title: Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.
abstract: Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.
authors.affiliation: Caris Life Sciences, Phoenix, AZ, United States of America.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.affiliation: Department of Pathology, University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: Semir
authors.initials: S
authors.lastname: Vranic
authors.affiliation: Caris Life Sciences, Phoenix, AZ, United States of America.
authors.forename: Anatole
authors.initials: A
authors.lastname: Ghazalpour
authors.affiliation: Caris Life Sciences, Phoenix, AZ, United States of America.
authors.forename: Joanne
authors.initials: J
authors.lastname: Xiu
authors.affiliation: Mayo Clinic, Scottsdale, AZ, United States of America.
authors.forename: Idris Tolgay
authors.initials: IT
authors.lastname: Ocal
authors.affiliation: Miraca Life Sciences, Phoenix, AZ, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: McGill
authors.affiliation: Caris Life Sciences, Phoenix, AZ, United States of America.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Bender
authors.affiliation: Caris Life Sciences, Phoenix, AZ, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Discianno
authors.affiliation: Caris Life Sciences, Phoenix, AZ, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schlum
authors.affiliation: Division of Anatomic and Molecular Pathology, Washington University School of Medicine, Saint Louis, MO, United States of America.
authors.forename: Souzan
authors.initials: S
authors.lastname: Sanati
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Philadelphia, PA, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Palazzo
authors.affiliation: Caris Life Sciences, Phoenix, AZ, United States of America.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Mayo Clinic, Scottsdale, AZ, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pockaj
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D003557:Phyllodes Tumor / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors
keywords: biomarkers; breast; fibroepithelial tumors; malignant phyllodes tumor; molecular profiling