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
• oxazoly MeSH
• paliativní péče * MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• pyridiny 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

Cholesterol, the essential building block of cellular membranes, has proven to be a useful tool for increasing the biocompatibility and bioavailability of drug delivery systems in cancer treatment. Resveratrol, a natural polyphenolic compound with promising anticancer properties, faces significant limitations due to its low solubility and bioavailability, hindering its clinical utility. Therefore, in the present study, we aimed to design cholesterol-functionalized cyclodextrin nanosponges (Chol-NSs) with a tunable cholesterol content to optimize resveratrol encapsulation and delivery. Both formulations, free carbonyl diimidazole (CDI) NSs and functionalized Chol-NSs, demonstrated high drug loading and encapsulation efficiency. In vitro experiments revealed that cholesterol incorporation significantly improved the cellular uptake of nanocarriers and potentiated the cytotoxic effects of resveratrol on breast cancer cells. Importantly, both free CDI NSs and functionalized Chol-NSs, even at varying cholesterol percentages, demonstrated a safe profile against both fibroblast and breast cancer cell lines. These results indicate that cholesterol-functionalized nanosponges represent a promising platform for the effective and safe delivery of natural compounds in cancer therapy.

• Klíčová slova
• cholesterol, crosslinked polymer, drug delivery, functionalization, nanosponge,
• MeSH
• biologická dostupnost MeSH
• buňky 3T3 MeSH
• cholesterol * chemie   MeSH
• cyklodextriny * chemie   MeSH
• imidazoly chemie   MeSH
• lékové transportní systémy * metody   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myši MeSH
• nádory prsu * farmakoterapie   patologie   MeSH
• nanostruktury * chemie   MeSH
• příprava léků metody   MeSH
• protinádorové látky aplikace a dávkování   farmakokinetika   MeSH
• resveratrol * aplikace a dávkování   farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholesterol * MeSH
• cyklodextriny * MeSH
• imidazoly MeSH
• N,N-carbonyldiimidazole MeSH Prohlížeč
• protinádorové látky MeSH
• resveratrol * MeSH

Current assays fail to address breast cancer's complex biology and accurately predict treatment response. On a retrospective cohort of 1082 female breast tissues, we develop and validate mFISHseq, which integrates multiplexed RNA fluorescent in situ hybridization with RNA-sequencing, guided by laser capture microdissection. This technique ensures tumor purity, unbiased whole transcriptome profiling, and explicitly quantifies intratumoral heterogeneity. Here we show mFISHseq has 93% accuracy compared to immunohistochemistry. Our consensus subtyping and risk groups mitigate single sample discordance, provide early and late prognostic information, and identify high risk patients with enriched immune signatures, which predict response to neoadjuvant immunotherapy in the multicenter, phase II, prospective I-SPY2 trial. We identify putative antibody-drug conjugate (ADC)-responsive patients, as evidenced by a 19-feature T-DM1 classifier, validated on I-SPY2. Deploying mFISHseq as a research-use only test on 48 patients demonstrates clinical feasibility, revealing insights into the efficacy of targeted therapies, like CDK4/6 inhibitors, immunotherapies, and ADCs.

• MeSH
• dospělí MeSH
• hybridizace in situ fluorescenční * metody   MeSH
• imunohistochemie MeSH
• imunokonjugáty terapeutické užití   MeSH
• imunoterapie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery * genetika   metabolismus   MeSH
• nádory prsu * genetika   farmakoterapie   metabolismus   MeSH
• neoadjuvantní terapie MeSH
• prognóza MeSH
• prospektivní studie MeSH
• retrospektivní studie MeSH
• sekvenční analýza RNA metody   MeSH
• stanovení celkové genové exprese metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• imunokonjugáty MeSH
• nádorové biomarkery * MeSH

Breast cancer is a prevalent and aggressive disease characterized by high metastasis, recurrence, and mortality rates. While cisplatin is an effective chemotherapy drug, its use is limited by its toxic effects on the body. Despite advancements in therapeutic strategies, the therapeutic response is often unsatisfactory due to drug resistance, leading to poor prognosis. Recent studies have shown that cisplatin interacts with long non-coding RNAs (lncRNAs) and accelerates the development of resistance in tumor cells to therapy. This interaction highlights the complex mechanisms involved in the response of cancer cells to chemotherapy. Several lncRNAs have been identified as key players in mediating cisplatin resistance in breast cancer. These lncRNAs include SNHG15, HULC, HCP5, MT1JP, LncMat2B, DLX6-ASL, Linc00665, CARMN, and Lnc-EinRP44-3:6. These lncRNAs have been shown to target microRNAs and mRNAs and modulate the expression of genes involved in cisplatin resistance, which is important in treating breast cancer.

