@article{MTMT:33939277, title = {Description of a Retrospective Cohort of Epithelial Ovarian Cancer Patients with Brain Metastases: Evaluation of the Role of PARP Inhibitors in this Setting}, url = {https://m2.mtmt.hu/api/publication/33939277}, author = {Alizzi, Z. and Roxburgh, P. and Cartwright, D. and McLaren, A. and Park, S. and Jones, R. and Greening, S. and Hudson, E. and Green, C. and Gray, S. and Khalique, S. and Karteris, E. and Hall, M.}, doi = {10.3390/jcm12072497}, journal-iso = {J CLIN MED}, journal = {JOURNAL OF CLINICAL MEDICINE}, volume = {12}, unique-id = {33939277}, year = {2023}, eissn = {2077-0383} } @article{MTMT:34629748, title = {Triple Negative Breast Cancer and Brain Metastases}, url = {https://m2.mtmt.hu/api/publication/34629748}, author = {Bansal, Rani and Van Swearingen, Amanda E. D. and Anders, Carey K.}, doi = {10.1016/j.clbc.2023.07.008}, journal-iso = {CLIN BREAST CANCER}, journal = {CLINICAL BREAST CANCER}, volume = {23}, unique-id = {34629748}, issn = {1526-8209}, keywords = {Clinical Trials; systemic therapy; Local therapy}, year = {2023}, eissn = {1938-0666}, pages = {825-831} } @article{MTMT:33688010, title = {Molecular signaling network and therapeutic developments in breast cancer brain metastasis}, url = {https://m2.mtmt.hu/api/publication/33688010}, author = {Benjamin, M. and Malakar, P. and Sinha, R.A. and Nasser, M.W. and Batra, S.K. and Siddiqui, J.A. and Chakravarti, B.}, doi = {10.1016/j.adcanc.2022.100079}, journal-iso = {ADV CANCER BIOL-METASTASIS}, journal = {ADVANCES IN CANCER BIOLOGY-METASTASIS}, volume = {7}, unique-id = {33688010}, abstract = {Breast cancer (BC) is one of the most frequently diagnosed cancers in women worldwide. It has surpassed lung cancer as the leading cause of cancer-related death. Breast cancer brain metastasis (BCBM) is becoming a major clinical concern that is commonly associated with ER-ve and HER2+ve subtypes of BC patients. Metastatic lesions in the brain originate when the cancer cells detach from a primary breast tumor and establish metastatic lesions and infiltrate near and distant organs via systemic blood circulation by traversing the BBB. The colonization of BC cells in the brain involves a complex interplay in the tumor microenvironment (TME), metastatic cells, and brain cells like endothelial cells, microglia, and astrocytes. BCBM is a significant cause of morbidity and mortality and presents a challenge to developing successful cancer therapy. In this review, we discuss the molecular mechanism of BCBM and novel therapeutic strategies for patients with brain metastatic BC. © 2022 The Authors}, keywords = {SIGNALING PATHWAYS; Blood-Brain Barrier; breast cancer; brain metastasis; Targeted therapies}, year = {2023}, eissn = {2667-3940} } @article{MTMT:34229243, title = {Poly(ADP-ribose) polymerase inhibitors in the treatment landscape of triple-negative breast cancer (TNBC)}, url = {https://m2.mtmt.hu/api/publication/34229243}, author = {El, Gazzar Walaa Bayoumie and Albakri, Khaled Anwer and Hasan, Hanan and Badr, Amira M. and Farag, Amina A. and Saleh, Othman Mohammad}, doi = {10.1177/10781552231188903}, journal-iso = {J ONCOL PHAR PRAC}, journal = {JOURNAL OF ONCOLOGY PHARMACY PRACTICE}, volume = {29}, unique-id = {34229243}, issn = {1078-1552}, abstract = {Objective: Chemotherapy is the mainstay for triple-negative breast cancer (TNBC) patients. Over the years, the use of chemotherapy for these patients has demonstrated many adversities, including toxicity and resistance, which suggested the need to develop novel alternative therapeutic options, such as poly(ADP-ribose) polymerase inhibitors (PARPi). Herein, we provide an overview on PARPi, mechanisms of action and the role of biomarkers in PARPi sensitivity trials, clinical advances in PARPi therapy for TNBC patients based on the most recent studies and findings of clinical trials, and challenges that prevent PARP inhibitors from achieving high efficacy such as resistance and overlapping toxicities with other chemotherapies.Data sources: Searching for relevant articles was done using PubMed and Cochrane Library databases by using the keywords including TNBC; chemotherapy; PARPi; BRCA; homologous recombination repair (HRR). Studies had to be published in full-text in English in order to be considered.Data summary: Although PARPi have been used in the treatment of local/metastatic breast malignancies that are HER2 nega-tive and has a germline BRCA mutation, several questions are still to be answered in order to maximize the clinical benefit of PARP inhibitors in TNBC treatment, such as questions related to the optimal use in the neoadjuvant and metastatic settings as well as the best combinations with various chemotherapies.Conclusions: PARPi are emerging treatment options for patients with gBRCA1/2 mutations. Determining patients that are most likely to benefit from PARPi and identifying the optimal treatment combinations with high efficacy and fewer side effects are currently ongoing.}, keywords = {Oncology; DNA-REPAIR; NEOADJUVANT CHEMOTHERAPY; RANDOMIZED PHASE-III; Triple-negative breast cancer; HOMOLOGOUS RECOMBINATION REPAIR; stereotactic radiosurgery; BRCA; sacituzumab govitecan; PARP inhibitor; PARPi; whole-brain radiotherapy; replication fork stability; GRADE SEROUS OVARIAN}, year = {2023}, eissn = {1477-092X}, pages = {1467-1479}, orcid-numbers = {Badr, Amira M./0000-0003-3983-868X} } @article{MTMT:34229240, title = {BRCAness of brain lesions reflects a worse outcome for patients with metastatic breast cancer}, url = {https://m2.mtmt.hu/api/publication/34229240}, author = {Ishizuka, Yumiko and Horimoto, Yoshiya and Eguchi, Hidetaka and Murakami, Fumi and Nakai, Katsuya and Onagi, Hiroko and Hayashi, Takuo and Ishikawa, Takashi and Arai, Masami and Watanabe, Junichiro}, doi = {10.1007/s10549-023-07115-7}, journal-iso = {BREAST CANCER RES TR}, journal = {BREAST CANCER RESEARCH AND TREATMENT}, volume = {203}, unique-id = {34229240}, issn = {0167-6806}, abstract = {PurposeBreast cancer often metastasizes to the central nervous system. Although the prognosis of brain metastases from breast cancer has been considered poor, and systemic therapy has not contributed to an improved prognosis, newer agents are expected to be more effective. BRCAness is defined as the status of homologous recombination deficiency (HRD) in tumor tissue, regardless of the presence of pathogenic germline BRCA1/2 variants. A study employing next-generation sequencing analysis showed that HRD was found relatively frequently in brain metastases of breast cancer patients. However, there have been no studies evaluating BRCAness in brain metastases of breast cancer with more efficient, rapid, and cost-effective methods.MethodsWe retrospectively investigated 17 brain metastases of breast cancer that were surgically resected at our hospital from January 2007 to December 2022. Of these, samples from 15 patients were evaluable for BRCAness by employing multiplex ligation-dependent probe amplification (MLPA) assay.ResultsOf the 15 patients, five patients (33%) had tumors with BRCAness. Clinicopathological factors of patients with brain metastases with BRCAness were not statistically different from those of patients who possessed tumors without BRCAness. Patients with brain metastases with BRCAness had shorter overall survival compared to those without BRCAness (BRCAness, median 15 months (95% CI 2-30) vs. non-BRCAness, median 28.5 months (95% CI 10-60); P = 0.013).ConclusionIn this study, we evaluated BRCAness in brain metastases of breast cancer with the MLPA method, and found that about one-third of patients had BRCAness-positive tumors. The analysis of BRCAness using MLPA has the potential for practical clinical use.}, keywords = {EXPRESSION; CHEMOTHERAPY; breast cancer; brain metastasis; BRCAness}, year = {2023}, eissn = {1573-7217}, pages = {49-55}, orcid-numbers = {Ishizuka, Yumiko/0000-0002-1588-3067; Horimoto, Yoshiya/0000-0001-8935-0768; Watanabe, Junichiro/0000-0001-9226-895X} } @article{MTMT:34431455, title = {Patient Assessment and Therapy Planning Based on Homologous Recombination Repair Deficiency}, url = {https://m2.mtmt.hu/api/publication/34431455}, author = {Li, Wenbin and Gao, Lin and Yi, Xin and Shi, Shuangfeng and Huang, Jie and Shi, Leming and Zhou, Xiaoyan and Wu, Lingying and Ying, Jianming}, doi = {10.1016/j.gpb.2023.02.004}, journal-iso = {GENOM PROTEOM BIOINF}, journal = {GENOMICS PROTEOMICS & BIOINFORMATICS}, volume = {21}, unique-id = {34431455}, issn = {1672-0229}, year = {2023}, eissn = {2210-3244}, pages = {962-975} } @article{MTMT:34629750, title = {Homologous Recombination Deficiency Detection Algorithms: A Systematic Review}, url = {https://m2.mtmt.hu/api/publication/34629750}, author = {Mark, Lasse Ringsted and Terp, Simone Karlsson and Krarup, Henrik Bygum and Thomassen, Mads and Pedersen, Inge Sokilde and Bogsted, Martin}, doi = {10.3390/cancers15235633}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {15}, unique-id = {34629750}, keywords = {CANCER; ALGORITHM; bioinformatics; Homologous recombination deficiency; HRD}, year = {2023}, eissn = {2072-6694}, orcid-numbers = {Terp, Simone Karlsson/0000-0003-2635-3667; Bogsted, Martin/0000-0001-9192-1814} } @article{MTMT:34229245, title = {Growth exponents reflect evolutionary processes and treatment response in brain metastases}, url = {https://m2.mtmt.hu/api/publication/34229245}, author = {Ocana-Tienda, Beatriz and Perez-Beteta, Julian and Jimenez-Sanchez, Juan and Molina-Garcia, David and Ortiz, de Mendivil Ana and Asenjo, Beatriz and Albillo, David and Perez-Romasanta, Luis A. and Valiente, Manuel and Zhu, Lucia and Garcia-Gomez, Pedro and Gonzalez-Del, Portillo Elisabet and Llorente, Manuel and Carballo, Natalia and Arana, Estanislao and Perez-Garcia, Victor M.