Targeted genomic analysis of 364 adrenocortical carcinomas

2021 ◽  
Vol 28 (10) ◽  
pp. 671-681
Author(s):  
Nikita Pozdeyev ◽  
Lauren Fishbein ◽  
Laurie M Gay ◽  
Ethan S Sokol ◽  
Ryan Hartmaier ◽  
...  
Keyword(s):  
Tumor Suppressor Genes ◽  
Wnt Signaling Pathway ◽  
Genomic Analysis ◽  
Genomic Alteration ◽  
Genomic Alterations ◽  
Dna Mismatch ◽  
Significant Incidence ◽  
Adrenocortical Carcinomas ◽  
Telomere Lengthening ◽  
Gene Alterations

Despite recent advances in elucidating molecular pathways underlying adrenocortical carcinoma (ACC), this orphan malignancy is associated with poor survival. Identification of targetable genomic alterations is critical to improve outcomes. The objective of this study was to characterize the genomic profile of a large cohort of patient ACC samples to identify actionable genomic alterations. Three hundred sixty-four individual patient ACC tumors were analyzed. The median age of the cohort was 52 years and 60.9% (n = 222) were female. ACC samples had common alterations in epigenetic pathways with 38% of tumors carrying alterations in genes involved in histone modification, 21% in telomere lengthening, and 21% in SWI/SNF complex. Tumor suppressor genes and WNT signaling pathway were each mutated in 51% of tumors. Fifty (13.7%) ACC tumors had a genomic alteration in genes involved in the DNA mismatch repair (MMR) pathway with many tumors also displaying an unusually high number of mutations and a corresponding MMR mutation signature. In addition, genomic alterations in several genes not previously associated with ACC were observed, including IL7R, LRP1B, FRS2 mutated in 6, 8 and 4% of tumors, respectively. In total, 58.5% of ACC (n = 213) had at least one potentially actionable genomic alteration in 46 different genes. As more than half of ACC have one or more potentially actionable genomic alterations, this highlights the value of targeted sequencing for this orphan cancer with a poor prognosis. In addition, significant incidence of MMR gene alterations suggests that immunotherapy is a promising therapeutic for a considerable subset of ACC patients.

scholarly journals Insights From Targeted Genetic Analysis of 364 Adrenocortical Carcinomas

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A168-A168
Author(s):  
Nikita Pozdeyev ◽  
Lauren Michelle Fishbein ◽  
Laurie M Gay ◽  
Ethan S Sokol ◽  
Ryan Hartmaier ◽  
...  
Keyword(s):  
Demographic Data ◽  
Genomic Analysis ◽  
Enrichment Analysis ◽  
Median Number ◽  
Therapeutic Modality ◽  
Pathway Enrichment Analysis ◽  
Single Nucleotide Variants ◽  
Genomic Alterations ◽  
Dna Mismatch ◽  
Adrenocortical Carcinomas

Abstract Adrenocortical carcinoma (ACC) is a rare endocrine malignancy affecting individuals across a broad age spectrum. Disease rarity, scarcity of pre-clinical models, lack of effective targeted therapy and limited clinical trials have contributed to poor prognosis for patients with ACC. Identifying targetable genetic drivers and pathways to guide precision medicine approaches is therefore critical to improve outcomes. The purpose of this study was to analyze the genomic profile of a large cohort of ACC to identify potential therapeutic targets. FoundationOne (Foundation Medicine Inc.; FMI, Cambridge, MA) is a next-generation sequencing-based platform for somatic genetic testing in solid tumors. The FoundationOne genomic data and limited demographic data through 2018 for 364 unique ACC specimens were analyzed. The cohort of 364 tumors were from 222 females and 141 males (1 gender unknown). The mean age (SD) was 48.6 (13.6) for females and 50.6 (12.20) for males with overall median age of 52 years. A total of 3117 genomic alterations were identified impacting 457 genes. The median number of genomic alterations per tumor was 7 (range 1–56), with single nucleotide variants and indels being the most common alterations (median=4), followed by copy number alterations (median=1) and rearrangements (median=0). The most frequently altered genes were TP53 (38%), CTNNB1 (28%), ZNRF3 (17%), CDKN2A (13%), ATRX (11%), TERT promoter (10%). Several novel recurrent alterations were identified including IL7R (6%), LRP1B (8%), FRS2 (4%), PTCH1 (4%) and KRAS (3%). Pathway enrichment analysis confirmed that tumor suppressor genes (51%) and Wnt signaling pathways (51%) are the most commonly dysregulated in ACC tumors. Epigenetic alterations, including histone modification (38%), SWI/SNF (21%) and DNA methylation (8%), affected upwards of one third of ACC tumors. Mutation signature analysis identified tumors with signatures 6, 15 and 26 associated with defective DNA mismatch repair (MMR), which was not reported previously. In addition, fifty ACCs (13.7%) exhibited 60 genomic alterations in MMR genes, MLH1, MSH2, MSH6 and PMS2, which included 49 SNVs/indels, 10 CNAs and one truncating rearrangement. In addition to MMR gene alterations, potentially actionable (www.oncokb.org) genomic alterations were found in 46 genes in 213 (58.5%) ACCs. In summary, this study represents the largest to date genomic analysis of ACC that showed that over 50% of ACC tumors had potentially actionable genomic alterations. Approximately 13% of tumors had an alteration in MMR pathway, suggesting that immunotherapy is a relevant therapeutic modality in a significant subset of patients with ACC.

