Lung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers1,2 and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies3-5. Here we use data from the Sherlock-Lung study to evaluate mutagenic exposures in LCINS by examining the cancer genomes of 871 treatment-naive individuals with lung cancer who had never smoked, from 28 geographical locations. KRAS mutations were 3.8 times more common in adenocarcinomas of never smokers from North America and Europe than in those from East Asia, whereas a higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas of never smokers from East Asia. Signature SBS40a, with unknown cause6, contributed the largest proportion of single base substitutions in adenocarcinomas, and was enriched in cases with EGFR mutations. Signature SBS22a, which is associated with exposure to aristolochic acid7,8, was observed almost exclusively in patients from Taiwan. Exposure to secondhand smoke was not associated with individual driver mutations or mutational signatures. By contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations and shorter telomeres. They also exhibited an increase in most types of mutations, including a 3.9-fold increase in signature SBS4, which has previously been linked with tobacco smoking9, and a 76% increase in the clock-like10 signature SBS5. A positive dose-response effect was observed with air-pollution levels, correlating with both a decrease in telomere length and an increase in somatic mutations, mainly attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

• MeSH
• adenokarcinom genetika   MeSH
• erbB receptory genetika   MeSH
• genom lidský * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * genetika   MeSH
• mutageneze * genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory plic * genetika   patologie   MeSH
• nekuřáci * MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři MeSH
• znečištění ovzduší škodlivé účinky   MeSH
• znečištění tabákovým kouřem škodlivé účinky   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• KRAS protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny p21(ras) MeSH
• TP53 protein, human MeSH Prohlížeč
• znečištění tabákovým kouřem MeSH

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.

• Klíčová slova
• HER2, Immunohistochemistry, Low-grade serous carcinoma, Ovarian tumors,
• MeSH
• dospělí MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory vaječníků * patologie   genetika   metabolismus   MeSH
• receptor erbB-2 * genetika   metabolismus   MeSH
• senioři MeSH
• serózní cystadenokarcinom * patologie   genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ERBB2 protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• receptor erbB-2 * MeSH

NTRK-rearranged spindle cell neoplasm represents an emerging entity included in the latest 5th edition of WHO classification of both soft tissue and female genital tumors. By immunohistochemistry, they are commonly positive for CD34, S100 protein, and CD30 and typically harbor fusions of kinase genes such as NTRK1/2/3, RET, and BRAF. In the gynecological tract, they typically affect the uterine cervix or uterine body. Most of the reported cases had fibrosarcoma-like morphology, occasionally showing perivascular and stromal hyalinization with only a few cases showing a less cellular spindle cell proliferation. Except for one case with RET fusion, all other gynecological cases harbored exclusively NTRK1/2/3 fusions. Besides kinase gene fusions, the analogous tumors in soft tissues may also harbor activating EGFR or BRAF point mutations, but no such case has been described in the uterus. Herein we are reporting two cases from the uterine cervix showing morphology and molecular features previously unreported at this anatomic site. The patients were 46 and 34 years old and clinically presented with unremarkable cervical polyps each measuring 8 mm in diameter. Histologically, both cases had a rounded polypoid outline and were composed of hypocellular proliferation of bland spindle cells lacking mitotic activity and growing in a fibrotic stroma which was punctuated by prominent small vessels with thick hyalinized walls. Immunohistochemically, both showed a diffuse expression of CD34, CD30, and S100 protein, whereas SOX10 was negative. Both cases harbored exon 20 EGFR mutation and did not reveal any fusions or significant copy number changes. The patient in case 1 was treated by hysterectomy with salpingectomy with no other residual tumor detected, and she was alive and well 27 months after the diagnosis. The patient in case 2 had no other known tumors at the time of diagnosis, but no follow-up is available. We believe the reported cases represent a hitherto unrecognized variant of "NTRK-rearranged spindle cell neoplasms" of the uterine cervix with novel EGFR mutations.

• Klíčová slova
• EGFR mutation, NTRK-rearranged spindle cell neoplasms, Perivascular and stromal hyalinization, S100 and CD34 co-expression, Soft tissues, Uterine cervix,
• MeSH
• antigeny CD34 * analýza   MeSH
• dospělí MeSH
• erbB receptory genetika   MeSH
• fenotyp MeSH
• genová přestavba MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádory dělohy * genetika   patologie   MeSH
• nádory děložního čípku * genetika   patologie   MeSH
• proteiny S100 * analýza   MeSH
• receptor trkA * genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antigeny CD34 * MeSH
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• nádorové biomarkery * MeSH
• NTRK1 protein, human MeSH Prohlížeč
• proteiny S100 * MeSH
• receptor trkA * MeSH

