Abstract PO4-24-08: Genomic Landscape of Malignant Phyllodes Tumors Identifies Subsets for Targeted Therapy

Abstract Introduction: Phyllodes tumors (PT) are rare fibroepithelial tumors of the breast, comprising ~1% of all breast cancers, a subset of which have considerable malignant potential. Malignant phyllodes tumors (MPTs) have aggressive biological behavior and high local and distant recurrence rates. Distant metastases of MPTs have a poor prognosis given the limited treatment options available. Surgery remains the primary treatment modality for these patients; however, initial investigations suggest a potential for targeted therapies in managing this disease. The identification of targetable opportunities and a comprehensive understanding of the mutational profiles of MPTs could greatly enhance treatment options. Therefore, we aimed to assess the molecular landscape of these tumors. Methods: Phyllodes tumor samples underwent molecular profiling at Caris Life Sciences through DNA (592-gene panel or whole exome) and RNA sequencing (whole transcriptome). The MPTs were classified into primary and metastatic based on the specimen biopsy site. PD-L1+ expression was tested by IHC (SP142; ≥2+, ≥5%). Tumor mutational burden (TMB)-High was defined as ≥10 mutation/Mb. Immune cell fractions in the tumor microenvironment (TME) were estimated using quanTIseq (Finotello, 2019). Mann-Whitney U, Chi-square, and Fisher-Exact tests were applied where appropriate. Results: We identified 57 analyzed MPTs, all from female patients, with a median age of 53 years (range: 19-88). Approximately half of samples (53%, n=30) were labeled as from primary breast sites, and the remaining sites were metastatic (47%, n= 27). Of metastatic sites, lung was the most common location (74.1%, n=20/27), followed by bone, sacrum, pancreas and small bowel. Alterations in MPT include TERT promoter (56.8%, n=21/37), MED12 (51.6%, n=16/31), TP53 (40.0%, n=22/55), and NF1 (31.8%, n=14/44) mutations, with less frequent mutations of EGFR (10.5%, n=6/57), PIK3CA (7.0%, n=4/57), and BRAF (3.5%, n=2/57). As compared to primary MPT, metastatic MPT had roughly 2-fold higher prevalence of NF1 (45.5%: n=10/22 vs 18.2% n=4/22, p=0.05), KMT2D (25.9%: n=7/27 vs 10.7%: n=3/28, p=0.18), and RB1 (25.0%: n=6/24 vs 9.5%: n=2/21, p=0.25) though not significant. Multiple gene mutations were observed exclusively in lung metastases, as compared to non-lung sites including: TERT promoter (64.3%: n=9/14 vs 0.0%, p=0.08), MED12 (60.0%: n=6/10 vs 0.0%, p =0.044), and RB1 (35.3%: n=6/17 vs 0.0%, p=0.01). Conversely, NF1 (43.8%: n=7/16 vs 50.0%: n=3/6, p=1.0) and KMT2D (20.0%: n=4/20 vs 42.9%: n=3/7, p=0.32) mutation prevalence was higher in other metastatic sites. PD-L1+ expression was observed in 13.3% (n=7) of MPT overall, with similar prevalence among local and metastatic sites. No dMMR/MSI-H was observed, while low LOH (those with genomic LOH in < 16% of segment analyzed) was seen across MPT. Compared to a large cohort of breast adenocarcinoma samples (n=9,926) representing both HER2+ and HER2- tumors, MPT had low ERBB2 expression comparable to HER2- samples. B cells, M2 macrophages and neutrophils had the highest median cell fractions in the TME of MPT. Additionally, one MPT sample harbored a pathogenic NTRK1 fusion (TPM4:NTRK1), and treatment with larotrectinib for over 16 months suggests a clinical response to therapy. Conclusions: Our study demonstrates the importance of employing next generation sequencing (NGS) in MPTs to detect actionable genomic alterations. To effectively analyze fusions, an NGS panel that include RNA sequencing is recommended, considering the occurrence of NTRK1 fusion reported herein. Although HER2 transcriptional expression was low, further investigations examining HER2 IHC in PTs are still necessary. These finding therefore highlight the importance of NGS in phyllodes tumors research, as it may uncover potential targeted treatment options for patients. Citation Format: Rani Bansal, Tolulope Adeyelu, Andrew Elliott, Antoinette Tan, Jane Meisel, Matthew Oberley, Stephanie Graff, Jorge Reis-Filho, George Sledge Jr, Sarah Sammons, Laura Rosenberger. Genomic Landscape of Malignant Phyllodes Tumors Identifies Subsets for Targeted Therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-24-08.