Genomic landscape of malignant phyllodes tumors reveals multiple targetable opportunities

Author:

Rosenberger Laura H12ORCID,Riedel Richard F23ORCID,Diego Emilia J4,Nash Amanda L1,Grilley-Olson Juneko E23,Danziger Natalie A5,Sokol Ethan S5,Ross Jeffrey S56,Sammons Sarah L789

Affiliation:

1. Department of Surgery, Duke University Medical Center , Durham, NC 27710 , United States

2. Duke Cancer Institute, Duke University , Durham, NC 27710 , United States

3. Department of Medicine, Duke University Medical Center , Durham, NC 27710 , United States

4. Department of Surgery, University of Pittsburgh Medical Center , Pittsburgh, PA 15213 , United States

5. Foundation Medicine, Inc. , Cambridge, MA 02141 , United States

6. Department of Pathology, Urology, and Oncology, Upstate Medical University , Syracuse, NY 13210 , United States

7. Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School , Boston, MA 02215 , United States

8. Breast Oncology Program, Dana-Farber Brigham Cancer Center , Boston, MA 02215 , United States

9. Harvard Medical School , Boston, MA 02115 , United States

Abstract

Abstract Background Malignant phyllodes tumors (MPT) are rare fibroepithelial breast cancers with no known effective systemic therapy; metastatic progression portends a dismal prognosis. We sought to describe the genomic landscape of MPTs through genomic profiling and immunotherapeutic biomarker analysis. Materials and methods Cases of sequenced MPT were identified from a Clinical Laboratory Improvement Amendments-certified, College of American Pathologists-accredited laboratory (Foundation Medicine). All cases underwent genomic profiling using adaptor ligation-based, next-generation sequencing assay of 324 genes. Tumor agnostic immunotherapy biomarkers, microsatellite instability, tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression were evaluated. Fisher’s Exact Tests and analysis of variance were used to test for differences between groups and for continuous variables as appropriate. Results Of 135 MPT cases identified; 94 (69.6%) were localized/locally recurrent and 41 (30.4%) were metastatic. Median age was 54 years (range 14-86). The median TMB was 2.5 mut/Mb and 3 were TMB-high (≥10 mut/Mb). 21.4% were PD-L1+ via Dako 22C3 assay (CPS ≥1). Most commonly altered genes included TERT-promoter (69.7%), CDKN2A (45.9%), TP53 (37.8%), NF1 (35.6%), CDKN2B (33.3%), MED12 (28.9%), MTAP (27.7%), KMT2D (22.2%), PIK3CA (20.0%), PTEN (18.5%), and RB1 (18.5%). Several tumors harboring genomic alterations with US Food and Drug Administration-approved indications in other tumor types were found including NF1, PIK3CA, EGFR Exon 19/20 insertions, and BRAF V600E mutations. Conclusions In the largest genomic evaluation of MPT to date, multiple clinically actionable mutations were found. Routine sequencing of metastatic MPT may provide additional information to guide treatment decisions and clinical trial enrollment.

Publisher

Oxford University Press (OUP)

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