}, doi = {10.1038/s41540-023-00298-1}, journal-iso = {NPJ SYST BIOL APPL}, journal = {NPJ SYSTEMS BIOLOGY AND APPLICATIONS}, volume = {9}, unique-id = {34229245}, abstract = {Tumor growth is the result of the interplay of complex biological processes in huge numbers of individual cells living in changing environments. Effective simple mathematical laws have been shown to describe tumor growth in vitro, or simple animal models with bounded-growth dynamics accurately. However, results for the growth of human cancers in patients are scarce. Our study mined a large dataset of 1133 brain metastases (BMs) with longitudinal imaging follow-up to find growth laws for untreated BMs and recurrent treated BMs. Untreated BMs showed high growth exponents, most likely related to the underlying evolutionary dynamics, with experimental tumors in mice resembling accurately the disease. Recurrent BMs growth exponents were smaller, most probably due to a reduction in tumor heterogeneity after treatment, which may limit the tumor evolutionary capabilities. In silico simulations using a stochastic discrete mesoscopic model with basic evolutionary dynamics led to results in line with the observed data.}, keywords = {HETEROGENEITY; BREAST-CANCER; trastuzumab; GENERAL-MODEL}, year = {2023}, eissn = {2056-7189}, orcid-numbers = {Perez-Beteta, Julian/0000-0003-0317-6215; Perez-Romasanta, Luis A./0000-0001-8117-5459; Perez-Garcia, Victor M./0000-0002-6575-495X} } @article{MTMT:33923905, title = {Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis}, url = {https://m2.mtmt.hu/api/publication/33923905}, author = {Su, Zhou and Zhang, Li and Xue, Shaolong and Wang, Youke and Ding, Ruining}, doi = {10.1515/biol-2022-0559}, journal-iso = {OPEN LIFE SCI}, journal = {OPEN LIFE SCIENCES}, volume = {18}, unique-id = {33923905}, issn = {2391-5412}, abstract = {Advances in brain imaging have led to a higher incidence of brain metastases (BM) being diagnosed. Stereotactic radiotherapy (SRS), systemic immunotherapy, and targeted drug therapy are commonly used for treating BM. In this study, we summarized the differences in overall survival (OS) between several treatments alone and in combination. We carried out a systematic literature search on Pubmed, EMBASE, and Cochrane Library. Differences in OS associated with Immune checkpoint inhibitors (ICI) alone versus targeted therapy alone and SRS + ICI or ICI alone were evaluated. This analysis was conducted on 11 studies involving 4,154 patients. The comprehensive results of fixed effect model showed that the OS of SRS + ICI group was longer than that of the ICI group (hazard ratio, 1.72; 95% CI: 1.41-2.11; P = 0.22; I (2) = 30%). The combined fixed-effect model showed that the OS time of ICI was longer than that of targeted therapy (hazard ratio, 2.09; 95% CI: 1.37-3.20; P = 0.21; I (2) = 35%). The study had a low risk of bias. In conclusion, our analysis confirmed that immunotherapy alone showed a higher OS benefit in BM patients than targeted therapy alone. The total survival time of patients with SRS combined with ICI was higher than that of patients with single ICI.}, keywords = {Meta-analysis; immunotherapy; RADIOTHERAPY; overall survival; brain metastases}, year = {2023}, eissn = {2391-5412} } @article{MTMT:34629747, title = {ATM-Inhibitor AZD1390 Is a Radiosensitizer for Breast Cancer CNS Metastasis}, url = {https://m2.mtmt.hu/api/publication/34629747}, author = {Tew, Ben Yi and Kalfa, Alex J. and Yang, Zeyi and Hurth, Kyle M. and Simon, Thomas and Abnoosian, Eric and Durant, Stephen T. and Hamerlik, Petra and Salhia, Bodour}, doi = {10.1158/1078-0432.CCR-23-0290}, journal-iso = {CLIN CANCER RES}, journal = {CLINICAL CANCER RESEARCH}, volume = {29}, unique-id = {34629747}, issn = {1078-0432}, year = {2023}, eissn = {1557-3265}, pages = {4492-4503}, orcid-numbers = {Tew, Ben Yi/0009-0007-6397-7512; Yang, Zeyi/0009-0000-2672-4734; Simon, Thomas/0000-0002-3280-2716} } @article{MTMT:33923906, title = {Molecular aspects of brain metastases in breast cancer}, url = {https://m2.mtmt.hu/api/publication/33923906}, author = {Tomasik, Bartlomiej and Bienkowski, Michal and Gorska, Zuzanna and Gutowska, Klaudia and Kumiega, Paulina and Jassem, Jacek and Duchnowska, Renata}, doi = {10.1016/j.ctrv.2023.102521}, journal-iso = {CANCER TREAT REV}, journal = {CANCER TREATMENT REVIEWS}, volume = {114}, unique-id = {33923906}, issn = {0305-7372}, abstract = {Brain metastases (BM) are a common and devastating manifestation of breast cancer (BC). BM are particularly frequent in the HER2-positive and triple-negative breast cancer phenotypes and usually occur following the metastatic spread to extracranial sites. Several genes mediating BM and biomarkers predicting their risk in BC have been reported in the past decade. These findings have advanced the understanding of BM pathobiology and paved the way for developing new therapeutic strategies but they still warrant a thorough clinical validation. Hence, a better understanding of the mechanistic aspects of BM and delineating the interactions of tumor cells with the brain microenvironment are of utmost importance. This review discusses the molecular basis of the metastatic cascade: the epithelial-mesenchymal transition, cancer, and tumor microenvironment interaction and intravasation, priming of the metastatic niche in the brain, and survival in the new site. We also outline the postulated mechanisms of BC cells' brain tropism. Finally, we discuss advances in the field of biomarkers (both tissue-based and liquid-based) that predict BM from BC.}, keywords = {Biomarkers; breast cancer; brain metastases; brain microenvironment}, year = {2023}, eissn = {1532-1967} } @article{MTMT:33586595, title = {Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases}, url = {https://m2.mtmt.hu/api/publication/33586595}, author = {Wilcox, Jessica A. and Boire, Adrienne A.}, doi = {10.1007/s40263-022-00975-5}, journal-iso = {CNS DRUGS}, journal = {CNS DRUGS}, volume = {37}, unique-id = {33586595}, issn = {1172-7047}, abstract = {Leptomeningeal metastases represent an aggressive stage of cancer with few durable treatment options. Improved understanding of cancer biology, neoplastic reliance on oncogenic driver mutations, and complex immune system interactions have resulted in an explosion in cancer-directed therapy in the last two decades to include small molecule inhibitors and immune checkpoint inhibitors. Most of these therapeutics are underexplored in patients with leptomeningeal metastases, limiting extrapolation of extracranial and even intracranial efficacy outcomes to the unique leptomeningeal space. Further confounding our interpretation of drug activity in the leptomeninges is an incomplete understanding of drug penetration through the blood-cerebrospinal fluid barrier of the choroid plexus. Nevertheless, a number of retrospective studies and promising prospective trials provide evidence of leptomeningeal activity of several small molecule and immune checkpoint inhibitors and underscore potential areas of further therapeutic development for patients harboring leptomeningeal disease.}, keywords = {CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR RECEPTOR; BLOOD-BRAIN-BARRIER; CELL LUNG-CANCER; HER2-POSITIVE BREAST-CANCER; Pharmacology & Pharmacy; Clinical Neurology; LAPATINIB PLUS CAPECITABINE; MULTICENTER PHASE-II; TRASTUZUMAB EMTANSINE T-DM1; NON-CNS PROGRESSION}, year = {2023}, eissn = {1179-1934}, pages = {45-67}, orcid-numbers = {Wilcox, Jessica A./0000-0002-2919-1360; Boire, Adrienne A./0000-0002-9029-1248} } @article{MTMT:32686131, title = {Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities}, url = {https://m2.mtmt.hu/api/publication/32686131}, author = {Cosgrove, Nicola and Vareslija, Damir and Keelan, Stephen and Elangovan, Ashuvinee and Atkinson, Jennifer M. and Cocchiglia, Sinead and Bane, Fiona T. and Singh, Vikrant and Furney, Simon and Hu, Chunling and Carter, Jodi M. and Hart, Steven N. and Yadav, Siddhartha and Goetz, Matthew P. and Hill, Arnold D. K. and Oesterreich, Steffi and Lee, Adrian V and Couch, Fergus J. and Young, Leonie S.}, doi = {10.1038/s41467-022-27987-5}, journal-iso = {NAT COMMUN}, journal = {NATURE COMMUNICATIONS}, volume = {13}, unique-id = {32686131}, issn = {2041-1723}, abstract = {The molecular landscape of breast cancer brain metastases (BCBM) is still understudied, especially for different breast cancer subtypes. Here, the authors characterise subtype-specific BCBMs using genomics and transcriptomics and identify homologous recombination deficiency as a key therapeutic vulnerability. The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recombination deficiency operative in transcriptomic and genomic data with recurrent breast mutational signatures A, F and K, associated with mismatch repair defects, TP53 mutations and homologous recombination deficiency (HRD) respectively. Utilizing PARP inhibition in patient-derived brain metastatic tumor explants we functionally validate HRD as a key vulnerability. Here, we demonstrate a functionally relevant HRD evident at genomic and transcriptomic levels pointing to genomic instability in breast cancer brain metastasis which is of potential translational significance.}, keywords = {SURVIVAL; PATTERNS; R/BIOCONDUCTOR PACKAGE}, year = {2022}, eissn = {2041-1723}, orcid-numbers = {Vareslija, Damir/0000-0003-1000-0357; Keelan, Stephen/0000-0002-3632-5128} } @article{MTMT:33123863, title = {Systemic Therapy Approaches for Breast Cancer Brain and Leptomeningeal Metastases}, url = {https://m2.mtmt.hu/api/publication/33123863}, author = {Dhakal, Ajay and Van Swearingen, Amanda E. D. and O’Regan, Ruth and Anders, Carey K.