| 1. |
- Ketabi, Zohreh, et al.
(författare)
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Ovarian cancer linked to lynch syndrome typically presents as early-onset, non-serous epithelial tumors
- 2011
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 1095-6859 .- 0090-8258. ; 121:3, s. 462-465
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Heredity is a major cause of ovarian cancer and during recent years the contribution from germline mismatch repair (MMR) gene mutations linked to Lynch syndrome has gradually been recognized. Methods. We characterized clinical features, tumor morphology and mismatch repair defects in all ovarian cancers identified in Swedish and Danish Lynch syndrome families. Results. In total, 63 epithelial ovarian cancers developed at mean 48 (range 30-79) years of age with 47% being early stage (FIGO stage I). Histologically, endometrioid (35%) and clear cell (17%) tumors were overrepresented. The underlying MMR gene mutations in these families affected MSH2 in 49%, MSH6 in 33% and MLH1 in 17%. Immunohistochemical loss of the corresponding MMR protein was demonstrated in 33/36 (92%) tumors analyzed. Conclusion. The combined data from our cohorts demonstrate that ovarian cancer associated with Lynch syndrome typically presents at young age as early-stage, non-serous tumors, which implicates that a family history of colorectal and endometrial cancer should be specifically considered in such cases. (C) 2011 Elsevier Inc. All rights reserved.
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| 2. |
- Arildsen, Nicolai Skovbjerg, et al.
(författare)
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Detecting TP53 mutations in diagnostic and archival liquid-based Pap samples from ovarian cancer patients using an ultra-sensitive ddPCR method
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- High-grade serous ovarian cancer (HGSOC) is the most common subtype of epithelial ovarian cancer and early detection is challenging. TP53 mutations are a hallmark of HGSOC and detection of these mutations in liquid-based Pap samples could provide a method for early diagnosis. Here we evaluate the use of IBSAFE, an ultra-sensitive droplet digital PCR (ddPCR) method, for detecting TP53 mutations in liquid-based Pap samples collected from fifteen women at the time of diagnosis (diagnostic samples) and/or up to seven years prior to diagnosis (archival samples). We analysed tumours for somatic TP53 mutations with next generation sequencing and were able to detect the corresponding mutations in diagnostic samples from six of eight women, while one patient harboured a germline mutation. We further detected a mutation in an archival sample obtained 20 months prior to the ovarian cancer diagnosis. The custom designed IBSAFE assays detected minor allele frequencies (MAFs) with very high assay sensitivity (MAF = 0.0068%) and were successful despite low DNA abundance (0.17-206.14 ng, median: 17.27 ng). These results provide support for further evaluation of archival liquid-based Pap samples for diagnostic purposes and demonstrate that ultra-sensitive ddPCR should be evaluated for ovarian cancer screening in high-risk groups or in the recurrent setting.
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| 3. |
- Arildsen, Nicolai Skovbjerg, et al.
(författare)
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Involvement of chromatin remodeling genes and the Rho GTPases RhoB and CDC42 in ovarian clear cell carcinoma
- 2017
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 7:MAY, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30-50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome. Methods: Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2). Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3) was used for validation by immunohistochemistry and chromogenic in situ hybridization. Results: Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors. Conclusion: OCCCs appear genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.
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| 4. |
- Asp, Mihaela, et al.
(författare)
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Ovarian tumor frozen section, a multidisciplinary affair
- 2022
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Ingår i: Acta Oncologica. - 1651-226X. ; 61:7, s. 785-792
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOvarian Cancer (OC) constitute the eighth most common cancers among women worldwide. Surgery remains the cornerstone in the management of OC. Intraoperative frozen section (FS) diagnosis is widely used to decide the surgery course. We aimed to assess the reliability of intraoperative FS diagnosis for treatment planning of patients with suspected OC from a multidisciplinary perspective. The clinical consequences of reclassification and the multidisciplinary management of the therapy plan, is the secondary aim of this study. To our knowledge, this information is sparely investigated.MethodsA single-center, retrospective population-based study of patients who underwent surgery for suspected OC between 2018 and 2020. Histopathological outcomes were classified as benign, borderline, or malignant. The FS diagnosis was the diagnostic test, and the final histopathology report was the gold standard. Diagnostic capability for treatment planning was assessed, and modifications made possible by overall clinical knowledge were discussed.ResultsA total of 358 patients were identified, of whom 187 were included in the FS group. Overall accuracy was 89.8%, and 19 patients were reclassified; the malignancy grade of 15 tumors was underestimated. Prevalence, sensitivity, specificity, positive predictive value, and negative predictive value for invasive malignancies on FS were 54.0% (CI 46.6–61.3%), 88.1% (CI 80.2–93.7%), 98.8% (CI 93.7–99.9%), 98.9% (CI 92.7–99.8%), and 87.6% (CI 80.6–92.4%), respectively. Tumors incorrectly graded by FS tended to be of borderline-related.ConclusionsThe reliability of the FS methodology was an accurate test to help perform appropriate surgery and plan swift oncological treatment. FS is a reliable method to diagnose invasive malignancies and benign pathology. The communication between the pathologist, surgeon, and medical oncologist is highly important for both intraoperative decision-making and postoperative patient care.
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| 5. |
- Asp, Mihaela, et al.
