11: Genomic Landscape of Malignant Phyllodes Tumors Reveals Multiple Targetable Opportunities

Friday, March 24, 2023

5:41 PM – 5:51 PM

Location: Veterans Memorial Auditorium

Abstract Presenter(s)

Laura H. Rosenberger, MD, MS (she/her/hers)

Associate Professor of Surgery
Duke University Medical Center
Durham, North Carolina, United States

Disclosure(s): No financial relationships to disclose

Author(s)

Laura H. Rosenberger, MD, MS (she/her/hers)

Associate Professor of Surgery
Duke University Medical Center
Durham, North Carolina, United States

Disclosure(s): No financial relationships to disclose
RR

Richard F. Riedel, MD

Associate Professor of Medicine
Duke Univesity Medical Center, United States

Disclosure information not submitted.
Emilia Diego, MD

Chief, Section of Breast Surgery
University of Pittsburgh
Pittsburgh, PA, United States

Disclosure information not submitted.
ND

Natalie A. Danziger, BS

Senior Research Associate
Foundation Medicine Inc, United States

Disclosure information not submitted.
ES

Ethan Sokol, PhD

Principal Scientist
Foundation Medicine Inc, United States

Disclosure information not submitted.
JR

Jeffrey S. Ross, MD

Medical Director, Foundation Medicine
Foundation Medicine Inc, United States

Disclosure information not submitted.
SS

Sarah L. Sammons, MD

Assistant Professor of Medicine
Duke University, United States

Disclosure information not submitted.

Disclosure(s):

Laura H. Rosenberger, MD, MS: No financial relationships to disclose

Introduction: Malignant phyllodes tumors (MPT) are rare fibroepithelial breast tumors that disproportionately affect young women. Despite high recurrence rates, treatment is almost exclusively surgical. With no known effective systemic therapy, metastatic progression portends dismal prognosis. Guidelines do not recommend biomarker testing in the non-metastatic setting. We sought to describe the genomic landscape of MPTs through comprehensive genomic profiling (CGP) and immunotherapeutic biomarker analysis.

Methods: Cases of sequenced MPT were identified from a CLIA-certified, CAP-accredited lab database (Foundation Medicine, Cambridge, MA), and categorized as localized/locally recurrent or metastatic. All cases underwent CGP, and all classes of genomic alterations, microsatellite instability (MSI), and tumor mutational burden (TMB) were evaluated. PD-L1 expression by IHC was measured by the DAKO 22C3 assay (scored CPS) or the Ventana SP142 assay (scored as IC). Results of CGP of MPT were summarized and compared to all cases of breast carcinoma using Fisher’s Exact Tests and analysis of variance, as appropriate.

Results: Of 135 MPT cases; 94 (69.6%) were localized/locally recurrent and 41 (30.4%) were metastatic (73% lung). Median age was 54 years (range 14-86), the median TMB across samples was 2.5 mut/Mb and only 3 were TMB-high ( >10mut/Mb). Over 1/3 (36.8%) were PD-L1+ via Ventana SP142 assay (≥1) and 21.4% were PD-L1+ via Dako 22C3 assay (CPS ≥10). The 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%); notably distinct in frequency from the breast carcinoma cohort (Table 1). Alterations in genes affecting cell cycle regulation (i.e. CDKN2A/B and TP53) were mutually exclusive from one another (p < 0.001). Several tumors harbored genomic alterations with FDA-approved indications in other tumor types including: NF1, PIK3CA, EGFR Exon 19/20 insertions, and BRAF V600E mutations. There were no significant differences between localized/locally recurrent versus metastatic specimens.

Conclusions: In the largest genomic evaluation of MPTs to date, multiple clinically actionable mutations for further exploration were found. TERT-promoter was altered in the majority of cases. PDL-1 was expressed in over 1/3 of cases suggesting that clinical investigation of immunotherapeutic strategies is warranted. Routine sequencing of metastatic MPT may provide additional information to guide treatment decisions and clinical trial enrollment.
Learning Objectives:
Participants will be able to describe the most commonly altered genes in malignant phyllodes tumors.
Participants will be able to recognize that multiple genomic alterations identified in malignant phyllodes tumors have FDA-approved therapies in other tumor types.
Participants will be able to demonstrate that multiple clinically actionable mutations have been identified in malignant phyllodes and investigation into these is warranted.