}, doi = {10.1007/s11864-022-01011-w}, journal-iso = {CURR TREAT OPTION ON}, journal = {CURRENT TREATMENT OPTIONS IN ONCOLOGY}, volume = {23}, unique-id = {33123863}, issn = {1527-2729}, year = {2022}, eissn = {1534-6277}, pages = {1457-1476}, orcid-numbers = {Van Swearingen, Amanda E. D./0000-0002-4287-9741} } @article{MTMT:32791587, title = {Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer}, url = {https://m2.mtmt.hu/api/publication/32791587}, author = {Garber, Haven R. and Raghavendra, Akshara Singareeka and Lehner, Michael and Qiao, Wei and Gutierrez-Barrera, Angelica M. and Tripathy, Debu and Arun, Banu and Ibrahim, Nuhad K.}, doi = {10.1038/s41523-022-00407-z}, journal-iso = {NPJ BREAST CANCER}, journal = {NPJ BREAST CANCER}, volume = {8}, unique-id = {32791587}, abstract = {Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA1/2) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA1/2 patients. Patients with gBRCA1/2, stage I-Ill invasive breast cancer seen between 2000-2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BM's. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients {2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12-2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers.}, keywords = {EFFICACY; carboplatin}, year = {2022}, eissn = {2374-4677} } @{MTMT:33202322, title = {Brain metastases in breast cancer}, url = {https://m2.mtmt.hu/api/publication/33202322}, author = {Gasparri, M.L. and Siconolfi, A. and Papadia, A. and Di, Micco R. and Zuber, V. and Gentilini, O.D. and Farooqi, A.A. and Di, Bartolomeo G. and Caserta, D. and Bellati, F. and Ruscito, I.}, booktitle = {Unraveling the Complexities of Metastasis}, doi = {10.1016/B978-0-12-821789-4.24001-0}, unique-id = {33202322}, year = {2022}, pages = {63-85} } @article{MTMT:32791588, title = {Emerging Biomarkers for Diagnosis, Prevention and Treatment of Brain Metastases-From Biology to Clinical Utility}, url = {https://m2.mtmt.hu/api/publication/32791588}, author = {Kalita-de, Croft Priyakshi and Joshi, Vaibhavi and Saunus, Jodi M. and Lakhani, Sunil R.}, doi = {10.3390/diseases10010011}, journal-iso = {DISEASES}, journal = {DISEASES}, volume = {10}, unique-id = {32791588}, abstract = {Primary malignancies of the lung, skin (melanoma), and breast have higher propensity for metastatic spread to the brain. Advances in molecular tumour profiling have aided the development of targeted therapies, stereotactic radiotherapy, and immunotherapy, which have led to some improvement in patient outcomes; however, the overall prognosis remains poor. Continued research to identify new prognostic and predictive biomarkers is necessary to further impact patient outcomes, as this will enable better risk stratification at the point of primary cancer diagnosis, earlier detection of metastatic deposits (for example, through surveillance), and more effective systemic treatments. Brain metastases exhibit considerable inter- and intratumoural heterogeneity-apart from distinct histology, treatment history and other clinical factors, the metastatic brain tumour microenvironment is incredibly variable both in terms of subclonal diversity and cellular composition. This review discusses emerging biomarkers; specifically, the biological context and potential clinical utility of tumour tissue biomarkers, circulating tumour cells, extracellular vesicles, and circulating tumour DNA.}, keywords = {CENTRAL-NERVOUS-SYSTEM; BREAST-CANCER; TUMOR-CELLS; diagnostic; Lung; RADIATION-THERAPY; brain metastasis; Extracellular vesicles; liquid biopsy; liquid biopsy; MELANOMA PATIENTS; predictive; Circulating tumour cells; GRADED PROGNOSTIC ASSESSMENT; PARTITIONING ANALYSIS RPA}, year = {2022}, eissn = {2079-9721}, orcid-numbers = {Joshi, Vaibhavi/0000-0002-1309-1664} } @article{MTMT:32831079, title = {Brain metastases in patients with ovarian cancer}, url = {https://m2.mtmt.hu/api/publication/32831079}, author = {Limon, Dror and Shachar, Eliya and Wolf, Ido and Adar, Lyri and Hasson, Shira Peleg and Ferro, Leora and Safra, Tamar}, doi = {10.1080/0284186X.2022.2066985}, journal-iso = {ACTA ONCOL}, journal = {ACTA ONCOLOGICA}, volume = {61}, unique-id = {32831079}, issn = {0284-186X}, abstract = {Background Brain metastasis (BM) are uncommon among women with epithelial ovarian cancer (EOC). The frequency, risk factors and clinical repercussions of BM in these patients are not well described. Methods We retrospectively evaluated EOC patients treated at our center from 2002 to 2020 and assessed their clinical parameters, risk for BM development and association with overall survival (OS). This cohort has a known high frequency of BRCA mutation carriers (BRCAm) due to women of Ashkenazi Jewish descent. Results Among 1035 EOC patients, 29 (2.8%) were diagnosed with BM. The prevalence of BRCA mutations was more common among women with BM (56.5% vs. 34.3%, p = 0.033). The BM rate in patients with BRCAm was higher than the BM rate in those with wildtype BRCA (BRCAw; 5.1% vs. 2.1%, OR = 2.6; 95% CI: 1.2-5.4, p = 0.013). Median time from diagnosis to BM and from disease recurrence to BM was longer among patients with BRCAm. Median OS was not significantly different among patients with BM versus those without BM (59.4 vs. 73.4 months, p = 0.243). After BM diagnosis, median OS was not statistically significantly different between patients with BRCAm and those with BRCAw (20.6 vs. 12.3 months, p = 0.441). Treatment with poly (ADP-ribose) polymerase inhibitors and bevacizumab had no impact on subsequent development of BM. Conclusions BM are rare among EOC patients. However, the risk is three-fold higher among patients with BRCAm. BM do not significantly alter OS among EOC patients. The higher rate of BM in patients with BRCAm may be related to longer OS in this subpopulation.}, keywords = {CENTRAL-NERVOUS-SYSTEM; BREAST-CANCER; RADIOTHERAPY; PROGNOSTIC-FACTORS; RADIATION-THERAPY; overall survival; RANDOMIZED-TRIAL; SUSCEPTIBILITY GENE; brain metastases; epithelial ovarian cancer; Homologous recombination deficiency; MOTEXAFIN GADOLINIUM}, year = {2022}, eissn = {1651-226X}, pages = {757-763} } @article{MTMT:32831078, title = {Alterations in homologous recombination repair genes in prostate cancer brain metastases}, url = {https://m2.mtmt.hu/api/publication/32831078}, author = {Rodriguez-Calero, Antonio and Gallon, John and Akhoundova, Dilara and Maletti, Sina and Ferguson, Alison and Cyrta, Joanna and Amstutz, Ursula and Garofoli, Andrea and Paradiso, Viola and Tomlins, Scott A. and Hewer, Ekkehard and Genitsch, Vera and Fleischmann, Achim and Vassella, Erik and Rushing, Elisabeth J. and Grobholz, Rainer and Fischer, Ingeborg and Jochum, Wolfram and Cathomas, Gieri and Osunkoya, Adeboye O. and Bubendorf, Lukas and Moch, Holger and Thalmann, George and Ng, Charlotte K. Y. and Gillessen, Silke and Piscuoglio, Salvatore and Rubin, Mark A.}, doi = {10.1038/s41467-022-30003-5}, journal-iso = {NAT COMMUN}, journal = {NATURE COMMUNICATIONS}, volume = {13}, unique-id = {32831078}, issn = {2041-1723}, abstract = {Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi. The diagnosis of prostate cancer brain metastasis (PCBM) has increased. Here, the authors investigate the landscape of somatic genetic alterations in brain metastases in a PCBM cohort of 51 patients with non-synchronous matched primary samples available for 20 patients.}, keywords = {DEFICIENCY; INSTABILITY; SURVIVAL; BREAST-CANCER; GENOMICS; DISCOVERY; CARCINOMAS; Mutational signatures}, year = {2022}, eissn = {2041-1723} } @article{MTMT:33031104, title = {Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer}, url = {https://m2.mtmt.hu/api/publication/33031104}, author = {Ruscitto, Federica and Roda, Niccolo and Priami, Chiara and Migliaccio, Enrica and Pelicci, Pier Giuseppe}, doi = {10.3390/ijms23116271}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {33031104}, issn = {1661-6596}, abstract = {Metastatic disease represents the primary cause of breast cancer (BC) mortality, yet it is still one of the most enigmatic processes in the biology of this tumor. Metastatic progression includes distinct phases: invasion, intravasation, hematogenous dissemination, extravasation and seeding at distant sites, micro-metastasis formation and metastatic outgrowth. Whole-genome sequencing analyses of primary BC and metastases revealed that BC metastatization is a non-genetically selected trait, rather the result of transcriptional and metabolic adaptation to the unfavorable microenvironmental conditions which cancer cells are exposed to (e.g., hypoxia, low nutrients, endoplasmic reticulum stress and chemotherapy administration). In this regard, the latest multi-omics analyses unveiled intra-tumor phenotypic heterogeneity, which determines the polyclonal nature of breast tumors and constitutes a challenge for clinicians, correlating with patient poor prognosis. The present work reviews BC classification and epidemiology, focusing on the impact of metastatic disease on patient prognosis and survival, while describing general principles and current in vitro/in vivo models of the BC metastatic cascade. The authors address here both genetic and phenotypic intrinsic heterogeneity of breast tumors, reporting the latest studies that support the role of the latter in metastatic spreading. Finally, the review illustrates the mechanisms underlying adaptive stress responses during BC metastatic progression.