(författare)
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Prognostic Value of Peritoneal Cancer Index After Complete Cytoreductive Surgery in Advanced Ovarian Cancer
- 2022
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Ingår i: Anticancer research. - : Anticancer Research USA Inc.. - 1791-7530 .- 0250-7005. ; 42:5, s. 2541-2551
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Tidskriftsartikel (refereegranskat)abstract
- Background/aim: Residual disease (RD) after primary debulking surgery (PDS) is a prognostic factor for survival in advanced ovarian cancer (AOC). This study aimed to examine whether the tumor extent affects overall survival (OS) and progression-free survival (PFS) in AOC patients treated with PDS.Patients and methods: A total of 118 patients treated with PDS were included. Age, ECOG score, AOC International Federation of Gynecology and Obstetrics (FIGO) stage, CA-125, RD, peritoneal cancer index (PCI), preoperative imaging (CT-PCI) and macroscopic visualization at the surgery start (S-PCI) were analyzed. Tumor extent was quantified using the PCI, and by CT-PCI and S-PCI. Cox regression, Kaplan-Meier and receiver operating curves (ROC) were performed for survival analyses.Results: S-PCI correlated with both OS (1.067, 95%CI=1.018-1.119, p<0.007) and PFS. Patients exhibiting S-PCI≥18.5, adjusted to age, performance status, and RD, had a two-fold risk of dying (HR=2.070, 95%CI=1.061-4.038, p=0.033) compared those with PCI<18.5. CT-PCI correlated with OS in crude data (1.037, 95%CI=1.005-1.071, p=0.025), but this was not sustained in multivariate analyses. RD of any size doubled the risk of dying (2.177, 95%CI=1.235-3.838, p=0.007).Conclusion: The tumor extent at the beginning of surgery seemed to affect OS in patients with AOC, regardless of the extent of RD at the end of the surgery. PCI above 18.5 doubled the risk of dying of the disease. No difference in major complications was noted in the two groups of patients. CT-PCI seemed to play a prognostic role for PFS; however, it is still to be investigated as a prognostic factor for OS.
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| 6. |
- Asp, Mihaela, et al.
(författare)
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The role of computed tomography in the assessment of tumour extent and the risk of residual disease after upfront surgery in advanced ovarian cancer (AOC)
- 2022
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Ingår i: Archives of Gynecology and Obstetrics. - : Springer Science and Business Media LLC. - 1432-0711.
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Tidskriftsartikel (refereegranskat)abstract
- PurposeEpithelial ovarian cancer is usually diagnosed in the advanced stages. To choose the best therapeutic approach, an accurate preoperative assessment of the tumour extent is crucial. This study aimed to determine whether the peritoneal cancer index (PCI), the amount of ascites, and the presence of cardiophrenic nodes (CPLNs) visualized by computed tomography (CT) can assess the tumour extent (S-PCI) and residual disease (RD) for advanced ovarian cancer (AOC) patients treated with upfront surgery.MethodsIn total, 118 AOC cases were included between January 2016 and December 2018 at Skåne University Hospital, Lund, Sweden. Linear regression and interclass correlation (ICC) analyses were used to determine the relationship between CT-PCI and S-PCI. The patients were stratified in complete cytoreductive surgery (CCS) with no RD or to non-CCS with RD of any size. The amount of ascites on CT (CT-ascites), CA-125 and the presence of radiological enlarged CPLNs (CT-CPLN) were analysed to evaluate their impact on estimating RD.ResultsCT-PCI correlated well with S-PCI (0.397; 95% CI 0.252–0.541; p < 0.001). The risk of RD was also related to CT-PCI (OR 1.069 (1.009–1.131), p < 0.023) with a cut-off of 21 for CT-PCI (0.715, p = 0.000). The sensitivity, specificity, positive predictive value and negative predictive value were 58.5, 70.3, 52.2 and 75.4%, respectively. CT-ascites above 1000 ml predicted RD (OR 3.510 (1.298–9.491) p < 0.013).ConclusionCT is a reliable tool to assess the extent of the disease in advanced ovarian cancer. Higher CT-PCI scores and large volumes of ascites estimated on CT predicted RD of any size.
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| 7. |
- Asp, Mihaela, et al.
(författare)
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Tru-Cut Biopsy in Gynecological Cancer: Adequacy, Accuracy, Safety and Clinical Applicability
- 2023
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Ingår i: Journal of Multidisciplinary Healthcare. - 1178-2390. ; 16, s. 1367-1377
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Tru-cut biopsy is a minimally invasive technique used to obtain tissue samples for the diagnosis of tumors, especially in patients where primary surgery is not indicated. The aim of this study was to assess the adequacy, accuracy and safety of the tru-cut biopsy for diagnosis in gynecological cancer.Methods: A retrospective population-based review of 328 biopsies was conducted. The indications for tru-cut biopsies were diagnosis of primary tumors, metastases of gynecological and non-gynecological tumors, and suspected recurrences. A tissue sample was considered adequate when the quality/quality was sufficient to identify the subtype/origin of the tumor. Potential factors affecting adequacy were analyzed using logistic regressions analyses. Accuracy was defined as agreement between the diagnosis of the tru-cut biopsy and the postoperative histology. The therapy plan was registered, and the clinical applicability of the tru-cut biopsy was investigated. Complications within 30 days after the biopsy procedure were registered.Results: In total, 300 biopsies were identified as tru-cut biopsies. The overall adequacy was 86.3%, varying between 80.8% and 93.5%, respectively, when performed by a gynecological oncologist or a gynecologist with a subspecialty in ultrasound diagnosis. Sampling of a pelvic mass had a lower adequacy (81.6%) compared with sampling of the omentum (93.9%) or carcinomatosis (91.5%). The accuracy was 97.5%, and the complication rate was 1.3%.Conclusion: The tru-cut biopsy is a safe and reliable diagnostic method with a high accuracy and a good adequacy, depending on the site of the tissue sample, indications for the biopsy and the experience of the operator.