• Klíčová slova
• Breast cancer, Cisplatin, Long non-coding RNAs, Resistance,
• MeSH
• chemorezistence * genetika   MeSH
• cisplatina * terapeutické užití   farmakologie   MeSH
• lidé MeSH
• nádory prsu * farmakoterapie   genetika   patologie   metabolismus   MeSH
• protinádorové látky * terapeutické užití   farmakologie   MeSH
• regulace genové exprese u nádorů * účinky léků   MeSH
• RNA dlouhá nekódující * genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cisplatina * MeSH
• protinádorové látky * MeSH
• RNA dlouhá nekódující * 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

Several commercially available triorganotin compounds were previously found to function as agonist ligands for nuclear retinoid X receptor (RXR) molecules. Triphenyltin isoselenocyanate (TPT-NCSe), a novel selenium atom containing a derivative of triorganotin origin, was found to represent a new cognate bioactive ligand for RXRs. TPT-NCSe displayed a concentration- and time-dependent decrease in the cell viability in both human breast carcinoma MCF-7 (estrogen receptor positive) and MDA‑MB‑231 (triple negative) cell lines. Reactive oxygen species levels generated in response to TPT-NCSe were significantly higher in both carcinoma cell lines treated with TPT-NCSe when compared to mock-treated samples. Treatment with 500 nM TPT-NCSe caused a decrease in SOD1 and increased SOD2 mRNA in MCF-7 cells. The levels of SOD2 mRNA were more increased following the treatment with TPT-NCSe along with 1 μM all-trans retinoic acid (AtRA) in MCF-7 cells. An increased superoxide dismutase SOD1 and SOD2 mRNA levels were also detected in combination treatment of 500 nM TPT-NCSe and 1 μM AtRA in TPT-NCSe-treated MDA-MB-231 cells. The data have also shown that TPT-NCSe induces apoptosis via a caspase cascade triggered by the mitochondrial apoptotic pathway. TPT-NCSe modulates the expression levels of apoptosis‑related proteins, Annexin A5, Bcl‑2 and BAX family proteins, and finally, it enhances the expression levels of its cognate nuclear receptor subtypes RXRalpha and RXRbeta.

• Klíčová slova
• Apoptosis, Breast cancer, Retinoid X receptor, Triorganotin isoselenocyanates,
• MeSH
• apoptóza účinky léků   MeSH
• lidé MeSH
• ligandy MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• nádory prsu * farmakoterapie   metabolismus   patologie   MeSH
• organocínové sloučeniny * farmakologie   MeSH
• organoselenové sloučeniny farmakologie   chemie   MeSH
• proliferace buněk účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• retinoidní X receptory metabolismus   MeSH
• superoxiddismutasa 1 metabolismus   genetika   MeSH
• superoxiddismutasa metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ligandy MeSH
• organocínové sloučeniny * MeSH
• organoselenové sloučeniny MeSH
• reaktivní formy kyslíku MeSH
• retinoidní X receptory MeSH
• SOD1 protein, human MeSH Prohlížeč
• superoxiddismutasa 1 MeSH
• superoxiddismutasa MeSH
• superoxide dismutase 2 MeSH Prohlížeč
• triphenyltin MeSH Prohlížeč

A series of new indole-pyrazole hybrids 8a-m were synthesized through the palladium-catalyzed ligandless Heck coupling reaction from easily accessible unsubstituted, methoxy- or fluoro-substituted 4-ethenyl-1H-pyrazoles and 5-bromo-3H-indoles. These compounds exerted cytotoxicity to melanoma G361 cells when irradiated with blue light (414 nm) and no cytotoxicity in the dark at concentrations up to 10 µM, prompting us to explore their photodynamic effects. The photodynamic properties of the example compound 8d were further investigated in breast cancer MCF-7 cells. Evaluation revealed comparable anticancer activities of 8d in both breast and melanoma cancer cell lines within the submicromolar range. The treatment induced a massive generation of reactive oxygen species, leading to different types of cell death depending on the compound concentration and the irradiation intensity.

• Klíčová slova
• cytotoxicity, indole, photodynamic effect, pyrazole, reactive oxygen species,
• MeSH
• fotochemoterapie * MeSH
• fotosenzibilizující látky * farmakologie   chemická syntéza   chemie   MeSH
• indoly * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• palladium chemie   farmakologie   MeSH
• protinádorové látky * farmakologie   chemická syntéza   chemie   MeSH
• pyrazoly * farmakologie   chemická syntéza   chemie   MeSH
• reaktivní formy kyslíku * metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fotosenzibilizující látky * MeSH
• indoly * MeSH
• palladium MeSH
• protinádorové látky * MeSH
• pyrazoly * MeSH
• reaktivní formy kyslíku * MeSH

We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.