BACKGROUND: HER2-positive breast cancer occurs in about 15-20 % of all breast cancers. It is both a prognostic and predictive biomarker and the introduction of anti-HER2 therapy over the last 20 years has significantly improved outcomes in this subset of patients, so that they are now comparable to or better than those of patients with HER2-negative tumors. Approximately 5-10% of patients are diagnosed with metastatic breast cancer. It was good news for these patients when, on April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer who had received one or more prior anti-HER2-based regimens in the metastatic setting. The efficacy of the regimen was demonstrated in the HER2CLIMB trial, which enrolled 612 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab, pertuzumab, and/or trastuzumab emtansine. Median overall survival for patients in the tucatinib arm was 21.9 months (95% CI 18.3-31.0) compared with 17.4 months (95% CI 13.6-19.9) for patients in the control arm (HR 0.66; 95% CI 0.50-0.87; P = 0.00480). CASE: Our patient is a middle-aged woman without visceral metastatic involvement, but with extensive nodal involvement, skeletal metastatic involvement and left breast almost completely consumed by tumor. This woman had a more or less successful three lines of anti-HER2 therapy and the fourth line of one-year-long systemic treatment with the cytostatic eribulin. The inclusion of tucatinib with trastuzumab and capecitabine in the fifth line of systemic therapy achieved a very nice partial regression of the primary tumor without significant toxicity. CONCLUSION: In this case report, we describe the case of a highly pretreated patient with HER-2 positive metastatic breast cancer.

• Klíčová slova
• HER2 positivity, breast cancer, highly pretreated patient, palliative biotherapy,
• MeSH
• capecitabinum aplikace a dávkování   MeSH
• chinazoliny MeSH
• lidé MeSH
• nádory prsu * farmakoterapie   patologie   metabolismus   MeSH
• paliativní péče * MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• receptor erbB-2 * metabolismus   antagonisté a inhibitory   MeSH
• trastuzumab aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• capecitabinum MeSH
• chinazoliny MeSH
• ERBB2 protein, human MeSH Prohlížeč
• oxazoly MeSH
• pyridiny MeSH
• receptor erbB-2 * MeSH
• trastuzumab MeSH
• tucatinib MeSH Prohlížeč

This work presents a multifaceted mechanism of the anticancer action of a 2-styrylquinazoline derivative. Extensive analysis of various aspects related to tyrosine kinase inhibition and effects on cellular targets at both the gene and protein levels revealed the potential of this IS20 compound for future research. This study presents a detailed analysis of the relationship between ABL and SRC kinase affecting the inhibition of the EGFR/mTOR signaling pathway in a non-obvious manner. The study was supported by experiments using various molecular biology techniques to confirm the induction of oxidative stress, inhibition of the cell cycle in the G2/M phase and the triggering of cell death via both the apoptosis and autophagy pathways. The cell models included those with different p53 protein status, which affected the cellular response in the form of altered Ndrg1 expression. Finally, the appropriate physicochemical properties of IS20 for adequate bioavailability and toxicity to the body were observed in an in vivo model.

• Klíčová slova
• Ndrg1, Anticancer drug, Apoptosis, Autophagy, Iron chelator, Oxidative stress, Styrylquinazoline, p53 protein,
• MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• chinazoliny * farmakologie   chemie   MeSH
• erbB receptory metabolismus   MeSH
• intracelulární signální peptidy a proteiny * genetika   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• oxidační stres * účinky léků   MeSH
• proteiny buněčného cyklu * genetika   metabolismus   MeSH
• protinádorové látky * farmakologie   chemie   MeSH
• signální transdukce účinky léků   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chinazoliny * MeSH
• erbB receptory MeSH
• intracelulární signální peptidy a proteiny * MeSH
• N-myc downstream-regulated gene 1 protein MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• proteiny buněčného cyklu * MeSH
• protinádorové látky * MeSH
• TOR serin-threoninkinasy MeSH

BACKGROUND: Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti-EGFR therapy, as compared to whole-tissue analysis. METHODS: We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild-type metastatic colorectal cancer (CRC) patients receiving anti-EGFR therapy. Deep next-generation sequencing was performed on whole-tumour sections and six morphology-defined tumour regions. RESULTS: Mutations in genes linked to anti-EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non-responder group, with substantial variability across morphological sub-regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub-regions provided more details than that of the whole-tumour profile. CONCLUSION: Our findings highlight that comprehensive analysis, considering morphological heterogeneity, is crucial for personalised CRC treatment strategies.

• Klíčová slova
• BRAF, KRAS, NRAS, PIK3CA, PTEN, anti‐EGFR therapy, invasion front, metastatic cancer, morphological sampling, tumour heterogeneity,
• MeSH
• chemorezistence * genetika   MeSH
• dospělí MeSH
• erbB receptory antagonisté a inhibitory   MeSH
• fosfohydroláza PTEN genetika   MeSH
• GTP-fosfohydrolasy genetika   MeSH
• inhibitory proteinkinas * terapeutické užití   MeSH
• kolorektální nádory * genetika   farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• pilotní projekty MeSH
• protinádorové látky * terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• fosfohydroláza PTEN MeSH
• GTP-fosfohydrolasy MeSH
• inhibitory proteinkinas * MeSH
• KRAS protein, human MeSH Prohlížeč
• protinádorové látky * MeSH
• protoonkogenní proteiny B-Raf MeSH
• protoonkogenní proteiny p21(ras) MeSH

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.

