bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical validation of EndoPredict in premenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer.
Authors: Constantinidou Anastasia , Marcou Yiola , Simmons Timothy , Bernhisel Ryan , Hughes Elisha , Meek Stephanie , Kakouri Eleni I. , Georgiou Georgios , Zouvani Ioanna , Savvidou Gabriella , Kuhl Vanessa , Doedt Jennifer , Wagner Susanne , Gutin Alexander , Lanchbury Jerry , Kronenwett Ralf , Rakha Emad A. 
Published: June 2021

537 Background: The EndoPredict 12-gene prognostic assay is validated to predict distant recurrence-free survival (DRFS) and response to chemotherapy in post-menopausal women with ER+, HER2- breast cancer. This study evaluated the performance of EndoPredict in pre-menopausal women. Methods: Stored tumor samples from women with ER+, HER2- primary breast cancer who were pre-menopausal at the time of diagnosis and were systemically treated with endocrine therapy alone were obtained from two sites (University of Nottingham and University of Cyprus). These samples were tested with EndoPredict to produce a 12-gene molecular score (EP). Pathologic tumor size and nodal status were algorithmically combined with the EP score to produce the clinicomolecular EPclin score. Cases with tumors > pT3, which were treated with chemotherapy, or for whom the EPclin score was missing or invalid were excluded. Associations of EP and EPclin with 10-year DRFS were evaluated in terms of hazard ratios (HRs) from Cox proportional hazards models stratified by cohort. 10-year DRFS was estimated for EPclin high-risk and low-risk women by Kaplan-Meier analysis. Results: Out of 411 eligible cases, 385 had a valid EPclin score and were included in the analysis. Mean age at breast cancer diagnosis was 46.5 years (standard deviation 4.7). Most women (N = 239, 62.6%) had grade II tumors and 16.1% (N = 62) had node-positive disease. Over the observation period (median 9.7 years, interquartile range 6.6-13.9 years), 35 women had a distant recurrence within 10 years. Both the molecular EP score and the molecular-clinicopathologic EPclin score were associated with increased risk of distant recurrence [HR 1.3, 95% confidence interval (CI) 1.2-1.5; p < 0.001 and HR 3.6, 95% CI 2.3-5.7; p < 0.001, respectively]. Of these patients, 249 (64.7%) were categorized as low risk by EPclin score while the remaining 136 (35.3%) were categorized as high risk. Compared to EPclin low-risk women, EPclin high-risk patients were more likely to experience distant recurrence (HR 4.6, 95% CI 1.4-15.2; p = 0.004). At 10 years post-diagnosis, EPclin low-risk women who received endocrine therapy alone had a DRFS of 97% (95% CI 93-99%). Conversely, EPclin high-risk women had a DRFS of only 76% (95% CI 67-82%). Conclusions: The EPclin score is highly associated with DRFS in pre-menopausal women who received adjuvant endocrine therapy alone. Based on these data, pre-menopausal women with EPclin low-risk breast cancer may safely forgo adjuvant chemotherapy in addition to endocrine therapy.
Subgroup analysis of rucaparib versus chemotherapy as treatment for BRCA-mutated, advanced, relapsed ovarian carcinoma: Effect of platinum sensitivity in the randomized, phase 3 study ARIEL4.
