Abstract P2-23-03: Genomic Evaluation of Malignant Phyllodes Tumors Reveals Multiple Targetable Opportunities
Authors: Rosenberger Laura H. , Riedel Richard F. , Danziger Natalie A. , Sokol Ethan , Ross Jeffrey S. , Sammons Sarah L. 
Published: March 2023

Abstract
Background: Malignant phyllodes tumors (MPT) are rare fibroepithelial breast tumors that disproportionately affect young women. Despite high local and distant recurrence rates, treatment is almost exclusively surgical. With no known effective chemotherapy or targeted systemic therapy options, metastatic progression portends dismal prognosis. Current national guidelines do not recommend biomarker testing in the non-metastatic setting. Management of metastatic disease follows principles of soft tissue sarcoma recommending Next-Generation Sequencing on an individual basis for patients who may qualify for clinical trials or are refractory to standard therapies. In the largest genomic profiling effort of MPT to date, 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 laboratory database (Foundation Medicine, Cambridge, MA). Cases were categorized as localized/locally recurrent or metastatic. All cases underwent CGP by DNA extraction from FFPE samples using a hybrid capture, adaptor ligation-based next generation sequencing assay, 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). Patient characteristics and results of CGP of MPT were summarized by either N (%) or median (range). Factors from MPT were compared to all cases of breast carcinoma in the lab database. Fisher’s Exact Tests were used to test for differences between groups and analysis of variance was used to test for differences for continuous variables.
Results: Of 135 MPT cases identified; 94 (69.6%) were localized/locally recurrent (breast, chest wall, soft tissue, skin, or lymph node) and 41 (30.4%) were metastatic (73% lung, followed by bone, liver, other intraabdominal). All patients were female with a median age of 54 years (range 14-86). The median TMB across samples was 2.5 mut/Mb and only 3 were TMB-high tumors (&gt;10mut/Mb). Over 1/3 (36.8%) of samples were PD-L1+ via Ventana SP142 assay (≥1) and 21.4% were PD-L1+ via Dako 22C3 assay (CPS ≥10). All evaluable cases (N=132) were microsatellite stable. The ten 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&lt; 0.001). Several tumors harbored genomic alterations with FDA-approved indications in other tumor types were found including: NF1, PIK3CA, EGFR Exon 19/20 insertions, and BRAF V600E mutations. There were no statistically significant differences between alterations in localized/locally recurrent versus metastatic specimens.
Conclusions: In the largest genomic evaluation of localized/locally recurrent or metastatic 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.
Table 1. Frequency of Genomic Alterations identified in 135 cases of Malignant Phyllodes Tumors.
Citation Format: Laura H. Rosenberger, Richard F. Riedel, Natalie A. Danziger, Ethan Sokol, Jeffrey S. Ross, Sarah L. Sammons. Genomic Evaluation of Malignant Phyllodes Tumors Reveals Multiple Targetable Opportunities [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-03.