bluuebunny/crossref_metadata_2025 huggingface dataset:
Artificial intelligence assisted bone lesion detection and classification in computed tomography scans of prostate cancer patients.
Authors: Masoudi Samira , Mehralivand Sherif , Harmon Stephanie , Walker Stephanie , Pinto Peter A. , Wood Bradford J. , Citrin Deborah E. , Karzai Fatima , Gulley James L. , Madan Ravi Amrit , Dahut William L. , Choyke Peter L. , Turkbey Baris
Published: May 2020

e17567

Background: Patients diagnosed with prostate cancer undergo computed tomography (CT) for pretreatment staging to rule out bone metastases. However, detection and classification of bone lesions on CT is challenging and subject to inter-reader variability. We present a cascaded deep learning algorithm for automatic detection and classification of bone lesions on staging CT in patients diagnosed with prostate cancer. Methods: CT scans from 56 patients with histopathologically proven prostate cancer were included. An expert radiologist annotated the extent of individual bone lesions (N = 4217) and labelled all regions as either benign or malignant. All scans were anonymized and normalized at the patient-level prior to training. Our method can be described as a two-stage framework, 1) A detection algorithm: Inspired by Yolo-v3 detection method, we designed a network with a backbone of darknet-53 pretrained on Coco dataset and four final scaling blocks to compensate for wide range of lesion diameters, 2) A classification algorithm: we formed a binary classifier based on ResNet-50 pretrained using the ImageNet dataset. We used a train/validation split equal to 90%/10% for this study. To facilitate the learning process, horizontal flipping, relative zooming and mean weighted averaging were used for data augmentation in stage 1. Instead, the classification algorithm took advantage of synthesized patches generated by Deep Convolutional Generative Adversarial Network (DC-GAN) for augmentation. Results: We could achieve a real-time (~120ms per slice) performance on our validation set with a median penalty of 0.3(0.02-0.78) false positives per true positive within each patient. Overall performance of our detection algorithm was 81% sensitivity and 86% positive predictive value. In stage 2, we obtained an accuracy of 89% for correct classification of benign from malignant bone lesions with no augmentation which was improved to 91% when we incorporated the augmented data for training. Conclusions: Our 2-stage algorithm sequentially detects and classifies bone lesions on CT of prostate cancer patients with a significant performance. To further improve our results and for generalizability we are accruing more data from different centers. Eventually, with greater dataset, both algorithms will be cascaded and trained as a whole unit to become one single tool for fully automatic detection and classification which serves as an aid for radiologists who read the staging CTs.
Single nucleotide polymorphisms (SNPs) as predictors of efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rivera Daniel Herrero , Duran Ignacio , Marcos Kovandzic Laura , Puente Javier , Mellado Begona , Grande Enrique , Virizuela Juan Antonio , Rodriguez-Moreno Juan Francisco , Azueta Ainara , Alonso Buznego Lucia Andrea , Luque Raquel , Garrigos Carmen
Published: May 2020

e17582

Background: Cabazitaxel is a semi-synthetic derivative of a natural taxoid approved for the treatment of mCRPC patients (pts) after failure to docetaxel. Despite its proven efficacy, there is variability in the response, progression-free survival (PFS) and overall survival (OS) of pts. Changes in the genetic constitution of the individual such as the SNPs could explain this variability. The aim of this study was to evaluate the impact of certain SNPs in cabazitaxel activity. Methods: Clinical data from 67 mCRPC pts treated with cabazitaxel between March 2011 and October 2016 were collected. DNA was isolated from formalin fixed paraffin-embedded tumor samples. 56 SNPs in 5 genes related with metabolism and/or mechanism of action of cabazitaxel (CYP3A4, CYP3A5, ABCB1, TUBB1, CYP2C8) were chosen based on their Minor Allele Frequency, linkage disequilibrium and information from dbSNP and analyzed by TaqMan OpenArray (Lifetech). The presence/absence of mutant alleles of the selected SNPs was correlated with clinical features, progression free survival (PFS) and overall survival (OS) of prostate cancer. Chi-square test and Kaplan-Meier with log-rank test were used for statistical analyses. Results: The median age was 61 years (range 44-82). 56.7% (n = 38) had a Gleason score ≥8 and 94% had received docetaxel in first line. Type of response to cabazitaxel was associated with median OS (Partial response = 24.35 months, Stable disease = 11.16 months, Progression disease = 5.8 months; p= 0.045). Univariate analysis, showed worsed OS at 1 year for wild type status of SNP rs151352 (OR = 4, 95%CI 1.27-12.58, p= 0.029). In addition, two SNPs (rs11773597, rs1202186) were associated with radiological response to cabazitaxel ( p= 0.031 and p= 0.030 respectively). Other 7 SNPs (rs11773597, rs2235040, rs1045642, rs1419745, rs1202170, rs6949448, rs11572093) were associated ( p<0.05) with Gleason score, pain, PSA doubling time, febrile neutropenia and asthenia. Conclusions: A particular SNP profile could be predictive of efficacy and related with toxicity in mCRPC population treated with cabazitaxel after progression to docetaxel. These outcomes become particularly relevant in patient selection given the recent results of the CARD trial.
Prognostic implications of gene amplifications identified by circulating tumor DNA (ctDNA) analysis in metastatic prostate cancer (mPC).
Authors: Dincman Toros , Giordano Antonio , Li Hong , Gourdin Theodore Stewart , Drusbosky Leylah , Howe Philip , Lilly Michael B.
Published: May 2020