Authors: Oza Amit M. , Lisyanskaya Alla Sergeevna , Fedenko Alexander A. , Dvorkin Mikhail , de Melo Andreia Cristina , Shparyk Yaroslav V. , Rakhmatullina Irina , Bondarenko Igor , Colombo Nicoletta , Svintsitskiy Valentyn , Cibula David , Póka Róbert , Oaknin Ana , Safra Tamar , Mackowiak-Matejczyk Beata , Ma Ling , McLachlan Karen Retta , Goble Sandra , Kristeleit Rebecca Sophie 
Published: June 2021

5517 Background: In ARIEL4 (NCT02855944), rucaparib significantly improved the primary endpoint of progression-free survival (PFS) vs chemotherapy (CT) in patients with advanced, relapsed ovarian carcinoma (OC) harboring a deleterious BRCA1/2 (BRCA) mutation (median PFS 7.4 [95% CI 7.3–9.1] vs 5.7 [5.5–7.3] months; hazard ratio (HR) 0.64 [95% CI 0.49–0.84]; P=0.001). This prespecified exploratory analysis investigated the effect of platinum sensitivity on the efficacy of rucaparib vs CT in ARIEL4. Methods: Patients were randomized 2:1 to oral rucaparib 600 mg twice daily or CT and stratified based on progression-free interval (≥1 to <6 months = platinum resistant; ≥6 to <12 months = partially platinum sensitive; ≥12 months = fully platinum sensitive). In the CT group, patients with platinum-resistant or partially platinum-sensitive disease received weekly paclitaxel 60–80 mg/m2; patients with fully platinum-sensitive disease received investigator’s choice of platinum-based CT (single-agent carboplatin or cisplatin, or platinum doublet). Patients could crossover from CT to rucaparib following radiologic disease progression. Efficacy endpoints were explored in patients with a confirmed BRCA mutation (patients with a reversion mutation were excluded), based on the randomization strata of platinum sensitivity. Results: The visit cutoff date was September 30, 2020. PFS and objective response rates (ORR) per RECIST v1.1 for rucaparib vs CT across subgroups are presented in the Table. The most common treatment-emergent adverse events in the rucaparib group were anemia/decreased hemoglobin (platinum-resistant patients: rucaparib 47% vs CT 40%; partially platinum-sensitive patients: 63% vs 27%; fully platinum-sensitive patients: 58% vs 20%) and nausea (52% vs 21%; 51% vs 23%; 60% vs 68%). In the intent-to-treat population, 74/116 (64%) patients in the CT group crossed over to receive rucaparib: 39/59 (66%) with platinum-resistant, 25/31 (81%) with partially platinum-sensitive, and 10/26 (38%) with fully platinum-sensitive disease. Conclusions: Results from this exploratory subgroup analysis suggest that rucaparib is a reasonable treatment option for heavily pretreated patients across all platinum sensitivity subgroups. Safety was consistent with prior rucaparib studies. Clinical trial information: NCT02855944. [Table: see text]
Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer.
Authors: Michels Judith , Ghiringhelli François , Frenel Jean-Sebastien , Brard Caroline , You Benoit , Floquet Anne , Eberst Lauriane , Bahleda Rastilav , Genestie Catherine , Balleyguier Corinne , Broutin Sophie , Pautier Patricia , Colomba Emeline , Pommeret Fanny , Massard Christophe , Marabelle Aurelien , Leary Alexandra 
Published: June 2021

5522 Background: There is a medical unmet need for effective treatments in platinum resistant ovarian cancer patients. We assessed the safety and efficacy of a combination of pembrolizumab with bevacizumab and pegylated liposomal doxorubicin (PLD). Methods: This is an open-label phase 1b trial in patients ECOG 0 or 1 with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The safety of the dual combinations of pembrolizumab with bevacizumab or with PLD were previously evaluated in 6 patients respectively. In the absence of dose limiting toxicities (DLT) the triple combination was evaluated at a maximum tolerated dose (MTD)-1 for PLD in 3 patients and in the absence of DLT at MTD. The sample size was calculated according to the modified toxicity probability interval design. The primary evaluation criteria was the safety, the secondary endpoint was the outcome. Pharmacokinetics of the flat dose of bevacizumab will be evaluated. Results: 22 patients were enrolled from September 2019 until June 2020 in six French centers. 3 initial patients have been treated at 20mg/m2 of PLD (MTD-1) and 19 patients were treated at the dose of 30mg/m2 of PLD (MTD) combined with 200mg of pembrolizumab until progression, unacceptable toxicity, or withdrawal of consent and 400mg of bevacizumab for a total of six cycles. The patients’ characteristics are reported in the table. No DLT occurred. Grade 3 palmar-plantar erythrodysesthesia were reported in 4 patients. The recommended phase II dose of PLD was 30mg/m2 in combination with pembrolizumab and bevacizumab. For patients treated at MTD, the overall response rate was 32% (6 partial responses) with 74% of clinical benefit with a durable response in 10 patients (53%). Median number of cycles was 7.5 (2 to not reached). Two patients are still on treatment. Correlative studies are ongoing. Conclusions: The combination was well tolerated and demonstrated clinical benefit in 74% platinum resistant ovarian cancer patients with durable response (>6 months) in 53% of patients. Clinical trial information: NCT03596281. [Table: see text]
Association of homologous recombination deficiency in ovarian cancer with neoantigen load and expression of immune checkpoints.
Authors: Fenerty Kathleen , Fares Charlene Marie , Konecny Gottfried E. 