}, keywords = {breast cancer; PROGNOSTIC-SIGNIFICANCE; Unfolded protein response; EPITHELIAL-MESENCHYMAL TRANSITION; SINGLE-CELL; Biochemistry & Molecular Biology; metastatic cascade; tumor heterogeneity; endothelial barrier; PROMOTES METASTASIS; Mutational profile; Stem-like; Intra-tumor heterogeneity; MUTATIONAL EVOLUTION}, year = {2022}, eissn = {1422-0067}, orcid-numbers = {Roda, Niccolo/0000-0003-2798-2035} } @article{MTMT:33202323, title = {Breast Cancer Patients with Brain Metastases: A Cross-Sectional Study}, url = {https://m2.mtmt.hu/api/publication/33202323}, author = {Simsek, M. and Aliyev, A. and Baydas, T. and Besiroglu, M. and Demir, T. and Shbair, A.T.M. and Seker, M. and Turk, H.M.}, doi = {10.1155/2022/5763810}, journal-iso = {BREAST J}, journal = {BREAST JOURNAL}, volume = {2022}, unique-id = {33202323}, issn = {1075-122X}, year = {2022}, eissn = {1524-4741} } @article{MTMT:32791590, title = {A Novel Nomogram Model to Identify Candidates and Predict the Possibility of Benefit From Primary Tumor Resection Among Female Patients With Metastatic Infiltrating Duct Carcinoma of the Breast: A Large Cohort Study}, url = {https://m2.mtmt.hu/api/publication/32791590}, author = {Wang, Ziqiong and Chen, Bo and Chen, Jiyang and Wu, Zhixuan and Gu, Hongyi and Wang, Ying and Dai, Xuanxuan}, doi = {10.3389/fonc.2022.798016}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {12}, unique-id = {32791590}, issn = {2234-943X}, abstract = {BackgroundThe impact of primary site surgery on survival remains controversial in female patients with stage IV breast cancer. The purpose of this study was to investigate the role of primary tumor surgery in patients with stage IV breast cancer and concurrently develop a nomogram to identify which patients will benefit from surgery. MethodsWe retrospectively searched the SEER database for female patients newly diagnosed with stage IV breast infiltrating duct carcinoma (BIDC) between 2010 and 2015 and then divided them into surgery and non-surgery groups. The propensity score matching (PSM) method was implemented to eliminate the bias, and Kaplan-Meier survival analysis was generated to compare the overall survival (OS) and cancer-specific survival (CSS) between the two groups. After PSM, Cox regression analyses were performed to determine the independent protective value of primary tumor surgery, while logistic regression analyses were utilized to uncover significant predictors of surgical benefit and establish a screening nomogram for female patients with stage IV BIDC. Nomogram performance was evaluated by calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Result5,475 patients with stage IV BIDC were included in this study, and 2,375 patients (43.38%) received primary tumor surgery. After PSM, the median CSS was 53 months (95% CI: 46.84-59.16) in the surgery group compared with only 33 months (95% CI: 30.05-35.95) in the non-surgery group. We further found that primary tumor surgery was an independent protective factor for patients with stage IV BIDC. The independent factors affecting the benefit of locoregional surgery in patients with stage IV BIDC included histological grade, T stage, molecular subtype, lung metastasis, liver metastasis, brain metastasis, and marital status. The AUC of the nomogram was 0.785 in the training set and 0.761 in the testing set. The calibration curves and DCA confirmed that the nomogram could precisely predict the possibility of benefit from primary tumor resection. ConclusionOur study suggested that primary tumor surgery improved the prognosis of female patients with stage IV BIDC and developed a nomogram to quantify the probability of surgical benefit to help identify surgical candidates clinically.}, keywords = {DISEASE; Prognosis; Therapy; surgery; surgery; GUIDELINES; IMPROVED SURVIVAL; propensity score matching; Stage IV breast cancer; CANCER STATISTICS}, year = {2022}, eissn = {2234-943X} } @article{MTMT:32294895, title = {Prospective high-throughput genome profiling of advanced cancers: results of the PERMED-01 clinical trial}, url = {https://m2.mtmt.hu/api/publication/32294895}, author = {Bertucci, Francois and Goncalves, Anthony and Guille, Arnaud and Adelaide, Jose and Garnier, Severine and Carbuccia, Nadine and Billon, Emilien and Finetti, Pascal and Sfumato, Patrick and Monneur, Audrey and Pecheux, Christophe and Khran, Martin and Brunelle, Serge and Mescam, Lenaig and Thomassin-Piana, Jeanne and Poizat, Flora and Charafe-Jauffret, Emmanuelle and Turrini, Olivier and Lambaudie, Eric and Provansal, Magali and Extra, Jean-Marc and Madroszyk, Anne and Gilabert, Marine and Sabatier, Renaud and Vicier, Cecile and Mamessier, Emilie and Chabannon, Christian and Pakradouni, Jihane and Viens, Patrice and Andre, Fabrice and Gravis, Gwenaelle and Popovici, Cornel and Birnbaum, Daniel and Chaffanet, Max}, doi = {10.1186/s13073-021-00897-9}, journal-iso = {GENOME MED}, journal = {GENOME MEDICINE}, volume = {13}, unique-id = {32294895}, issn = {1756-994X}, abstract = {Background: The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome arraycomparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores.Methods: Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 "candidate cancer" genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a "matched therapy" and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES).Results: Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68-75%). Only 94/550 patients (17%, 95%CI 14-21) received an "AGA-matched therapy" on progression. The most frequent AGAs leading to "matched therapy" included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such "matched therapy" improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of "matched therapy" was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with "matched therapy," and 6-month overall survival (OS) was 62% (95%CI 52-73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/ aCGH.Conclusions: Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a "matched therapy" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results.}, keywords = {MUTATION; Sequencing; Precision Medicine; WES; aCGH; Advanced cancers; PERMED-01 trial; t-NGS}, year = {2021}, eissn = {1756-994X}, orcid-numbers = {Mamessier, Emilie/0000-0002-3516-0093; Birnbaum, Daniel/0000-0001-7920-9883} } @article{MTMT:32344728, title = {Molecular Mechanisms Associated with Brain Metastases in HER2-Positive and Triple Negative Breast Cancers}, url = {https://m2.mtmt.hu/api/publication/32344728}, author = {Bryan, Sarah and Witzel, Isabell and Borgmann, Kerstin and Oliveira-Ferrer, Leticia}, doi = {10.3390/cancers13164137}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {13}, unique-id = {32344728}, abstract = {Simple Summary Breast cancer, the most common malignant tumor among women worldwide, remains an incurable disease once it has spread to the brain. Past research has shown that a primary breast cancer's biology is an important determining factor predisposing its ability to form brain metastases. This review summarizes our current understanding of which genes, mutations, and molecules cause this increased ability to spread to and survive in the brain, specifically focusing on the different stages of this process. This knowledge may help us develop more effective, tumor-specific therapies and, as such, increase the chance of recovery for patients with breast cancer brain metastases. Breast cancer (BC) is the most frequent cause of cancer-associated death for women worldwide, with deaths commonly resulting from metastatic spread to distant organs. Approximately 30% of metastatic BC patients develop brain metastases (BM), a currently incurable diagnosis. The influence of BC molecular subtype and gene expression on breast cancer brain metastasis (BCBM) development and patient prognosis is undeniable and is, therefore, an important focus point in the attempt to combat the disease. The HER2-positive and triple-negative molecular subtypes are associated with an increased risk of developing BCBM. Several genetic and molecular mechanisms linked to HER2-positive and triple-negative BC breast cancers appear to influence BCBM formation on several levels, including increased development of circulating tumor cells (CTCs), enhanced epithelial-mesenchymal transition (EMT), and migration of primary BC cells to the brain and/or through superior local invasiveness aided by cancer stem-like cells (CSCs). These specific BC characteristics, together with the ensuing developments at a clinical level, are presented in this review article, drawing a connection between research findings and related therapeutic strategies aimed at preventing BCBM formation and/or progression. Furthermore, we briefly address the critical limitations in our current understanding of this complex topic, highlighting potential focal points for future research.