| 1. |
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| 2. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 3. |
- Kang, E. Y., et al.
(författare)
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CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 129:5, s. 697-713
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
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| 4. |
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| 5. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 6. |
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| 7. |
- Kang, E. Y., et al.
(författare)
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MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma
- 2022
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Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 480, s. 855-871
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Tidskriftsartikel (refereegranskat)abstract
- Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naive HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naive tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naive HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
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| 8. |
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| 9. |
- Oonk, M. H. M., et al.
(författare)
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Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II
- 2021
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 39:32
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (<= 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL. (C) 2021 by American Society of Clinical Oncology
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| 10. |
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| 11. |
- Van der Kolk, W. L., et al.
(författare)
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Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe
- 2022
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 167:1, s. 3-10
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN.Methods. We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up.Results. Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was di-agnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor >= 30 mm. Bilateral ra-diotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence.Conclusion. The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
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| 12. |
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| 13. |
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| 14. |
- Oonk, Maaike H. M., et al.
(författare)
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Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node : Results of GROINSS-V II
- 2021
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Ingår i: Journal of Clinical Oncology. - : Lippincott, Williams & Wilkins. - 0732-183X .- 1527-7755. ; 39:32, s. 3623-3632
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (<= 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Oonk, M. H. M., et al.
(författare)
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European Society of Gynaecological Oncology Guidelines for the Management of Patients With Vulvar Cancer
- 2017
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Ingår i: International Journal of Gynecological Cancer. - : BMJ. - 1048-891X .- 1525-1438. ; 27:4, s. 832-837
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this study was to develop clinically relevant and evidence-based guidelines as part of European Society of Gynaecological Oncology's mission to improve the quality of care for women with gynecologic cancers across Europe. Methods The European Society of Gynaecological Oncology Council nominated an international development group made of practicing clinicians who provide care to patients with vulvar cancer and have demonstrated leadership and interest in the management of patients with vulvar cancer (18 experts across Europe). To ensure that the statements are evidence based, the current literature identified from a systematic search has been reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group (expert agreement). The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 181 international reviewers including patient representatives independent from the development group. Results The guidelines cover diagnosis and referral, preoperative investigations, surgical management (local treatment, groin treatment including sentinel lymph node procedure, reconstructive surgery), radiation therapy, chemoradiation, systemic treatment, treatment of recurrent disease (vulvar recurrence, groin recurrence, distant metastases), and follow-up.
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| 20. |
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| 21. |
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| 22. |
- Kristensen, G B, et al.
(författare)
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First-line treatment of ovarian cancer FIGO stages IIb-IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin.
- 2003
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Ingår i: International Journal of Gynecological Cancer. - : Lippincott Williams & Wilkins. - 1048-891X .- 1525-1438. ; 13:s2, s. 172-177
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to compare the safety and efficacy of carboplatin plus epirubicin and paclitaxel (TEC) to carboplatin and paclitaxel (TC), in the treatment of epithelial ovarian, peritoneal, or tubal carcinoma. Between March 1999 and August 2001, 887 patients were randomized to receive six to nine cycles of paclitaxel (175 mg/m2, 3 h intravenously) followed by carboplatin (AUC 5, Calvert formula) with or without epirubicin (75 mg/m2 intravenously prior to paclitaxel), on a 3-weekly schedule. The primary endpoint was progression-free survival. Demographic information: Residual disease <1 cm was reported on 41% of patients. At the end of treatment, 65% in the TEC and 55% in the TC arm had achieved a clinical complete response, and 18 and 25% a clinical partial response resulting in an overall response rate of 83% in the TEC and 80% in the TC arm, whereas 7 and 9% had progressive disease, respectively. The three-drug combination produced a markedly higher myelotoxicity, resulting in a higher frequency of febrile neutropenia (12.5% of the TEC and 1.5% of the TC patients) and a higher number of dose reductions and treatment delays. Cycle prolongation above seven days was seen in 7 and 5% of cycles in the TEC and TC arm, respectively. Stomatitis > or = grade 3 was also higher with TEC (4% TEC and 0.5% TC). Reductions in left ventricular ejection fraction of more than 15% after six courses were slightly more common with the TEC regimen (3% versus 1.5%), but the difference was not statistically significant (P = 0.2). In conclusion, treatment with the TEC combination produced a higher rate of complete responses than treatment with the TC combination. Toxicity was manageable. Long-term survival data are awaited.