Published: June 2021

5536 Background: Immune checkpoint blockade (ICB) is being explored as a treatment option in ovarian cancer, but objective response rates for single agent ICB are modest at around 10-15%. Validated biomarkers are needed to predict which patients will respond to ICB. BRCA mutations and homologous recombination deficiency (HRD) status are the only validated integral biomarkers in ovarian cancer. HRD tumors exhibit defective DNA repair mechanisms that promote increased mutational burden, which we postulate may correlate with higher neoantigen load and increased expression of targetable immune checkpoints. Methods: The Cancer Genome Atlas (TCGA) ovarian cancer dataset was evaluated and previously published, well annotated samples were obtained for HRD status. HLA type was determined with OptiType. Nonsynonymous mutations were annotated with Ensembl VEP. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 amino acids in length for MHC class I, reporting only those with a predicted IC50 less than 500 nM. Immune checkpoint gene expression counts were normalized with TCGAbiolinks. Correlation between HRD status and neoantigen load was assessed by Wilcoxon test. After log2 transformation, Wilcoxon tests evaluated for association between HRD status and expression of immune checkpoints. The relationship between HRD status and PD-L1 protein abundance with reverse phase protein array was measured. Results: Data from 154 HRD positive and 198 HRD negative tumors were analyzed. HRD positive status correlated with higher neoantigen load (p = 0.038) and increased expression of the immune checkpoints CTLA4 (p = 0.024), TIGIT (p = 0.027), and PVR (p = 0.002), but not PD-L1 (p = 0.238), LAG3 (p = 0.583), HVEM (p = 0.805), GAL9 (p = 0.750), NECTIN2 (p = 0.874), VSIG3 (p = 0.438), PSGL1 (p = 0.205) or VISTA (p = 0.531). TIM3 (p = 0.064) and B7H3 (p = 0.052) both demonstrated a trend towards increased expression in HRD tumors. Interestingly, HRD status showed a negative association with PVRIG (p = 0.028). There was no association between PD-L1 protein abundance and HRD status. Conclusions: HRD positive ovarian tumors demonstrate higher neoantigen load than HRD negative tumors, as well as increased expression of certain immune checkpoints. This supports the hypothesis that increased neoantigen load leads to compensatory induction of immune checkpoints, and suggests that HRD status may predict response to ICB, particularly to drugs that target CTLA4, TIGIT, PVR, TIM3 and B7H4.
Circulating tumor DNA as a noninvasive marker of resectability in ovarian carcinomas.
Authors: Mari Roxane , Pomel Christophe , Colombo Pierre-Emmanuel , Narducci Fabrice , Garnier Séverine , Carbuccia Nadine , Guille Arnaud , Provansal Magali , Cappiello Maria-Antonietta , Rousseau Fréderique , Blache Guillaume , Lambaudie Eric , Birnbaum Daniel , Bertucci Francois , Sabatier Renaud 
Published: June 2021

5548 Background: Ovarian cancer is the leading cause of death by gynecological cancer. Complete surgery remains one of the main prognostic factors. Laparoscopic exploration is mandatory to assess surgical resectability at diagnosis or after neoadjuvant chemotherapy. However, there is no clinical or biological marker that can correctly predict resectability and may be able to avoid a second laparoscopic exploration for initially unresectable diseases. Our aim was to assess circulating tumor DNA (ctDNA) value as a predictive non-invasive marker of evolution towards resectability for patients with epithelial ovarian cancer receiving first-line chemotherapy. Methods: We explored in this work one of the secondary objectives of the CIDOC study (NCT03302884). CIDOC is a multicenter prospective study aiming to explore ctDNA value as early marker of disease relapse after first-line treatment for epithelial ovarian cancer. Patients with mucinous histology or early stages not requiring chemotherapy are excluded. Plasma samples are collected at diagnosis, during neoadjuvant chemotherapy, and during follow-up. After DNA extraction, panel-based next generation sequencing is performed on both tumor samples and germline DNA, and somatic mutations of interest are selected for ctDNA monitoring. ctDNA analyses are conducted using droplet digital PCR (BioRad QX200) by measuring the variant allele fraction (VAF) of previously identified mutations. Results: This intermediary analysis has included 47 patients diagnosed between March 2017 and December 2019. Median age was 69 years old (48 – 84). Most of the patients had advanced disease (89.4% stage FIGO III or IV), serous histology (94.8%), and high grade tumor (92.3%). Most of the patients underwent complete interval cytoreductive surgery (76.3% vs 17.4% complete upfront surgery). Most of the tumors had TP53 mutations (85.1%), following by alterations involving DNA repair genes (38.3%). Median cell-free DNA concentration at baseline was 0.38 ng/µL (0 – 12.8). ctDNA was identified in 92.1% of patients at baseline with a median VAF of 1.84% (0 – 42.52%). ctDNA VAF was correlated to the peritoneal dissemination ( p= 0.039) assessed with the peritoneal cancer index. ctDNA clearance after preoperative chemotherapy tended to be correlated to achievement of complete interval surgery for patients receiving neoadjuvant chemotherapy ( p= 0.108). Conclusions: ctDNA may be a promising non-invasive marker to assess peritoneal cancer spreading and to predict surgical resectability after neoadjuvant chemotherapy. If confirmed in larger populations, this may enable to avoid additional surgical explorations for patients who remain ctDNA positive after chemotherapy. Clinical trial information: NCT03302884.
