Pacienti s adenokarcinomy žaludku a gastroezofageální junkce s pozitivitou receptoru 2 pro lidský epidermální růstový faktor (human epidermal growth factor receptor 2, HER2) mají obecně špatnou prognózu. Na základě klinické studie ToGA byl do klinické praxe zaveden trastuzumab v první linii paliativní léčby, když kombinace trastuzumabu s chemoterapií jednoznačně prokázala benefit v porovnání se samotnou chemoterapií. Nově se u těchto pacientů na základě klinické studie KEYNOTE-811 etablovala do léčebných standardů imunoterapie v kombinaci s trastuzumabem a získala registraci Evropské lékové agentury pro pacienty s nádory s kombinovaným hodnocením (combined positive score, CPS) exprese ligandu programované buněčné smrti 1 (programmed death-iigand 1, PD-L1) ≥ 1. V České republice byla pembrolizumabu přiznána úhrada z prostředků veřejného zdravotního pojištění od července 2025. Ve vyšších liniích léčby po progresi na trastuzumabu se na základě klinických studií DESTINY-Gastric01 a DESTINY-Gastric02 dostal do léčebných algoritmů trastuzumab emtansin, a pokud tato možnost nepřichází v úvahu, je stále možno podle ustanovení paragrafu 16 indikovat kombinaci pakiitaxeiu s ramucirumabem. Imunoterapie v první linii paliativní léčby v kombinaci s trastuzumabem představuje nový standard u pacientů s pozitivitou receptoru HER2.
Patients with gastric and gastroesophageal junction adenocarcinoma overexpressing human epidermal growth factor receptor 2 (HER2) have generally poor prognosis. Based on the clinical trial ToGA trastuzumab in combination with chemotherapy was introduced as the general standard of care when this combination proved the benefit compared with chemotherapy alone. Nowadays based on the results of the trial KEYNOTE-811 immunotherapy in combination with trastuzumab gained the approval of European Medicines Agency (EMA) for the use in patients with programmed death-ligand 1 combined positive score (PD-L1 CPS) expression ≥ 1. In the Czech Republic, pembrolizumab is covered by public health insurance from July 2025. In the further palliative lines after progression on the therapy based on trastuzumab according to clinical trials DESTINY-Gastric01 and DESTINY-Gastric02 the trastuzumab emtansine should be considered. Otherwise the combination of ramucirumab and paclitaxel is the treatment of choice after approval of the insurance company. Immunotherapy in combination with trastuzumab is the new gold standard of care for the patients overexpressing HER2 receptor.
Using immunohistochemistry, we examined a large cohort of 135 ovarian tumors, made up of 96 low-grade serous carcinomas (LGSCs) and 39 serous borderline tumors (micropapillary variant, mSBT), with the aim of exploring their HER2 status (overexpression). We followed with comprehensive genomic analyses on this sample set from our previous study, which revealed HER2 mutation in 5% (4/75) of LGSC and 10% (3/29) of mSBT. No cases were evaluated as HER2-positive, but 6 LGSCs and 1 mSBT were scored as HER2 1+, and 2 LGSCs and 1 mSBT showed the so-called HER2 "ultra-low" phenotype. This could be of clinical value as a potential therapeutical target concerning emerging therapeutic treatments (antibody conjugates). However, the clinical significance of this expression still needs to be established.
- MeSH
- Adult MeSH
- Immunohistochemistry MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation MeSH
- Biomarkers, Tumor genetics metabolism MeSH
- Ovarian Neoplasms * pathology genetics metabolism MeSH
- Receptor, ErbB-2 * genetics metabolism MeSH
- Aged MeSH
- Cystadenocarcinoma, Serous * pathology genetics metabolism MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Léčba pacientů s karcinomem žaludku by měla být plánována prakticky ve všech případech v prostředí multidisciplinárního týmu. V případě resekabilního onemocnění používáme ve většině případů kombinaci systémové léčby a chirurgie, chemoterapie je podávána jako perioperační, méně často jako adjuvantní. Indikace chemoradioterapie v adjuvantní indikaci je vyhrazena jako možnost jen pro případy, kdy operace nebyla dostatečně radikální. Základem léčby pokročilého a metastatického onemocnění je paliativní chemoterapie FOLFOX nebo FLOT. Podle výsledků prediktorů je volena cílená léčba a/nebo imunoterapie. V případě pozitivity HER2 je do kombinace s chemoterapií indikován trastuzumab, v případě exprese claudinu 18.2 lze do kombinace s chemoterapií nově zvážit zolbetuximab. Chemoimunoterapie s nivolumabem nebo pembrolizumabem je vhodná pro pacienty s expresí PD-L1, pacienti s nádory s MSI-high jsou kandidáty pro imunoterapii.
