Demarest Kaitlin, Anantharajah Arravinth, Maxwell Kara N, Rohanizadegan Mersedeh, Bradbury Angela, Nathanson Katherine L, McCarthy Anne Marie, Domchek Susan M, Nayak Anupma, Shah Payal D
Basser Center for BRCA, University of Pennsylvania, Philadelphia.
Department of Medicine, Perelman School of Medicine, Hospital of the University of Pennsylvania, Philadelphia.
JAMA Netw Open. 2025 Feb 3;8(2):e2460312. doi: 10.1001/jamanetworkopen.2024.60312.
Metaplastic breast cancer (MpBC) is a rare, heterogeneous disease often associated with inferior outcomes. A growing body of literature describes the clinical and molecular features of MpBC, yet limited data describe the pathogenic germline variants (PGVs) in breast cancer susceptibility genes among affected individuals.
To examine the frequency and types of PGVs in breast cancer genes among patients with MpBC.
DESIGN, SETTING, AND PARTICIPANTS: This is a descriptive retrospective cohort study of patients who received a diagnosis of MpBC at the University of Pennsylvania between January 2010 and May 2023. Electronic medical records were reviewed for demographic, clinicopathologic, and germline genetic testing information. Germline variant status was independently confirmed by a licensed genetic counselor and a physician with expertise in genetics. MpBC diagnosis and subtype were confirmed by a breast pathologist. Participants were identified via query of an institutional pathology database for reports signed between January 2010 and May 2023 including the term metaplastic. Among 320 initially obtained reports, 272 individuals had confirmed MpBC and were included in the study.
Germline genetic testing to investigate the presence of PGVs in breast cancer susceptibility genes.
The primary outcome measurement was the prevalence of PGVs in breast cancer susceptibility genes among participants. The hypothesis that individuals with MpBC have an enrichment of PGVs in genes associated with inherited breast cancer risk was formulated before data collection.
The total sample size was 272 women, and the median age at diagnosis was 58 years (range, 20-102 years); all were biological female patients; 143 of 272 (52.6%) had documentation of germline genetic testing; and participants with testing were significantly younger than those without (median age, 53 years [range, 20-79 years] vs 63 years [range, 29-102 years]; P < .001). Of the 143 patients, 24 (16.8%) had a PGV in a breast cancer susceptibility gene (BRCA1, n = 17; BRCA2, n = 5; PALB2, n = 1; CHEK2, n = 1). Patients with PGV-associated MpBC received a diagnosis at a younger age than those with sporadic disease, but there were no significant differences in hormone receptor positivity, ERBB2 status, or metaplastic subtype.
In this cohort study of patients with MpBC, a substantial proportion of clinically tested patients had a PGV in a breast cancer susceptibility gene, most commonly BRCA1. Germline testing was high yield in patients with MpBC, many of whom would be included in current germline testing eligibility criteria.
化生性乳腺癌（MpBC）是一种罕见的异质性疾病，其预后往往较差。越来越多的文献描述了MpBC的临床和分子特征，但关于受影响个体中乳腺癌易感基因的致病种系变异（PGV）的数据有限。
研究MpBC患者中乳腺癌基因PGV的频率和类型。
设计、背景和参与者：这是一项描述性回顾性队列研究，研究对象为2010年1月至2023年5月在宾夕法尼亚大学被诊断为MpBC的患者。对电子病历进行了回顾，以获取人口统计学、临床病理和种系基因检测信息。种系变异状态由一名持牌遗传咨询师和一名遗传学专家独立确认。MpBC的诊断和亚型由一名乳腺病理学家确认。通过查询机构病理数据库，查找2010年1月至2023年5月期间签署的包含“化生性”一词的报告，确定参与者。在最初获得的320份报告中，272名个体被确诊为MpBC并纳入研究。
进行种系基因检测以调查乳腺癌易感基因中PGV的存在情况。
主要结局指标是参与者中乳腺癌易感基因PGV的患病率。在数据收集之前，就提出了MpBC患者在与遗传性乳腺癌风险相关基因中PGV富集的假设。
总样本量为272名女性，诊断时的中位年龄为58岁（范围20 - 102岁）；均为生物学女性患者；272名患者中有143名（52.6%）有关于种系基因检测的记录；接受检测的参与者明显比未接受检测的参与者年轻（中位年龄，53岁[范围20 - 79岁]对63岁[范围29 - 102岁]；P <.001）。在这143名患者中，24名（16.8%）在乳腺癌易感基因中有PGV（BRCA1，n = 17；BRCA2，n = 5；PALB2，n = 1；CHEK2，n = 1）。与PGV相关的MpBC患者比散发性疾病患者诊断时年龄更小，但在激素受体阳性、ERBB2状态或化生亚型方面没有显著差异。
在这项针对MpBC患者的队列研究中，很大一部分接受临床检测的患者在乳腺癌易感基因中有PGV，最常见的是BRCA1。种系检测对MpBC患者的检出率很高，其中许多患者符合当前种系检测的资格标准。