}, keywords = {breast cancer; breast cancer subtype; Breast cancer brain metastasis; mechanisms of metastasis}, year = {2021}, eissn = {2072-6694} } @article{MTMT:32076418, title = {A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures}, url = {https://m2.mtmt.hu/api/publication/32076418}, author = {Diossy, Miklos and Sztupinszki, Zsófia and Borcsok, Judit and Krzystanek, Marcin and Tisza, Viktoria and Spisák, Sándor and Rusz, Orsolya and Tímár, József and Csabai, István and Fillinger, János and Moldvay, Judit and Pedersen, Anders Gorm and Szüts, Dávid and Szállási, Zoltán}, doi = {10.1038/s41698-021-00199-8}, journal-iso = {NPJ PRECIS ONCOL}, journal = {NPJ PRECISION ONCOLOGY}, volume = {5}, unique-id = {32076418}, year = {2021}, eissn = {2397-768X}, orcid-numbers = {Diossy, Miklos/0000-0003-0308-6615; Borcsok, Judit/0000-0002-3290-3971; Rusz, Orsolya/0000-0001-5726-4072; Tímár, József/0000-0001-9183-0859; Szüts, Dávid/0000-0001-7985-0136; Szállási, Zoltán/0000-0001-5395-7509} } @article{MTMT:32343828, title = {Long-term response to olaparib in BRCA1-related ovarian cancer with brain metastases}, url = {https://m2.mtmt.hu/api/publication/32343828}, author = {Gallego, Alejandro and Garrido, Diego and Yebenes, Laura and Mendiola, Marta and Castelo, Beatriz and Redondo, Andres}, doi = {10.1136/ijgc-2020-002225}, journal-iso = {INT J GYNECOL CANCER}, journal = {INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER}, volume = {31}, unique-id = {32343828}, issn = {1048-891X}, keywords = {Neoplasm Metastasis; Ovarian cancer; BRCA1 protein}, year = {2021}, eissn = {1525-1438}, pages = {1292-1296} } @article{MTMT:32062157, title = {Characterization of evolution trajectory and immune profiling of brain metastasis in lung adenocarcinoma}, url = {https://m2.mtmt.hu/api/publication/32062157}, author = {Jiang, Tao and Yan, Yan and Zhou, Kun and Su, Chunxia and Ren, Shengxiang and Li, Nan and Hou, Likun and Guo, Xianchao and Zhu, Wei and Zhang, Henghui and Lin, Jie and Zhang, Jun and Zhou, Caicun}, doi = {10.1038/s41698-021-00151-w}, journal-iso = {NPJ PRECIS ONCOL}, journal = {NPJ PRECISION ONCOLOGY}, volume = {5}, unique-id = {32062157}, abstract = {Characterizing the evolutionary trajectory and immune profiling of brain metastasis (BM) may provide insights in the development of novel therapeutic strategies. Here, we performed whole-exome sequencing and multiplex immunofluorescence (MIF) of 40 samples from 12 lung adenocarcinoma (LUAD) patients with BM and compared to their paired primary tumors. We observed significantly higher intertumor heterogeneity between paired primary tumors and BMs, with only a median of 8.3% of genetic mutations identified as shared. Phylogenetic analysis revealed that BM-competent clones genetically diverged from their primary tumors at relatively early stage, suggesting that the parallel progression model is dominant. In cases with synchronous lymph node metastasis (LNM), phylogenetic analysis suggested that BM is a later event than LNM. MIF analysis found that BMs exhibited significantly lower CD8(+) T cell infiltration (P=0.048), and elevated CD4(+)Foxp3(+) T cell infiltration (P=0.036) and PD-1 expression (P=0.047) in comparison to the matched primary tumors, indicating an immunosuppressive microenvironment in BMs. The current study revealed the discrepancy of mutational landscape as well as tumor immune microenvironment between BM and its primary tumor - such findings shall help us better understand the unique biological features of BM and develop innovative strategies accordingly for our patients with LUAD.}, year = {2021}, eissn = {2397-768X}, orcid-numbers = {Zhang, Jun/0000-0001-7886-6187} } @article{MTMT:32474745, title = {Comprehensive genomic profiling-guided niraparib treatment of triple-negative breast cancer in a patient with extensive brain metastasis: Case report and literature review}, url = {https://m2.mtmt.hu/api/publication/32474745}, author = {Lam, T.-C.}, doi = {10.36401/JIPO-20-24}, journal-iso = {J IMMUNOTHER PREC ONC}, journal = {JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY}, volume = {4}, unique-id = {32474745}, issn = {2666-2345}, year = {2021}, eissn = {2590-017X}, pages = {16-20} } @article{MTMT:32686132, title = {MutScape: an analytical toolkit for probing the mutational landscape in cancer genomics}, url = {https://m2.mtmt.hu/api/publication/32686132}, author = {Lu, Cheng-Hua and Wu, Chia-Hsin and Tsai, Mong-Hsun and Lai, Liang-Chuan and Chuang, Eric Y.}, doi = {10.1093/nargab/lqab099}, journal-iso = {NAR GENOM BIOINF}, journal = {NAR GENOMICS AND BIOINFORMATICS}, volume = {3}, unique-id = {32686132}, abstract = {Cancer genomics has been evolving rapidly, fueled by the emergence of numerous studies and public databases through next-generation sequencing technologies. However, the downstream programs used to preprocess and analyze data on somatic mutations are scattered in different tools, most of which require specific input formats. Here, we developed a user-friendly Python toolkit, MutScape, which provides a comprehensive pipeline of filtering, combination, transformation, analysis and visualization for researchers, to easily explore the cohort-based mutational characterization for studying cancer genomics when obtaining somatic mutation data. MutScape not only can preprocess millions of mutation records in a few minutes, but also offers various analyses simultaneously, including driver gene detection, mutational signature, large-scale alteration identification and actionable biomarker annotation. Furthermore, MutScape supports somatic variant data in both variant call format and mutation annotation format, and leverages caller combination strategies to quickly eliminate false positives. With only two simple commands, robust results and publication-quality images are generated automatically. Herein, we demonstrate the ability of MutScape to correctly reproduce known results using breast cancer samples from The Cancer Genome Atlas. More significantly, discovery of novel results in cancer genomic studies is enabled through the advanced features in MutScape. MutScape is freely available on GitHub, at https://github.con danitalu724/MutScape.}, keywords = {Genetics & Heredity; Homologous recombination deficiency}, year = {2021}, eissn = {2631-9268}, orcid-numbers = {Chuang, Eric Y./0000-0003-2530-0096} } @article{MTMT:32062158, title = {The genomic landscape of breast cancer brain metastases: a systematic review}, url = {https://m2.mtmt.hu/api/publication/32062158}, author = {Morgan, Alexander J. and Giannoudis, Athina and Palmieri, Carlo}, doi = {10.1016/S1470-2045(20)30556-8}, journal-iso = {LANCET ONCOL}, journal = {LANCET ONCOLOGY}, volume = {22}, unique-id = {32062158}, issn = {1470-2045}, abstract = {Breast cancer brain metastases are an increasing clinical problem. Studies have shown that brain metastases from breast cancer have a distinct genomic landscape to that of the primary tumour, including the presence of mutations that are absent in the primary breast tumour. In this Review, we aim to review and evaluate genomic sequencing data for breast cancer brain metastases by searching PubMed, Embase, and Scopus for relevant articles published in English between database inception and May 30, 2020. Extracted information includes data for mutations, receptor status (eg, immunohistochemistry and Prediction Analysis of Microarray 50 [PAM50]), and copy number alterations from published manuscripts and supplementary materials. Of the 431 articles returned by the database search, 13 (3%) breast cancer brain metastases sequencing studies, comprising 164 patients with sequenced brain metastases, met all our inclusion criteria. We identified 268 mutated genes that were present in two or more breast cancer brain metastases samples. Of these 268 genes, 22 (8%) were mutated in five or more patients and pathway enrichment analysis showed their involvement in breast cancer-related signalling pathways, regulation of gene transcription, cell cycle, and DNA repair. Actionability analysis using the Drug Gene Interaction Database revealed that 15 (68%) of these 22 genes are actionable drug targets. In addition, immunohistochemistry and PAM50 data showed receptor discordancy between primary breast cancers and their paired brain metastases. This systematic review provides a detailed overview of the most commonly mutated genes identified in samples of breast cancer brain metastases and their clinical relevance. These data highlight the differences between primary breast cancers and brain metastases and the importance of acquiring and analysing brain metastasis samples for further study.}, keywords = {MUTATIONS; SURVIVAL; EVOLUTION}, year = {2021}, eissn = {1474-5488}, pages = {E7-E17}, orcid-numbers = {Giannoudis, Athina/0000-0002-7200-1497} } @article{MTMT:32529350, title = {Organ specific copy number variations in visceral metastases of human melanoma}, url = {https://m2.mtmt.hu/api/publication/32529350}, author = {Papp, Orsolya and Doma, Viktória and Gil, J. and Markó-Varga, G. and Kárpáti, Sarolta and Tímár, József and Vízkeleti, Laura}, doi = {10.3390/cancers13235984}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {13}, unique-id = {32529350}, year = {2021}, eissn = {2072-6694}, orcid-numbers = {Papp, Orsolya/0000-0002-0708-0010; Kárpáti, Sarolta/0000-0002-8472-0712; Tímár, József/0000-0001-9183-0859; Vízkeleti, Laura/0000-0001-6870-3499} } @article{MTMT:32344729, title = {ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody}, url = {https://m2.mtmt.hu/api/publication/32344729}, author = {Rattray, Zahra and Deng, Gang and Zhang, Shenqi and Shirali, Anupama and May, Christopher K. and Chen, Xiaoyong and Cuffari, Benedette J. and Liu, Jun and Zou, Pan and Rattray, Nicholas J. W. and Johnson, Caroline H. and Dubljevic, Valentina and Campbell, James A. and Huttner, Anita and Baehring, Joachim M. and Zhou, Jiangbing and Hansen, James E.}, doi = {10.1172/jci.insight.145875}, journal-iso = {JCI INSIGHT}, journal = {JCI INSIGHT}, volume = {6}, unique-id = {32344729}, abstract = {The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response. We found that DX1 penetrated brain endothelial cells and crossed the BBB, and mechanistic studies identify ENT2 as the key transporter. In efficacy studies, DX1 crosses the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases. ENT2-linked transport of autoantibodies across the BBB has potential to be exploited in brain tumor immunotherapy, and its discovery raises hypotheses on actionable mechanisms of CNS penetration by neurotoxic autoantibodies in CNS lupus.}, year = {2021}, eissn = {2379-3708}, orcid-numbers = {Rattray, Zahra/0000-0002-8371-8549} } @article{MTMT:33939299, title = {Advances in the management of breast cancer brain metastases}, url = {https://m2.mtmt.hu/api/publication/33939299}, author = {Sammons, S. and Van, Swearingen A.E.D. and Chung, C. and Anders, C.K.