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Updated: Mar 7, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Comprehensive genomic profiling of malignant phyllodes tumors of the breast
Sahar Nozad1, Christine E Sheehan1, Laurie M Gay2
1Albany Medical College, Albany, NY, USA.
Purpose:
Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease.
Methods:
DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions.
Results:
The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549-BRAF or FGFR3-TACC3 were identified in 2/24 (8.3%) tumors.
Conclusions:
This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.
Insights
Malignant phyllodes tumors (MPTs) are rare, but this study identified key genomic alterations like TP53 and TERT-promoter mutations. These findings may guide new targeted therapies for MPT patients, including those with advanced disease.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Malignant phyllodes tumors (MPTs) are rare neoplasms with poorly understood genomic drivers.
- Identifying these drivers is crucial for developing targeted therapies, especially for advanced or refractory cases.
Purpose of the Study:
- To perform comprehensive genomic profiling (CGP) on MPTs.
- To identify actionable genomic alterations for targeted therapy development in MPT patients.
Main Methods:
- DNA from 24 MPT cases underwent CGP using next-generation sequencing.
- Analysis included short variants, rearrangements, copy number changes, and tumor mutational burden (TMB).
Main Results:
- TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), and MED12 (45.8%) were the most frequently mutated genes.
- Microsatellite stable in all evaluable cases; median TMB was 2.7 mut/Mb.
- Targetable kinase fusions were found in 8.3% of tumors.
Conclusions:
- This study reveals clinically relevant genomic alterations in MPT.
- These findings support novel targeted therapy strategies for MPT patients.
