DNA extracted from 139 ovarian cancer Formalin-Fixed Paraffin- Embedded samples, in 4 independent clinical laboratories. We sequenced to the equivalent of 1X coverage (̃10 million reads, 150 base paired end reads, Illumina) and performed HRD classification data using GII using manufacturer’s recommended thresholds. Results: The GII demonstrated high analytical concordance with Myriad myChoice CDx with 91.7% PPA, 95.5% NPA and 94.5% OPA (Table). The HRD status obtained by GII from a subset of positive and negative samples was 100% reproducible (n = 4) between runs. Conclusions: The HRD status obtained by GII is highly concordant with that obtained from standard method, supporting that GII allows accurate and reproducible detection of HRD from lpWGS data. LpWGS is amongst the most cost-effective and easy to implement genome profiling methods, making it uniquely suited for clinical applications. [Table: see text]
Liquid-biopsy-derived glycoproteomic profiling as a novel means for noninvasive diagnosis of ovarian cancer.
Authors: Serie Danie , Moser Kaitlynn , Pickering Chad , Aiyetan Paul , Xu Gege , Rice Rachel , Ramachandran Prasanna , Lindpaintner Klaus 
Published: June 2022

e17604 Background: Ovarian cancer (OC) is the fifth- leading cause of cancer-related deaths among women, and the most lethal gynecological cancer. Currently available biomarkers, including CA-125 and HE4, show suboptimal diagnostic performance for differentiating among benign and malignant pelvic tumors, and the early recognition of OC. Differentiation of benign and malignant pelvic tumors is required for proper patient triaging and management, yet non-invasive methods remain a largely unmet medical need. Methods: We applied a novel platform for characterizing peripheral blood glycoproteomic biomarkers, combining liquid-chromatography/mass spectrometry (LC-MS) with artificial intelligence/neural networks (AI-NN) for the targeted quantification of serum protein glycosylation at intact glycopeptide level to analyze serum samples from 296 treatment-naïve women with histopathology-confirmed diagnosis of either benign (n = 151) or malignant (n = 145) tumors, and from 55 healthy control subjects, procured from a commercial biobank. Using data-dependent acquisition, a panel of 683 serum glycosylated and non-glycosylated peptides, representing 71 serum proteins, was interrogated. Samples were randomly divided into a training and a testing set for multivariable analysis. Data processing was performed using PB-Net, an in-house-developed high-throughput peak integration software. Raw data were normalized, processed by statistical analysis, and applied to machine learning models. Results: Comparison of glycopeptide abundances among patients with OC and benign pelvic tumors yielded 428 statistically significantly differentially expressed glycopeptides/peptides (at FDR < 0.05). A subpanel of these markers used to generate a score for predicting OC yielded areas under the receiver-operating-characteristic of 0.955 and 0.894 in the training and testing sets, respectively. The predicted probability of malignancy increased with cancer stage, and probability distributions were similar across training and test sets. Applying the model to healthy subjects, not utilized in training, resulted in few misclassifications and a spread nearly equivalent to that of the benign tumor cases. This indicates the signature robustly predicts malignancy and severity of disease. Conclusions: Our novel approach exhibited impressive levels of accuracy for the noninvasive differentiation of benign and malignant pelvic masses, compared with existing biomarkers and algorithms, thereby demonstrating the utility of glycoprotein profiles as a powerful, noninvasive new diagnostic modality.
Defining a prognostic risk score in ovarian cancer patients by integrated analysis of serum mesothelin, HE4, CA125 and surgical outcome.
Authors: Wimberger Pauline , Klotz Daniel , Göckenjan Maren , Link Theresa , Kuhlmann Jan Dominik 
Published: June 2022

e17611 Background: In ovarian cancer, serum CA125 is currently the only biomarker used in routine clinical practice and has several limitations, e.g. it is not entirely specific for ovarian malignancy. Alternative serum biomarkers have been proposed for ovarian cancer, such as mesothelin or human epididymis protein 4 (HE4). Although it is known that single marker analysis is often insufficient for diagnostic purposes or relapse prediction, no comprehensive studies on the combination of these markers have been conducted, yet. Using a multi-marker prediction model, we herein investigated the clinical usefulness of mesothelin and HE4, detected in a sequence of pre- and post-operative serum samples, in complementing the standard marker CA125. Methods: Serum mesothelin, HE4 and CA125 were quantified by Lumipulse G chemiluminescent enzyme immunoassay (Fujirebio) in a total of 432 serum samples from 90 healthy controls and 192 ovarian cancer patients (thereof 81.8% with FIGO III/IV), including 151 paired pre- and post-operative samples. Results: Pre-operative serum mesothelin and HE4 were significantly elevated compared to healthy controls with a median ratio (IQR) to controls of 2.6 and 9.6, respectively (p < 0.0001). High pre-operative levels of mesothelin or HE4 alone were significantly correlated with advanced FIGO-stage (p < 0.0001) and predicted surgical outcome (p < 0.0001). We retrospectively compiled mesothelin and HE4 levels with CA125, BRCA mutational status and surgical outcome, in order to define a multi-marker setting. Both, mesothelin and HE4 levels were independent from BRCA mutational status, however they positively correlated with CA125. Detection of pre-operative HE4 > 498pM (OR = 4.1, p < 0.0001) combined with pre-operative CA125 > 516U/mL (OR = 2.2, p = 0.001) was the best combination to predict surgical outcome (AUC = 0.815). Finally, we defined a prognostic signature, including pre-operative CA125, post-operative mesothelin, HE4 and surgical outcome, which was superior to the individual prognostic capacity of all included parameters. Our model allowed the calculation of a weighted risk score, stratifying patient at “lower risk” (score 0-4) or at “higher risk” (score 5-10). Patients with higher risk had significantly shorter PFS (19.0 months (95%CI = 16.1-21.8) vs 64.1 months (95%CI = 56.8-71.3) p < 0.0001) and OS (34.0 months (95%CI = 28.6-39.3) vs 71.2 months (95%CI = 64.6-77.7) p < 0.0001). Conclusions: This is the first study, proposing an integrated prognostic risk score for ovarian cancer patients, which could easily be implemented into routine diagnostics and may guide personalized treatment decisions. Patients at “higher risk”, as identified by this model, could potentially benefit from an intensified therapy regime, whereas patients at “lower risk” might be suitable for treatment de-escalation.