}, doi = {10.1093/noajnl/vdab119}, journal-iso = {NEUROONCOL ADV}, journal = {NEURO-ONCOLOGY ADVANCES}, volume = {3}, unique-id = {33939299}, year = {2021}, eissn = {2632-2498}, pages = {V63-V74} } @article{MTMT:32474433, title = {Comparative Assessment of Diagnostic Homologous Recombination Deficiency-Associated Mutational Signatures in Ovarian Cancer}, url = {https://m2.mtmt.hu/api/publication/32474433}, author = {Sztupinszki, Zsófia and Diossy, Miklos and Borcsok, Judit and Prosz, Aurel and Cornelius, Nanna and Kjeldsen, Maj K. and Mirza, Mansoor R. and Szállási, Zoltán}, doi = {10.1158/1078-0432.CCR-21-0981}, journal-iso = {CLIN CANCER RES}, journal = {CLINICAL CANCER RESEARCH}, volume = {27}, unique-id = {32474433}, issn = {1078-0432}, abstract = {Purpose: Homologous recombination (HR) deficiency (HRD) is one of the key determinants of PARP inhibitor response in ovarian cancer, and its accurate detection in tumor biopsies is expected to improve the efficacy of this therapy. Because HRD induces a wide array of genomic aberrations, mutational signatures may serve as a companion diagnostic to identify PARP inhibitor-responsive cases. Experimental Design: From the The Cancer Genome Atlas (TCGA) whole-exome sequencing (WES) data, we extracted different types of mutational signature-based HRD measures, such as the HRD score, genome-wide LOH, and HRDetect trained on ovarian and breast cancer-specific sequencing data. We compared their performance to identify BRCA1/2-deficient cases in the TCGA ovarian cancer cohort and predict survival benefit in platinum-treated, BRCA1/2 wild-type ovarian cancer. Results: We found that the HRD score, which is based on large chromosomal alterations alone, performed similarly well to an ovarian cancer-specific HRDetect, which incorporates mutations on a finer scale as well (AUC = 0.823 vs. AUC = 0.837). In an independent cohort these two methods were equally accurate predicting long- term survival after platinum treatment (AUC = 0.787 vs. AUC = 0.823). We also found that HRDetect trained on ovarian cancer was more accurate than HRDetect trained on breast cancer data (AUC = 0.837 vs. AUC = 0.795; P = 0.0072). Conclusions: When WES data are available, methods that quantify only large chromosomal alterations such as the HRD score and HRDetect that captures a wider array of HRD-induced genomic aberrations are equally efficient identifying HRD ovarian cancer cases.}, keywords = {CARCINOMA; Therapy; MAINTENANCE; REPAIR; rucaparib}, year = {2021}, eissn = {1557-3265}, pages = {5681-5687}, orcid-numbers = {Diossy, Miklos/0000-0003-0308-6615; Borcsok, Judit/0000-0002-3290-3971; Szállási, Zoltán/0000-0001-5395-7509} } @article{MTMT:32344730, title = {Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies}, url = {https://m2.mtmt.hu/api/publication/32344730}, author = {Wang, Yajie and Ye, Fangzhou and Liang, Yiran and Yang, Qifeng}, doi = {10.1038/s41416-021-01424-8}, journal-iso = {BRIT J CANCER}, journal = {BRITISH JOURNAL OF CANCER}, volume = {125}, unique-id = {32344730}, issn = {0007-0920}, abstract = {Breast cancer is one of the most prevalent malignancies in women worldwide. Early-stage breast cancer is considered a curable disease; however, once distant metastasis occurs, the 5-year overall survival rate of patients becomes significantly reduced. There are four distinct metastatic patterns in breast cancer: bone, lung, liver and brain. Among these, breast cancer brain metastasis (BCBM) is the leading cause of death; it is highly associated with impaired quality of life and poor prognosis due to the limited permeability of the blood-brain barrier and consequent lack of effective treatments. Although the sequence of events in BCBM is universally accepted, the underlying mechanisms have not yet been fully elucidated. In this review, we outline progress surrounding the molecular mechanisms involved in BCBM as well as experimental methods and research models to better understand the process. We further discuss the challenges in the management of brain metastases, as well as providing an overview of current therapies and highlighting innovative research towards developing novel efficacious targeted therapies.}, year = {2021}, eissn = {1532-1827}, pages = {1056-1067}, orcid-numbers = {Yang, Qifeng/0000-0003-0576-8513} } @article{MTMT:32013902, title = {Evolutionary Trajectories and Genomic Divergence in Localized Breast Cancers after Ipsilateral Breast Tumor Recurrence}, url = {https://m2.mtmt.hu/api/publication/32013902}, author = {Wu, Chia-Hsin and Yeh, Hsien-Tang and Hsieh, Chia-Shan and Huang, Chi-Cheng and Chattopadhyay, Amrita and Chung, Yuan-Chiang and Tu, Shih-Hsin and Li, Yung-Hua and Lu, Tzu-Pin and Lai, Liang-Chuan and Hou, Ming-Feng and Chang, King-Jen and Tsai, Mong-Hsun and Chuang, Eric Y.}, doi = {10.3390/cancers13081821}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {13}, unique-id = {32013902}, abstract = {Simple Summary Ipsilateral breast tumor relapse (IBTR) occurs in 5-10% of localized breast cancers (BCs) within 10 years of incidence, despite proper treatment of the primary lesion. However, the clinical consequences of evolutionary trajectories of BC cells and their impact on IBTR remain poorly understood. Here, we conducted a longitudinal genomic analysis of 10 matched localized BC patients with IBTR. Overall, we identified the differences in homologous recombination deficiency, chromosomal instability, and somatic mutation drivers between primary and relapsed lesions. Our analyses highlighted three clonal architectures that shape by distinct mutagenic processes and subclonal diversification during relapse progression. Finally, this study provided a framework, which integrated actionable biomarkers with clonal architectures, towards improvement of future treatment decisions. The evolutionary trajectories that drive clinical and therapeutic consequences in localized breast cancers (BCs) with ipsilateral breast tumor relapse (IBTR) remain largely unknown. Analyses of longitudinal paired whole-exome sequencing data from 10 localized BC patients with IBTR reveal that, compared to primary breast tumors, homologous recombination (HR) deficiency, inactivation of the HR pathway, chromosomal instability, and somatic driver mutations are more frequent. Furthermore, three major models of evolution in IBTR are summarized, through which relative contributions of mutational signatures shift, and the subclonal diversity expansions are shown. Optimal treatment regimens are suggested by the clinically relevant molecular features, such as HR deficiency (20%) or specific alterations (30%) with sensitivity to available FDA-approved drugs. Finally, a rationale for the development of the therapeutic management framework is provided. This study sheds light on the complicated evolution patterns in IBTR and has significant clinical implications for future improvement of treatment decisions.}, keywords = {whole-exome sequencing; Alteration; clonal architecture; ipsilateral breast tumor relapse}, year = {2021}, eissn = {2072-6694}, orcid-numbers = {Hou, Ming-Feng/0000-0001-6030-9702} } @article{MTMT:32686133, title = {PARP5B is required for nonhomologous end joining during tumorigenesis in vivo}, url = {https://m2.mtmt.hu/api/publication/32686133}, author = {Wu, Jianchun and Crowe, David L.}, doi = {10.1002/mc.23363}, journal-iso = {MOL CARCINOGEN}, journal = {MOLECULAR CARCINOGENESIS}, volume = {61}, unique-id = {32686133}, issn = {0899-1987}, abstract = {Poly(ADP-ribose) polymerases (PARP) act as DNA damage sensors that produce poly(ADP-ribose) (PAR) chains at double-strand breaks, facilitating the recruitment of repair factors. Cancers with homologous recombination defects are sensitive to small molecule PARP inhibitors. Despite PARP5B gene copy number changes in many cancers, the effects of this genetic alteration on tumor phenotype are largely unknown. To better understand this clinical finding, we characterized a PARP5B null mutation in a carcinogen-induced in vivo head and neck squamous cell carcinoma (SCC) model. Reduced PARP5B expression inhibited tumor growth, induced primary tumor differentiation and apoptosis, and inhibited cell proliferation and metastasis. Loss of PARP5B expression-induced ataxia telangiectasia and Rad3 related (ATR) activation and depleted the cancer stem cell fraction. PARP5B null tumor cells lacked 53BP1+ double-strand break foci, ATM activation, and p53 induction compared to PARP5B+/+ cancers. PARP5B null SCC expresses a multiprotein complex containing PML, pRPA, Rad50, Rad51, XRCC1, proliferating cell nuclear antigen (PCNA), and Mcm2, suggesting an HR-mediated repair mechanism at DNA replication foci. Low doses of etoposide combined with the PARP5B inhibitor XAV939 induced senescence and apoptosis in human SCC lines. NBS1 overexpression in these cells inhibited the effects of low-dose etoposide/XAV939 treatment. Our results indicate that PARP5B inhibition is new targeted cancer therapy.}, keywords = {CELLS; APOPTOSIS; BREAST-CANCER; MAINTENANCE; DNA-DAMAGE; CONTRIBUTES; poly(ADP-ribose) polymerase; REPAIR; cancer stem cell; ADP-RIBOSYLATION; Homologous recombination; Homologous recombination; Biochemistry & Molecular Biology; DNA damage signaling}, year = {2021}, eissn = {1098-2744}, pages = {85-98} } @article{MTMT:32474744, title = {RNA Sequence Profiling Reveals Unique Immune and Metabolic Features of Breast Cancer Brain Metastases}, url = {https://m2.mtmt.hu/api/publication/32474744}, author = {Xiao, L. and Zhou, J. and Liu, H. and Zhou, Y. and Chen, W. and Cui, W. and Zhao, Y.