scholarly journals Genomic Alteration Characterization in Colorectal Cancer Identifies a Prognostic and Metastasis Biomarker: FAM83A|IDO1

2021 ◽  
Vol 11 ◽  
Author(s):  
Zaoqu Liu ◽  
Yuyuan Zhang ◽  
Qin Dang ◽  
Kunpeng Wu ◽  
Dechao Jiao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Information ◽  
Global Perspective ◽  
Genomic Alteration ◽  
Genomic Alterations ◽  
Dna Mismatch ◽  
Frequent Mutations ◽  
Public Datasets ◽  
Carcinogenic Process ◽  
Relationship Of

Genomic alterations constitute crucial elements of colorectal cancer (CRC). However, a comprehensive understanding of CRC genomic alterations from a global perspective is lacking. In this study, a total of 2,778 patients in 15 public datasets were enrolled. Tissues and clinical information of 30 patients were also collected. We successfully identified two distinct mutation signature clusters (MSC) featured by massive mutations and dominant somatic copy number alterations (SCNA), respectively. MSC-1 was associated with defective DNA mismatch repair, exhibiting more frequent mutations such as ATM, BRAF, and SMAD4. The mutational co-occurrences of BRAF-HMCN and DNAH17-MDN1 as well as the methylation silence event of MLH-1 were only found in MSC-1. MSC-2 was linked to the carcinogenic process of age and tobacco chewing habit, exhibiting dominant SCNA such as MYC (8q24.21) and PTEN (10q23.31) deletion as well as CCND3 (6p21.1) and ERBB2 (17q12) amplification. MSC-1 displayed higher immunogenicity and immune infiltration. MSC-2 had better prognosis and significant stromal activation. Based on the two subtypes, we identified and validated the expression relationship of FAM83A and IDO1 as a robust biomarker for prognosis and distant metastasis of CRC in 15 independent cohorts and qRT-PCR data from 30 samples. These results advance precise treatment and clinical management in CRC.

scholarly journals Clinical Applications of Genomic Alterations in ATLL: Predictive Markers and Therapeutic Targets

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1801
Author(s):  
Noriaki Yoshida ◽  
Hiroaki Miyoshi ◽  
Koichi Ohshima
Keyword(s):  
T Cell ◽  
Immune Escape ◽  
Leukemia Virus ◽  
Genomic Analysis ◽  
Genomic Alteration ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Genomic Alterations ◽  
Cell Leukemia Virus Type ◽  
Human T Cell

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma (PTCL) caused by human T-cell leukemia virus type 1 (HTLV-1). Recent comprehensive genomic analyses have revealed the genomic landscape. One of the important findings of genomic alterations in ATLL is that almost all alterations are subclonal, suggesting that therapeutic strategies targeting a genomic alteration will result in partial effects. Among the identified alterations, genes involved in T-cell receptor signaling and immune escape mechanisms, such as PLCG1, CARD11, and PD-L1 (also known as CD274), are characteristic of ATLL alterations. From a geographic perspective, ATLL patients in Caribbean islands tend to be younger than those in Japan and the landscape differs between the two areas. Additionally, young Japanese ATLL patients frequently have CD28 fusions, compared with unselected Japanese cases. From a clinical perspective, PD-L1 amplification is an independent prognostic factor among every subtype of ATLL case. Recently, genomic analysis using deep sequencing identified a pre-ATLL clone with ATLL-common mutations in HTLV-1 carriers before development, indicating that genomic analysis can stratify cases based on the risks of development and mortality. In addition to genomic alterations, targetable super-enhancers have been identified in ATLL. These data can be leveraged to improve the prognosis of ATLL.