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| 8. |
- Bagge, Ebba, et al.
(författare)
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Pattern of endocrine treatment for epithelial ovarian cancer in the Southeast medical region of Sweden: a population-based study
- 2019
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Ingår i: Acta Oncologica. - : TAYLOR & FRANCIS LTD. - 0284-186X .- 1651-226X. ; 58:3, s. 320-325
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Tidskriftsartikel (refereegranskat)abstract
- Aim of the study: Endocrine treatment (ET) is an alternative as salvage therapy in epithelial ovarian cancer (EOC) but the usage in routine care is unknown. We evaluated the treatment patterns and outcome of patients receiving ET for EOC in the Southeast medical region in Sweden.Method: Patients were identified through the population-based Southeast Quality Registry for gynaecological cancer. Inclusion criteria were: age 18 years, histologically verified EOC diagnosed 2000-2013, ET for 4 weeks. Coverage compared with the Swedish National Cancer Registry was 100%. Data extracted from medical records was collected by means of a study-specific Case Report Form. Last date of follow-up was February 1st, 2018. All statistics were descriptive.Results: Altogether 248 (18%) of 1414 patients were treated with ET. Most (49%) had received only one, and 34% two previous lines of chemotherapy. Time from last chemotherapy to ET was 4 months, range 0-55months. The reason for initiating ET was tumor progression (66%), chemotherapy related toxicity (29%) and maintenance (4%). Tamoxifen was prescribed in 94% of cases. Best response was partial (amp;lt; 5%) and stable disease (50%). No patient had a complete response. 194 (78%) patients received subsequent chemotherapy, of these 27% had 3-7 lines of chemotherapy. Duration of ET was a median 4 months (range 1-80 months). Median time from ET to subsequent chemotherapy was 5 months (range 0-79). The median overall survival was 45 months (range 9-173).Conclusion: In the Southeast region of Sweden, endocrine treatment for EOC was prescribed inconsistently and in various settings, usually initiated by a rising CA-125 level. Poorer documentation and irregular tumor response assessment were observed for endocrine treatment compared to chemotherapy.
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| 9. |
- Bartuma, Katarina, et al.
(författare)
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Genetic profiles distinguish different types of hereditary ovarian cancer.
- 2010
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 24:4, s. 885-895
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Tidskriftsartikel (refereegranskat)abstract
- Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian cancer (HBOC) syndrome and the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Genome-wide array comparative genomic hybridization was applied to 12 HBOC associated tumors with BRCA1 mutations and 8 HNPCC associated tumors with mismatch repair gene mutations with 24 sporadic ovarian cancers as a control group. Unsupervised cluster analysis identified two distinct subgroups related to genetic complexity. Sporadic and HBOC associated tumors had complex genetic profiles with an average 41% of the genome altered, whereas the mismatch repair defective tumors had stable genetic profiles, with an average 18% of the genome altered. Losses of 4q34, 13q12-q32 and 19p13 were overrepresented in the HBOC subset. Discriminating genes within these regions include BRCA2, FOXO1A and RB1. Gains on chromosomes 17 and 19 characterized the HNPCC tumors, but target genes herein are unknown. The results indicate that HBOC and HNPCC associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer.
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| 10. |
- Bartuma, Katarina, et al.
(författare)
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Ovarian cancer at young age: the contribution of mismatch-repair defects in a population-based series of epithelial ovarian cancer before age 40.
- 2007
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Ingår i: International Journal of Gynecological Cancer. - : BMJ. - 1048-891X .- 1525-1438. ; 17, s. 789-793
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Tidskriftsartikel (refereegranskat)abstract
- At least one of ten patients with ovarian cancer is estimated to develop their tumor because of heredity with the breast and ovarian cancer syndrome due to mutations in the BRCA1 and BRCA2 genes and hereditary nonpolyposis colorectal cancer (HNPCC) being the major genetic causes. Cancer at young age is a hallmark of heredity, and ovarian cancers associated with HNPCC have been demonstrated to develop at a particularly early age. We used the Swedish Cancer Registry to identify a population-based series of 98 invasive epithelial ovarian cancers that developed before 40 years. Mucinous and endometrioid cancers were overrepresented and were diagnosed in 27% and 16% of the tumors, respectively. Immunostaining using antibodies against MLH1, PMS2, MSH2, and MSH6 was used to assess the mismatch-repair status and revealed loss of expression of MLH1/PMS2 in two cases, loss of MSH2/MSH6 in one case, and loss of MSH6 only in three tumors. A microsatellite instability–high phenotype was verified in five of six tumors. Based on the identified mutations and family history of cancer, several of these individuals are likely to be affected by HNPCC. We conclude that although the causes of the vast majority of epithelial ovarian cancer at young age are unknown, HNPCC should be considered because of the high risk of metachronous colorectal cancer in the individual and the possibility of preventing additional cancers in the family through control programs.
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| 11. |
- Bartuma, Katarina, et al.
(författare)
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Response to letter of Escobar et al.
- 2008
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Ingår i: International Journal of Gynecological Cancer. - : BMJ. - 1048-891X .- 1525-1438. ; 18, s. 1386-1386
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Tidskriftsartikel (refereegranskat)
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| 12. |
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| 13. |
- Bååth, Maria, et al.
(författare)
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MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer
- 2021
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.
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| 14. |
- Bååth, Maria, et al.
