Accumulation of Genetic Alterations in Brain Metastases of Sporadic Breast Carcinomas Is Associated with Reduced Survival after Metastasis

1998 ◽  
Vol 18 (2) ◽  
pp. 81-95 ◽  
Author(s):  
Monika Hampl ◽  
Jürgen Anton Hampl ◽  
Peter Schwarz ◽  
Stephan Frank ◽  
Matthias Hahn ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Genetic Alterations ◽  
Breast Carcinomas

scholarly journals Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 731
Author(s):  
Renáta Váraljai ◽  
Susanne Horn ◽  
Antje Sucker ◽  
Daniela Piercianek ◽  
Verena Schmitt ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Genetic Variants ◽  
Genetic Alterations ◽  
Metastasis Formation ◽  
Driver Genes ◽  
Targeted Next Generation Sequencing ◽  
Paired Samples ◽  
Melanoma Metastases ◽  
Frequent Event ◽  
Genetic Landscape

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

scholarly journals 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

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 665 ◽  
Author(s):  
Marguerite Tyran ◽  
Nadine Carbuccia ◽  
Séverine Garnier ◽  
Arnaud Guille ◽  
José Adelaïde ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Copy Number ◽  
Genomic Analysis ◽  
Mtor Inhibitors ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Tyrosine Kinase Receptor ◽  
Cdk Inhibitors ◽  
Breast Cancers

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.

scholarly journals The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas

2017 ◽  
Vol 23 (14) ◽  
pp. 3859-3870 ◽  
Author(s):  
Charlotte K.Y. Ng ◽  
Salvatore Piscuoglio ◽  
Felipe C. Geyer ◽  
Kathleen A. Burke ◽  
Fresia Pareja ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Breast Carcinomas

Presence of genetic aberrations in patients with brain metastases from non-small cell lung cancer (NSCLC) and clinical outcomes.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20604-e20604 ◽  
Author(s):  
Robert H. Press ◽  
Xinyan Zhang ◽  
Richard John Cassidy ◽  
Matthew Jeffrey Ferris ◽  
Jim Zhong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Brain Metastases ◽  
Clinical Outcomes ◽  
Performance Status ◽  
Multivariable Analysis ◽  
Genetic Alterations ◽  
Kras Mutations ◽  
Brain Radiotherapy ◽  
Systemic Therapies

e20604 Background: Historically, survival in patients (pts) with NSCLC brain metastases (BM) is poor, however, improved systemic therapies are now available including targeted therapies and immunotherapy. We sought to evaluate the prevalence of genetic alterations in pts with BM from non-squamous (NS) lung cancer, and to determine clinical outcomes in the modern era. Methods: With IRB approval, pts with BM from NS-NSCLC from 1/2010-1/2016 with genetic testing were captured and retrospectively reviewed. Snapshot genotyping was performed prior to 1/2014, after which Next Generation Sequencing was utilized, along with FISH lung cancer panel. Genes examined included: EGFR, ALK, RET, ROS1, TP53, KRAS, NRAS, MET, PTEN, BRAF, FBXW7, MAP2K1, APC, PIK3CA, CTNNB1, and SMAD4. Univariable and multivariable analysis (MVA) were utilized to assess factors associated with overall survival (OS). Results: 92 pts were included. Median number of BM was 4 (range 1-45). Median age was 64 (32-90 years). 59.8% were male. 38% received targeted therapy, 11% received immunotherapy, and 70% received conventional chemotherapy. 52.2% and 47.8% received whole brain radiotherapy and stereotactic radiosurgery, respectively. Median OS from first brain radiotherapy (RT) was 10.7 months (0.1-56.4). EGFR mutation, ALK fusion, ROS1 rearrangement, and RET rearrangement occurred in 27.5%, 5.2%, 1.7%, and 0% of pts. EGFR L858 and EGFR T790 mutations occurred in 19.2% and 2.7% of all pts. TP53, KRAS, and NRAS mutations occurred in 63.9%, 28.8% and 7% of pts. All other mutations had an incidence of less than 3%. On MVA, targeted therapy (HR 0.43 95% CI 0.22-0.86), immunotherapy (HR 0.04 95% CI 0.01-0.3), surgical resection (HR 0.38 95% CI 0.18-0.81), and ECOG performance status (0.23 95% CI 0.1-0.54) were associated with improved OS. No specific genetic aberration, RT modality, or number of BM was associated with OS. Conclusions: In pts with BM from NS-NSCLC, the most common molecular aberrations include TP53, EGFR, and KRAS mutations. Treatment with brain RT and modern systemic therapies yields a median survival greater than ten months. The use of targeted therapy or immunotherapy was associated with increased OS.