e17594

Background: mPC is a dynamic disease that confers a poor prognosis- particularly in the metastatic castration-resistant prostate cancer (mCRPC) setting. Analysis of ctDNA provides an opportunity to identify and monitor somatic alterations (SAs) in a patient’s treatment course. However, how certain SAs can inform disease management is not fully characterized. We evaluated whether the presence of specific gene amplifications (GAs) and changes in plasma copy number (PCN) are associated with disease features and prognosis. Methods: This is a retrospective study of mPC patients seen at the Hollings Cancer Center between 2015-2019 who underwent ctDNA profiling using Guardant360 (Guardant Health Inc). Guardant360 identifies SAs and GAs of select genes by NGS. Descriptive statistics were used to summarize baseline patient characteristics. The chi-square test and odds ratio (OR) were used to evaluate associations between clinical factors and GAs. The Kaplan-Meier method was used to estimate OS from either the date of GA detection or the initiation of systemic therapy. Results: 130 men with mPC were identified as having ≥1 GA. The presence of liver and/or lung metastases were associated with GAs of BRAF (OR 2.5; 95%CI 1.1-5.8, p < 0.05) , CDK6 (OR 2.3; 95%CI 1.4-8.0, p < 0.01) , PI3KCA (OR 4.4; 95%CI 1.8-10.7, p < 0.01) , and FGFR1 (OR 3.1; 95%CI 1.1-9.0, p = 0.038). These GAs were also associated with having ≥2 concurrent GAs (p < 0.01 for each gene). From this cohort, survival analyses were completed on 59 patients with mCRPC. Men with only 1 GA, compared to men with ≥2 GAs, had improved median survival (mo.) from date of initial GA(s) detection (16.5 vs 9.4, p < 0.01) or therapy initiation (16.0 vs 9.0, p < 0.01). Among men with mCRPC, AR and/or MYC GA, median survival improved in men who had reduction in AR or MYC PCN during therapy compared to men without a PCN decrease (25.1 vs 15.9 p < 0.01). Conclusions: Patients with mPC who had liver and/or lung metastases were associated with having specific GAs in BRAF, CDK6, PI3KCA, and FGFR1. Notably, the presence of liver or lung metastases was not associated with AR GA. In mCRPC, patients with ≥2 GAs had decreased OS compared to men with one GA. Having an increased number of GAs is likely reflective of greater chromosomal instability and be associated with more aggressive disease. Our study reveals serial monitoring of AR and MYC PCN during therapy demonstrated reduced OS in patients without PCN reduction. This supports the use of serial ctDNA monitoring of PCN to inform therapeutic response and prognosis.
Genomic alterations associated with the progression from castration-sensitive to castration-resistant metastatic prostate cancer based on machine learning analysis of cell-free DNA genomic profile.
Authors: Lin Edwin , Hahn Andrew W. , Nussenzveig Roberto , Wesolowski Sergiusz , Maughan Benjamin Louis , McFarland Taylor Ryan , Rathi Nityam , Sartor A. Oliver , Sonpavde Guru , Swami Umang , Kohli Manish , Rich Thereasa A. , Yandell Mark , Agarwal Neeraj
Published: May 2020

e17596

Background: Metastatic castration-sensitive prostate cancer (mCSPC) eventually progresses to metastatic castration-resistant prostate cancer (mCRPC), which has few treatment options and carries a poor prognosis. We hypothesize that there are specific genomic alterations (GAs) associated with the progression from mCSPC to mCRPC. Methods: Patients (Pts) with mCSPC and mCRPC undergoing next-generation sequencing of cell-free DNA by a CLIA certified lab (G360, Guardant Health Inc., Redwood City, CA) as a part of routine care were retrospectively identified. Principal components analysis, an unsupervised ML algorithm, was used for data exploration and visualization. A combination of feature selection and supervised machine learning classification algorithms were used to identify genes associated with mCRPC. Gene Ontology enrichment analysis was used to identify pathways enriched for mCRPC-associated GAs. Patterns of mCRPC-associated GAs at a gene- and pathway-level were identified by Bayesian networks fitted using an exact structure learning algorithm. Results: 154 Pts with mCSPC and 187 Pts with mCRPC were included. A set of 16 GAs that robustly distinguished mCRPC from mCSPC (PPV = 94%, specificity = 91%) using supervised machine learning algorithms. These GAs, primarily amplifications, corresponded to AR, MAPK signaling, PI3K signaling, G1/S cell cycle, and receptor tyrosine kinases (RTKs). Positive statistical dependencies were observed between genes in these pathways. At a pathway-level, the presence of G1/S GAs in mCRPC samples increased the likelihood of harboring GAs in RTK, MAPK, and PI3K signaling. Limitations: The retrospective nature of our study means that unknown exposures could act as confounding variables, however this is representative of real-world clinical settings. Although the strength of this study is inclusion of clinically annotated patient samples, the limitation is that patients with mCSPC and mCRPC were unmatched. Conclusions: These results provide evidence that progression from mCSPC to mCRPC is associated with stereotyped concomitant gain-of-function in the RTK, PI3K, MAPK, and G1/S pathways in addition to AR. Upon external validation, these hypothesis generating data may warrant further investigation into combinatorial therapies that target these pathways.
Prostate specific antigen testing as disease surveillance and monitoring five years after definitive therapy for localized prostate cancer.
Authors: Asiri Ibrahim M. , Cobran Ewan Kemar
Published: May 2020

