scholarly journals Complexities of Next-Generation Sequencing in Solid Tumors: Case Studies

2020 ◽  
Vol 18 (9) ◽  
pp. 1150-1155
Author(s):  
Alexandra O. Sokolova ◽  
Brian H. Shirts ◽  
Eric Q. Konnick ◽  
Ginger J. Tsai ◽  
Bernardo H.L. Goulart ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Case Studies ◽  
Checkpoint Inhibitors ◽  
Hereditary Cancer Syndrome ◽  
Next Generation ◽  
Cancer Syndrome ◽  
Expert Review ◽  
Tumor Boards ◽  
Tumor Sequencing ◽  
Generation Sequencing

With the promise and potential of clinical next-generation sequencing for tumor and germline testing to impact treatment and outcomes of patients with cancer, there are also risks of oversimplification, misinterpretation, and missed opportunities. These issues risk limiting clinical benefit and, at worst, perpetuating false conclusions that could lead to inappropriate treatment selection, avoidable toxicity, and harm to patients. This report presents 5 case studies illustrating challenges and opportunities in clinical next-generation sequencing interpretation and clinical application in solid tumor oncologic care. First is a case that dissects the origin of an ATM mutation as originating from a hematopoietic clone rather than the tumor. Second is a case illustrating the potential for tumor sequencing to suggest germline variants associated with a hereditary cancer syndrome. Third are 2 cases showing the potential for variant reclassification of a germline variant of uncertain significance when considered alongside family history and tumor sequencing results. Finally, we describe a case illustrating challenges with using microsatellite instability for predicting tumor response to immune checkpoint inhibitors. The common theme of the case studies is the importance of examining clinical context alongside expert review and interpretation, which together highlight an expanding role for contextual examination and multidisciplinary expert review through molecular tumor boards.

Genetic counseling referrals after next generation sequencing testing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1515-1515
Author(s):  
Rafael Gonzalez ◽  
Emma Ryan ◽  
Catherine Watson ◽  
Gloria Broadwater ◽  
Noah D. Kauff ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Next Generation Sequencing ◽  
Hereditary Cancer ◽  
Germline Mutations ◽  
Tumor Board ◽  
Hereditary Cancer Syndrome ◽  
Next Generation ◽  
Cancer Syndrome ◽  
Generation Sequencing ◽  
Germline Testing

1515 Background: Next generation sequencing (NGS) testing of tumor tissue or blood is performed to identify ‘actionable’ mutations that might guide patient care. NGS testing might incidentally identify germline mutations associated with cancer syndromes. No distinction is made between germline and somatic alterations on NGS reports, thus confirmatory germline testing is required. In this quality improvement (QI) initiative, we evaluated the frequency of referrals to genetic counseling (GC) for patients with potentially heritable germline mutations identified through NGS testing. Methods: We generated a list of high-risk mutations (HRMs) which merit GC referral based on NCCN guidelines. NGS test results for 3,400 consecutive patients with solid tumor malignancies were reviewed by the molecular tumor board from 1/2014-9/2019 and were screened for pathogenic HRMs. Basic demographic, oncologic, and GC data were retrospectively abstracted for each patient. The outcomes of interest were the frequency of HRMs identified through NGS testing, the proportion of patients subsequently referred to GC, and the proportion of patients ultimately diagnosed with a hereditary cancer syndrome. Results: 472 individual patients (14%) had NGS testing with one or more HRM identified; 465 patients were evaluable which corresponded to 519 HRMs that were included in the analysis (Table). Malignancies included were gastrointestinal 199 (42.8%), lung 83 (17.8%), genitourinary/renal 56 (12.0%), breast 49 (10.5%), gynecologic 35 (7.5%), and other 43 (9.2%). 75 (16.1%) patients had germline testing prior to NGS testing. Of those patients without prior germline genetic testing, 62 (15.9%) were referred to GC, and 19 (4.9%) patients were diagnosed with a hereditary cancer syndrome. Conclusions: Tumor NGS testing identifies HRMs that may represent an undiagnosed heritable germline mutation. Providers ordering NGS tests should review results for HRMs, refer to GC when appropriate, and offer confirmatory germline testing for patients and their families. [Table: see text]

scholarly journals Design and validation of a next generation sequencing assay for hereditaryBRCA1andBRCA2mutation testing