scholarly journals RARE-07. THE LANDSCAPE OF GENOMIC ALTERATIONS IN ADAMANTINOMATOUS CRANIOPHARYNGIOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii443-iii443
Author(s):  
Prasidda Khadka ◽  
Eric Prince ◽  
Sophie Lu ◽  
Sandro Santagata ◽  
Keith Ligon ◽  
...  
Keyword(s):  
Wnt Signaling Pathway ◽  
Genomic Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Structural Variations ◽  
Genomic Alterations ◽  
Normal Tissues ◽  
Activating Mutations ◽  
Ctnnb1 Gene ◽  
Recurrent Mutations

Abstract INTRODUCTION Adamantinomatous craniopharyngiomas (ACPs) are characterized by activating mutations in the CTNNB1 gene. Here we perform a comprehensive genomic analysis of 23 ACPs to define the landscape of genomic alterations in this disease. METHODS We performed whole-genome sequencing of 24 ACPs and their matched normal tissues. We used Mutect 2.0 to detect mutations and indels in these samples and MutSig2CV to identify significant mutations. Copy numbers were called using the GATK4 pipeline and GISTIC 2.0 was applied to identify significant alterations. Finally, SvABA was applied to identify genome-wide structural variants and rearrangements. RESULTS 18/24 (75%) of the sequenced ACPs harbored activating mutations in exon 3 of CTNNB1 gene with an average variant allele fraction (VAF) of 0.4±0.1. These mutations have previously been shown to activate the WNT signaling pathway in these tumors. No other significantly recurrent mutations were detected in our samples. The ACPs were quiet with regard to copy number alterations and no recurrent amplifications or deletions were detected. 528 structural variations and rearrangements were detected in total in all 24 samples with an average of 22 variants per sample. Gene-Set Enrichment Analysis (GSEA) of the RNAseq data revealed upregulation of WNT/B-catenin (FDR q-value <0.25) in the CTNNB1 mutant samples compared to CTNNB1 WT samples. CONCLUSION Our study identified previously described activating CTNNB1 mutations in the majority of ACPs. In addition, we identified several rearrangements and structural variations in these tumors that could play an important role in the pathogenesis of the disease.

scholarly journals Next-Generation Sequencing Approach to Non–Small Cell Lung Carcinoma Yields More Actionable Alterations

2017 ◽  
Vol 142 (3) ◽  
pp. 353-357 ◽  
Author(s):  
Mitra Mehrad ◽  
Somak Roy ◽  
Humberto Trejo Bittar ◽  
Sanja Dacic
Keyword(s):  
Next Generation Sequencing ◽  
Lung Adenocarcinoma ◽  
Small Cell ◽  
Gene Panel ◽  
Next Generation ◽  
Small Cell Lung ◽  
Genomic Alterations ◽  
Generation Sequencing ◽  
Gene Alterations ◽  
Cancer Panel

