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Published on: July 25, 2020
Genomic Landscape of Malignant Phyllodes Tumors Identifies Subsets for Targeted Therapy
Rani Bansal1, Tolulope Adeyelu2, Andrew Elliott2
1Duke Cancer Institute, Duke University Hospital, Durham, NC.
Purpose:
Malignant phyllodes tumors (MPTs) are rare fibroepithelial tumors of the breast with aggressive biologic behavior and high recurrence rates. Surgery remains the primary treatment modality for these tumors; however, initial investigations suggest a potential for targeted therapies in managing this disease. Therefore, we aimed to assess the molecular landscape of MPTs to reveal possible treatment opportunities.
Methods:
MPTs (n = 57) from primary and metastatic sites underwent genomic sequencing (592-gene panel or whole exome), whole-transcriptome sequencing, and immunohistochemistry (PD-L1, human epidermal growth factor receptor 2 [HER2]) at Caris Life Sciences (Phoenix, AZ). Immune cell fractions in the tumor microenvironment were estimated using quanTIseq. Mann-Whitney U, chi-square, and Fisher's exact tests were used to determine significance (P < .05).
Results:
MPTs had low ERBB2 expression, comparable with the HER2-negative subset of a large cohort of breast adenocarcinoma samples (N = 9,926). Frequent alterations included TERT promoter; MED12, TP53, and NF1 mutations; and less frequently EGFR, PIK3CA, and BRAF. Differences in mutation prevalences were observed between primary sites, lung metastases, and nonlung metastases. One MPT specimen harbored a pathogenic TPM4:NTRK1 fusion, and treatment with larotrectinib for over 16 months suggested a clinical response to therapy. PD-L1+ status was observed in 15.2% of MPTs overall, with similar prevalence in primary sites and lung metastases. B cells, M2 macrophages, neutrophils, and natural killer cells had the highest median cell fractions in MPTs.
Conclusion:
Considering the occurrence of several actionable alterations including a TPM4:NTRK1 fusion reported herein, these results support the use of next-generation sequencing (NGS) including RNA analysis for fusion detection to identify such alterations in patients with MPTs. These findings highlight the importance of comprehensive NGS in MPT research to uncover potential targeted treatment options for these patients.
Insights
Malignant phyllodes tumors (MPTs) harbor actionable molecular alterations, including a TPM4:NTRK1 fusion, suggesting targeted therapies may benefit patients. Comprehensive next-generation sequencing (NGS) is crucial for identifying these opportunities.
Area of Science:
- Oncology
- Genomics
- Molecular Pathology
Background:
- Malignant phyllodes tumors (MPTs) are rare breast cancers with aggressive behavior and high recurrence rates.
- Current treatment relies on surgery, but targeted therapies show promise.
- Understanding the molecular landscape of MPTs is essential for identifying new treatment strategies.
Purpose of the Study:
- To investigate the molecular characteristics of MPTs.
- To identify potential therapeutic targets for MPT management.
- To explore differences in molecular profiles between primary and metastatic sites.
Main Methods:
- Genomic and whole-transcriptome sequencing were performed on 57 MPT samples.
- Immunohistochemistry for PD-L1 and HER2 was conducted.
- Immune cell fractions in the tumor microenvironment were analyzed using quanTIseq.
Main Results:
- MPTs showed low ERBB2 expression, similar to HER2-negative breast cancer.
- Frequent alterations included TERT promoter, MED12, TP53, and NF1 mutations.
- A TPM4:NTRK1 fusion was identified, leading to a clinical response with larotrectinib.
Conclusions:
- The study identified actionable molecular alterations in MPTs, including a TPM4:NTRK1 fusion.
- Comprehensive next-generation sequencing (NGS) with RNA analysis is recommended for MPTs.
- These findings support the development of targeted therapies for MPT patients.
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