High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co-analyze the expression and mutational profiles of other key cancer genes.
- MeSH
- chemorezistence * genetika MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- nádorový supresorový protein p53 * genetika MeSH
- nádory vaječníků * genetika farmakoterapie patologie MeSH
- platina terapeutické užití farmakologie MeSH
- regulace genové exprese u nádorů MeSH
- sekvenování exomu metody MeSH
- senioři MeSH
- serózní cystadenokarcinom * genetika farmakoterapie patologie MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.
- MeSH
- benzimidazoly škodlivé účinky terapeutické užití MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- doxorubicin analogy a deriváty terapeutické užití MeSH
- inhibitory proteinkinas škodlivé účinky terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- MAP kinasa-kinasa 1 antagonisté a inhibitory MeSH
- MAP kinasa-kinasa 2 antagonisté a inhibitory MeSH
- mladý dospělý MeSH
- nádory vaječníků farmakoterapie enzymologie patologie MeSH
- nádory vejcovodů farmakoterapie enzymologie patologie MeSH
- paclitaxel terapeutické užití MeSH
- peritoneální nádory farmakoterapie enzymologie patologie MeSH
- polyethylenglykoly terapeutické užití MeSH
- senioři MeSH
- serózní cystadenokarcinom farmakoterapie enzymologie patologie MeSH
- stupeň nádoru MeSH
- topotekan terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
Multidrug resistance to anticancer drugs, which is often associated with enhanced expression of the ATP‑binding cassette (ABC) transporter P‑glycoprotein (encoded by the ABCB1 gene) may limit the effects of cancer therapy. Epigenetic regulation of ABCB1 expression may thus have a clinical impact. A detailed assessment of ABCB1 promoter methylation is of importance for predicting therapy outcome and prognosis. Thus, validated methods for the analysis of ABCB1 promoter methylation are urgently required. In the present study, high‑resolution melting (HRM) analysis of the CpG island regions covering the distal promoter of the ABCB1 gene was developed and compared with pyrosequencing. In addition, the clinical effects of the methylation status of the ABCB1 promoter were analyzed in patients with breast and ovarian carcinoma prior and subsequent to chemotherapy treatment. HRM analysis of ABCB1 methylation correlated with the results of pyrosequencing (P=0.001) demonstrating its analytical validity and utility. Hypermethylation of the analyzed ABCB1 promoter region was significantly correlated with low levels of the ABCB1 transcript in tumors from a subset of patients with breast and ovarian carcinoma prior to chemotherapy but not following treatment. Finally, high ABCB1 transcript levels were observed in tumors of patients with short progression‑free survival prior to chemotherapy. Our data suggest the existence of functional epigenetic changes in the ABCB1 gene with prognostic value in tumor tissues of patients with breast and ovarian carcinoma. The clinical importance of such changes should be further evaluated.