e17602

Background: The National Comprehensive Cancer Network, in 2007, recommends prostate specific antigen (PSA) testing every 6-12 months for the first 5 years following definitive treatment for localized prostate cancer. We compared guideline-concordant PSA testing, as disease surveillance and monitoring, in African-American (AA) and Caucasian (CA) men 5-years after definitive therapy. Methods: A total of 19,377 CA and 1,995 AA men from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database diagnosed with prostate cancer and received definitive treatments from 2007 through 2016 were included. Multivariate log-binomial regression model were used to examine the effect of demographic and clinical characteristics on the likelihood of not receiving at least one PSA surveillance test annually for the first 5 years following definitive treatment. Results: Overall, receipt of surveillance testing and monitoring was high, with 97% of CA men and 94% of AA men receiving at least one test the first year after treatment and approximately 81% of CA men and 77% of AA men receiving at least one test in the fifth year after treatment. Risk of not receiving a test in AA men declined with time compared to CA men, in the first year (Relative Risk [RR], 1.68, 95% CI, 1.37-2.07) and the fifth year (RR, 1.07, 95% CI, 0.98-1.18) since treatment. Further, non-married men and men with intermediate risk had a higher risk of not receiving a surveillance test. Conclusions: Most men received guideline-concordant PSA testing 5-years after definitive therapy. The decline in PSA surveillance overtime reflects the need for continued long-term survivorship care planning and coordination. [Table: see text]
Outcomes of statin use in veterans with prostate cancer: A retrospective single-center experience.
Authors: Warnecke Brian , Garza Juan , Datta Paromita , Hung Annie , Mader Michael , Wangjam Tamna
Published: May 2020

e17612

Background: Prostate cancer is the most common cancer in men in the United States. Death in prostate cancer patients is often reported to be non-prostate cancer related, attributed to other medical conditions. As prostate cancer is associated with a prolonged survival, care of these patients includes optimizing other co-morbidities, such as cardiovascular disease. There are multiple reports and epidemiological studies of statins decreasing the risk, progression, and overall mortality of prostate cancer. Previously we had gathered data on 300 patients diagnosed with prostate cancer at the VA in San Antonio. The results indicated that using statins has a statistically significant positive effect at delaying death by prostate cancer, with a p-value of 0.018. We have updated our results with the addition of 105 patients. Methods: This is a retrospective observational study with chart review of 405 patients diagnosed with prostate cancer from 1995 to 2010, in a VA Hospital in San Antonio, Texas. Variables included age of diagnosis, statin use, type of statin (1st, 2nd, or 3rd generation), dose of statin (6 levels of dosage were identified), length of statin use, time followed in months (from time of diagnosis to either death or the end of the study period), death, and cause of death. The Cox proportional hazards regression model was used to estimate the hazard function, with age at diagnosis used as a covariate. Primary end point was death by prostate cancer (33 patients) and secondary end points- death by any cancer (71 patients), and death by all causes (205 patients). Results: The hazard ratio for use of statins at least 6 months was 0.56, with 95% confidence limits of 0.41 to 1.13, and a p-value of 0.118, indicating no statistically significant effect of statin usage and delay in death by prostate cancer. Secondary endpoint of death by all causes was significantly affected by statins, while death by any cancer showed no significant effect. The study was unable to conclude if the type of statin, dose of statin or the length of statin use had a significant effect in reaching the different end points. Conclusions: The addition of 105 more patients to this study has changed our previous statistically significant primary endpoint results.Concomitant statin use may not help prevent death from prostate cancer or death from any cancer, but may help prevent death from all causes. This updated primary endpoint data conflicts with multiple prior epidemiological studies and raises questions on the impact of statin usage on men with prostate cancer.
Synthetic-lethal interactions between ATR inhibition and functional genetic and proteomic biomarkers to predict responses in endometriosis-associated cancers.
Authors: Gilad Oren , Li Dansu , George Erin , Chettier Rakesh , Simpkins Fiona , Ward Kenneth , Brown Eric J
Published: May 2020

e18000

Background: Endometriosis is a common gynecologic disorder proven to be a precursor to several cancer types. We developed a potent and selective inhibitor (ATRN-119) of a critical DNA damage response (DDR) protein kinase: the ataxia telangiectasia and Rad3-related protein (ATR). Treatment with ATRN-119 is synthetically lethal with multiple cancer-associated changes in DDR pathways, representing a new and effective strategy to treat cancer. The objective of this study is to evaluate the overlap of DDR genes that respond to ATRN-119 and those mutated in endometriosis. Methods: We sequenced the exomes of 2,932 unrelated women with surgically-confirmed endometriosis (GERMLINE) and 274 tissue blocks containing endometriosis lesions (LESION). DNA was extracted using standard methods. Missense and truncation variants were analyzed. These data were compared to analysis of a whole proteome screen for factors that respond to exposure to ATRN-119 and may influence responsiveness to treatment. Factors observed in both methods were considered high-priority biomarker candidates and were experimentally tested for synthetic lethality with ATRN-119 treatment. Results: Analysis of endometriosis patients found 89% of the LESION samples had 2 or more DDR mutations vs 83% of the GERMLINE samples. There is an excess of DDR mutations per sample in LESION (5.5 mutations) vs GERMLINE (3.89 mutations) [p = 4.66x10-6, Mann Whitney test]. In parallel, we identified 92 genes as protein responders to ATRN-119 treatment. Mutations in 21 of these 92 genes show nominal association with surgical endometriosis (p < 0.05). However, of these responsive genes, 18 are known TIER 1 cancer-driver genes and well-characterized mutations were found in three dominant genes in the LESION tissue (ATM, DDB1, and ARID1A). Overall 20% of the patients who’s LESION we examined subsequently developed an endometriosis-associated cancer. Both in vitro and in vivo studies confirmed synthetic-lethal interactions between ATRN-119 treatment and alteration of these genes. Conclusions: The overlap between DDR genes responding to ATRN-119 and those mutated in endometriosis-associated cancer suggest that genetic markers underlying response and resistance will be critical to extend the use of these drugs while increasing efficacy and minimizing toxicities. Furthermore, our data support the inclusion of endometriosis-associated cancer patients in planned ATRN-119 clinical trials.
Prognostic value of dendritic cells in locally advanced cervical cancer patients.
Authors: Joseph Adrien , Castedo-Delrieu Maria , Bloy Norma , Labaied Nizar , Mondini Michele , Loi Mauro , Klein Christophe , Genestie Catherine , Pautier Patricia , Morice Philippe , Gouy Sebastien , Deutsch Eric , Chargary Cyrus , Kroemer Guido , Michels Judith
Published: May 2020