Context.— Different testing algorithms and platforms for EGFR mutations and ALK rearrangements in advanced-stage lung adenocarcinoma exist. The multistep approach with single-gene assays has been challenged by more efficient next-generation sequencing (NGS) of a large number of gene alterations. The main criticism of the NGS approach is the detection of genomic alterations of uncertain significance. Objective.— To determine the best testing algorithm for patients with lung cancer in our clinical practice. Design.— Two testing approaches for metastatic lung adenocarcinoma were offered between 2012–2015. One approach was reflex testing for an 8-gene panel composed of DNA Sanger sequencing for EGFR, KRAS, PIK3CA, and BRAF and fluorescence in situ hybridization for ALK, ROS1, MET, and RET. At the oncologist's request, a subset of tumors tested by the 8-gene panel was subjected to a 50-gene Ion AmpliSeq Cancer Panel. Results.— Of 1200 non–small cell lung carcinomas (NSCLCs), 57 including 46 adenocarcinomas and NSCLCs, not otherwise specified; 7 squamous cell carcinomas (SCCs); and 4 large cell neuroendocrine carcinomas (LCNECs) were subjected to Ion AmpliSeq Cancer Panel. Ion AmpliSeq Cancer Panel detected 9 potentially actionable variants in 29 adenocarcinomas that were wild type by the 8-gene panel testing (9 of 29, 31.0%) in the following genes: ERBB2 (3 of 29, 10.3%), STK11 (2 of 29, 6.8%), PTEN (2 of 29, 6.8%), FBXW7 (1 of 29, 3.4%), and BRAF G469A (1 of 29, 3.4%). Four SCCs and 2 LCNECs showed investigational genomic alterations. Conclusions.— The NGS approach would result in the identification of a significant number of actionable gene alterations, increasing the therapeutic options for patients with advanced NSCLCs.

Novel Genomic Alterations in MCL1 and ARID1A Identified in Pediatric Burkitt Lymphoma Using Targeted High-Throughput Sequencing

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 899-899
Author(s):  
Lisa Giulino Roth ◽  
Kai Wang ◽  
Theresa MacDonald ◽  
Susan Mathew ◽  
YiFang Tam ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Burkitt Lymphoma ◽  
Genomic Analysis ◽  
Ffpe Tissue ◽  
Sub Saharan Africa ◽  
Genomic Alterations ◽  
Employment Equity ◽  
Truncating Mutation ◽  
Equity Ownership

Abstract Abstract 899 While the majority of children with Burkitt lymphoma (BL) are cured with conventional chemotherapy, outcome for patients with relapsed disease is poor (overall survival <30%). Cure rates are lower in developing countries, which bear the brunt of this disease, including the endemic form in sub-Saharan Africa. Targeted therapy would be of benefit to all patients with BL to improve outcomes and decrease the reliance on conventional toxic chemotherapy. In order to develop such therapies a comprehensive understanding of the BL cancer genome is needed. The hallmark of BL is the translocation of MYC to either the immunoglobulin heavy or light chains. In contrast to adult cases, pediatric tumors often have multiple additional cytogenetic abnormalities, the consequences of which are less well understood. In order to characterize the genomic landscape of pediatric BL and to investigate potential therapeutic targets, we performed targeted massively parallel sequencing on a cohort of primary pediatric BL samples. Large genomic studies in rare tumors such as pediatric BL have been limited by the need for frozen tissue. In the current study we utilized a platform that has been adapted for genomic analysis of formalin-fixed, paraffin-embedded (FFPE) tissue, which allows the use of archival FFPE cases (Lipson, et al Nat Med. 2012 Feb 12;18(3):382-4). Targeted genomic sequencing was performed on 29 pediatric BL cases evaluating 3,230 exons of 182 cancer related genes and 37 introns from 14 genes often rearranged in cancer. Tumor samples were collected at diagnosis from patients in the US, Brazil, and Kenya and included the sporadic (n=24), endemic (n=3) and HIV associated (n=2) forms of disease. At an average coverage of 653-fold, 89% of cases were found to have at least one genetic alteration. The number of observed alterations correlated with EBV status. EBV negative cases demonstrated significantly more genomic alterations than EBV-positive cases. Among the EBV(–) cases, 13/15 had >1 alteration compared with 2/13 EBV(+) cases with >1 alteration (p<0.001). This is consistent with a tumorigenic role of EBV in BL. The most common mutations observed were in MYC (58.6%) and p53 (41.4%). MYC mutations spanned the coding region and included hot spots previously documented in lymphomas. Cases with MYC mutations also demonstrated MYC translocations, confirming that mutations may functionally cooperate with translocation to promote MYC-mediated oncogenesis. Novel recurrent alterations were identified in the chromatin remodeling gene, ARID1A as well as the anti-apoptotic gene, MCL1. ARID1A is a member of the SWI/SNF family of complexes that regulate chromatin structure and has been implicated as a tumor suppressor in a variety of solid tumors, but has not yet been described in BL. We identified truncating mutations in 5/29 cases (17.2%), including one case that had a secondary mutation in SWF5, also a member of the SWI/SNF family. Immunohistochemistry for ARID1A demonstrated decreased expression in cases where the truncating mutation was upstream of the antibody epitope. MCL1 is a member of the Bcl2 family of apoptotic proteins and has been implicated as an oncogene in lymphomas. Of the 29 cases sequenced, 6 (20.7%) had alterations in the MCL1 pathway including amplification of MCL1 (n=5) and point mutation in FBWX7, a ubiquitin ligase that targets MCL1 for degradation (n=1). Amplification of MCL1 was confirmed by FISH. In an independent cohort, 5/17 (29.4%) cases demonstrated MCL1 amplification by FISH. MCL1 protein expression, as evaluated by immunohistochemistry, was increased in 19/40 cases including the cases known to have MCL1 amplification. This study is the first genomic analysis of BL using FFPE tissue and demonstrates the feasibility of next generation sequencing of rare lymphomas using archival FFPE tissue. Our findings highlight the potential role of anti-apoptotic and chromatin remodeling genes in BL pathogenesis. Disclosures: Wang: Foundation Medicine: Employment, Equity Ownership. Cronin:Foundation Medicine: Employment, Equity Ownership. Palmer:Foundation Medicine: Employment, Equity Ownership. Yelensky:Foundation Medicine: Employment, Equity Ownership. Stephens:Foundation Medicine: Employment, Equity Ownership.