Treatment of patients with gastric cancer should be planned in practically all cases in a multidisciplinary team. In the case of resectable disease, we use in most cases a combination of systemic treatment and surgery. Chemotherapy is administered perioperatively, less often as adjuvant treatment. The indication of chemoradiotherapy in adjuvant indication is reserved as an option only for cases where the surgery was not radical enough. The basis of treatment of advanced and metastatic disease is palliative chemotherapy FOLFOX or FLOT. According to the results of predictors, targeted therapy and/or immunotherapy is indicated. In the case of HER2 positivity, trastuzumab is indicated in combination with chemotherapy; in the case of claudin 18.2 expression, zolbetuximab can be newly considered in combination with chemotherapy. Chemoimmunotherapy with nivolumab or pembrolizumab is suitable for patients with PD-L1 expression, patients with MSI-high tumours are candidates for immunotherapy.
Kolorektální karcinom patří mezi nejčastější nádorová onemocnění s významným podílem metastatických případů. Systémová léčba metastatického kolorektálního karcinomu (mCRC) je dnes určována na základě molekulárního profilu nádoru, který zahrnuje stav mikrosatelitové nestability (MSI), mutační status genů KRAS, NRAS, BRAF a HER2. U pacientů s MSI/dMMR je preferována imunoterapie, zatímco u mikrosatelitově stabilních (MSS) forem závisí léčebná sekvence na přítomnosti mutací KRAS, BRAF a expresi HER2. Standardní terapeutické možnosti zahrnují kombinaci chemoterapie s cílenou terapií (anti-EGFR, antiangiogenní léčba) a novější přístupy, včetně inhibitorů KRAS G12C nebo HER2 cílené terapie. Lokální metody, jako jsou chirurgické resekce a ablační techniky, mohou významně přispět k dlouhodobému přežití. Správná volba léčby v kontextu multidisciplinárního přístupu je klíčová pro optimalizaci výsledků pacientů s mCRC.
Colorectal cancer is one of the most common malignancies, with a significant proportion of metastatic cases. The systemic treatment of metastatic colorectal cancer (mCRC) is now guided by the tumor's molecular profile, including microsatellite instability (MSI) status, mutational status of KRAS, NRAS, BRAF, and HER2 expression. Patients with MSI/dMMR benefit from immunotherapy, while treatment sequencing for microsatellite-stable (MSS) tumors depends on the presence of KRAS, BRAF mutations, and HER2 overexpression. Standard therapeutic options include chemotherapy combined with targeted therapy (anti-EGFR, antiangiogenic agents) and novel approaches such as KRAS G12C inhibitors or HER2-targeted treatments. Local therapies, including surgical resections and ablative techniques, can significantly improve long-term survival. The proper selection of treatment within a multidisciplinary approach is essential for optimizing outcomes in mCRC patients.
of the original article, 'Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02'. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate, which is a chemotherapy with a linker (deruxtecan) joined to an antibody (trastuzumab). Trastuzumab binds to the human epidermal growth factor receptor 2 (HER2) protein on cancer cells, where it releases the chemotherapy to kill these cells. The DESTINY-PanTumor02 clinical study tested the effectiveness of T-DXd for people with various HER2-expressing cancers and the safety of treatment. Previous results from DESTINY-PanTumor02 showed that T-DXd had antitumor activity, and the greatest effects were seen in people with the highest tumor level of HER2 [defined as immunohistochemistry (IHC) 3+]. In this previous analysis, the HER2 expression was measured at a central laboratory. In clinical practice, HER2 expression will likely be measured at a local laboratory, so understanding whether T-DXd has similar effects regardless of how HER2 expression is measured is important. Here, we looked at the effects of T-DXd based on the HER2 test result used to determine a person's eligibility for the study, which could be measured using a local or central laboratory. In people with IHC 3+ tumors (where HER2 was measured at a local or central laboratory), 51% had a decrease in the size or number of tumors, according to established criteria (referred to as an objective response), while, in people with IHC 2+ tumors, 26% had an objective response. Side effects with T-DXd were consistent with previous studies. These results confirm T-DXd has antitumor effects in HER2-expressing cancers where the HER2 expression is measured by a local or central laboratory.