e18016

Background: Cervical cancer is a Human papillomaviruses (HPV)-related disease. T cell infiltration is reported to be associated with a positive prognosis. We evaluated the prognostic value of the tumor-infiltrating dendritic cells (DC). Targeting this immune compartment might be clinically relevant. Methods: We characterized by immunohistochemistry the Dendritic cell lysosomal associated membrane glycoprotein (DC-Lamp) and CD8 T cell infiltration (high/low according to the median density) in patients with locally advanced cervical cancer (LACC) undergoing curative-intent concurrent chemoradiation followed by uterovaginal brachytherapy boost. They were treated in our institution between March 2004 and August 2011. The image acquisition was performed with a Zeiss Axio Scan Z1 microscope. CD8 T cells were detected using an algorithm created in Visiopharm software on manually selected regions of interest (ROI) and DC-Lamp was detected manually. We exported the number of cells and the surface of ROI to calculate the density. Results: A total of 91 patients were identified, with a median follow-up of 4.2 years (range: 0.1-10.3). Patient’s characteristics are listed in the table. DC-Lamphigh (n = 45) LACC patients showed a positive prognosis for overall survival (OS) by univariate (Odds Ratio (OR) = 0.20 [0.06 – 0.72], p = 0.013) and multivariate analyses (incorporating FIGO stage) (OR = 0.17 [0.05 – 0.61], p = 0.006). There was a positive correlation between DC-Lamp and CD8 (R = 0,25 et p = 0,095), which is significant in squamous cell carcinoma patients (R = 0.38, p = 0.039). There was a trend for improved risk stratification for the simultaneous assessment of DC-Lamp and CD8 levels, with DC-Lamphigh/CD8high patients having the best prognosis and DC-Lamplow/CD8low patients having the worst prognosis (p = 0.074). Conclusions: LACC patients with high intratumoral DC density have a favorable outcome. These results underscore the clinical potential of therapeutic strategies that target DC (e.g. Toll like receptor agonists) to render more patients responsive to immune checkpoint blockers. [Table: see text]
Evaluation of the constructed device along with the software for digital archiving, sending the data, and supporting the diagnosis of cervical cancer.
Authors: Gronwald Jacek , Lasyk Lukasz , Barbasz Jakub , Zuk Pawel , Prusaczyk Artur , Włodarczyk Tomasz , Prokurat Ewa , Olszewski Wlodzimierz Tadeusz , Bidziński Mariusz
Published: May 2020

e18017

Background: The incidence and mortality of cervical cancer are high in Poland. There are effective methods of the prevention and the early diagnosis, however they require well-trained medical professionals including cytologists. Within this project we built a prototype of a new device together with implemented software to convert the currently used optical microscopes to fully independent scanning systems for cytological samples. The use of the device is intended to improve the effectiveness of cytological screening, and registration of cytological tests’ results. The features of the software include digital backup as well as transmission and telemedicine evaluation. Methods: The software uses the artificial neural network (U-NET architecture) designed to be able to recognize suspicious regions and enhanced CNN neural network (VGG) allowing to determine the type of disorder such as: ASCUS, ASC-H, HIS, AGC, cancer. 7128 liquid based (LBC) and 1700 conventional cytology samples were evaluated by trained cyto-sreeners. Cytological abnormalities like: ASCUS, ASC-H, HIS, AGC, cancer were found in 254 (3.6%) LBC cases and 51 (3.0%) conventional cytology cases. All samples were scanned and archived. Selected samples with diagnosed abnormality were a model to teach the artificial neural networks. Results: Preliminary results obtained with use of U-NET and VGG (CNN networks) so far indicate 90-96% (LBC samples) and 85-95% (conventional cytology) compliance with results obtained using standard methods. Conclusions: Further refinement of neural networks is necessary to reduce the number of false positives and false negatives. A study with a larger sample size is required to evaluate the software. This project is co-financed with European Regional Development Fund within the Priority Axis I, Support for R&D activities for companies, Measure 1.2, Sectoral R&D Programmes, Sectoral Programme: “INNOMED – scientific research and development programme for innovative medicine economy sector”.
Correlation of PR and ER expression in tumors in various growth patterns of cervical cancer as a prognostic factor.
Authors: Ulianova Elena P. , Spiridonova Diana A. , Nikitina Vera P. , Novikova Inna A. , Sagakyants Aleksandr B. , Nepomnyashchaya Evgeniya M. , Shulgina Oksana G. , Nikitin Ivan S. , Kit Oleg I.
Published: May 2020