High Risk Myeloma Is Characterized By the Bi-Allelic Inactivation of CDKN2C and RB1

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4416-4416
Author(s):  
Shweta S. Chavan ◽  
Christoph Heuck ◽  
Jie He ◽  
Rusiana Tytarenko ◽  
Shayu Deshpande ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Prognostic Markers ◽  
Medical Sciences ◽  
Genomic Alterations ◽  
Employment Equity ◽  
Prognostic Effect ◽  
Equity Ownership ◽  
Gene Alterations

Abstract Introduction Gene expression and comprehensive genomic profiling (CGP) underscore the importance of multiple myeloma (MM) being driven by diverse genomic abnormalities and are increasingly being integrated into personalized treatment algorithms to optimize clinical outcomes, in particular that of high risk disease. Furthermore, CGP allow for ultra-deep sequencing of various clinically relevant and targetable genomic alterations using a single assay, with an advantage of detection of low frequency variants. Methods Samples from 578 patients (monoclonal gammopathy of undetermined significance, MGUS, (n=19); smoldering multiple myeloma, SMM, (n=42); or multiple myeloma, MM, (n=517; 87 newly diagnosed (NDMM), 107after treatment (TRMM), and 323 at relapse (RLMM)) were analyzed using the FoundationOne® Heme (F1H) assay. 50 ng of DNA and RNA from CD138+ selected cells were analyzed for genomic alterations including base substitutions, indels, copy number alterations, and rearrangements. Sequencing was performed to a median depth of 468x in 405 genes, as well as selected introns of 31 genes involved in rearrangements. Additionally, matched Gene Expression Profiling (GEP) was performed using Affymetrix U133 Plus 2 array, and GEP70-defined risk status and molecular subgroups were calculated. Results Results of the F1H assay revealed the most common alterations in MM to be: KRAS (28.8%), NRAS (23.2%), TP53 (17.4%), BRAF (6.8%), CDKN2C (6.0%), RB1 (5.8%), TRAF3 (5.8%), DNMT3A (3.9%), TET2 (3.7%) and ATM (2.5%), including mutations, homozygous loss and rearrangements. When these frequencies were split across GEP70 risk groups, TP53, CDKN2C/FAF1, RB1, and the t(4;14) were significantly different (p<0.05). As the disease progressed from MGUS to relapse, the number of mutations showed an increasing trend. Likewise, there were significant differences in the number of mutations between CCND1/CCND3 (CD-1) and low bone disease, CD-1 and hyperdiploid, and hyperdiploid and proliferation groups. In order to identify independent prognostic genomic alterations, we performed a multivariate Cox regression analysis on all the gene alterations that were present in at least 5% of the patient cohort, resulting in identification of four significant alterations: the t(4;14), mutation/loss of TP53, CDKN2C/FAF1 or RB1. Alterations in CDKN2C and RB1 were associated with the PR group. When the MM samples were split according to type (NDMM, TRMM, RLMM) the effect on survival of each of these alteration was more pronounced at relapse, but still present at diagnosis for CDKN2C and t(4;14). Bi-allelic events in CDKN2C, TP53 and RB1 were examined, by both homozygous deletion and monosomy with accompanying mutation, showing the rate of inactivation increased from 9.2% in NDMM to 17.9% at relapse, indicating that bi-allelic inactivation of these genes are correlated with relapse. CDKN2C and TP53 are known prognostic markers but the prognostic significance of RB1 has been debated. Previous data have shown that the association of t(4;14) with del(13q) results in insignificance of del(13q) as a prognostic marker in multivariate analyses. Here, we confirmed that the prognostic effect of RB1 is not due to association with t(4;14), and show that patients with either the t(4;14) or alteration of RB1 have a poor prognosis, which is worse when both lesions are present. Conclusions Using the F1H assay, we establish the mutational spectrum in MM, identifying lesions associated with high risk. This is the first study in MM to identify and confirm the poor prognostic effect of RB1 driven by bi-allelic inactivation, which is more prevalent at relapse. Furthermore, we determined the gene alterations that are independent prognostic markers in relapsed MM, thereby identifying novel therapeutic targets. Disclosures He: Foundation Medicine, Inc: Employment, Equity Ownership. Bailey:Foundation Medicine, Inc: Employment, Equity Ownership. Ashby:University of Arkansas for Medical Sciences: Employment. Zhong:foundation medicine: Employment. Nahas:Foundation medicine: Employment. Ali:Foundation Medicine: Employment, Equity Ownership. Vergillo:Foundation Medicine, Inc: Employment. Ross:Foundation Medicine, Inc: Employment. Miller:Foundation Medicine: Employment, Equity Ownership. Stephens:Foundation Medicine: Employment, Equity Ownership. Barlogie:Signal Genetics: Patents & Royalties. Mughal:Foundation Medicine: Employment, Equity Ownership. Davies:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Morgan:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment.