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2162 ◽  
Author(s):  
Hyunseok P. Kang ◽  
Jared R. Maguire ◽  
Clement S. Chu ◽  
Imran S. Haque ◽  
Henry Lai ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number Variants ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Cancer Syndrome ◽  
Cancer Screen ◽  
Inherited Cancer ◽  
Increased Risk ◽  
Large Rearrangements ◽  
Generation Sequencing

Hereditary breast and ovarian cancer syndrome, caused by a germline pathogenic variant in theBRCA1orBRCA2(BRCA1/2) genes, is characterized by an increased risk for breast, ovarian, pancreatic and other cancers. Identification of those who have aBRCA1/2mutation is important so that they can take advantage of genetic counseling, screening, and potentially life-saving prevention strategies. We describe the design and analytic validation of the Counsyl Inherited Cancer Screen, a next-generation-sequencing-based test to detect pathogenic variation in theBRCA1andBRCA2genes. We demonstrate that the test is capable of detecting single-nucleotide variants (SNVs), short insertions and deletions (indels), and copy-number variants (CNVs, also known as large rearrangements) with zero errors over a 114-sample validation set consisting of samples from cell lines and deidentified patient samples, including 36 samples withBRCA1/2pathogenic germline mutations.

scholarly journals Next-Generation Sequencing in Order to Better Characterize a BRCA Variant of Uncertain Significance

2017 ◽  
Vol 10 (2) ◽  
pp. 634-637 ◽  
Author(s):  
Steven Sorscher ◽  
Shakti Ramkissoon
Keyword(s):  
Next Generation Sequencing ◽  
Germline Mutations ◽  
Allelic Frequency ◽  
Breast Cancers ◽  
Next Generation ◽  
Cancer Syndrome ◽  
Predisposing Factor ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Generation Sequencing

BRCA germline mutations are the most common predisposing factor in familial breast-ovarian cancer syndrome families. However, many screened patients are identified as harboring BRCA variants of uncertain significance (VUS), rather than carrying deleterious germline mutations [Calo et al.: Cancers 2010; 2:1644–1660]. While such VUSs are typically reclassified as benign polymorphisms, this may occur years after the VUS is first identified [Murray et al.: Genet Med 2011; 13; 998–1005]. Loss of heterozygosity (LOH) of BRCA is nearly always the gatekeeper event in inherited BRCA-related breast cancer and LOH of BRCA is rare in sporadic cancers [Osorio et al.: Int J Cancer 2002; 99:305–309]. Here, we describe a patient identified as carrying a germline BRCA VUS. Tumor next-generation sequencing (NGS) demonstrated a very high mutation allelic frequency for that BRCA VUS, consistent with LOH. This case illustrates that since BRCA LOH is the typical mechanism of transformation in inherited BRCA-related breast cancers, NGS might be used to suggest that the BRCA VUS is actually cancer predisposing in a particular family. As a result, this may help patients make more informed decisions regarding screening and prophylactic therapy, long before official reclassification of the VUS occurs.

Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 500-500 ◽  
Author(s):  
Jianzhen Lin ◽  
Weiwei Shi ◽  
Songhui Zhao ◽  
Jinwei Hu ◽  
Zheng Hou ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Checkpoint Inhibitors ◽  
Clinical Stage ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Cancer Genes ◽  
Next Generation ◽  
Multikinase Inhibitor ◽  
Generation Sequencing

