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Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors
Erin F Cobain1, Yi-Mi Wu2,3, Pankaj Vats2
1Department of Internal Medicine, University of Michigan, Ann Arbor.
Importance:
Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain.
Objective:
To determine which patients derived the greatest degree of clinical benefit from NGS profiling.
Design, Setting, And Participants:
Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020.
Main Outcomes And Measures:
Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer.
Results:
During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses.
Conclusions And Relevance:
The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.
Insights
Next-generation sequencing (NGS) identified actionable genomic alterations in 80.5% of advanced cancer patients. NGS-directed therapy benefited 37.1%, with 19.7% achieving exceptional responses, supporting its role in cancer care.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Next-generation sequencing (NGS) is increasingly used for advanced solid tumors, but its clinical utility needs further evaluation.
- Identifying actionable genomic targets is crucial for personalized cancer treatment.
Purpose of the Study:
- To determine which patients benefit most from next-generation sequencing (NGS) profiling.
- To assess the clinical utility of comprehensive genomic profiling in advanced cancers.
Main Methods:
- Whole-exome or targeted-exome capture and RNA sequencing of tumor and normal DNA from 1015 patients.
- Annotation and classification of somatic and germline genomic alterations for clinical actionability.
- Tracking of subsequent therapy and treatment response to determine clinical benefit rates.
Main Results:
- Actionable genomic alterations were found in 80.5% of patients; 16.2% received NGS-directed therapy, with 37.1% achieving clinical benefit.
- Exceptional responses (≥12 months) were observed in 19.7% of treated patients.
- Therapeutically relevant pathogenic germline variants (PGVs) were identified in 15.8% of patients, supporting germline testing.
Conclusions:
- Comprehensive NGS profiling is valuable for advanced cancers, especially rare types and carcinoma of unknown primary.
- High rates of actionable somatic and germline alterations support NGS as a standard care component.
- Directed germline testing is recommended for all advanced cancer patients due to high PGV detection rates.
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