Cancer gene profile of metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1015-1015 ◽  
Author(s):  
Funda Meric-Bernstam ◽  
Garrett Frampton ◽  
Jaime Ferrer-Lozano ◽  
Roman Yelensky ◽  
Gary A. Palmer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Point Mutations ◽  
Metastatic Breast ◽  
Genomic Alteration ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Primary Tumors ◽  
Recurrent Tumors

1015 Background: There is great interest in using genomic information to guide therapy selection in cancer patients. The aim of this study was to determine the spectrum of genomic alterations identified in MBC patients, and evaluate the concordance of alterations between primary and recurrent tumors. Methods: We performed comprehensive profiling on formalin-fixed paraffin embedded samples from 42 patients with MBC using a targeted next generation sequencing (NGS) assay in a CLIA laboratory (Foundation Medicine). Genomic libraries were captured for 3,230 exons in 182 cancer related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to an average depth of 390X with 99% of bases covered >100X. In total 30 primary and 37 recurrent tumors were profiled, including 3 separate recurrences in 1 patient and matched primary-recurrences in 22 patients. Point mutations, indels, copy number alterations and rearrangements were assessed. Alterations that are targetable with established or investigational therapeutics were considered “actionable”. Results: At least 1 genomic alteration was identified in all but 2 breast samples (both primary tumors). Point mutations were identified in several cancer-related genes including PIK3CA, TP53, PTEN, CDH1, ARID1A, AKT1, NF1, FBXW7 and FGFR3. Amplification was observed in HER2; 11 of 12 HER2 IHC positive samples were found to have HER2 gains by NGS; in addition, a HER2 gain was identified by NGS in a HER2- (1+ IHC) sample. Amplification of PIK3CA, IGF1R, FGFR2, AKT2, MDM2, and MCL1 plus a CDKN2A homozygous deletion were also identified. While the majority of known driver alterations (85%) were concordant in the matched pairs of primary and recurrent tumors, in 11 of 22 sets there was at least 1 discordant driver alteration, and these included both gains and losses of potential therapeutic targets. Overall 32 of 42 patients (76%) had an actionable genomic alteration. Conclusions: Genomic profiling of breast cancer samples reveals genomic alterations in most metastatic breast cancer patients. Over three quarters of patients have actionable findings, suggesting that genomic profiling may assist in individualized pathway-directed therapy.

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