• Klíčová slova
• Advanced/metastatic solid tumors, HER2 testing, HER2-expressing, Trastuzumab deruxtecan,
• MeSH
• imunohistochemie MeSH
• imunokonjugáty * terapeutické užití   škodlivé účinky   MeSH
• kamptothecin * analogy a deriváty   terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• klinické zkoušky, fáze II jako téma MeSH
• lidé MeSH
• nádory * farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky imunologicky aktivní * terapeutické užití   MeSH
• receptor erbB-2 * metabolismus   MeSH
• sekundární analýza dat MeSH
• trastuzumab * terapeutické užití   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ERBB2 protein, human MeSH Prohlížeč
• imunokonjugáty * MeSH
• kamptothecin * MeSH
• protinádorové látky imunologicky aktivní * MeSH
• receptor erbB-2 * MeSH
• trastuzumab deruxtecan MeSH Prohlížeč
• trastuzumab * MeSH

Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the World Health Organization distinguishes between human papillomavirus (HPV)-related and HPV-independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR alterations were associated with significantly shortened overall survival in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high-grade, lymphatic invasion, programmed death ligand-1 negativity/weak expression, and low TMB. FAT1, TP53, CDKN2A, CASP8, and HRAS were more often mutated in HPV-independent pSCC. In contrast, HPV-associated pSCCs were enriched by EPHA7, ATM, GRIN2A, and CHEK1 mutations. PIK3CA, FAT1, FBXW7, and KMT2D mutations were associated with high TMB. NOTCH1, TP53, CDKN2A, POT1, KMT2D, ATM, CHEK1, EPHA3, and EGFR alterations were related to adverse clinicopathologic signs, such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination repair pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular pathologic, clinical, and prognostic analysis correlating with prognosis.

• Klíčová slova
• human papillomavirus, next-generation sequencing, penile, squamous cell carcinoma, tumor mutational burden,
• MeSH
• ATM protein genetika   MeSH
• dospělí MeSH
• erbB receptory genetika   MeSH
• infekce papilomavirem MeSH
• inhibitor p16 cyklin-dependentní kinasy genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory penisu * genetika   mortalita   patologie   virologie   MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spinocelulární karcinom * genetika   mortalita   patologie   virologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• CDKN2A protein, human MeSH Prohlížeč
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• inhibitor p16 cyklin-dependentní kinasy MeSH
• nádorové biomarkery * MeSH
• nádorový supresorový protein p53 MeSH
• POT1 protein, human MeSH Prohlížeč
• proteiny vázající telomery MeSH
• shelterinový komplex MeSH
• TP53 protein, human MeSH Prohlížeč

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.

• Klíčová slova
• HER2/ERBB2, gene copy number, gene expression, quantitative PCR assessment,
• MeSH
• DNA * genetika   MeSH
• genová dávka MeSH
• hybridizace in situ fluorescenční metody   MeSH
• imunohistochemie metody   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory prsu * genetika   diagnóza   metabolismus   MeSH
• receptor erbB-2 * genetika   metabolismus   MeSH
• RNA * genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA * MeSH
• ERBB2 protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• receptor erbB-2 * MeSH
• RNA * MeSH

BACKGROUND: Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. METHODS: SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. FINDINGS: Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9-19·4) for the camizestrant 75 mg group, 16·3 months (12·9-18·3) for the camizestrant 150 mg group, and 14·7 months (12·7-20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7-10·9) with camizestrant 75 mg, 7·7 months (5·5-12·9) with camizestrant 150 mg, and 3·7 months (2·0-6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42-0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46-0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. INTERPRETATION: Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer. FUNDING: AstraZeneca.

• MeSH
• antagonisté estrogenového receptoru aplikace a dávkování   terapeutické užití   MeSH
• aplikace orální MeSH
• azetidiny MeSH
• dospělí MeSH
• fulvestrant * aplikace a dávkování   MeSH
• hormonální protinádorové látky aplikace a dávkování   terapeutické užití   MeSH
• isochinoliny MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu * farmakoterapie   patologie   mortalita   MeSH
• postmenopauza * MeSH
• receptor erbB-2 * analýza   metabolismus   MeSH
• receptory pro estrogeny * metabolismus   analýza   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antagonisté estrogenového receptoru MeSH
• AZD9833 MeSH Prohlížeč
• azetidiny MeSH
• ERBB2 protein, human MeSH Prohlížeč
• fulvestrant * MeSH
• hormonální protinádorové látky MeSH
• isochinoliny MeSH
• receptor erbB-2 * MeSH
• receptory pro estrogeny * MeSH