(författare)
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SOX2 is a promising predictor of relapse and death in advanced stage high-grade serous ovarian cancer patients with residual disease after debulking surgery
- 2020
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Ingår i: Molecular and Cellular Oncology. - : Informa UK Limited. - 2372-3556. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor SOX2 is a well-established and important stem cell marker. Its role in cancer biology remains unclear, but it has been proposed to also be a marker of cancer stem cells. We investigated the role of SOX2 protein expression in women with high-grade serous ovarian cancer (HGSOC) to determine its potential prognostic and treatment predictive value. We constructed a tissue microarray of 130 advanced stage HGSOC tumors with an average of 6 cores each, stained for SOX2 protein expression and evaluated survival outcomes. We also treated two HGSOC cell lines with carboplatin and paclitaxel and measured SOX2 expression by RT-PCR and immunoblotting at different doses and time-points. Among patients with non-radical debulking surgery overall and progression-free survival were shorter for patients with SOX2 positive tumors (mean 26 vs. 39 months, log-rank test: p = .0076, and mean 14 vs. 19 months, p = .055, respectively). Knockdown of SOX2 in cell lines did not affect growth inhibition following chemotherapy treatment. Our results show that SOX2 has a strong prognostic potential among HGSOC patients with residual tumor tissue after debulking surgery and suggest that SOX2 expressing cells remaining after non-radical debulking surgery may constitute a subpopulation of cancer stem cells with greater tumor-initiating potential.
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| 15. |
- Corvigno, Sara, et al.
(författare)
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High density of stroma-localized CD11c-positive macrophages is associated with longer overall survival in high-grade serous ovarian cancer.
- 2020
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 159:3, s. 860-868
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Pre-clinical studies have identified marker- and tumor compartment-defined functionally distinct macrophage subsets. Our study analyzes marker-defined macrophage subsets in different tumor compartments of high-grade serous ovarian cancer (HGSC).METHODS: A discovery cohort (N = 113) was subjected to immunohistochemistry (IHC) analyses. CD68-positivity was confirmed for CD11c-, CD80- and CD163-positive cells. Subset-marker-positive cells were scored in the total tumor and in four tumor compartments. Correlation analyses investigated co-expression of subsets, relationship to CD8+ cells and survival associations. A validation cohort (N = 121) was used to confirm selected findings from the discovery cohort.RESULTS: CD163-positve cells was the most abundant subtype in all compartments. CD11c and CD163 subsets were strongly correlated with each other in stroma and epithelial areas, whereas CD80 and CD163 were correlated in epithelial areas. CD80 and CD11c in perivascular areas showed low correlations. Strong associations were detected between CD8 and CD80 in the tumor epithelium-dominated areas, and between CD8 and CD11c in stroma areas. High stromal CD11c density was associated with a longer median overall survival in the discovery cohort (HR 0.39; CI 95%, 0.23-0.68; p = 0.001) and in the validation cohort (HR 0.46; CI 95%, 0.22-0.93; p = 0.03).CONCLUSIONS: Our study supports the existence of clinically relevant marker- and localization defined macrophage subsets in HGSC, which are independently regulated. Moreover, it suggests stromal CD11c as a novel prognostic marker in HGSC.
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| 16. |
- Huttenhain, Ruth, et al.
(författare)
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A targeted mass spectrometry strategy for developing proteomic biomarkers : a case study of epithelial ovarian cancer
- 2019
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Ingår i: Molecular and Cellular Proteomics. - 1535-9484. ; 18:9, s. 1836-1850
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Tidskriftsartikel (refereegranskat)abstract
- Protein biomarkers for epithelial ovarian cancer are critical for the early detection of the cancer to improve patient prognosis and for the clinical management of the disease to monitor treatment response and to detect recurrences. Unfortunately, the discovery of protein biomarkers is hampered by the limited availability of reliable and sensitive assays needed for the reproducible quantification of proteins in complex biological matrices such as blood plasma. In recent years, targeted mass spectrometry, exemplified by Selected Reaction Monitoring (SRM) has emerged as a method, capable of overcoming this limitation. Here, we present a comprehensive SRM-based strategy for developing plasma-based protein biomarkers for epithelial ovarian cancer and illustrate how the SRM platform, when combined with rigorous experimental design and statistical analysis, can result in detection of predictive analytes.Our biomarker development strategy first involved a discovery-driven proteomic effort to derive potential N-glycoprotein biomarker candidates for plasma-based detection of human ovarian cancer from a genetically engineered mouse model of endometrioid ovarian cancer, which accurately recapitulates the human disease. Next, 65 candidate markers selected from proteins of different abundance in the discovery dataset were reproducibly quantified with SRM assays across a large cohort of over 200 plasma samples from ovarian cancer patients and healthy controls. Finally, these measurements were used to derive a 5-protein signature for distinguishing individuals with epithelial ovarian cancer from healthy controls. The sensitivity of the candidate biomarker signature in combination with CA125 ELISA-based measurements currently used in clinic, exceeded that of CA125 ELISA-based measurements alone. The SRM-based strategy in this study is broadly applicable. It can be used in any study that requires accurate and reproducible quantification of selected proteins in a high-throughput and multiplexed fashion.
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| 17. |
- Jönsson, Jenny-Maria, et al.
(författare)
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Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome.
- 2014
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 13:4, s. 537-545
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics.
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| 18. |
- Jönsson, Jenny-Maria, et al.
(författare)
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Molecular subtyping of serous ovarian tumors reveals multiple connections to intrinsic breast cancer subtypes.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.
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| 19. |
- Jönsson, Jenny-Maria, et al.
