| 1. |
- Björn, Niclas, et al.
(författare)
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ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
- 2018
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : WILEY. - 1742-7835 .- 1742-7843. ; 123:3, s. 277-287
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Tidskriftsartikel (refereegranskat)abstract
- The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199Gamp;gt;A (rs2229109), 1236Camp;gt;T (rs1128503), 2677Gamp;gt;T/A (rs2032582), 3435Camp;gt;T (rs1045642) in ABCB1, and 1196Aamp;gt;G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n=260) or Taxol((R)) (Arm B, n=265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR=0.590) and in Arm B (HR=0.627), as well as increased OS in All (HR=0.443) and in Arm A (HR=0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p=0.039) and less neutrophil decrease in All (p=0.048) and in Arm B (p=0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.
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| 4. |
- Froyman, Wouter, et al.
(författare)
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Risk of complications in patients with conservatively managed ovarian tumours (IOTA5) : a 2-year interim analysis of a multicentre, prospective, cohort study
- 2019
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 20:3, s. 448-458
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ovarian tumours are usually surgically removed because of the presumed risk of complications. Few large prospective studies on long-term follow-up of adnexal masses exist. We aimed to estimate the cumulative incidence of cyst complications and malignancy during the first 2 years of follow-up after adnexal masses have been classified as benign by use of ultrasonography. Methods: In the international, prospective, cohort International Ovarian Tumor Analysis Phase 5 (IOTA5) study, patients aged 18 years or older with at least one adnexal mass who had been selected for surgery or conservative management after ultrasound assessment were recruited consecutively from 36 cancer and non-cancer centres in 14 countries. Follow-up of patients managed conservatively is ongoing at present. In this 2-year interim analysis, we analysed patients who were selected for conservative management of an adnexal mass judged to be benign on ultrasound on the basis of subjective assessment of ultrasound images. Conservative management included ultrasound and clinical follow-up at intervals of 3 months and 6 months, and then every 12 months thereafter. The main outcomes of this 2-year interim analysis were cumulative incidence of spontaneous resolution of the mass, torsion or cyst rupture, or borderline or invasive malignancy confirmed surgically in patients with a newly diagnosed adnexal mass. IOTA5 is registered with ClinicalTrials.gov, number NCT01698632, and the central Ethics Committee and the Belgian Federal Agency for Medicines and Health Products, number S51375/B32220095331, and is ongoing. Findings: Between Jan 1, 2012, and March 1, 2015, 8519 patients were recruited to IOTA5. 3144 (37%) patients selected for conservative management were eligible for inclusion in our analysis, of whom 221 (7%) had no follow-up data and 336 (11%) were operated on before a planned follow-up scan was done. Of 2587 (82%) patients with follow-up data, 668 (26%) had a mass that was already in follow-up at recruitment, and 1919 (74%) presented with a new mass at recruitment (ie, not already in follow-up in the centre before recruitment). Median follow-up of patients with new masses was 27 months (IQR 14–38). The cumulative incidence of spontaneous resolution within 2 years of follow-up among those with a new mass at recruitment (n=1919) was 20·2% (95% CI 18·4–22·1), and of finding invasive malignancy at surgery was 0·4% (95% CI 0·1–0·6), 0·3% (<0·1–0·5) for a borderline tumour, 0·4% (0·1–0·7) for torsion, and 0·2% (<0·1–0·4) for cyst rupture. Interpretation: Our results suggest that the risk of malignancy and acute complications is low if adnexal masses with benign ultrasound morphology are managed conservatively, which could be of value when counselling patients, and supports conservative management of adnexal masses classified as benign by use of ultrasound. Funding: Research Foundation Flanders, KU Leuven, Swedish Research Council.
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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. |
- 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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| 7. |
- 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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| 8. |
- Pujade-Lauraine, Eric, et al.
(författare)
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Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer : A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study
- 2016
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 34:7, s. 706-
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. Patients and Methods Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator's choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. Results Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. Conclusion Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.
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| 9. |
- Timmerman, Dirk, et al.
(författare)
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Predicting the risk of malignancy in adnexal masses based on the Simple Rules from the International Ovarian Tumor Analysis (IOTA) group.
- 2016
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Ingår i: American Journal of Obstetrics and Gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 214:4, s. 424-437
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Tidskriftsartikel (refereegranskat)abstract
- Accurate methods to preoperatively characterize adnexal tumors are pivotal for optimal patient management. A recent meta-analysis concluded that the International Ovarian Tumor Analysis (IOTA) algorithms such as the Simple Rules are the best approaches to preoperatively classify adnexal masses as benign or malignant. We sought to develop and validate a model to predict the risk of malignancy in adnexal masses using the ultrasound features in the Simple Rules. STUDY DESIGN: This was an international cross-sectional cohort study involving 22 oncology centers, referral centers for ultrasonography, and general hospitals. We included consecutive patients with an adnexal tumor who underwent a standardized transvaginal ultrasound examination and were selected for surgery. Data on 5020 patients were recorded in 3 phases from 2002 through 2012. The 5 Simple Rules features indicative of a benign tumor (B-features) and the 5 features indicative of malignancy (M-features) are based on the presence of ascites, tumor morphology, and degree of vascularity at ultrasonography. Gold standard was the histopathologic diagnosis of the adnexal mass (pathologist blinded to ultrasound findings). Logistic regression analysis was used to estimate the risk of malignancy based on the 10 ultrasound features and type of center. The diagnostic performance was evaluated by area under the receiver operating characteristic curve, sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), positive predictive value (PPV), negative predictive value (NPV), and calibration curves. RESULTS: Data on 4848 patients were analyzed. The malignancy rate was 43% (1402/3263) in oncology centers and 17% (263/1585) in other centers. The area under the receiver operating characteristic curve on validation data was very similar in oncology centers (0.917; 95% confidence interval, 0.901-0.931) and other centers (0.916; 95% confidence interval, 0.873-0.945). Risk estimates showed good calibration. In all, 23% of patients in the validation data set had a very low estimated risk (<1%) and 48% had a high estimated risk (≥30%). For the 1% risk cutoff, sensitivity was 99.7%, specificity 33.7%, LR+ 1.5, LR- 0.010, PPV 44.8%, and NPV 98.9%. For the 30% risk cutoff, sensitivity was 89.0%, specificity 84.7%, LR+ 5.8, LR- 0.13, PPV 75.4%, and NPV 93.9%. CONCLUSION: Quantification of the risk of malignancy based on the Simple Rules has good diagnostic performance both in oncology centers and other centers. A simple classification based on these risk estimates may form the basis of a clinical management system. Patients with a high risk may benefit from surgery by a gynecological oncologist, while patients with a lower risk may be managed locally.
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