• Klíčová slova
• C10 taxane derivatives, C2 taxane derivatives, C3´ and C3´N taxane derivatives, Resistant breast cancer cells, Resistant ovarian cancer cells,
• MeSH
• benzoáty farmakologie   chemie   MeSH
• chemorezistence * účinky léků   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• nádory vaječníků farmakoterapie   patologie   MeSH
• P-glykoproteiny * metabolismus   genetika   MeSH
• paclitaxel farmakologie   MeSH
• protinádorové látky farmakologie   chemie   MeSH
• taxoidy farmakologie   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• benzoáty MeSH
• P-glykoproteiny * MeSH
• paclitaxel MeSH
• protinádorové látky MeSH
• taxoidy MeSH

A tumour suppressor miRNA, miR-128-3p, is widely involved in various biological processes and has been found to get downregulated in breast cancer patients. We previously published that ectopically expressed miR-128-3p suppressed migration, invasion, cell cycle arrest, and breast cancer stem cells. In the present study, we explored the role of Empagliflozin (EMPA) as a miR-128-3p functionality-mimicking drug in inducing ferroptosis by inhibiting CD98hc. Given that CD98hc is one of the proteins critical in triggering ferroptosis, we confirmed that miR-128-3p and EMPA inhibited SP1, leading to inhibition of CD98hc expression. Further, transfection with siCD98hc, miR-128-3p mimics, and inhibitors was performed to assess their involvement in the ferroptosis of anoikis-resistant cells. We proved that anoikis-resistant cells possess high ROS and iron levels. Further, miR-128-3p and EMPA treatments induced ferroptosis by inhibiting GSH and enzymatic activity of GPX4 and also induced lipid peroxidation. Moreover, EMPA suppressed bioluminescence of 4T1-Red-FLuc induced thoracic cavity, peritoneal tumour burden and lung nodules in an in-vivo metastatic model of breast cancer. Collectively, we revealed that EMPA sensitized the ECM detached cells to ferroptosis by synergically activating miR-128-3p and lowering the levels of SP1 and CD98hc, making it a potential adjunct drug for breast cancer chemotherapy.

• Klíčová slova
• 4T1 cells, Anoikis resistance, Breast cancer, Ferroptosis, Metastasis, Reactive oxygen species,
• MeSH
• anoikis * účinky léků   genetika   MeSH
• benzhydrylové sloučeniny * farmakologie   MeSH
• ferroptóza * účinky léků   genetika   MeSH
• glifloziny farmakologie   MeSH
• glukosidy * farmakologie   MeSH
• kotransportní proteiny pro sodík a fosfát - typ IIb MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prsu * patologie   metabolismus   farmakoterapie   genetika   MeSH
• peroxidace lipidů účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulace genové exprese u nádorů * účinky léků   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzhydrylové sloučeniny * MeSH
• empagliflozin MeSH Prohlížeč
• glifloziny MeSH
• glukosidy * MeSH
• kotransportní proteiny pro sodík a fosfát - typ IIb MeSH
• mikro RNA * MeSH
• MIRN128 microRNA, human MeSH Prohlížeč
• reaktivní formy kyslíku MeSH
• SLC34A2 protein, human MeSH Prohlížeč

INTRODUCTION: In silico tools capable of predicting the functional consequences of genomic differences between individuals, many of which are AI-driven, have been the most effective over the past two decades for non-synonymous single nucleotide variants (nsSNVs). When appropriately selected for the purpose of the study, a high predictive performance can be expected. In this feasibility study, we investigate the distribution of nsSNVs with an allele frequency below 5%. To classify the putative functional consequence, a tier-based filtration led by AI-driven predictors and scoring system was implemented to the overall decision-making process, resulting in a list of prioritised genes. METHODS: The study has been conducted on breast cancer patients of homogeneous ethnicity. Germline rare variants have been sequenced in genes that influence pharmacokinetic parameters of anticancer drugs or molecular signalling pathways in cancer. After AI-driven functional pathogenicity classification and data mining in pharmacogenomic (PGx) databases, variants were collapsed to the gene level and ranked according to their putative deleterious role. RESULTS: In breast cancer patients, seven of the twelve genes prioritised based on the predictions were found to be associated with response to oncotherapy, histological grade, and tumour subtype. Most importantly, we showed that the group of patients with at least one rare nsSNVs in cystic fibrosis transmembrane conductance regulator (CFTR) had significantly reduced disease-free (log rank, p = 0.002) and overall survival (log rank, p = 0.006). CONCLUSION: AI-driven in silico analysis with PGx data mining provided an effective approach navigating for functional consequences across germline genetic background, which can be easily integrated into the overall decision-making process for future studies. The study revealed a statistically significant association with numerous clinicopathological parameters, including treatment response. Our study indicates that CFTR may be involved in the processes influencing the effectiveness of oncotherapy or in the malignant progression of the disease itself.

• Klíčová slova
• Breast cancer, Cystic fibrosis transmembrane conductance regulator, Gene prioritisation, Machine learning, Survival,
• MeSH
• dospělí MeSH
• frekvence genu MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu * genetika   farmakoterapie   patologie   MeSH
• protein CFTR * genetika   MeSH
• senioři MeSH
• studie proveditelnosti * MeSH
• umělá inteligence * MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CFTR protein, human MeSH Prohlížeč
• protein CFTR * MeSH