}, doi = {10.3389/fonc.2021.679262}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {11}, unique-id = {32474744}, issn = {2234-943X}, year = {2021}, eissn = {2234-943X} } @article{MTMT:32061900, title = {The source of the tumor tissue should be taken into consideration when distinguishing tumor mutational burden scores}, url = {https://m2.mtmt.hu/api/publication/32061900}, author = {Zhang, Chenyue and Wang, Haiyong}, doi = {10.1016/j.lungcan.2021.02.007}, journal-iso = {LUNG CANCER-J IASLC}, journal = {LUNG CANCER}, volume = {154}, unique-id = {32061900}, issn = {0169-5002}, keywords = {Oncology}, year = {2021}, eissn = {1872-8332}, pages = {214-215} } @article{MTMT:32062156, title = {Targeted exome sequencing for the identification of common mutational signatures and potential driver mutations for brain metastases and prognosis}, url = {https://m2.mtmt.hu/api/publication/32062156}, author = {Zhang, Dainan and Wang, Xi and Ma, Shunchang and Li, Peiliang and Xue, Fei and Mao, Beibei and Guan, Xiudong and Zhou, Wenjianlong and Peng, Jiayi and Su, Kun and Zhang, Chuanbao and Jia, Wang}, doi = {10.3892/ol.2021.12440}, journal-iso = {ONCOL LETT}, journal = {ONCOLOGY LETTERS}, volume = {21}, unique-id = {32062156}, issn = {1792-1074}, abstract = {Brain metastases (BMs) are malignancies in the central nervous system with poor prognosis. Genetic landscapes of the primary tumor sites have been extensively profiled; however, mutations associated with BMs are poorly understood. In the present study, target exome sequencing of 560 cancer-associated genes in samples from 52 patients with brain metastasis from various primary sites was performed. Recurrent mutations for BMs from distinct origins were identified. There were both genetic homogeneity and heterogeneity between BMs and primary lung tumor tissues. The mutation rate of the major cancer driver gene, TP53, was consistently high in both the primary lung cancer sites and BMs, while some genetic alterations, associated with DNA damage response deficiency, were specifically enriched in BMs. The mutational signatures enriched in BMs could serve as actionable targets for treatment. The mutation in the primary site of the potential brain metastasis driver gene, nuclear mitotic apparatus protein 1 (NUMA1), affected the progression-free survival time of patients with lung cancer, and patients with the NUMA1 mutation in BMs had a good prognosis. This suggested that the occurrence and clinical outcome of brain metastases could be independent of each other.}, keywords = {HETEROGENEITY; DEFICIENCY; BREAST-CANCER; GENETIC-VARIATION; p53; brain metastasis; TP53 mutations; lung adenocarcinomas; PI3K pathway; targeted exome sequencing; BRANCHED EVOLUTION}, year = {2021}, eissn = {1792-1082} } @{MTMT:32145170, title = {Neurological complications of targeted therapies}, url = {https://m2.mtmt.hu/api/publication/32145170}, author = {Chukwueke, U.N. and Lee, E.Q. and Wen, P.Y.}, booktitle = {Central Nervous System Metastases}, doi = {10.1007/978-3-030-23417-1_27}, unique-id = {32145170}, year = {2020}, pages = {341-363} } @article{MTMT:31717172, title = {Using whole-genome sequencing data to derive the homologous recombination deficiency scores}, url = {https://m2.mtmt.hu/api/publication/31717172}, author = {de Luca, Xavier M. and Newell, Felicity and Kazakoff, Stephen H. and Hartel, Gunter and Reed, Amy E. McCart and Holmes, Oliver and Xu, Qinying and Wood, Scott and Leonard, Conrad and Pearson, John V and Lakhani, Sunil R. and Waddell, Nicola and Nones, Katia and Simpson, Peter T.}, doi = {10.1038/s41523-020-0172-0}, journal-iso = {NPJ BREAST CANCER}, journal = {NPJ BREAST CANCER}, volume = {6}, unique-id = {31717172}, abstract = {The homologous recombination deficiency (HRD) score was developed using whole-genome copy number data derived from arrays as a way to infer deficiency in the homologous recombination DNA damage repair pathway (in particularBRCA1orBRCA2deficiency) in breast cancer samples. The score has utility in understanding tumour biology and may be indicative of response to certain therapeutic strategies. Studies have used whole-exome sequencing to derive the HRD score, however, with increasing use of whole-genome sequencing (WGS) to characterise tumour genomes, there has yet to be a comprehensive comparison between HRD scores derived by array versus WGS. Here we demonstrate that there is both a high correlation and a good agreement between array- and WGS-derived HRD scores and between the scores derived from WGS and downsampled WGS to represent shallow WGS. For samples with an HRD score close to threshold for stratifying HR proficiency or deficiency there was however some disagreement in the HR status between array and WGS data, highlighting the importance of not relying on a single method of ascertaining the homologous recombination status of a tumour.}, year = {2020}, eissn = {2374-4677}, orcid-numbers = {Hartel, Gunter/0000-0002-5454-6450; Leonard, Conrad/0000-0002-4131-2065} } @article{MTMT:30883383, title = {Immunologic and immunogenomic aspects of tumor progression}, url = {https://m2.mtmt.hu/api/publication/30883383}, author = {Ladányi, Andrea and Tímár, József}, doi = {10.1016/j.semcancer.2019.08.011}, journal-iso = {SEMIN CANCER BIOL}, journal = {SEMINARS IN CANCER BIOLOGY}, volume = {60}, unique-id = {30883383}, issn = {1044-579X}, year = {2020}, eissn = {1096-3650}, pages = {249-261}, orcid-numbers = {Ladányi, Andrea/0000-0001-9304-8473; Tímár, József/0000-0001-9183-0859} } @article{MTMT:30956606, title = {Molecular comparison of interval and screen-detected breast cancers}, url = {https://m2.mtmt.hu/api/publication/30956606}, author = {Cheasley, Dane and Li, Na and Rowley, Simone M. and Elder, Kenneth and Mann, G. Bruce and Loi, Sherene and Savas, Peter and Goode, David L. and Kader, Tanjina and Zethoven, Magnus and Semple, Tim and Fox, Stephen B. and Pang, Jia-Min and Byrne, David and Devereux, Lisa and Nickson, Carolyn and Procopio, Pietro and Lee, Grant and Hughes, Siobhan and Saunders, Hugo and Fujihara, Kenji M. and Kuykhoven, Keilly and Connaughton, Jacquie and James, Paul A. and Gorringe, Kylie L. and Campbell, Ian G.}, doi = {10.1002/path.5251}, journal-iso = {J PATHOL}, journal = {JOURNAL OF PATHOLOGY}, volume = {248}, unique-id = {30956606}, issn = {0022-3417}, abstract = {Breast cancer (BC) diagnosed after a negative mammogram but prior to the next screening episode is termed an 'interval BC' (IBC). Understanding the molecular differences between IBC and screen-detected BCs (SDBC) could improve mammographic screening and management options. Therefore, we assessed both germline and somatic genomic aberrations in a prospective cohort. Utilising the Lifepool cohort of >54 000 women attending mammographic screening programs, 930 BC cases with screening status were identified (726 SDBC and 204 IBC). Clinico-pathological and family history information were recorded. Germline and tumour DNA were collected where available and sequenced for BC predisposition and driver gene mutations. Compared to SDBC, IBCs were significantly associated with a younger age at diagnosis and tumour characteristics associated with worse prognosis. Germline DNA assessment of BC cases that developed post-enrolment (276 SDBCs and 77 IBCs) for pathogenic mutations in 12 hereditary BC predisposition genes identified 8 carriers (2.27%). The germline mutation frequency was higher in IBC versus SDBC, although not statistically significant (3.90% versus 1.81%, p = 0.174). Comparing somatic genetic features of IBC and SDBC matched for grade, histological subtype and hormone receptor revealed no significant differences, with the exception of higher homologous recombination deficiency scores in IBC, and copy number changes on chromosome Xq in triple negative SDBCs. Our data demonstrates that while IBCs are clinically more aggressive than SDBC, when matched for confounding clinico-pathological features they do not represent a unique molecular class of invasive BC, but could be a consequence of timing of tumour initiation and mammographic screening. Copyright (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.}, keywords = {GENOMICS; breast cancer; genetic predisposition; somatic mutation; COPY NUMBER ALTERATION; Mammographic screening; Next generation sequencing; Mammographic density; Screen-detected breast cancer; Interval breast cancer}, year = {2019}, eissn = {1096-9896}, pages = {243-252}, orcid-numbers = {Cheasley, Dane/0000-0002-1170-4690; Loi, Sherene/0000-0001-6137-9171} } @article{MTMT:30625426, title = {Corrigendum to: Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors}, url = {https://m2.mtmt.hu/api/publication/30625426}, author = {Diossy, M and Reiniger, Lilla and Sztupinszki, Zsófia and Krzystanek, M and Timms, K M and Neff, C and Solimeno, C and Pruss, D and Eklund, A C and Tóth, Erika and Kiss, O and Rusz, O and Cserni, G and Zombori, Tamás and Székely, Borbála and Kulka, Janina and Tímár, J and Csabai, István and Szállási, Zoltán}, doi = {10.1093/annonc/mdz081}, journal-iso = {ANN ONCOL}, journal = {ANNALS OF ONCOLOGY}, volume = {30}, unique-id = {30625426}, issn = {0923-7534}, year = {2019}, eissn = {1569-8041}, pages = {1406-1406}, orcid-numbers = {Reiniger, Lilla/0000-0003-2248-4264; Tóth, Erika/0000-0003-2054-8447; Zombori, Tamás/0000-0002-0654-563X; Kulka, Janina/0000-0001-6498-5943; Csabai, István/0000-0001-9232-9898; Szállási, Zoltán/0000-0001-5395-7509} } @article{MTMT:31127339, title = {Poly (ADP-ribose) Polymerase Inhibition in Patients with Breast Cancer and BRCA 1 and 2 Mutations}, url = {https://m2.mtmt.hu/api/publication/31127339}, author = {Jerez, Y. and Márquez-Rodas, I. and Aparicio, I. and Alva, M. and Martín, M. and López-Tarruella, S.