(författare)
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Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival.
- 2015
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Ingår i: Translational Oncology. - : Elsevier BV. - 1936-5233. ; 8:5, s. 424-433
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Tidskriftsartikel (refereegranskat)abstract
- Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival in epithelial ovarian cancer.
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| 20. |
- Koul, Anjila, et al.
(författare)
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Two BRCA1-positive epithelial ovarian tumors with metastases to the central nervous system: a case report
- 2001
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 1095-6859 .- 0090-8258. ; 80:3, s. 399-402
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cerebral metastasis secondary to ovarian cancer is a rare phenomenon. While no clear relationship to known prognostic factors is found, others suggest this as a biologically diverse behavior of ovarian cancer. CASES: In a pilot study, 37 invasive epithelial ovarian cancer samples were analyzed to detect the frequency of BRCA1/BRCA2 mutations in the south of Sweden (results published). A retrospective follow-up revealed that 2 of these (2/37; 5.4%) patients developed central nervous system metastases during the course of their disease. Both patients had advanced surgical stage disease at the time of diagnosis, with histopathological serous type tumors that were negative for estrogen and progesterone receptors. One of these patients carried a germline BRCA1 mutation, whereas a somatic BRCA1 mutation was identified in the other patient. CONCLUSIONS: To the best of our knowledge the molecular genetic profile of these tumors is not found in the literature and it is suggested that such analyses could provide some insight for a better understanding of this rare phenomenon.
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| 21. |
- Kuokkanen, M, et al.
(författare)
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Lactase persistence and ovarian carcinoma risk in Finland, Poland and Sweden
- 2005
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 117:1, s. 90-94
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian carcinoma is the fourth most common cause of cancer death in women. The cause and pathogenesis of this disease has remained obscure. Galactose, the hydrolyzing product of the milk sugar lactose, has been hypothesized to be toxic to ovarian epithelial cells and consumption of dairy products and lactase persistence has been suggested to be a risk factor for ovarian carcinoma. In adults, downregulation of lactase depends on a variant C/T-13910 at the 5' end of the lactase gene. To explore whether lactase persistence is related to the risk of ovarian carcinoma we determined the C/T-13910 genotype in a cohort of 782 women with ovarian carcinoma. The C/T-13910 genotype was defined by solid phase minisequencing from 327 Finnish, 303 Polish, 152 Swedish patients and 938 Finnish, 296 Polish and 97 Swedish healthy individuals served as controls. Lactase persistence did not associate significantly with increased risk for ovarian carcinoma in the Finnish odds ratio (OR = 0.77, 95% confidence interval [CI] = 0.57-1.05, p = 0.097), in the Polish (OR = 0.95, 95% Cl = 0.68-1.33, p = 0.75), or in the Swedish populations (OR = 1.63, 95% Cl = 0.65-4.08, p = 0.29). Our results do not support the hypothesis that lactase persistence increases the ovarian carcinoma risk. On the contrary, lactase persistence may decrease the ovarian carcinoma risk at least in the Finnish population.
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| 22. |
- Leandersson, Pia, et al.
(författare)
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A multiplex biomarker assay improves the diagnostic performance of HE4 and CA125 in ovarian tumor patients
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:10 October
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Tidskriftsartikel (refereegranskat)abstract
- Objective Survival in epithelial ovarian cancer (EOC) remains poor. Most patients are diagnosed in late stages. Early diagnosis increases the chance of survival. We used the proximity extension assay from Olink Proteomics to search for new protein biomarkers with the potential to improve the diagnostic performance of CA125 and HE4 in patients with ovarian tumors. Material and methods Plasma samples were obtained from 180 women with ovarian tumors; 30 cases of benign tumor, 28 cases with borderline tumors, 25 early EOC cases (FIGO stage I) and 97 advanced EOC cases (FIGO stages II-IV). Proteins were measured using the Olink® Oncology II and Inflammation panels. For statistical analyses, patients were categorized into benign tumors versus cancer and benign tumors versus borderline + cancer, respectively. Results We analyzed 177 biomarkers. Thirty-four proteins had ROC AUC > 0.7 for discrimination between benign tumors and cancer. Fifteen proteins had ROC AUC > 0.7 for discrimination between benign tumors and borderline tumors + cancer. HE4 ranked highest for both comparisons. A reference model with HE4, CA125 and age (AUC 0.838 for benign tumors vs. cancer and AUC 0.770 for benign tumors vs. borderline tumors + cancer) was compared to the reference model with the addition of each of the remaining proteins with AUC > 0.7. ITGAV was the only individual biomarker found to improve diagnostic performance of the reference model, to AUC 0.874 for benign tumors vs. cancer and AUC 0.818 for benign tumors vs. borderline tumors + cancer (p < 0.05). Cross-validation and LASSO regression was combined to select multiple biomarker combinations. The best performing model for discrimination between benign tumors and borderline tumors + cancer was a 6-biomarker combination (HE4, CA125, ITGAV, CXCL1, CEACAM1, IL-10RB) and age (AUC 0.868, sensitivity 0.86 and specificity 0.82, p = 0.016 for comparison with the reference model). Conclusion HE4 was the best performing individual biomarker for discrimination between benign ovarian tumors and EOC including borderline tumors. The addition of other carcinogenesis-related biomarkers in a multiplex biomarker panel can improve the diagnostic performance of the established biomarkers HE4 and CA125.
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| 23. |
- Leandersson, Pia, et al.