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| 23. |
- Mirza, M. R., et al.
(författare)
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Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer
- 2016
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Ingår i: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 375:22, s. 2154-2164
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2: 1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTS Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P amp;lt; 0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONS Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274.)
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| 24. |
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| 25. |
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| 26. |
- Vergote, I., et al.
(författare)
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European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer
- 2022
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 33:3, s. 276-287
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Forskningsöversikt (refereegranskat)abstract
- Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition.Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive.Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.
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| 27. |
- Landolfo, C., et al.
(författare)
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Benign descriptors and ADNEX in two-step strategy to estimate risk of malignancy in ovarian tumors : retrospective validation on IOTA 5 multicenter cohort
- 2023
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Ingår i: Ultrasound in Obstetrics and Gynecology. - : Wiley. - 0960-7692 .- 1469-0705. ; 61:2, s. 231-242
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Previous work suggested that the ultrasound-based benign Simple Descriptors can reliably exclude malignancy in a large proportion of women presenting with an adnexal mass. We aim to validate a modified version of the Benign Simple Descriptors (BD), and we introduce a two-step strategy to estimate the risk of malignancy: if the BDs do not apply, the ADNEX model is used to estimate the risk of malignancy. Methods: This is a retrospective analysis using the data from the 2-year interim analysis of the IOTA5 study, in which consecutive patients with at least one adnexal mass were recruited irrespective of subsequent management (conservative or surgery). The main outcome was classification of tumors as benign or malignant, based on histology or on clinical and ultrasound information during one year of follow-up. Multiple imputation was used when outcome based on follow-up was uncertain according to predefined criteria. Results: 8519 patients were recruited at 36 centers between 2012 and 2015. We included all masses that were not already in follow-up at recruitment from 17 centers with good quality surgical and follow-up data, leaving 4905 patients for statistical analysis. 3441 (70%) tumors were benign, 978 (20%) malignant, and 486 (10%) uncertain. The BDs were applicable in 1798/4905 (37%) tumors, and 1786 (99.3%) of these were benign. The two-step strategy based on ADNEX without CA125 had an area under the receiver operating characteristic curve (AUC) of 0.94 (95% CI, 0.91-0.95). The risk of malignancy was slightly underestimated, but calibration varied between centers. A sensitivity analysis in which we expanded the definition of uncertain outcome resulted in 1419 (29%) tumors with uncertain outcome and an AUC of the two-step strategy without CA125 of 0.93 (95% CI, 0.91-0.95). Conclusion: A large proportion of adnexal masses can be classified as benign by the BDs. For the remaining masses the ADNEX model can be used to estimate the risk of malignancy. This two-step strategy is convenient for clinical use.
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| 28. |
- Lee, C.K., et al.
(författare)
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Prognostic nomogram to predict progression-free survival in patients with platinum-sensitive recurrent ovarian cancer
- 2011
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Ingår i: British Journal of Cancer. - : Cancer Research UK. - 0007-0920 .- 1532-1827. ; 105:8, s. 1144-1150
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n = 955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n = 340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.
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| 31. |
- Cibula, D., et al.