Association of the Khorana Score with development of venous thromboembolism in ovarian cancer.
Authors: Marcus Ellen , Kuo Dennis Yi-Shin , Nevadunsky Nicole Suzanne , Gressel Gregory M. 
Published: June 2021

5555 Background: The Khorana score is a previously validated method to identify patients at high risk of VTE during chemotherapy who would potentially benefit from thromboprophylaxis. The objectives of our study were to evaluate risk factors and timing associated with VTE in a large cohort of ovarian cancer patients and to assess the predictive ability of the Khorana score in this population. Methods: After IRB approval, a retrospective analysis was performed of all patients with ovarian cancer in the Albert Einstein Tumor Registry who received treatment between 2000 and 2020. Demographic, clinical, surgical and histologic data and information regarding timing of VTE were abstracted from the medical record. Khorana scores were retrospectively calculated for all patients who received chemotherapy based on their pre-chemotherapy laboratory indices. Bivariate analysis and multivariable logistic regression were used to examine the association between Khorana score and VTE. Results: A total of 472 patients were included over a median follow-up time of 33.7 (13.3, 61.1) months of whom 142 (31%) underwent diagnostic imaging to rule out VTE. A total of 62 patients (15%) were diagnosed with VTE with a median time from presentation to VTE of 8.7 (2.7, 30.3) months. Individual covariates which were significantly associated with VTE included stage III-IV disease, epithelial histology, open surgery, radical tumor debulking, and presence of residual disease after surgery. Of the 254 patients who received chemotherapy for their disease, 36 (14%) developed VTE within 3 weeks of receiving chemotherapy. Patients with Khorana scores of 2 (OR 1.73 95% CI 0.88-3.42) or 3 (OR 0.89 95% CI 0.33-2.44) were not significantly more likely to develop VTE during chemotherapy compared to patients with a score of 1. However, patients with a score of 4 were 6.74 times more likely to develop a VTE during chemotherapy (95% CI 1.39 - 32.73). Overall, a Khorana score of 2 or higher conferred no significant increased risk of developing VTE during chemotherapy than a score of 1 (OR 1.61 95% CI 0.85- 3.02). In a multivariable model, the Khorana score was not significantly associated with risk of VTE and a Khorana score of 2 or higher could explain only 0.86% of the variability in predicting VTE. The only variables significantly associated with VTE after adjustment were stage III-IV disease and hyperlipidemia. Conclusions: Patients with ovarian cancer are at high risk of developing VTE many months after diagnosis and initiation of chemotherapy. Current ASCO and SGO guidelines recommend thromboprophylaxis for those initiating chemotherapy with a Khorana score of 2 or higher, however our study found that these patients are not at increased risk compared to those with a score of 1. Future models should be developed and validated in large population-based cohorts to determine if there is a more accurate strategy to identify women with ovarian cancer who are at risk for VTE.
Improving the prediction of surgical outcome at secondary cytoreduction in patients with ovarian cancer: Results from retrospective part of HELP-ER study NOGGO TR2/ENGOT OV47-TR.