(författare)
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Incidence and survival of epithelial ovarian, fallopian tube, peritoneal, and undesignated abdominal/pelvic cancers in Sweden 1960–2014 : A population-based cohort study
- 2021
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite improved surgical and oncological treatment, ovarian cancer continues to be the most lethal of the gynecologic malignancies. We aimed to analyze survival trends in epithelial ovarian cancer with regard to age, tumor site, and morphology in Sweden 1960 to 2014. Methods: A nationwide population-based study was conducted using data from the Swedish Cancer Registry on 46,350 women aged 18 or older with a diagnosis of epithelial ovarian, fallopian tube, peritoneal, or undesignated abdominal/pelvic cancer 1960 to 2014. Analyses of age-standardized incidence and relative survival (RS) were performed and time trends modelled according to age, tumor site, and morphology. Results: Overall incidence of ovarian, tubal, peritoneal, and undesignated abdominal/pelvic cancers declined since 1980. Median age at diagnosis increased. Serous carcinoma increased in incidence. RS at 1, 2 and 5 years from diagnosis improved since 1960, although not for the youngest and the oldest patients. Ten-year RS did not improve. The best RS was found for fallopian tube cancer and the worst RS for undesignated abdominal/pelvic cancer. Among the morphologic subgroups, endometrioid carcinoma had the best RS. Conclusions: Survival in epithelial ovarian, tubal, peritoneal, and undesignated abdominal/pelvic cancers in Sweden has improved over the last six decades. Advances in epithelial ovarian cancer treatment have extended life for the first 5 years from diagnosis but 10-year survival remains poor.
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| 24. |
- Lindemann, Kristina, et al.
(författare)
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Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO)
- 2014
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. Methods: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Results: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Conclusion: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients.
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| 25. |
- Malander, Susanne
(författare)
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Hereditary Ovarian Cancer mutation frequencies and genetic profiles
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian cancer is a leading cause of gynecological cancer death and in Sweden nearly 700 cases are diagnosed annually. Ovarian cancer has one of the highest frequencies of hereditary cancer. This thesis focuses on estimates of the contribution of hereditary breast and ovarian cancer (HBOC) and hereditary nonpolyposis colorectal cancer (HNPCC) to the development of ovarian cancer and investigates the genomic profiles in HBOC associated ovarian cancer. In a prospective population-based study, mutations in BRCA1 and BRCA2 were assessed in 161 patients (study I) and mismatch repair (MMR) status was assessed using MMR protein immunostaining from 128 of these tumors (study II). BRCA mutations suggestive of HBOC were identified in 10% of the patients and an additional 2% had MMR defective tumors suggestive of HNPCC. Whereas more than half of the women with HBOC were diagnosed after age 50, the women with HNPCC were young. We therefore investigated the contribution of defective MMR in a population-based cohort of 99 young under age 40 women with ovarian cancer (study III). MMR defects were found in 6% of the tumors, which together with previous studies suggest that HNPCC and HBOC contribute equally to ovarian cancer development in young women. HBOC associated ovarian cancer does not differ clinically and histopathologically from sporadic cancer and we therefore aimed to study whether a hereditary genomic profile could be identified. Genetic complexity was demonstrated in the vast majority of the 12 BRCA1 associated and 25 sporadic ovarian cancers. Gains and high-level amplifications were particularly common in the sporadic tumors, whereas losses characterized the hereditary tumors with losses of 4q, 8p, 13q, 18p, and 19p being significantly more common in the HBOC associated ovarian cancers.
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| 26. |
- Malander, Susanne, et al.
(författare)
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Ovarialcancer är på många sätt en heterogen sjukdom
- 2015
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Ingår i: Läkartidningen. - 1652-7518. ; 112
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian cancer develops due to a complex interplay between hereditary and environmental factors. Although often described as one disease, ovarian cancer is actually a group of distinct tumor types. Recent research has indicated that a large percentage of ovarian cancers may originate from the fallopian tube epithelium. Although most cancers develop in patients without a known hereditary syndrome, it is clear that the number of familial cancers is larger than previously supposed. The two most common hereditary syndromes where ovarian cancer can develop are hereditary breast ovarian cancer syndrome (HBOC) and Lynch syndrome.
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| 27. |
- Malander, Susanne, et al.
(författare)
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The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer.
- 2006
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 1095-6859 .- 0090-8258. ; 101:2, s. 238-243
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Ovarian cancer has one of the highest fractions of hereditary cases. The hereditary breast and ovarian cancer syndrome, primarily due to mutations in BRCA1 and BRCA2, is the main cause of heredity, but also the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome confers an increased risk of ovarian cancer. In order to clarify the contribution of HNPCC to the development of ovarian cancer, we collected data on family history of cancer and characterized MMR function in a consecutive series of 128 tumors unselected for age at diagnosis and previously characterized for BRCA gene mutations. Methods. Expression of the MMR proteins MLH1 PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry using tissue microarray sections. Tumors with reduced staining or loss of staining were also analyzed for microsatellite instability (MSI). Results. Loss of MMR protein expression was identified in 3 ovarian cancers, all of which had a MSI-high phenotype. DNA sequence analysis revealed disease-causing germline mutations (deletions of exons 4-6 in MLHI and a 1-nucleotide deletion in exon 5 of MSH6) in two patients diagnosed at ages 40 and 49 years, both of whom had family histories suggestive of HNPCC. The genetic defect in the third case, which was a 47-year old woman without knowledge about her family history with loss of MLH1/PMS2 expression in the tumor tissue, remains elusive. A family history suggestive of HNPCC was identified in an additional case, but this tumor showed normal, retained MMR protein expression and a microsatellite stable phenotype. Conclusions. About 2% of ovarian cancer is caused by germline mutations in the MMR-genes, a minor proportion as compared to the contribution of the BRCA-genes (11% in the present series). However, identification of HNPCC patients is important since it allows inclusion of high-risk individuals into control programs aimed at preventing the more frequent colorectal and endometrial cancers. Tumors within the HNPCC-spectrum should therefore be included when recording a family history of cancer among patients diagnosed with ovarian cancer. (c) 2005 Elsevier Inc. All rights reserved.