(författare)
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Completion of radical hysterectomy does not improve survival of patients with cervical cancer and intraoperatively detected lymph node involvement : ABRAX international retrospective cohort study
- 2021
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049. ; 143, s. 88-100
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Tidskriftsartikel (refereegranskat)abstract
- Background: The management of cervical cancer patients with intraoperative detection of lymph node involvement remains controversial. Since all these patients are referred for (chemo)radiation after the surgery, the key decision is whether radical hysterectomy should be completed as originally planned, taking into account an additional morbidity associated with extensive surgical dissection prior to adjuvant treatment. The ABRAX study investigated whether completing a radical uterine procedure is associated with an improved oncological outcome of such patients. Patients and methods: We performed retrospective analyses of 515 cervical cancer patients (51 institutions, 19 countries) who were referred for primary curative surgery between 2005 and 2015 (stage IA–IIB, common tumour types) in whom lymph node involvement was detected intraoperatively. Patients were stratified according to whether the planned uterine surgery was completed (COMPL group, N = 361) or abandoned (ABAND group, N = 154) to compare progression-free survival. Definitive chemoradiation was given to 92.9% patients in the ABAND group and adjuvant (chemo)radiation or chemotherapy to 91.4% of patients in the COMPL group. Results: The risks of recurrence (hazard ratio [HR] 1.154, 95% confidence intervals [CI] 0.799–1.666, P = 0.45), pelvic recurrence (HR 0.836, 95% CI 0.458–1.523, P = 0.56), or death (HR 1.064, 95% CI 0.690–1.641, P = 0.78) were not significantly different between the two groups. No subgroup showed a survival benefit from completing radical hysterectomy. Disease-free survival reached 74% (381/515), with a median follow-up of 58 months. Prognostic factors were balanced between the two groups. FIGO stage and number of pelvic lymph nodes involved were significant prognostic factors in the whole study cohort. Conclusion: We showed that the completion of radical hysterectomy does not improve survival in patients with intraoperatively detected lymph node involvement, regardless of tumour size or histological type. If lymph node involvement is confirmed intraoperatively, abandoning uterine radical procedure should be considered, and the patient should be referred for definitive chemoradiation. Clinical trials identifier: NCT04037124.
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| 32. |
- Garcia-Dios, Diego A, et al.
(författare)
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High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma.
- 2013
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 128:2, s. 327-334
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Endometrial cancer patients may benefit from systemic adjuvant chemotherapy, alone or in combination with targeted therapies. Prognostic and predictive markers are needed, however, to identify patients amenable for these therapies. METHODS: Primary endometrial tumors were genotyped for >100 hot spot mutations in genes potentially acting as prognostic or predictive markers. Mutations were correlated with tumor characteristics in a discovery cohort, replicated in independent cohorts and finally, confirmed in the overall population (n=1063). RESULTS: PIK3CA, PTEN and KRAS mutations were most frequently detected, respectively in 172 (16.2%), 164 (15.4%) and 161 (15.1%) tumors. Binary logistic regression revealed that PIK3CA mutations were more common in high-grade tumors (OR=2.03; P=0.001 for grade 2 and OR=1.89; P=0.012 for grade 3 compared to grade 1), whereas a positive TP53 status correlated with type II tumors (OR=11.92; P<0.001) and PTEN mutations with type I tumors (OR=19.58; P=0.003). Conversely, FBXW7 mutations correlated with positive lymph nodes (OR=3.38; P=0.045). When assessing the effects of individual hot spot mutations, the H1047R mutation in PIK3CA correlated with high tumor grade and reduced relapse-free survival (HR=2.18; P=0.028). CONCLUSIONS: Mutations in PIK3CA, TP53, PTEN and FBXW7 correlate with high tumor grade, endometrial cancer type and lymph node status, whereas PIK3CA H1047R mutations serve as prognostic markers for relapse-free survival in endometrial cancer patients.
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| 33. |
- Heitz, F., et al.