- MeSH
- Immunohistochemistry MeSH
- Immunoconjugates * therapeutic use adverse effects MeSH
- Camptothecin * analogs & derivatives therapeutic use administration & dosage adverse effects MeSH
- Clinical Trials, Phase II as Topic MeSH
- Humans MeSH
- Neoplasms * drug therapy metabolism pathology MeSH
- Antineoplastic Agents, Immunological * therapeutic use MeSH
- Receptor, ErbB-2 * metabolism MeSH
- Secondary Data Analysis MeSH
- Trastuzumab * therapeutic use adverse effects MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
The immunohistochemical (IHC) or fluorescence/chromogenic in situ hybridization (FISH/CISH) assays for assessing HER2 are now recommended by the American Society of Clinical Oncologists and the College of American Pathologists, but there are an increasing number of published studies describing alternative diagnoses at the molecular level. Inspired by these studies, we established a laboratory-developed test (LDT) to analyze HER2 status not only at the gene expression level but also at the gene copy number. A precise copy number calculation was fulfilled including the Control Genomic DNA of known concentration, which allowed subsequent assay validation at the DNA level. The results were reported according to the concordant results of the DNA and RNA approaches. By comparing with IHC determination, completely identical results were found in ten blank samples, which underlines the legitimacy of molecular biological approaches in this diagnostic field. An equivocal sample that was positive by IHC and qPCR was found to be negative by the FISH and so it may change the choice of personalized medicine. The topic of this short communication will hopefully contribute to allowing IVD-certified diagnostics based on the HER2 gene expression profile or copy number to be tested in the Czech Republic as well.
- MeSH
- DNA genetics metabolism MeSH
- Gene Dosage * MeSH
- In Situ Hybridization, Fluorescence * methods MeSH
- Immunohistochemistry * methods MeSH
- Humans MeSH
- Biomarkers, Tumor genetics metabolism MeSH
- Breast Neoplasms genetics metabolism diagnosis MeSH
- Receptor, ErbB-2 * genetics metabolism MeSH
- RNA metabolism genetics analysis MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Juvenile granulosa cell tumor (JGCT) of the ovary is a rare tumor with distinct clinicopathological and hormonal features primarily affecting young women and children. We conducted a complex clinicopathological, immunohistochemical, and molecular analysis of five cases of JGCT. METHODS: The immunohistochemical examination was performed with 32 markers, including markers that have not been previously investigated. Moreover, DNA next-generation sequencing (NGS) and PTEN methylation analysis was performed. RESULT: We found the expression of calretinin, inhibin A, SF1, FOXL2, CD99, CKAE1/3, ER, PR, AR in all cases. WT1 was expressed in one case. Conversely, the expression of p16, OCT3/4, SALL4, GATA3, Napsin A, SATB2, MUC4, TTF1, and CAIX was completely negative. All tumors showed the wild-type pattern of p53 expression. Regarding predictive markers, all tumors were HER2 negative and did not express PD-L1. Mismatch repair proteins (MMR) showed no loss or restriction of expression, similarly to ARID1A, DPC4, BRG1, and INI1. The molecular analysis revealed AKT1 internal tandem duplication in two tumors. Two other cases exhibited mutations in TERT and EP400 and both developed recurrence. All AKT1-wild type tumors exhibited immunohistochemical loss of PTEN expression. However, no mutations, deletions (as assessed by CNV analysis), or promoter hypermethylation in the PTEN gene were detected. CONCLUSION: The results of our study further support the hypothesis that the pathogenesis of JGCT may be driven by activation of the PIK3/AKT/mTOR pathway. These findings could potentially have future therapeutic implications, as treatment strategies targeting the PTEN/mTOR pathways are currently under investigation.
- MeSH
- Child MeSH
- Phosphatidylinositol 3-Kinases genetics metabolism MeSH
- PTEN Phosphohydrolase genetics metabolism MeSH
- Immunohistochemistry * MeSH
- Humans MeSH
- DNA Methylation MeSH
- Adolescent MeSH
- Granulosa Cell Tumor * pathology genetics metabolism MeSH
- Biomarkers, Tumor * genetics analysis metabolism MeSH
- Ovarian Neoplasms * pathology genetics metabolism MeSH
- Proto-Oncogene Proteins c-akt * metabolism genetics MeSH
- Signal Transduction * MeSH
- TOR Serine-Threonine Kinases * metabolism MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
U nádorů gastrointestinálního traktu dnes vedle stanovení histologické diagnózy, grade a stage hraje zásadní roli rovněž tzv. prediktivní testování. To slouží zejména k identifikaci molekulárních cílů pro moderní onkologickou terapii. U karcinomů jícnu a žaludku je dnes standardem vyšetření exprese a amplifikace HER2, exprese proteinů mismatch repair (MMR) systému a vyšetření exprese PD-L1. U karcinomu žaludku se v blízké budoucnosti testování rozšíří o další markery, zejména exprese claudinu 18.2 či receptoru FGFR2a. U kolorektálního karcinomu je standardem prediktivního vyšetření stanovení mutací RAS (KRAS a NRAS), BRAF a dále zhodnocení mikrosatelitní instability, jen vzácně lze nalézt rovněž terapeuticky cílitelné genové fúze. U karcinomu pankreatu se lze setkat s případy deficience MMR, mutacemi BRCA1/2, zcela raritně lze identifikovat další cílitelné aberace. U nádorů žlučníku a žlučových cest hledáme zejména mutace IDH1 a IDH2, fúze a mutace genu FGFR2, amplifikace či mutace HER2, mutace BRAF či mutace BRCA1/2. Všechny výsledky by měly být projednány v rámci molekulárního tumor boardu.