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| 28. |
- Martín De La Fuente, Laura, et al.
(författare)
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Claudin-4 Expression is Associated with Survival in Ovarian Cancer but Not with Chemotherapy Response
- 2018
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Ingår i: International Journal of Gynecological Pathology. - 0277-1691. ; 37:2, s. 101-109
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Tidskriftsartikel (refereegranskat)abstract
- The tight junction protein claudin-4 has been reported to be overexpressed in advanced ovarian cancer. We investigated the prognostic significance of claudin-4 overexpression and whether claudin-4 expression could predict platinum response in primary ovarian carcinoma (OC). Claudin-4 expression was evaluated by immunohistochemistry in a tissue microarray of 140 OCs. Multivariable Cox-regression models were used to assess the effect of claudin-4 overexpression on progression-free survival and overall survival (OS). Kaplan-Meier survival analyses and the logrank test were performed comparing claudin-4 high and low groups. The association between claudin-4 expression and platinum resistance was assessed using risk ratios and the Pearson χ 2 test. A dataset of >1500 epithelial ovarian cancers was used to study the association between CLDN4 mRNA and survival. Of 140 evaluable cases, 71 (51%) displayed high claudin-4 expression. Claudin-4 overexpression predicted shorter 5-yr progression-free survival and OS in univariable analyses [hazard ratio (HR)=1.6 (1.1-2.5), P=0.020 and HR=1.6 (1.0-2.4), P=0.041, respectively]. Hazard of relapse was similar [HR=1.5 (1.0-2.4)] after adjustment for age, stage, type, and BRCA1/2 status in a multivariable analysis, but the evidence was slightly weaker (P=0.076). Validation in an external cohort confirmed the association between high expression of CLDN4 and poor 10-yr OS [HR=1.3 (1.1-1.5), P<0.001]. However, no confident association between claudin-4 and platinum sensitivity was found in our cohort [risk ratio=1.2 (0.7-2.0), P=0.3]. These findings suggest that high expression of claudin-4 may have a prognostic value in OC. The role of claudin-4 in the development of platinum resistance remains unclear.
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| 29. |
- Martin de la Fuente, Laura, et al.
(författare)
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Copy number signatures for early diagnosis of high-grade serous ovarian carcinoma
- 2022
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundThe detection of ovarian carcinoma-derived somatic mutations in cervical samples and uterine lavages in several studies since 2013, has brought hope for the development of new biomarkers for early detection. High-grade serous ovarian carcinoma (HGSC) is strongly dominated by copy number alterations (CNAs). These CNAs are the consequence of underlying mutational processes in HGSC. We interrogated CNAs from low coverage whole-genome sequencing (WGS) data in HGSC tumors, plasma, endometrial biopsies, and cervical samples to explore if copy number signatures can be used as a biomarker for early detection of HGSC.Methods A total of 204 samples were included from 18 patients with HGSC, four BRCA mutation carriers and seven benign controls. Estimations of ploidy and cellularity, and thus calculation of absolute copy number, were optimized through a combination of the ACE, Rascal, and ichorCNA bioinformatic tools. Mixture modelling was used to subgroup the six fundamental copy number features and non-negative matrix factorization was used to generate the signatures and cluster the samples.ResultsWe extracted six fundamental copy number features from 69 diagnostic and pre-diagnostic cervical samples from patients diagnosed with HGSC and generated six CN signatures. We found different distributions of features in benign samples compared to tumors and cervical samples from HGSC patients. We also observed different exposures to the six signatures in different patient groups.ConclusionsFurther understanding of the components and cell types contributing to each signature, and inclusion of more cervical samples into the approach, will hopefully identify a novel tumorigenic signature for early detection of HGSC in cervical samples.
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| 30. |
- Martin de la Fuente, Laura, et al.
(författare)
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PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma
- 2020
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Ingår i: Virchows Archiv: an international journal of pathology. - : Springer Science and Business Media LLC. - 1432-2307. ; 477:1, s. 83-91
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Tidskriftsartikel (refereegranskat)abstract
- The response rate to checkpoint inhibitors for women with high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is modest, and development of predictive biomarkers is needed. The main focus has been on tumor cell PD-L1 expression, but its assessment alone is insufficient for patient selection in most malignancies. We mapped the presence of macrophages (CD68 and CD163) and lymphocytes (CD3) located within the tumor epithelium, the cell type-specific expression of PD-L1 and PD-1, and their impact on 5-year overall survival (OS) in a consecutive cohort of 130 women diagnosed with advanced HGSC between 2011 and 2015. PD-L1 was expressed mainly by macrophages (not by tumor cells) and PD-1 by lymphocytes. Women with higher CD3, PD-L1, and PD-1 expression had improved OS (P = 0.03, P = 0.007, and P = 0.02, respectively). In the external data set (203 women), high expression of CD274 (encoding PD-L1) was associated with improved OS (P = 0.03), in accordance with our results. Furthermore, higher CD163 expression was associated with better outcome in women with no residual tumor after primary surgery (P = 0.02). Thus, women with greater lymphocyte tumor infiltration had better outcome and PD-L1/PD-1 expression, regardless of PD-1/PD-L1 being markers for immune suppressive pathways, conferred a survival benefit in our cohort. Our results highlight that tumor immunity may be harnessed in subsets of HGSC.