500 Background: Lenvatinib (Len) is a multikinase inhibitor targeting VEGFR 1-3, FGFR 1-4 and other kinases. Pembrolizumab (Pem) and nivolumab (Nivo) are antibodies inhibiting programmed cell death 1 (PD-1) and reactivate T-cell cytotoxic effect. Len plus PD-1 inhibitors have shown promising results in treating various solid tumors. The role of this combination in ICC is undefined. Methods: 14 ICC pts (median age 49 years, range 34-68; 7 males and 7 females) with treatment of enrolled in a single center, observational study of Len plus Pem/Nivo. Objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were measured according to RECIST 1.1. Next generation sequencing (NGS) with deep coverage on 450 cancer genes and whole exome sequencing were performed in 7 pts to detect all classes of genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Results: All 14 pts had > = 2 prior anticancer therapy with clinical stage IV. ORR was 21.4% with 3 pts achieved partial response (PR), DCR was 92.9% and clinical benefit rate (ORR + durable stable disease > = 5 months) was 64.3%. Median PFS was 5.9 months (95% CI: 4.2-6.2). The most common adverse events (AEs) included hypertension, aminotransferase elevation and fatigue. The grade-3 AEs were occurred at 14% while no grade-4 AE was observed. The most altered genes in the 7 sequenced tumors were IDH1 (3 pts), ARID1A (3 pts), PIK3CA (3 pts), TP53 (2 pts) and BAP1 (2 pts). 4 out of the 7 pts had high TMB ( > 12 mut/Mb) and all responded to Len plus Pem/Nivo with 2 PR. One pt with low TMB and FGFR2 mutation had a response of 27% decreased target lesion. Two low TMB pts were progressed, including one with FGFR2 rearrangement. A responder harbored a 399 bp deletion on MLH1, and was identified as MSI-H. More data will be presented. Conclusions: Our study preliminarily indicates that combining Len with PD-1 inhibitors results in promising efficacy in advanced ICC. High TMB from 450-gene NGS panel was strongly associated with a better therapeutic response.

scholarly journals Design and validation of a next generation sequencing assay for hereditary breast and ovarian cancer

2015 ◽  
Author(s):  
Hyunseok P. Kang ◽  
Jared R Maguire ◽  
Clement S Chu ◽  
Imran S. Haque ◽  
Henry Lai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Next Generation Sequencing ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Cancer Syndrome ◽  
Breast And Ovarian Cancer ◽  
Cancer Screen ◽  
Inherited Cancer ◽  
Increased Risk ◽  
Generation Sequencing

Hereditary breast and ovarian cancer syndrome, caused by a germline deleterious variant in the BRCA1 or BRCA2 genes, is characterized by an increased risk for breast, ovarian, pancreatic and other cancers. Identification of those who have a BRCA1/2 mutation is important so that they can take advantage of genetic counseling, screening, and potentially life-saving prevention strategies. We describe the design and analytic validation of the Counsyl Inherited Cancer Screen, a next-generation-sequencing-based test to detect pathogenic variation in the BRCA1 and BRCA2 genes. We demonstrate that the test is capable of detecting single-nucleotide variants (SNVs), short insertions and deletions (indels), and copy-number variants (CNVs, also known as large rearrangements) with zero errors over a 96-sample validation set consisting of samples from cell lines and deidentified patient samples, including the well-characterized NA12878 sample from HapMap/1000 Genomes.

scholarly journals Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Jeffrey M. Conroy ◽  
Sarabjot Pabla ◽  
Mary K. Nesline ◽  
Sean T. Glenn ◽  
Antonios Papanicolau-Sengos ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Next Generation ◽  
Generation Sequencing

scholarly journals Real-World Data of Off-Label Drug Use in Patients with Actionable Genomic Alterations on Next-Generation Sequencing

2021 ◽  
Author(s):  
Gabriel Roman Souza ◽  
Ahmed Abdalla ◽  
Sukeshi Patel Arora ◽  
Daruka Mahadevan
Keyword(s):  
Next Generation Sequencing ◽  
Stable Disease ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Study Endpoint ◽  
Primary Study ◽  
Next Generation ◽  
Off Label ◽  
Generation Sequencing

Abstract We analyzed the outcomes of patients in our institution treated with off-label drugs targeting actionable genomic alteration based on next-generation sequencing when clinical trials were not available. Our study endpoint was objective tumor response or stable disease at 16 weeks or later after treatment initiation. Sixteen patients were included in this study, 8 were treated with immune checkpoint inhibitors targeting PD-L1 or TP53 mutations and 8 with other drugs. Tumors were analyzed based on PD-L1 expression, TP53 mutation, MSI, TMB, MMR status, and other targetable alterations. Of the 16 patients in the intention-to-treat group, no patients had an objective response after 16 weeks. Eleven patients met the primary study endpoint with stable disease, 8 in the immune checkpoint inhibitors group and 3 in the non-immune checkpoint inhibitors group. Using the log-rank test, the p-value for the difference between groups was 0.008. In this study with off-label drugs, immune checkpoint inhibitors targeting TP53 mutations or PD-L1 expression were superior to the other drugs. This suggests the possibility of off-label use of anti-cancer drugs based on next-generation sequencing to be beneficial for advanced cancer patients without other therapeutic options.

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