In addition to the histological diagnosis, grade and stage, predictive testing plays a crucial role in gastrointestinal tumours today. This is mainly used to identify molecular targets for modern cancer therapy. In esophageal and gastric cancers, HER2 expression and amplification, mismatch repair (MMR) system protein deficiency and PD-L1 expression are tested routinely. In colorectal cancer, it is namely detection of RAS (KRAS and NRAS) and BRAF mutations, as well as the assessment of microsatellite instability; targetable gene fusions are found rarely only. In pancreatic cancer, cases of MMR deficiency, BRCA1/2 mutations and other targetable aberrations can be identified quite rarely. In gallbladder and biliary tract cancers, we are mainly looking for IDH1 and IDH2 mutations, FGFR2 gene fusions and mutations, HER2 amplifications or mutations, as well as mutations of BRAF or BRCA1/2. All results should be discussed within the molecular tumor board.
- MeSH
- Molecular Diagnostic Techniques MeSH
- Gastrointestinal Neoplasms * diagnosis genetics classification MeSH
- Genetic Testing MeSH
- Humans MeSH
- Mutation genetics MeSH
- Biomarkers, Tumor * genetics MeSH
- Predictive Value of Tests MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Hormonálně dependentní HER2 negativní karcinom prsu je nejčastějším podtypem tohoto onemocnění. Kombinace hormonální léčby s inhibitory cyklin-dependentních kináz 4 a 6 (CDK 4/6) je v případě metastazujícího onemocnění jednoznačně preferovaným postupem v iniciálních fázích terapie, a to jak u premenopauzálních, tak postmenopauzálních pacientek. Díky této terapii došlo k výraznému zlepšení prognózy pacientek, a to jak ve smyslu prodloužení doby bez známek progrese onemocnění, tak celkového přežívání. Charakteristiky a chování onemocnění u premenopauzálních pacientek se liší od profilu onemocnění u pacientek postmenopauzálních; častěji se jedná o agresivnější onemocnění (vyšší proliferace, nižní exprese hormonálních receptorů, vyšší nádorový grade) s postižením viscerálních orgánů a s výraznějšími symptomy onemocnění. I v těchto případech je preferována kombinace hormonální léčby s inhibitory CDK 4/6 před chemoterapií. Předkládáme kazuistiku mladé premenopauzální pacientky s metastazujícím karcinomem prsu s postižením plic, hrudní dutiny a skeletu, s iniciálně výrazně symptomatickým a agresivním onemocněním, u které bylo dosaženo pomocí kombinace inhibitoru aromatázy a ribociklibu rychlé a dlouhodobé stabilizace onemocnění s výrazným zlepšením kvality života.
Hormone-dependent HER2-negative breast cancer is the most common subtype of this disease. Combination of hormonal therapy with cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors is clearly the preferred approach for metastatic disease in the initial phases of therapy in both premenopausal and postmenopausal patients. This therapy has significantly improved the prognosis of patients, both in terms of prolonged progression-free survival and overall survival. The characteristics and behavior of the disease in premenopausal patients differ from the disease profile in postmenopausal patients; more often it is a more aggressive disease (higher proliferation, lower hormone receptor expression, higher tumor grade) with visceral involvement and more pronounced symptoms. Even in these cases, the combination of hormonal therapy with CDK 4/6 inhibitors is preferred over chemotherapy. We present a case report of a young premenopausal patient with metastatic breast cancer involving the lung, thoracic cavity and skeleton, with initially highly symptomatic and aggressive disease, in whom a combination of aromatase inhibitor and ribociclib achieved rapid and long-term disease stabilization with significant improvement in quality of life.
PURPOSE: Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. METHODS: This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION: Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.
- MeSH
- Antibodies, Monoclonal, Humanized adverse effects MeSH
- Immunoconjugates * adverse effects MeSH
- Lung Diseases, Interstitial * chemically induced drug therapy MeSH
- Humans MeSH
- Lung Neoplasms * drug therapy MeSH
- Breast Neoplasms * drug therapy MeSH
- Carcinoma, Non-Small-Cell Lung * drug therapy MeSH
- Receptor, ErbB-2 metabolism MeSH
- Trastuzumab adverse effects MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