- MeSH
- denaturace nukleových kyselin MeSH
- duktální karcinom prsu farmakoterapie genetika patologie MeSH
- epigeneze genetická MeSH
- invazivní růst nádoru MeSH
- lidé MeSH
- metylace DNA * MeSH
- míra přežití MeSH
- nádorové biomarkery genetika MeSH
- nádory prsu farmakoterapie genetika patologie MeSH
- nádory vaječníků farmakoterapie genetika patologie MeSH
- následné studie MeSH
- P-glykoproteiny genetika MeSH
- polymerázová řetězová reakce metody MeSH
- prognóza MeSH
- promotorové oblasti (genetika) * MeSH
- regulace genové exprese u nádorů MeSH
- retrospektivní studie MeSH
- serózní cystadenokarcinom farmakoterapie genetika patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Karcinom ovaria patří k nejagresivnějším onkologickým onemocněním a mezi gynekologickými malignitami má nejvyšší mortalitu. Je pátou nejčastější příčinou úmrtí na zhoubný novotvar u žen na celém světě. Histologicky je zde zastoupena široká paleta jednotek a nejčastějším typem je serózní karcinom ovaria řadící se do skupiny epitelových nádorů.1 V roce 2016 bylo na území České republiky nově diagnostikováno 998 pacientek a ve stejném roce karcinomu ovaria podlehlo 628 žen.2 Čísla nám ukazují, že se nejedná o příliš častý novotvar, ale jeho mortalita patří k jedněm z nejvyšších. V téměř 75 % se v době stanovení diagnózy jedná již o lokálně pokročilé či metastazující onemocnění. Důvodem je jednak rychlý růst nádoru a jednak pozdní nástup příznaků. Navíc v dnešní době stále chybí účinné metody časného screeningu a diagnostiky. Pětileté přežití i přes agresivní léčbu je u stadia III 20-35 %, u stadia IV 10 %.3 Standardem terapie karcinomu ovaria s kurativním záměrem je kombinace chirurgické léčby a chemoterapie. Chirurgický výkon by měl dosáhnout maximálního debulkingu nádorových hmot a měl by být následován systémovou léčbou. Karcinom ovaria je obecně nádor vysoce chemosenzitivní a v léčbě je primárně využíváno přípravků platinových derivátů. Při relapsu onemocnění se přednostně používá systémová léčba a chirurgická léčba je využívána velmi okrajově. Podle doby od ukončení primární či předchozí léčby můžeme rozlišit platina rezistentní onemocnění (recidiva do šesti měsíců od ukončení léčby platinovým derivátem) a platina senzitivní onemocnění (recidiva za delší dobu, než je šest měsíců od ukončení léčby platinovým derivátem). Na základě tohoto rozdělení volíme další přípravky pro systémovou terapii onemocnění. Z chemoterapeutik se nejčastěji jedná o carboplatinu či cisplatinu, dále paclitaxel, docetaxel, gemcitabin či pegylovaný liposomální doxorubicin. Z léků s jiným než cytotoxickým mechanismem využívaných při paliativní systémové léčbě můžeme zmínit například bevacizumab nebo olaparib.
Ovarian cancer is one of the most aggressive oncological diseases and it has the highest mortality amongst gynecological malignancies. It is the fifth most common cause of death in women with malignant neoplasms all over the world. A wide variety of histological units is present in ovarian cancer and the most common type is a serosal ovarian cancer that belongs to a group called epithelial tumours.1 In 2016, 998 new patients were diagnosed with ovarian cancer and in the same year 628 women died from the ovarian cancer in the Czech Republic.2 The statistics show that this type of neoplasm is not very common, however, the mortality rates are one of the highest for this type of cancer. 75 % of diagnosed patients are already in advanced or metastatic stages. The main reasons are rapid tumour growth and late onset of symptoms. On top of that we are still very behind with getting tested and diagnosed in time. Despite aggressive treatment the percentage to survive at least five years is 23-35 % with Stage III, 10 % with Stage IV.3 The standard treatment of ovarian cancer is the combination of surgical treatment and chemotherapy. With surgery the tumours should drastically shrink and then systemic therapy should be in place. The ovarian cancer is generally highly chemo sensitive tumor and platinum derivative preparations are primarily used in the treatment. Primarily, for relapse we use systemic treatment, surgical treatment is used very rarely. Depending on the time when the primary or prior treatment ended we can distinguish platinum-resistant disease (relapse within six months of termination of the platinum-based treatment) and platinum-sensitive disease (relapse after more than six months after termination of the platinum-based treatment). Based on these two types of diseases we then choose other products for systemic therapy of the disease. Most common chemotherapeutic agents are carboplatin or cisplatin, paclitaxel, docetaxel, gemcitabine or pegylated liposomal doxorubicin. Medicine with a non-cytotoxic mechanism used in palliative systemic therapy can be for example bevacizumab or olaparib.