e18031

Background: Cervical cancer is the fourth leading cause of cancer deaths among women worldwide. Since the uterus has receptors through which hormonal effects are realized, studies on the tissue receptor apparatus for estrogen and progesterone are relevant. The purpose of the study was to evaluate the correlation of PR and ER expression as a prognostic factor in cervical cancer. Methods: The study included 60 patients aged 28-65 years diagnosed with cervical cancer. Patients were divided into two groups: group 1 – endophytic pattern of tumor growth (n = 30), group 2 – exophytic pattern (n = 30). Eligibility criteria included morphologically confirmed squamous cell carcinoma of the cervix T1b-2aN0M0, stage I-II. Rabbit monoclonal antibodies for ER (Thermo scientific) and PR (Cell Marque) with the Reveal Polyvalent HRP-DAB Detection System were used for the IHC analysis. Statisical analysis of the results was performed with the Statistica 10 program (StatSoft Inc., USA). Results: The average expression of the ER marker was 5.4±3.03% for group 1 (endophytic tumors) and 13.9±8.2% for group 2 (exophytic tumors). The average PR expression was 0.5±0.3% and 1.6±1.1%, respectively. The maximal accumulation of both PR and ER in the nuclei of tumor cells was registered in patients of group 2, being 3.2 times (p = 0.931) and 2.6 times (p = 0.815) higher than in group 1, respectively. However, the difference was not statistically significant (the Mann-Whitney test, p > 0.05). The Spearman rank correlation test did not show statistically significant correlation between the groups and the markers (r = -0.218, p = 0.338). Statistically significant correlation was observed only in the group with exophytic pattern of tumor growth (r = 0.786, p < 0.01). Conclusions: The IHC analysis revealed a tendency to an increase in the expression of PR and ER in patients with exophytic tumors. However, the correlation between the expression of these indicators cannot be considered as a predictive factor in cervical cancer.
Present-day management of uterine leiomyosarcoma: Evaluation of treatment sequencing and other prognostic factors.
Authors: Hinchcliff Emily , Rumpf Jennifer , Ratan Ravin , Fleming Nicole D. , Jazaeri Amir A. , Pitcher Brandelyn , Soliman Pamela T.
Published: May 2020

e18035

Background: Uterine leiomyosarcoma (ULMS) is a rare tumor with limited therapeutic options and no clearly established best treatment sequence strategy. Methods: Women with ULMS between 2013-2018 were identified. Clinical data was collected; descriptive statistics were performed and predictors of overall survival (OS) and progression free survival (PFS) were analyzed. Results: 189 patients were included. Median age was 53 (20-84), 91% had grade 3 tumors and 51.3% had stage IB disease. 50% underwent surgery followed by chemotherapy (n = 94, 49.7%) and 37% had surgery only (n = 70). 49 patients retained their ovaries; there was no difference in OS by oophorectomy status (p = 0.71). Estrogen and progesterone receptor (ER/PR) status, positive in 41% and 33% respectively, was not independently associated with OS (p = 0.23, p = 0.12) nor did it impact OS among those with oophorectomy and without (p = 0.70). The most common adjuvant therapy regimens were gemcitabine/docetaxel (gem/doce, 64%) or ifosphamide/doxorubicin (ifos/doxo, 19%). There were no differences in the regimens prescribed by physician specialty (gynecologic oncology vs other, p = 0.21). 147 patients (78%) experienced a recurrence or progression. For the 73 patients who received gem/doce as adjuvant therapy, 58.9% recurred and were most commonly treated with doxo containing regimens (67%). Of the 22 patients treated with ifos/doxo, only 3 recurred and each received a different second line regimen. For those not treated with adjuvant therapy (70 patients), 58.2% recurred and were treated with gem/doce (62%) and ifos/doxo (24%). In early stage patients, the majority received surgery only (45%) or surgery followed by chemotherapy (44%). There was no difference in OS in those who received adjuvant therapy and those who did not (p = 0.39). 46 (24%) had molecular testing and 37 had identified mutations. The most common mutation found was P53 (n = 25, 54%) followed by RB1 (8, 17%), PTEN (7, 15%), and BRCA (2, 4%). Conclusions: Recurrence occurred in 78% of patient despite many women undergoing adjuvant therapy after surgery. Oophorectomy did not influence OS, even though 41% of tumors were ER positive. The sequence of treatment was not associated with OS, however, the risk for recurrence in patient treated with adjuvant Ifos/Doxo was 14% compared to 59% in gem/doce. This finding warrants additional evaluation to determine the optimal adjuvant therapy for these women.
Test identifies ovarian cancer patients with hyperactive c-Met and ErbB signaling tumors who may benefit from c-Met and pan-HER combination therapy.
Authors: Laing Lance G. , Rossetti Stefano , Kuzmicki Catherine , Broege Aaron , Sabat Joanna , Khan Salmaan , MacNeil Ian A. , Sullivan Brian
Published: May 2020

