Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing

Schrock, Alexa B.; Frampton, Garrett M.; Herndon, Dana; Greenbowe, Joel; Wang, Kai; Lipson, Doron; Yelensky, Roman; Chalmers, Zachary R.; Chmielecki, Juliann; Elvin, Julia A.; Wollner, Mira; Dvir, Addie; Gutman, Lior Soussan; Bordoni, Rodolfo; Peled, Nir; Braiteh, Fadi; Raez, Luis E.; Erlich, Rachel; Ou, Sai‐Hong Ignatius; Mohamed, Mohamed; Ross, Jeffrey S.; Stephens, Philip J.; Ali, Siraj M.; Miller, Vincent A.

doi:10.1158/1078-0432.ccr-15-1668

Cited by 34 publications

(29 citation statements)

References 17 publications

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“…For case 15, SOC testing was negative on a bone biopsy, which may be attributable to the use of strong acids in decalcification prior to molecular testing. Assuming a sensitivity of 80% for both EGFR pm as seen in our results as well as EGFR exon 19 deletions as seen in the previous study , the negative predictive value of SOC EGFR testing ranges from 83% to 98% depending on the true prevalence of EGFR GA in various patient populations segmented by gender, ethnicity, and smoking history (negative predictive value (NPV) of 83% for 50% prevalence versus NPV of 98% for 10% prevalence). Based on these results, molecular test reports should specify the exact methodologies used so that physicians and patients are aware of technical limitations that may impact clinical management and outcomes, especially in populations known to harbor more frequent EGFR GA.…”

Section: Discussionmentioning

confidence: 99%

Hybrid Capture-Based Comprehensive Genomic Profiling Identifies Lung Cancer Patients with Well-Characterized Sensitizing Epidermal Growth Factor Receptor Point Mutations That Were Not Detected by Standard of Care Testing

Suh¹,

Schrock²,

Johnson³

et al. 2018

The Oncologist

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This study points out that genomic profiling, as based on hybrid capture next-generation sequencing, can identify lung cancer patients with point mutation in epidermal growth factor receptor (EGFR) missed by standard molecular testing who can likely benefit from anti-EGFR targeted therapy. Beyond the specific findings regarding false-negative point mutation testing for EGFR, this study highlights the need for oncologists and pathologists to be cognizant of the performance characteristics of testing deployed and the importance of clinical intuition in questioning the results of laboratory testing.

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Section: Discussionmentioning

confidence: 99%

Hybrid Capture-Based Comprehensive Genomic Profiling Identifies Lung Cancer Patients with Well-Characterized Sensitizing Epidermal Growth Factor Receptor Point Mutations That Were Not Detected by Standard of Care Testing

Suh¹,

Schrock²,

Johnson³

et al. 2018

The Oncologist

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“…Recent publications have suggested a broad spectrum of genomic changes in clinically relevant targets (29,(36)(37)(38), and expanded analyses are warranted to identify more patients predicted to be sensitive or resistant to targeted therapies. Furthermore, the identification of drug sensitivity and resistance biomarkers across multiple indications suggests that targeted agents may have broader utility beyond that for which they were approved originally.…”

Section: Spectrum Of Known Clinically Relevant Alterations Across Dismentioning

confidence: 99%

“…6E). The diversity of these mutations has implications for robust diagnostic detection and developing drugs to target this heterogeneous set of insertions (37).…”

Section: Spectrum Of Known Clinically Relevant Alterations Across Dismentioning

confidence: 99%

High-Throughput Genomic Profiling of Adult Solid Tumors Reveals Novel Insights into Cancer Pathogenesis