scholarly journals Characterization of genetic alterations in brain metastases from non‐small cell lung cancer

FEBS Open Bio ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. 1544-1552 ◽  
Author(s):  
Li Liao ◽  
Xiaoyu Ji ◽  
Mengxi Ge ◽  
Qiong Zhan ◽  
Ruofan Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung

Genomic Alterations in Human Breast Cancer: A Review

1989 ◽  
Vol 75 (4) ◽  
pp. 311-320 ◽  
Author(s):  
Renato Mariani-Costantinl ◽  
Giorgio Merlo ◽  
Luigi Frati
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Molecular Level ◽  
Genetic Material ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Breast Carcinomas ◽  
Human Breast ◽  
Human Breast Carcinomas ◽  
Chromosome 11P

We review and discuss data on the genetic alterations documented in human breast carcinomas at the molecular level. These alterations may result in: 1) deletion of genetic material (chromosome 11p, 13q, 3p, 1q, 17p); 2) amplification of genes or entire chromosomal segments (c-myc, c-erb-B2, locus DF3/PUM, loci on 11q13); 3) rearrangements (c-myc); 4) point mutations (c-ras). Presently available informations do not allow the development of cohesive pathogenetic models but indicate that the molecular basis of human breast cancer is heterogeneous.

scholarly journals The impact of EGFR mutation status and single brain metastasis on the survival of non-small-cell lung cancer patients with brain metastases

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Yuya Fujita ◽  
Manabu Kinoshita ◽  
Tomohiko Ozaki ◽  
Koji Takano ◽  
Kei Kunimasa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Egfr Mutation ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutation Status ◽  
The Impact

Abstract Background Molecular and genetic alterations of non-small-cell lung cancer (NSCLC) now play a vital role in patient care of this neoplasm. The authors focused on the impact of epidermal growth factor receptor mutation (EGFR-mt) status on the survival of patients after brain metastases (BMs) from NSCLC. The purpose of the study was to understand the most desirable management of BMs from NSCLC. Methods This was a retrospective observational study analyzing 647 patients with NSCLC, including 266 patients with BMs, diagnosed at our institute between January 2008 and December 2015. EGFR mutation status, overall survival (OS) following diagnosis, OS following BMs, duration from diagnosis to BMs, and other factors related to OS and survival after BMs were measured. Results Among 647 patients, 252 (38.8%) had EGFR mutations. The rate and frequency of developing BMs were higher in EGFR-mt patients compared with EGFR wildtype (EGFR-wt) patients. EGFR-mt patients showed longer median OS (22 vs 11 months, P < .001) and a higher frequency of BMs. Univariate and multivariate analyses revealed that good performance status, presence of EGFR-mt, single BM, and receiving local therapies were significantly associated with favorable prognosis following BM diagnosis. Single metastasis, compared with multiple metastases, exhibited a positive impact on patient survival after BMs in EGFR-mt patients, but not in EGFR-wt NSCLC patients. Conclusions Single BM with EGFR-mt performed better than other groups. Furthermore, effective local therapies were recommended to achieve better outcomes.

Toward Precision Medicine in Brain Metastases

2018 ◽  
Vol 38 (01) ◽  
pp. 095-103 ◽  
Author(s):  
Anna Berghoff ◽  
Priscilla Brastianos
Keyword(s):  
Brain Metastases ◽  
Genetic Divergence ◽  
Metastatic Cancer ◽  
Treatment Strategies ◽  
Whole Brain Radiotherapy ◽  
Genetic Alterations ◽  
Brain Radiotherapy ◽  
Genomic Technologies ◽  
New Treatment ◽  
The Brain

AbstractBrain metastases (BMs) reflect an area of high clinical need, as up to 40% of patients with metastatic cancer will develop this morbid and highly fatal complication. Historically, treatment strategies have relied on local approaches including radiosurgery, whole-brain radiotherapy, and neurosurgical resection. Recently, targeted and immune-modulating therapies have shown promising responses and have been introduced in the clinical management of patients with BMs. Recent improvements in genomic technologies have enriched our understanding of BMs and have demonstrated that BMs present with significant genetic divergence from the originating primary tumor, such that potentially targetable genetic alterations are detected only in the BMs. However, this genetic divergence also results in genetic alterations associated with resistance to targeted therapies. A deeper insight on the genetic alterations of BMs and the interaction with the brain microenvironment will likely reveal new treatment targets, moving toward more precision therapies for patients with BMs.

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