}, doi = {10.1007/s40265-019-01235-5}, journal-iso = {DRUGS}, journal = {DRUGS}, volume = {80}, unique-id = {31127339}, issn = {0012-6667}, year = {2019}, eissn = {1179-1950}, pages = {131-146} } @article{MTMT:30622858, title = {Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases}, url = {https://m2.mtmt.hu/api/publication/30622858}, author = {Lim, Malcolm and Puttick, Simon and Houston, Zachary and Thurecht, Kristofer and Kalita-de Croft, Priyakshi and Mahler, Stephen and Rose, Stephen and Jeffree, Rosalind and Mazzieri, Roberta and Dolcetti, Riccardo and Lakhani, Sunil and Saunus, Jodi}, doi = {10.3390/ijms20061280}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {20}, unique-id = {30622858}, issn = {1661-6596}, abstract = {Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the precision and efficacy of these life-prolonging treatments, with no reliable options for adjunct systemic therapy, brain recurrences are virtually inevitable. The factors limiting intracranial efficacy of existing agents are both physiological and molecular in nature. For example, heterogeneous permeability, abnormal perfusion and high interstitial pressure oppose the conventional convective delivery of circulating drugs, thus new delivery strategies are needed to achieve uniform drug uptake at therapeutic concentrations. Brain metastases are also highly adapted to their microenvironment, with complex cross-talk between the tumor, the stroma and the neural compartments driving speciation and drug resistance. New strategies must account for resistance mechanisms that are frequently engaged in this milieu, such as HER3 and other receptor tyrosine kinases that become induced and activated in the brain microenvironment. Here, we discuss molecular and physiological factors that contribute to the recalcitrance of these tumors, and review emerging therapeutic strategies, including agents targeting the PI3K axis, immunotherapies, nanomedicines and MRI-guided focused ultrasound for externally controlling drug delivery.}, year = {2019}, eissn = {1422-0067} } @article{MTMT:33364480, title = {Highlights of the inaugural ten - the launch of Neuro-Oncology Advances}, url = {https://m2.mtmt.hu/api/publication/33364480}, author = {Nassiri, Farshad and Aldape, Kenneth and Alhuwalia, Manmeet and Brastianos, Priscilla and Ducray, Francois and Galldiks, Norbert and Kim, Albert and Lamszus, Katrin and Mitchell, Duane and Nabors, L. Burt and Nam, Do-Hyun and Natsume, Atsushi and Ng, Ho-Keung and Niclou, Simone and Sahm, Felix and Short, Susan and Walsh, Kyle and Wick, Wolfgang and Zadeh, Gelareh}, doi = {10.1093/noajnl/vdz016}, journal-iso = {NEUROONCOL ADV}, journal = {NEURO-ONCOLOGY ADVANCES}, volume = {1}, unique-id = {33364480}, keywords = {MUTATIONS; Oncology; glioblastoma; AKT1; SMO}, year = {2019}, eissn = {2632-2498}, orcid-numbers = {Sahm, Felix/0000-0001-5441-1962; Walsh, Kyle/0000-0002-5879-9981} } @article{MTMT:33364481, title = {Efficacy and pharmacodynamics of niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models}, url = {https://m2.mtmt.hu/api/publication/33364481}, author = {Sambade, Maria J. and Van, Swearingen Amanda E. D. and McClure, Marni B. and Deal, Allison M. and Santos, Charlene and Sun, Kaiming and Wang, Jing and Mikule, Keith and Anders, Carey K.}, doi = {10.1093/noajnl/vdz005}, journal-iso = {NEUROONCOL ADV}, journal = {NEURO-ONCOLOGY ADVANCES}, volume = {1}, unique-id = {33364481}, abstract = {Background Despite the poor prognosis of triple-negative breast cancer (TNBC) brain metastases, there are no approved systemic therapies. We explored the DNA-damaging poly(ADP-ribose) polymerase inhibitor (PARPi) niraparib in intracranial mouse models of breast cancer susceptibility protein (BRCA)-mutant TNBC. Methods Mice bearing intracranial human-derived TNBC cell lines (SUM149, MDA-MB-231Br, or MDA-MB-436) were treated with niraparib and monitored for survival; intracranial tissues were analyzed for PAR levels and niraparib concentration by mass spectrometry. RNASeq data of primary breast cancers using The Cancer Genome Atlas were analyzed for DNA damage signatures. Combined RAD51 and PARP inhibition in TNBC cell lines was assessed in vitro by colony-forming assays. Results Daily niraparib increased median survival and decreased tumor burden in the BRCA-mutant MDA-MB-436 model, but not in the BRCA-mutant SUM149 or BRCA-wild-type MDA-MB-231Br models despite high concentrations in intracranial tumors. RAD51 inhibitor B02 was shown to sensitize all cell lines to PARP inhibition (PARPi). In the analysis of BRCA-mutant primary human TNBCs, gene expression predictors of PARPi sensitivity and DNA repair signatures demonstrate widespread heterogeneity, which may explain the differential response to PARPi. Interestingly, these signatures are significantly correlated to RAD51 expression including PARPi sensitivity (R-2 = 0.602, R-2= 0.758). Conclusions Niraparib penetrates intracranial tumor tissues in mouse models of TNBC with impressive single-agent efficacy in BRCA-mutant MDA-MB-436. Clinical evaluation of niraparib to treat TNBC brain metastases, an unmet clinical need desperate for improved therapies, is warranted. Further compromising DNA repair through RAD51 inhibition may further augment TNBC's response to PARPi.}, keywords = {Recurrence; ADP-RIBOSE POLYMERASE; TUMORS; Blood-Brain Barrier; targeted therapy; Oncology; poly(ADP-ribose) polymerase; PARP inhibition; brain metastases; brain metastases; PARP inhibitor; INHIBITOR NIRAPARIB}, year = {2019}, eissn = {2632-2498}, orcid-numbers = {McClure, Marni B./0000-0002-0807-4368} } @article{MTMT:30981375, title = {Central nervous system metastases in triple-negative breast cancer: A step in the right direction}, url = {https://m2.mtmt.hu/api/publication/30981375}, author = {Shreenivas, Aditya and Shapiro, Charles L.}, doi = {10.1111/tbj.13232}, journal-iso = {BREAST J}, journal = {BREAST JOURNAL}, volume = {25}, unique-id = {30981375}, issn = {1075-122X}, year = {2019}, eissn = {1524-4741}, pages = {361-362} } @article{MTMT:30981406, title = {Patterns of recurrence and metastasis in BRCA1/BRCA2-associated breast cancers}, url = {https://m2.mtmt.hu/api/publication/30981406}, author = {Song, Y. and Barry, W.T. and Seah, D.S. and Tung, N.M. and Garber, J.E. and Lin, N.U.}, doi = {10.1002/cncr.32540}, journal-iso = {CANCER-AM CANCER SOC}, journal = {CANCER}, volume = {126}, unique-id = {30981406}, issn = {0008-543X}, year = {2019}, eissn = {1097-0142}, pages = {271-280} } @article{MTMT:30622857, title = {Identification of hub genes to regulate breast cancer metastasis to brain by bioinformatics analyses}, url = {https://m2.mtmt.hu/api/publication/30622857}, author = {Tang, Dongyang and Zhao, Xin and Zhang, Li and Wang, Zhiwei and Wang, Cheng}, doi = {10.1002/jcb.28228}, journal-iso = {J CELL BIOCHEM}, journal = {JOURNAL OF CELLULAR BIOCHEMISTRY}, volume = {120}, unique-id = {30622857}, issn = {0730-2312}, year = {2019}, eissn = {1097-4644}, pages = {9522-9531} } @article{MTMT:30855311, title = {A tumorprogresszió immungenomikai aspektusai [A Immunogenomic aspects of tumor progression]}, url = {https://m2.mtmt.hu/api/publication/30855311}, author = {Tímár, József and Ladányi, Andrea}, journal-iso = {MAGYAR ONKOLÓGIA}, journal = {MAGYAR ONKOLÓGIA}, volume = {63}, unique-id = {30855311}, issn = {0025-0244}, year = {2019}, eissn = {2060-0399}, pages = {173-182}, orcid-numbers = {Tímár, József/0000-0001-9183-0859; Ladányi, Andrea/0000-0001-9304-8473} } @article{MTMT:30914154, title = {A Comparison of DNA Mutation and Copy Number Profiles of Primary Breast Cancers and Paired Brain Metastases for Identifying Clinically Relevant Genetic Alterations in Brain Metastases}, url = {https://m2.mtmt.hu/api/publication/30914154}, author = {Tyran, Marguerite and Carbuccia, Nadine and Garnier, Severine and Guille, Arnaud and Adelaide, Jose and Finetti, Pascal and Touzlian, Julien and Viens, Patrice and Tallet, Agnes and Goncalves, Anthony and Metellus, Philippe and Birnbaum, Daniel and Chaffanet, Max and Bertucci, Francois}, doi = {10.3390/cancers11050665}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {11}, unique-id = {30914154}, abstract = {Improving the systemic treatment of brain metastases (BM) in primary breast cancer (PBC) is impaired by the lack of genomic characterization of BM. To estimate the concordance of DNA copy-number-alterations (CNAs), mutations, and actionable genetic alterations (AGAs) between paired samples, we performed whole-genome array-comparative-genomic-hybridization, and targeted-next-generation-sequencing on 14 clinical PBC-BM pairs. We found more CNAs, more mutations, and higher tumor mutational burden, and more AGAs in BM than in PBC; 92% of the pairs harbored at least one AGA in the BM not observed in the paired PBC. This concerned various therapeutic classes, including tyrosine-kinase-receptor-inhibitors, phosphatidylinositol 3-kinase/AKT/mammalian Target of Rapamycin (PI3K/AKT/MTOR)-inhibitors, poly ADP ribose polymerase (PARP)-inhibitors, or cyclin-dependent kinase (CDK)-inhibitors. With regards to the PARP-inhibitors, the homologous recombination defect score was positive in 79% of BM, compared to 43% of PBC, discordant in 7 out of 14 pairs, and positive in the BM in 5 out of 14 cases. CDK-inhibitors were associated with the largest percentage of discordant AGA appearing in the BM. When considering the AGA with the highest clinical-evidence level, for each sample, 50% of the pairs harbored an AGA in the BM not detected or not retained from the analysis of the paired PBC. Thus, the profiling of BM provided a more reliable opportunity, than that of PBC, for diagnostic decision-making based on genomic analysis. Patients with BM deserve an investigation of several targeted therapies.}, keywords = {MUTATION; targeted therapy; breast cancer; brain metastasis; copy number profiling}, year = {2019}, eissn = {2072-6694}, orcid-numbers = {Viens, Patrice/0000-0003-1511-1048} }