Rosenberger Laura H, Riedel Richard F, Diego Emilia J, Nash Amanda L, Grilley-Olson Juneko E, Danziger Natalie A, Sokol Ethan S, Ross Jeffrey S, Sammons Sarah L
Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States.
Duke Cancer Institute, Duke University, Durham, NC 27710, United States.
Oncologist. 2024 Dec 6;29(12):1024-1031. doi: 10.1093/oncolo/oyae218.
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.
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.
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.
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.
恶性叶状肿瘤（MPT）是罕见的纤维上皮性乳腺癌，目前尚无已知有效的全身治疗方法；发生转移进展预示预后不佳。我们试图通过基因组分析和免疫治疗生物标志物分析来描述MPT的基因组特征。
从一家获得临床实验室改进修正案认证、美国病理学家协会认可的实验室（Foundation Medicine）中识别出已测序的MPT病例。所有病例均采用基于衔接子连接的下一代测序方法对324个基因进行基因组分析。评估了与肿瘤类型无关的免疫治疗生物标志物、微卫星不稳定性、肿瘤突变负荷（TMB）和程序性死亡配体1（PD-L1）表达。采用Fisher精确检验和方差分析来检验组间差异以及适当时检验连续变量。
在识别出的135例MPT病例中，94例（69.6%）为局限性/局部复发性病例，41例（30.4%）为转移性病例。中位年龄为54岁（范围14 - 86岁））。中位TMB为2.5个突变/Mb，3例为TMB高（≥10个突变/Mb）。通过Dako 22C3检测法（CPS≥1），21.4%为PD-L1阳性。最常发生改变的基因包括TERT启动子（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%）和RB1（18.5%）。发现了几例在其他肿瘤类型中具有美国食品药品监督管理局批准适应症的基因组改变的肿瘤，包括NF1、PIK3CA、表皮生长因子受体（EGFR）外显子19/20插入以及BRAF V600E突变。
在迄今为止对MPT进行的最大规模基因组评估中，发现了多个具有临床可操作性的突变。对转移性MPT进行常规测序可能会提供更多信息，以指导治疗决策和临床试验入组。