e18038

Background: No sub-groups of ovarian cancer patients with clinically actionable ErbB genetic variants have yet been found. Measurement of ErbB signaling activity rather than genetic variants may identify ovarian cancer patients likely to benefit from ErbB targeted therapies. We have previously reported studies detecting dysregulated ErbB and c-Met signaling activity in 20%-25% of HER2-negative breast cancer patient tumors using the CELx Signaling Function Test. To determine whether ErbB or c-Met signaling dysregulation is involved in ovarian cancer, the CELx Test was adapted to analyze ovarian tumor cells. The current study set out to: 1) characterize c-Met and ErbB family signaling activity in ovarian patient tumor cells and tumor cell lines; 2) evaluate in vivo response to pan-HER and c-Met inhibitors in an ovarian tumor xenograft model. Methods: For the ex vivo studies, a set of fresh tumor specimens from 15 ovarian cancer patients and a set of 12 ovarian cancer cell lines was obtained. Cell samples were cultured from each. Live cell response to ErbB and c-Met agonists (NRG1b, EGF, or HGF) with or without an antagonist (2C4, a HER2 dimerization inhibitor or tepotinib, a c-Met kinase inhibitor) was measured using an xCELLigence impedance biosensor (Agilent Technologies). Signaling activity above a previously established cut-off value was used to identify abnormal levels of EGFR, HER2 and c-Met signaling activity. For the xenograft study, OVCAR-4, an ovarian cancer cell line, determined to have abnormal HER2, EGFR, and c-Met signaling with the CELx Test, was studied. 40 female NSG mice were each injected with two million cells. Mice were randomly assigned to either a control group or a treatment group that received neratinib, tepotinib, or neratinib and tepotinib for 16 days. Results: Of the patient cell and cell lines samples tested ex vivo with the CELx Test, 4 of 27 (15%; 95% CI = 6%-32%) had hyperactive HER2 and c-Met signaling pathways. In the xenograft study, tumor volume change was 40% less in the tepotinib + neratinib treated group than in the control arm change. There was no significant difference in tumor volume between the control and tepotinib or neratinib groups. Conclusions: These findings suggest that a significant sub-group of ovarian cancer patients have abnormal ErbB and c-Met signaling activity that may respond to treatment with a combination of ErbB and c-Met inhibitors. A clinical trial to evaluate treatment response of this patient sub-set to combined c-Met and pan-HER inhibitors is warranted.
Uptake of targeted therapy in clinical practice among US patients with ovarian cancer.
Authors: Chan John K. , Meyer Larissa , Luhn Patricia , Flores Carlos , Bastiere-Truchot Lydie , Downer Mary K , Lin Yvonne Gail , Wright Jason Dennis
Published: May 2020

e18049

Background: Since first approvals for targeted therapies (TTs) in ovarian cancer (OC) patients (pts) in 2014, FDA approvals for TTs including bevacizumab (bev) and PARP inhibitors (PARPis) continue to expand. Approval of front line (1L) indications for bevacizumab (all-comers) and maintenance olaparib (BRCA-mutated) occurred in 2018. Here we describe real-world trends in the use of these TTs. Methods: Data were analyzed from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database of patient-level data, curated via technology-enabled abstraction. We used descriptive statistics and significance tests to describe TT use in pts with OC. Results: We included 2975 treated OC pts diagnosed from 2011-18, with treatment data through 2019. Median follow-up was 32 months. 47% of OC pts received TT during follow-up, 12% of whom received TT during 1L. TTs were given as maintenance therapy in 54% of 1L and 37% of recurrent (2L+) OC pts. 40% of OC pts received bevacizumab anytime, 24% of whom received bevacizumab during 1L. Bevacizumab was given as maintenance therapy in 43% of 1L and 26% of recurrent OC pts. 20% of 2L and 17% of 3L bevacizumab-treated pts were platinum sensitive. From 2012-19, bevacizumab use changed biennially from 10% to 10% to 8% to 18% in FL (p < 0.001), 24% to 35% to 34% to 38% in 2L (p = 0.008), and 21% to 34% to 35% to 36% in 3L (p = 0.06). Corresponding changes in PARPis use were 0% to 0% to 5% to 13% in FL (p = 0.03), 0% to 1% to 11% to 23% in 2L (p = 0.09), and 0% to 3% to 10% to 20% in 3L (p = 0.02). TT use (ever vs. never during follow-up) was more common among pts with stage III-IV tumors (81% vs. 55%), serous histology (90% vs. 75%), history of BRCA (82% vs. 61%) or NGS (38% vs. 13%) testing, and BRCA mutations (21% vs. 33%) (p < 0.001 for all). Conclusions: Bevacizumab and PARPi use is expanding in 1L and 2L treatment; in 1L bevacizumab was more common than PARPis in 2019 (31% vs. 19%). These data reflect the evolving treatment landscape in 1L OC, which is expected to further evolve based on recent evidence from maintenance PARPi monotherapy and PARPi + bevacizumab combination studies. [Table: see text]
Evaluation of the occurrence and management of PARP inhibitor toxicities.
Authors: Hatch Rachel , Patel Sweta , Cambareri Christine , Uritsky Tanya , Martin Lainie P.
Published: May 2020

e18073

Background: Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) have become a major cornerstone of therapy in the management of patients with ovarian cancer and other cancer types. The most common adverse events with PARPi therapy include bone marrow suppression, gastrointestinal (GI) toxicity, and fatigue. Currently, information is scarce regarding the management of some of these adverse events. Methods: A retrospective, descriptive observational study of adult patients with gynecologic malignancy, who received at least 2 weeks of PARPi therapy, was conducted at the University of Pennsylvania Health System. Data was collected on patients prescribed a PARPi between December 2014 and October 2019, from initiation of therapy through one-year post-initiation or last follow-up. The primary endpoint was the status of PARPi therapy at the end of the study period. Secondary endpoints included time to toxicity, progression free survival (PFS), and overall survival (OS). Descriptive statistics were used to analyze all endpoints. Results: Of the 85 patients included in the study, 45 (53%) received olaparib, 24 (28%) niraparib, and 16 (19%) rucaparib. Twenty-nine patients (34%) continued on PARPi therapy, 16 (19%) discontinued the due toxicity, and 40 (47%) discontinued due to progression. Of 147 unique toxicities, 67 (46%) were GI-related, 48 (33%) were hematologic, and 32 (22%) were other toxicities, including fatigue, elevated serum creatinine, hypertension, and rash. Twenty-three percent of all toxicities were categorized as grade 3 or 4 per the Common Terminology Criteria for Adverse Events v5.0. The median number of management strategies required for GI toxicities was 1 (range 1-7), hematologic toxicities was 2 (1-8), and fatigue was 1.5 (1-4). Primary management strategies included pharmacologic therapy (96%) for GI toxicities; transfusion support (65%), holding PARPi therapy (67%), and dose reduction (52%) for hematologic toxicities; and dose reduction (78%) for fatigue. Hospital admission due to PARPi toxicity occurred in 12% of patients. The median time to toxicity was 29 days (1-330) and the median time to discontinuation due to toxicity was 72.5 days (9-353). Fifty-four patients (64%) had progression of disease and 18 (21%) died within one-year of initiation. Median PFS was 181 days and median OS was 338 days, censored for time to last follow-up. Conclusions: This observational study outlines the incidence of PARPi toxicity and some of the management strategies within an academic health system, further guiding practitioners in an area with limited information.
OvarianTag biomarker panel in order guide treatment decisions cisplatin-based for women with epithelial ovarian cancer.
Authors: Braga Leticia da Conceição , Silva Luciana Maria , Souza Matheus Gomes de , Amaral Laurence Rodrigues do , Andrade Nara Rosana , Silva-filho Agnaldo Lopes da
Published: May 2020