(författare)
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Early tumor regrowth is a contributor to impaired survival in patients with completely resected advanced ovarian cancer. An exploratory analysis of the Intergroup trial AGO-OVAR 12
- 2019
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Ingår i: Gynecologic Oncology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0090-8258 .- 1095-6859. ; 152:2, s. 235-242
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Surgical assessment of residual tumor provides the strongest prognostic information in advanced ovarian cancer (AOC), with the best outcome observed after complete resection. Postoperative radiological assessment before initiation of chemotherapy can supplement the information obtained by surgical assessment; however, it may also reveal conflicting findings. Methods. Patients with AOC enrolled in the AGO-OVAR 12 trial underwent baseline imaging before the first chemotherapy cycle. The findings from surgical and radiologic assessment for disease extend were compared. Additionally, an integrated approach was assessed. Results. Complete data from all 3 assessment methods were available for 1345 patients. Of 689 patients with complete resection, tumor was observed in 28% and 22% of patients undergoing radiologic and integrated assessment, respectively. Patients with surgical- radiological and surgical-integrated concordant findings showed a 5-year overall survival (5Y-OS) of 72% and 71%, whereas patients with surgical-radiological and surgical-integrated discordant results showed inferior 5Y-OS of 47% and 49%, respectively. Patients with surgically assessed residual disease had a 5-YOS of 37%. The interval between surgery and baseline assessment was independently associated with discordance between assessment methods, which might reflect early tumor regrowth. Conclusions. Baseline tumor assessment before chemotherapy provides information that stratifies patients with complete resection into different prognostic groups. Integrating the data from different assessment methods might lead to improved definitions of prognostic groups. Further investigation to determine if earlier initiation of chemotherapy after debulking surgery could increase survival of patients with early tumor regrowth is warranted. (C) 2018 Published by Elsevier Inc.
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| 34. |
- Kaye, S. B., et al.
(författare)
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Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval
- 2011
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 22:1, s. 49-58
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Tidskriftsartikel (refereegranskat)abstract
- Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L. P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6-12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy. Patients and methods: A detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted. Results: Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357). Conclusion: The superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum.
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| 35. |
- Kurzeder, Christian, et al.
(författare)
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Double-blind, placebo-controlled, randomized phase III trial evaluating pertuzumab combined with chemotherapy for low tumor human epidermal growth factor receptor 3 mRNA-Expressing platinum-resistant ovarian Cancer (PENELOPE)
- 2016
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 34:21, s. 25-2516
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The AGO-OVAR 2.29/ENGOT-ov14/PENELOPE prospectively randomized phase III trial evaluated the addition of pertuzumab to chemotherapy in patients with platinum-resistant ovarian carcinoma with low tumor human epidermal growth factor receptor 3 (HER3)mRNA expression. We report the results of the primary efficacy analysis. Patients and Methods Eligible patients had ovarian carcinoma that progressed during or within 6 months of completing four or more platinum cycles, centrally tested low tumor HER3 mRNA expression (concentration ratio # 2.81 by quantitative reverse transcriptase polymerase chain reaction on cobas z480 [Roche Molecular Diagnostics, Pleasanton, CA]), and no more than two prior lines of chemotherapy. After investigators selection of the chemotherapy backbone (single-agent topotecan, weekly paclitaxel, or gemcitabine), patientswere randomly assigned to also receive either placebo or pertuzumab (840-mg loading dose followed by 420 mg every 3 weeks). Stratification factors were selected chemotherapy, prior antiangiogenic therapy, and platinum-free interval. The primary end point was independent review committee-assessed progression-free survival (PFS). Additional end points included overall survival, investigator-assessed PFS, objective response rate, safety, patient-reported outcomes, and translational research. Results Overall, 156 patientswere randomly assigned. Adding pertuzumab to chemotherapy did not significantly improve independent review committee-assessed PFS for the primary analysis (stratified hazard ratio, 0.74; 95% CI, 0.50 to 1.11; P = .14; median PFS, 4.3 months for pertuzumab plus chemotherapy v 2.6 months for placebo plus chemotherapy). Sensitivity analyses and secondary efficacy end point results were consistent with the primary analysis. The effect on PFS favoring pertuzumab was more pronounced in the gemcitabine and paclitaxel cohorts. No new safety signals were seen. Conclusion Although the primary objective was not met, subgroup analyses showed trends in PFS favoring pertuzumab in the gemcitabine and paclitaxel cohorts, meriting further exploration of pertuzumab in ovarian cancer.