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| 31. |
- Mirza, Mansoor Raza, et al.
(författare)
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A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer: NSGO AVANOVA1/ENGOT-OV24
- 2019
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Ingår i: Cancer Chemotherapy and Pharmacology. - : SPRINGER. - 0344-5704 .- 1432-0843. ; 84:4, s. 791-798
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Tidskriftsartikel (refereegranskat)abstract
- Background Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial. Materials and methods In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D). Results Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21. Conclusions There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.
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| 32. |
- Mirza, Mansoor Raza, et al.
(författare)
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Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial
- 2019
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Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 20:10, s. 1409-1419
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Tidskriftsartikel (refereegranskat)abstract
- Background Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer. Methods This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but amp;lt;= 1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov , number NCT02354131. Findings Between May 23,2016, and March 6,2017,97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16.9 months (IQR 15.4-20.9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11.9 months [95% CI 8.5-16.7] vs 5.5 months [3.8-6.3], respectively; adjusted hazard ratio [HR] 0.35 [95% CI 0.21-0.57], pamp;lt;0.0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27[56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred. Interpretation The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
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| 33. |
- Norbeck, Anna, et al.
(författare)
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Age and Referral Route Impact the Access to Diagnosis for Women with Advanced Ovarian Cancer
- 2023
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Ingår i: Journal of Multidisciplinary Healthcare. - 1178-2390. ; 16, s. 1239-1248
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The majority of women with ovarian cancer are diagnosed in late stages. Most women do have symptoms prior to diagnosis, sometimes several months before the diagnosis. The aim of this study was to evaluate the timeline from the first presentation of symptoms to a physician until there is a reasonable suspicion of cancer, among women diagnosed with advanced stage ovarian cancer. We wanted to investigate which symptoms were the most common and whether there are other factors affecting the time interval before the suspicion of cancer was confirmed.Patients and Methods: This was a retrospective population-based cohort study of women diagnosed with advanced ovarian cancer between January 1, 2017 and December 31, 2019 who were referred to Skane University Hospital Lund, Sweden. Data were collected from electronic medical records at Skane University Hospital. The time interval was recorded as the time from first physician consultation with predefined symptoms to the date when there was a reasonable suspicion of ovarian cancer. Data processing and statistical analysis were performed with the statistical software R.Results: Among the 249 patients included in this study, the median time interval from the first consultation to the reasonable suspicion of cancer was 24 days. The first consultation in specialized care had a 70% decrease in delay compared to primary care. Emergency consultations had a 52.2% decrease in time delay compared to planned consultations. Older age was associated with an increase in the geometric mean by 54.7%, comparing the first to the third quartile. The most common symptom was abdominal pain.Conclusion: The length of time interval from first presentation with symptoms relating to ovarian cancer to reasonable suspicion of cancer was associated with whether the consultation was in primary or specialized care, emergency or planned visit and the patient’s age.
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| 34. |
- Oza, Amit M., et al.
(författare)
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Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA) : results from a double-blind, phase 3, randomised controlled trial
- 2018
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Ingår i: The Lancet Oncology. - 1470-2045. ; 19:8, s. 1117-1125
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Tidskriftsartikel (refereegranskat)abstract
- Background: Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL. Methods: The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted-block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline BRCA (gBRCA) mutation status (determined by BRACAnalysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3–4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with ClinicalTrials.gov, number NCT01847274. Findings: Between Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the gBRCAmut cohort, n=234 in the non-gBRCAmut cohort) or placebo (n=65 in the gBRCAmut cohort, n=116 in the non-gBRCAmut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25·0–25·6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0·838 [0·0097] in the niraparib group vs 0·834 [0·0173] in the placebo group in the gBRCAmut cohort; and 0·833 [0·0077] in the niraparib group vs 0·815 [0·0122] in the placebo group in the non-gBRCAmut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects. Interpretation: These PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo. Funding: TESARO.
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| 35. |
- Sajic, Tatjana, et al.
(författare)
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Similarities and Differences of Blood N-Glycoproteins in Five Solid Carcinomas at Localized Clinical Stage Analyzed by SWATH-MS
- 2018
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 23:9, s. 5-2831
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is mostly incurable when diagnosed at a metastatic stage, making its early detection via blood proteins of immense clinical interest. Proteomic changes in tumor tissue may lead to changes detectable in the protein composition of circulating blood plasma. Using a proteomic workflow combining N-glycosite enrichment and SWATH mass spectrometry, we generate a data resource of 284 blood samples derived from patients with different types of localized-stage carcinomas and from matched controls. We observe whether the changes in the patient's plasma are specific to a particular carcinoma or represent a generic signature of proteins modified uniformly in a common, systemic response to many cancers. A quantitative comparison of the resulting N-glycosite profiles discovers that proteins related to blood platelets are common to several cancers (e.g., THBS1), whereas others are highly cancer-type specific. Available proteomics data, including a SWATH library to study N-glycoproteins, will facilitate follow-up biomarker research into early cancer detection. Sajic et al. perform a multi-tumor plasma proteomic study in which they enrich and analyze tissue-secreted plasma glycoproteins to examine blood protein changes in early-stage localized cancers. They demonstrate that many proteins secreted upon platelet activation are changed in several tissue carcinomas, whereas others have changes specific to a single carcinoma type.
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