e18075

Background: Ovarian cancer (OC) represents the most lethal gynecologic cancer. Late-stage diagnosis associated with a lack of effective markers to detect chemotherapy resistance contributes to high mortality and poor prognosis of epithelial ovarian cancer (EOC). OvarianTag Biomarkers Panel was developed as biopsy-based gene expression assay to discriminate prognosis in EOC patients, to understand the aggressiveness and relapse causes of these patients. Methods: Patients were admitted into this study in two phases. First, 45 women were included prospectively, and RNA was obtained from fresh normal ovarian (NO) tissues (n = 18), ovarian serous cystadenoma tumors (n = 11) and EOC (n = 16). The total RNA content was quantified and quantitative PCR (qRT-PCR) was performed to determine relative gene expression, starting set genes related to apoptosis and necroptosis regulated cell death pathway. Machine Learning algorithms were used to classify patient’s data associated and to characterize molecular targets as prognostic markers, named OvarianTag panel. Later, others 55 EOC patients, attended between 2008 and 2016, were included. Within this cohort, tissues were obtained from 106 FFPE samples and shared into primary and metastatic EOC, and from the same NO tissues (as control). RNA was extracted and qRT-PCR determined the OvarianTag panel expression level from each sample. Then, hierarchical clustering allowed us to classify the samples using the cut off obtained by classifier algorithm. Results: Significant differences in gene expression profile were observed between patients’ groups. Molecular classifier algorithm proved the prognostic value of genes evaluated. Decisions trees and biomarker clusters were constructed. In the full training, were obtained 90% of correct classifications and in cross-validation, 89%. In the second phase, the classifier reported specificity of 100% and sensibility of 79% to predict tumor recurrence and platinum resistance. Conclusions: OvarianTag panel is a putative prognosis biomarker of EOC subgroups and could be considered to drive the clinical practice of EOC treatment options, improving outcomes because providing an opportunity for guide clinical intervention for increasing survival rates. Besides of that, it will be allowed include patients in clinical trials of new target drugs or for repositioning of target drugs that have already been tested in humans.
Correlation of longtime efficacy maintenance PARP inhibitor therapy with pre-treatment in a single-institution experience.
Authors: Nicoletto Maria Ornella , Grego Andrea , Baldoni Alessandra , Tasca Giulia , Sommariva Antonio , Tonello Marco , Torri Valter , Pilati Pierluigi
Published: May 2020

e18084

Background: The use of PARP inhibitors (Olaparib-Niraparib) has shown an important benefit in PFS in patients with relapsed ovarian cancer both with gBRCA and non-BRCA mutation. Methods: This was a single-institution, retrospective cohort study of 93 patients. Clinical data were obtained by the review of the electronic medical report. The 93 patients were treated with PARP Inhibitors(PARP-I) between Apr 2014 and Dic 2019. The patients were evaluated according to age, BRCA mutation, pretreatment with Trabectedin, Bevacizumab, last line of pretreatment with Platinum-Gemcitabine+Paclitaxel versus Caelyx-Oxaliplatin, number of previous lines of chemotherapy, residual disease before PARP-I. Statistical analysis of survival was performed with Kaplan-Meyer, univariate and multivariate analysis with Cox regression. Disease Free Survival (DFS) was evaluated from the start of PARP-I therapy while Overall Survival (OS) from the diagnosis. Results: Median age was 64 (42-90), patients with germinal mutation BRCA were 34 (36.6%), 58 without mutation and 1 patient without genetical analysis. 20 (21,5%) patients were pretreated with Trabectedin plus Pegylated Liposomal Doxorubicine (PLD), while 8 (8,6%) with Trabectedin-Bevacizumab, 26 (28%) patients were pretreated with Bevacizumab +/- Trabectedin. Before PARP-I patients more frequently were pretreated with 2-3 line 60, 64.5%): in the last line of pretreatment chemotherapy 47 (50,4%) patients received PLD+-Oxaliplatin versus Carboplatin-Taxol or Carboplatin-Gemcitabine. In 64% of the patients CTscan or ecography showed residual disease > 1 cm before starting PARP-I treatment . Median follow-up was 17 months: 54 (58.1%) patients in PARP-I treatment relapsed, while 32 (34.1%) patients died. Multivariate analysis showed a significant association in the number of lines pretreatment: in more than 3 lines HR was 2.00 (CI 1.2-3.4, p = 0.012), according to residuum less or more 1 cm prior to start PARP therapy (logrank p = 0,0286). Conclusions: The administration of PARP is important for OS immediately after 2° line chemotherapy in platinum sensitive patients Logrank p = 0.0065, with higher response not significant, about OS specially if following non-anemic PLD-Oxaliplatin therapy (p = 0,0849 Logrank) Also significant is OS according to residuum less or more 1 cm prior to start PARP therapy (logrank p = 0,0286) The doses and relative reductions in PARP-I did not change efficacy.
The development of a homologous recombination deficiency (HRD) score to identify HR-deficient tumors.
Authors: Wu Xiaohua , Wen Hao , Feng Zheng , Shao Lin , Liu Chenglin , Liu Hao , Zhang Lu , Mao Xinru , Guan Xiaoqian , Hou Ting , Han-Zhang Han , Zhang Zhou
Published: May 2020