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| 36. |
- Lindemann, K., et al.
(författare)
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First-line treatment of advanced ovarian cancer with paclitaxel/carboplatin with or without epirubicin (TEC versus TC)-a gynecologic cancer intergroup study of the NSGO, EORTC GCG and NCIC CTG
- 2012
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 23:10, s. 31-2613
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Tidskriftsartikel (refereegranskat)abstract
- Background: The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel. Patients and methods: We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m(2)) with the same combination and epirubicin (TEC; 75 mg/m(2) i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB-IV were randomized to receive either TC (442 patients) or TEC (445 patients). Results: Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9-1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8-1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC. Conclusion: The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.
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| 37. |
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| 38. |
- Poveda, A., et al.
(författare)
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Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer : outcomes in the partially platinum-sensitive (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial
- 2011
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 22:1, s. 39-48
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Tidskriftsartikel (refereegranskat)abstract
- Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6-12 months platinum-free interval (PFI)] is unclear. Patients and methods: Within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup. Results: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) = 0.65, 95% confidence interval (CI), 0.45-0.92; P = 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR = 0.59; 95% CI, 0.43-0.82; P = 0.0015; median survival 23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR = 0.63; P = 0.0357; median 13.3 versus 9.8 months). Conclusion: This hypothesis-generating analysis demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 6-12 months).
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| 39. |
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| 40. |
- Tropé, C, et al.
(författare)
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Randomized study on adjuvant chemotherapy in stage I high-risk ovarian cancer with evaluation of DNA-ploidy as prognostic instrument
- 2000
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology. - : Elsevier BV. - 0923-7534. ; 11:3, s. 8-281
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Adjuvant chemotherapy versus observation and chemotherapy at progression was evaluated in 162 patients in a prospective randomized multicenter study. We also evaluated DNA-measurements as an additional prognostic factor.PATIENTS AND METHODS: Patients received adjuvant carboplatin AUC 7 every 28 days for six courses (n = 81) or no adjuvant treatment (n = 81). Eligibility included surgically staged and treated patients with FIGO stage I disease, grade 1 aneuploid or grade 2 or 3 non-clear cell carcinomas or clear cell carcinomas. Disease-free (DFS) and disease-specific (DSS) survival were end-points.RESULTS: Median follow-up time was 46 months and progression was observed in 20 patients in the treatment group and 19 in the control group. Estimated five-year DFS and DSS were 70% and 86% in the treatment group and 71% and 85% in the control group. The hazard ratio was 0.98 (95% confidence interval (95% CI): 0.52-1.83) regarding DFS and 0.94 (95% CI: 0.37-2.36) regarding DSS. No significant differences in DFS or DSS could be seen when the log-rank test was stratified for prognostic variables. Therefore, data from both groups were pooled for the analysis of prognostic factors. DNA-ploidy (P = 0.003), extracapsular growth (P = 0.005), tumor rupture (P = 0.04), and WHO histologic grade (P = 0.04) were significant independent prognostic factors for DFS with P < 0.0001 for the model in the multivariate Cox analysis. FIGO substage (P = 0.01), DNA ploidy (P < 0.05), and histologic grade (P = 0.05) were prognostic for DSS with a P-value for the model < 0.0001.CONCLUSIONS: Due to the small number of patients the study was inconclusive as regards the question of adjuvant chemotherapy. The survival curves were superimposable, but with wide confidence intervals. DNA-ploidy adds objective independent prognostic information regarding both DFS and DSS in early ovarian cancer.
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| 41. |
- Vetters, J, et al.
(författare)
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The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF
- 2019
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 216:9, s. 2010-2023
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20−/− cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20−/− cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.
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| 42. |
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