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Updated: Jan 4, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Integration of Comprehensive Genomic Analysis and Functional Screening of Affected Molecular Pathways to Inform
George Vasmatzis1, Minetta C Liu2, Sowjanya Reganti3
1Molecular Medicine and Biomarker Discovery Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN.
Objective:
To select optimal therapies based on the detection of actionable genomic alterations in tumor samples is a major challenge in precision medicine.
Methods:
We describe an effective process (opened December 1, 2017) that combines comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensiona ex vivo models for drug screening to assess response to therapeutic agents targeting specific genomic alterations. The process was applied to a patient with widely metastatic, weakly hormone receptor positive, HER2 nonamplified, infiltrating lobular breast cancer refractory to standard therapy.
Results:
Clinical testing of liver metastasis identified BRIP1, NF1, CDH1, RB1, and TP53 mutations pointing to potential therapies including PARP, MEK/RAF, and CDK inhibitors. The comprehensive genomic analysis identified 395 mutations and several structural rearrangements that resulted in loss of function of 36 genes. Meta-analysis revealed biallelic inactivation of TP53, CDH1, FOXA1, and NIN, whereas only one allele of NF1 and BRIP1 was mutated. A novel ERBB2 somatic mutation of undetermined significance (P702L), high expression of both mutated and wild-type ERBB2 transcripts, high expression of ERBB3, and a LITAF-BCAR4 fusion resulting in BCAR4 overexpression pointed toward ERBB-related therapies. Ex vivo analysis validated the ERBB-related therapies and invalidated therapies targeting mutations in BRIP1 and NF1. Systemic patient therapy with afatinib, a HER1/HER2/HER4 small molecule inhibitor, resulted in a near complete radiographic response by 3 months.
Conclusion:
Unlike clinical testing, the combination of tumor profiling, data integration, and functional validation accurately assessed driver alterations and predicted effective treatment.
Insights
This study presents a novel precision medicine approach combining genomic profiling and ex vivo drug screening to identify effective cancer therapies. The integrated method accurately predicted a patient's response to targeted treatment, leading to a significant clinical improvement.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Precision medicine aims to tailor treatments based on individual tumor molecular profiles.
- Identifying actionable genomic alterations remains a challenge in selecting optimal therapies.
- Current methods often struggle to accurately predict treatment response.
Observation:
- A patient with metastatic lobular breast cancer refractory to standard therapy underwent comprehensive genomic and transcriptomic profiling.
- Analysis revealed multiple mutations and gene fusions, including a novel ERBB2 mutation and BCAR4 overexpression.
- Preclinical ex vivo drug screening was used to validate potential targeted therapies.
Findings:
- The integrated approach identified ERBB-related therapies as most promising, while invalidating therapies targeting BRIP1 and NF1 mutations.
- The patient received afatinib, a HER1/HER2/HER4 inhibitor, resulting in a near complete radiographic response within 3 months.
- This highlights the effectiveness of combining multi-omic profiling with functional validation.
Implications:
- This integrated strategy accurately assesses driver alterations and predicts effective treatments, outperforming traditional clinical testing.
- It offers a powerful framework for advancing precision medicine in oncology.
- This approach has the potential to improve patient outcomes by enabling more targeted and effective cancer therapies.
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