e18085

Background: BRCA1/2 mutated cancers are homologous recombination repair (HRR) deficient and often sensitive to drugs targeting DNA repair pathway. Emerging evidences suggest tumors with mutations in other HRR genes might also respond favorably to DNA repair pathway targeted drugs; however, the results were inconclusive. Genomic instability is characterized by telomeric allelic imbalance (TAI), large-scale transition (LST) and loss of heterozygosity (LOH). Here, we developed an HRD score based on assessing the status of these patterns in tumors. Methods: 73 cancer patients, including 36 breast cancer (BC), 35 ovarian cancer (OC) and 2 prostate cancer (PC) patients were recruited. 28 were BRCA-deficient tumors (10 BCs, 17OCs and 1 PC) harboring pathogenic/likely pathogenic (P/LP) germline mutation in BRCA1/2 with LOH. 13 BRCA-mutated tumors (10 BCs, 2 OCs and 1 PC) carried P/LP BRCA1/2 mutation without LOH. The rest 33 were HRR wild type controls (16 BCs and 16 OCs). All samples were profiled using a panel consisting of 24 classic HRR genes and their adjacent SNPs. The scores for TAI, LST and LOH were developed separately and an incorporated HRD score based on the 3 patterns was established. Clinical data of 42 OC pts were collected to validate the algorithm. Results: All pairwise correlations of TAI, LST and LOH scores showed high correlations (TAI vs. LOH: r = 0.89; TAI vs. LST: r = 0.92; LST vs. LOH: r = 0.83). The univariate logistic regression was used to assess the correlation of the score with BRCA deficiency. In the cohort of BRCA-deficient vs. HRR-negative, the scores of TAI (P = 9.72 x 10−4), LST (P = 8.75 x 10−5), LOH (P = 0.01) and HRD (P = 3.35 x 10−4) all showed significant associations with BRCA-deficiency. In the cohort of BRCA-deficient vs. BRCA-mutated +HRR-negative, all the scores also highly correlated with BRCA-deficiency (TAI: P = 2.35 x 10−4, LST: P = 1.48 x 10−5; LOH: P = 2.36 x 10−4, HRD: P = 6.29 x 10−5). Using 42 as a cutoff, it achieved sensitivities of 94.1%, 60% and 82% for identifying BRCA-deficient tumors in the 35 OCs, 36 BCs and in all 73 tumors, respectively. We further validated the predictive value of HRD score in an additional 42 OC pts and found significantly higher HRD sore in pts sensitive to platinum therapy (P = 0.036). Patients having an HRD score > 42 had a significantly longer PFS than pts with a score < 42 (p = 0.04). Conclusions: Our study developed a HRD score base on assessing 3 patterns of genomic instability (TAI, LST and LOH). The HRD score revealed a promising value in detecting HR-deficient tumors (especially BRCA-deficient).
Real-world conditional survival analysis of women with newly diagnosed ovarian cancer.
Authors: Szamreta Elizabeth A. , Monberg Matthew J. , Desai Kaushal , Chen Xin , Othus Megan
Published: May 2020

e18087

Background: A critical question in determining long-term prognosis for women with newly diagnosed ovarian cancer (OC) is whether or not their risk of death changes with time. The emergence of large, well-populated real-world datasets permits assessment of conditional survival (CS) given prior overall survival (OS) or progression-free survival (PFS). Methods: The Tempus EMR clinical dataset consists of patients from both National Cancer Institute designated centers and a sample of community oncology centers in the U.S. This study included adult women with a primary diagnosis of ovarian, fallopian tube, or peritoneal cancer from 1982 to 2018; women treated with a poly-ADP ribose polymerase (PARP) inhibitor were excluded due to low numbers & limited follow-up (final n = 2,031). The effects of patient attributes on OS were estimated using Cox regression. We calculated CS as the Kaplan-Meier probability of surviving an additional y years (from first line chemotherapy initiation), given no OS or PFS event in the previous x (< y) years. Results: Median age was 61 years and 68% of patients were Caucasian. The majority (92%) had epithelial histology, 58% were stage 3 or 4, and 49% were ECOG 0 or 1. Median OS was 37 months (95% CI: 36-39), and OS differed by age, stage, and performance status; adjusted hazard ratios (HRs) for OS were 1.3 (95% CI: 1.0, 1.5) for age > 65 versus < 45, 2.4 for stage 4 versus stage 1 (95% CI: 1.7, 3.4), and 1.4 for ECOG 2 to 4 versus 0 or 1 (95% CI: 1.2, 1.7). Conditional 1- or 5-year survival rate did not vary based on prior OS. However, CS rates among women alive without disease progression increased with time: 1-year and 5-year survival rates (with 95% CI) were 86% (84-87) and 28% (26-31), respectively, in women alive without progression at 6 months, but increased to 94% (89-97) and 53% (44-62) in women alive without progression at 3 years. Conclusions: Long-term prognosis, as shown by conditional survival rates, did not improve based on time alive since initiation of chemotherapy. However, women with longer time without disease progression had lower rates of death and a better prognosis. [Table: see text]