- MeSH
- bevacizumab terapeutické užití MeSH
- dospělí MeSH
- doxorubicin terapeutické užití MeSH
- ftalaziny terapeutické užití MeSH
- kvalita života MeSH
- lidé MeSH
- metastázy nádorů diagnóza terapie MeSH
- nádory vaječníků * diagnóza klasifikace terapie MeSH
- piperaziny terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- serózní cystadenokarcinom farmakoterapie chirurgie terapie MeSH
- sloučeniny platiny * terapeutické užití MeSH
- taxoidy terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Despite progress in primary treatment of patients with advanced ovarian cancer, the majority develop recurrence of the disease. A platinum salt treatment, either as monotherapy or in combination with another cytostatic agent, is indicated for patients who have relapsed 6 or more months after primary treatment and thus have platinum-sensitive relapse. Because repeated use of paclitaxel treatment may lead to substantial neurotoxicity, the combination of gemcitabine with carboplatin represents a suitable treatment option, which is widely used in common clinical practice in the Czech Republic and Slovakia. This non-interventional, prospective study observed the effectiveness and tolerability of second-line treatment with gemcitabine and carboplatin in patients with platinum-sensitive relapse of ovarian cancer in routine clinical practice. The primary endpoint was to evaluate the survival and secondary endpoints were to evaluate time to disease progression, objective tumor response rate, and treatment toxicity. Patients were enrolled to planned second-line treatment with gemcitabine and carboplatin (gemcitabine 1000 mg/m2 and carboplatin AUC 5 on Day 1, and gemcitabine 1000 mg/m2 on Day 8 of a 21-day cycle) for platinum-sensitive relapse of ovarian cancer as a part of routine clinical practice and followed for 12 months. The events (death, tumor progression), tumor response, and maximal grades of toxicity were recorded according to common clinical practice. Survival time (using Kaplan-Meier analysis) and objective tumor response rate were calculated using data forms, and a subgroup analysis was performed using log rank tests for time-to-event endpoints; p-values were also calculated. Response rates were calculated for the whole population; for the subgroups, the Fisher's exact test was performed and only p-values were calculated. Between January 2004 and June 2005, 53 patients were enrolled in the study. The median age was 57 years and 96% of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 and 1 at baseline. Approximately 91% of patients were originally diagnosed with stage III or IV; 60% of patients had disease free intervals (DFIs) of 12 or more months from previous therapy, and the additional 40% less than 12 months. The 1-year survival rate was 83%. Median survival time was not determined within the 12-month period following the start of the treatment study due to the limited duration of follow-up. Objective tumour response rate was 67.3%. Most common reasons for discontinuation of therapy were "Planned treatment completed" (53%) and "Tumor progression" (11%). Most common toxicities were leukopenia, anaemia, neutropenia, and thrombocytopenia; grades 3 and 4 of these toxicity types did not exceed 30%. Febrile neutropenia was recorded in two patients. Most common non-haematological toxicities were nausea and vomiting, fatigue, and neuropathy; grades 3 and 4 of these were below 6%. Results on time to disease progression are not published due to inconsistent statistical analysis of reported data. Based on this observation from routine clinical practice, which corresponds with previously published results from controlled clinical trials, the gemcitabine and carboplatin combination seems to be a suitable therapeutic option for patients with platinum-sensitive relapse of ovarian cancer.
- MeSH
- deoxycytidin analogy a deriváty aplikace a dávkování MeSH
- dospělí MeSH
- endometroidní karcinom farmakoterapie sekundární MeSH
- imunoenzymatické techniky MeSH
- karboplatina aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie patologie MeSH
- míra přežití MeSH
- mladý dospělý MeSH
- mucinózní adenokarcinom farmakoterapie sekundární MeSH
- nádory endometria farmakoterapie sekundární MeSH
- nádory vaječníků farmakoterapie patologie MeSH
- prognóza MeSH
- progrese nemoci MeSH
- prospektivní studie MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- serózní cystadenokarcinom farmakoterapie sekundární MeSH
- staging nádorů MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- multicentrická studie MeSH
- práce podpořená grantem MeSH