Authors: Braicu Ioana , Kassuhn Wanja Nikolai , Kulbe Hagen , Wimberger Pauline , Taskiran Cagatay , Pietzner Klaus , Mustea Alexander , Armbrust Robert , Grabowski J.P. P. , Schmidt Felix , Ayhan Ali , Beteta Carmen Rosa , Fotopoulou Christina , Sehouli Jalid 
Published: June 2021

5558 Background: Complete resection at secondary cytoreductive surgery is associated with prolonged progression free and overall survival for patients with relapsed ovarian cancer. Secondary cytoreductive surgery has no impact on survival rates, if macroscopically tumor clearance cannot be achieved. Therefore, in order to avoid unnecessary perioperative morbidity and mortality, selection of patients who will undergo secondary tumor debulking is crucial. This study aims to improve upon the contemporary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score by including additional clinical variables like circulating HE4 and CA125 levels to predict surgical outcome at secondary cytoreduction. Methods: A total of 90 patients underwent secondary cytoreductive surgery and were retrospectively assigned a positive AGO score. Of those patients, 62 (68.9%) achieved optimal surgical outcome at secondary debulking with 28 (31.1%) patients retaining residual tumor mass ( > 0mm). Utilizing clinical variables including circulating HE4 and CA125 levels, we implemented a machine learning workflow to predict suboptimal surgical outcome in patients despite a positive AGO score. Results: We elucidated significantly lower levels of circulating HE4 (p = 0.0038) in patients with optimal surgical outcome compared to patients that retain macroscopic residual tumor at secondary cytoreductive surgery. Moreover, machine learning algorithms trained on clinical variables (e.g. serum HE4 level, serum CA125 level, age, Risk of Ovarian Malignancy Algorithmus (ROMA) score and occurrence of peritoneal carcinomatosis) achieved a mean area under the curve (AUC) of 78.4% based on 100 consecutive executions with randomized training and test sets. Conclusions: The application of machine learning allows to further improve the prediction of patients with high likelihood of achieving optimal surgical outcome at secondary cytoreduction. In turn, it might identify patients that would benefit from amplified treatment efforts. However, machine learning relies on large amounts of data to account for biological and clinical variation and produce predictions of sufficient/adequate quality. Given this limitation, we would validate this data within the prospective multicentric cohort of patients collected within NOGGO/ENGOT HELP_ER Trial.
Photodynamic therapy for preinvasive vaginal cancer.
Authors: Ivanova Viktoria A. , Verenikina Ekaterina V. , Nikitina Vera P. , Zhenilo Oksana E. , Ardzha Anna Yu. 
Published: June 2021

5592 Background: Photodynamic therapy (PDT) is an effective method for the treatment of various cancers resulting in apoptosis, autophagy and ischemic necrosis of irradiated tissues. The purpose of the study was to analyze the efficacy of PDT for pre-invasive vaginal cancer treatment. Methods: PDT results were studied in 20 patients aged 32-65 years with verified pre-invasive vaginal cancer. All patients received PDT with the Latus diode laser and Photolon or Photolan photosensitizers. The effect was evaluated with extended colposcopy. The criteria for efficiency included normalization of the colposcopic picture and the absence of atypical cells. The sizes of the irradiation fields varied from 1.5 to 2 cm, the number of fields - from 1 to 4, the power density - from 0.1 to 0.17 W/cm2, the light dose - from 40 to 100 J/cm2. The duration of a PDT session varied from 10 to 30 min, depending on the number of irradiation fields. The irradiation field necessarily included an area of normal tissue 3-5 mm surrounding the lesion. 4 to 6 sessions were required to restore the normal layer of stratified squamous epithelium. The antitumor efficacy of PDT was evaluated based on the results of visual observation of changes in the area of the treated pathological foci and information on the presence or absence of clinical symptoms of the disease 1 and 3 months after the treatment (WHO criteria). Results: Complete regression was registered in 100% of patients after 3 months. Repeated courses of PDT were required in cases with a wide spread of pathological foci and the impossibility of their simultaneous irradiation. At follow-up after 1 month, 3 of 20 patients (15%) showed local foci of atypical changes in the epithelium managed with repeated PDT courses. In 6 months, stable remission of the disease clinical symptoms in the treated pathological foci was registered. The results of the cytological study performed 3 months after PDT were normal in 100% patients; no negative changes were registered 6 and 12 months after PDT. Conclusions: The results of PDT in the treatment of patients with pre-invasive vaginal cancer demonstrated its high therapeutic efficacy and a minimal number of adverse reactions, which allows recommending PDT in the treatment of pre-invasive vaginal cancer.