Hartmaier¹,

Albacker²,

Chmielecki³

et al. 2017

Cancer Research

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115

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Genomic profiling is widely predicted to become a standard of care in clinical oncology, but more effective data sharing to accelerate progress in precision medicine will be required. Here, we describe cancer-associated genomic profiles from 18,004 unique adult cancers. The dataset was composed of 162 tumor subtypes including multiple rare and uncommon tumors. Comparison of alteration frequencies to The Cancer Genome Atlas identified some differences and suggested an enrichment of treatment-refractory samples in breast and lung cancer cohorts. To illustrate novelty within the dataset, we surveyed the genomic landscape of rare diseases and identified an increased frequency of NOTCH1 alterations in adenoid cystic carcinomas compared with previous studies. Analysis of tumor suppressor gene patterns revealed disease specificity for certain genes but broad inactivation of others. We identified multiple potentially druggable, novel and known kinase fusions in diseases beyond those in which they are currently recognized. Analysis of variants of unknown significance identified an enrichment of SMAD4 alterations in colon cancer and other rare alterations predicted to have functional impact. Analysis of established, clinically relevant alterations highlighted the spectrum of molecular changes for which testing is currently recommended, as well as opportunities for expansion of indications for use of approved targeted therapies. Overall, this dataset presents a new resource with which to investigate rare alterations and diseases, validate clinical relevance, and identify novel therapeutic targets. Cancer Res; 77(9); 2464–75. ©2017 AACR.

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“…For such therapies to be optimally delivered, there is an inherent mandate for specific and sensitive clinical testing to detect BRAF mutations. Two recent studies demonstrate that CGP applied in the course of clinical care can identify genomic alterations that guide targeted therapy for patients with advanced non‐small cell lung cancer who have been previously tested "negative" by standard‐of‐care molecular testing.…”

Section: Discussionmentioning

confidence: 99%

Hybrid Capture-Based Genomic Profiling Identifies BRAF V600 and Non-V600 Alterations in Melanoma Samples Negative by Prior Testing

Boussemart

Nelson²,

Wong

et al. 2019

The Oncologist

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Background BRAF and MEK inhibitors are approved for BRAF V600‐mutated advanced melanoma, with response rates of up to 70%. Responses to targeted therapies have also been observed for diverse non‐V600 BRAF alterations. Thus, sensitive, accurate, and broad detection of BRAF alterations is critical to match patients with available targeted therapies. Materials and Methods Pathology reports were reviewed for 385 consecutive melanoma cases with BRAF mutations or rearrangements identified using a hybrid capture‐based next‐generation sequencing comprehensive genomic profiling (CGP) assay during the course of clinical care. Results Records of prior BRAF molecular testing were available for 79 (21%) cases. Of cases with BRAF V600 mutations, 11/57 (19%) with available data were negative by prior BRAF testing. Prior negative BRAF results were also identified in 16/20 (80%) cases with non‐V600 mutations, 2 of which harbored multiple BRAF alterations, and in 2/2 (100%) cases with activating BRAF fusions. Clinical outcomes for a subset of patients are presented. Conclusion CGP identifies diverse activating BRAF alterations in a significant fraction of cases with prior negative testing. Given the proven clinical benefit of BRAF/MEK inhibitors in BRAF‐mutated melanoma, CGP should be considered for patients with metastatic melanoma, particularly if other testing is negative. Implications for Practice Published guidelines for melanoma treatment recommend BRAF mutational analysis, but little guidance is provided as to selection criteria for testing methodologies, or as to clinical implications for non‐V600 alterations. This study found that hybrid capture‐based next‐generation sequencing can detect BRAF alterations in samples from a significant fraction of patients with advanced melanoma with prior negative BRAF results. This study highlights the need for oncologists and pathologists to be critically aware of coverage and sensitivity limitations of various assays, particularly regarding non‐V600E alterations, of which many are potentially targetable.

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Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing

Cited by 34 publications

References 17 publications

Hybrid Capture-Based Comprehensive Genomic Profiling Identifies Lung Cancer Patients with Well-Characterized Sensitizing Epidermal Growth Factor Receptor Point Mutations That Were Not Detected by Standard of Care Testing

Hybrid Capture-Based Comprehensive Genomic Profiling Identifies Lung Cancer Patients with Well-Characterized Sensitizing Epidermal Growth Factor Receptor Point Mutations That Were Not Detected by Standard of Care Testing

High-Throughput Genomic Profiling of Adult Solid Tumors Reveals Novel Insights into Cancer Pathogenesis

Hybrid Capture-Based Genomic Profiling Identifies BRAF V600 and Non-V600 Alterations in Melanoma Samples Negative by Prior Testing

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