PO.MD01.02 · 分子诊断与数据
通过整合登记数据库与 GENIE 分析揭示化生性乳腺癌的基因组易感性与临床行为
Genomic vulnerabilities and clinical behavior of metaplastic breast cancer through integrated registry and GENIE analysis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：化生性乳腺癌（MpBC）是一种罕见且高度异质性的乳腺癌亚型，主要为三阴性，以化疗耐药、早期复发和生存不良为特征。尽管其被归类于三阴性乳腺癌（TNBC）谱系内，MpBC 的临床行为和分子景观仍未充分明确，限制了靶向治疗策略的开发。
方法：对来自 MD Anderson 癌症中心（2014-2025）的临床 MpBC 病例进行了亚型、分期和生存的注释。评估了来自 AACR GENIE MpBC 队列（v16.1；n=258）的基因组数据中的致病性突变和拷贝数改变。使用 Fisher 精确检验评估变异频率、热点模式和互斥性。分析在 R 中进行，统计学显著性定义为 p<0.05。
结果：在 MDACC 登记数据库的 105 例 MpBC 病例中，92.9% 为 TNBC，总体死亡率为 34.3%。HER2 阳性疾病罕见（3.5%），但显示出最高的比例死亡率（50%）。ER 阳性 ≥10% 的肿瘤（3.5%）死亡率为 25%，而 ER/PR 低阳性（<10%）的肿瘤则表现出与 TNBC 相似的临床结局。值得注意的是，即使在早期患者中也观察到死亡，突显了独立于分期的侵袭性肿瘤生物学特性。对来自 GENIE 的 258 例 MpBC 病例（267 个样本）的基因组分析识别出复发性 TP53 突变（57%），包括经典热点变异（R248Q、R175H、R273C），与广泛的基因组不稳定性一致。PIK3CA 改变（34%）主要由 H1047R 驱动，且常与 TP53 突变互斥（p=0.043），提示存在具有不同致癌驱动因素的独特分子亚类。染色质调控因子（KMT2C 17.1%，KMT2D 10.5%）中的额外复发性改变，以及涉及 AGO2（22.9%）、RAD21（20.4%）、RECQL4（19.8%）和 MYC（19.4%）的拷贝数增加，突显了 DNA 修复、复制应激反应和转录调控中的潜在易感性。该机构 MpBC 队列的基因组分析正在进行中。
结论：这些整合的临床和分子研究结果强化了 MpBC 尽管罕见但仍是 TNBC 人群中死亡的主要贡献者，并将 PI3K/AKT 通路改变、基因组不稳定性和表观遗传失调提名为潜在治疗靶点。这些发现进一步支持了对生物标志物驱动的精准肿瘤学试验的需求，包括篮子式设计和罕见肿瘤计划，以推进针对罕见、侵袭性乳腺癌亚型的靶向治疗。
查看英文原文 English abstract
Background: Metaplastic breast cancer (MpBC) is a rare and highly heterogeneous subtype of breast cancer, predominantly triple-negative and characterized by chemoresistance, early relapse, and poor survival. Despite its classification within the triple-negative breast cancer (TNBC) spectrum, the clinical behavior and molecular landscape of MpBC remain poorly defined, limiting the development of targeted therapeutic strategies.
Methods: Clinical MpBC cases from MD Anderson Cancer Center (2014-2025) were annotated for subtype, stage, and survival. Genomic data from the AACR GENIE MpBC cohort (v16.1; n=258) were evaluated for pathogenic mutations and copy-number alterations. Variant frequencies, hotspot patterns, and mutual exclusivity were assessed using Fisher's exact test. Analyses were performed in R, with statistical significance defined as p<0.05.
Results: Among 105 MpBC cases in the MDACC registry, 92.9% were TNBC, with an overall mortality rate of 34.3%. HER2-positive disease was rare (3.5%) but demonstrated the highest proportional mortality (50%). ER-positive tumors ≥10% (3.5%) had a 25% mortality rate, whereas ER/PR low-positive (<10%) tumors exhibited clinical outcomes similar to TNBC. Notably, mortality was observed even among early-stage patients, underscoring aggressive tumor biology that is independent of stage. Genomic analysis of 258 MpBC cases (267 samples) from GENIE identified recurrent TP53 mutations (57%), including canonical hotspot variants (R248Q, R175H, R273C), consistent with pervasive genomic instability. PIK3CA alterations (34%), driven predominantly by H1047R, were frequently mutually exclusive with TP53 mutations (p=0.043), suggesting distinct molecular subclasses with differential oncogenic drivers. Additional recurrent alterations in chromatin regulators ( KMT2C 17.1%, KMT2D 10.5%) and copy-number gains involving AGO2 (22.9%), RAD21 (20.4%), RECQL4 (19.8%), and MYC (19.4%) highlight potential vulnerabilities in DNA repair, replication stress response, and transcriptional regulation. Genomic profiling of the institutional MpBC cohort is ongoing.
Conclusion: These integrated clinical and molecular findings reinforce MpBC as a major contributor to mortality within the TNBC population despite its rarity and nominate PI3K/AKT pathway alterations, genomic instability, and epigenetic deregulation as potential therapeutic targets. These findings further support the need for biomarker-driven precision oncology trials, including basket-style designs and rare-tumor initiatives, to advance targeted therapies for rare, aggressive breast cancer subtypes.
利益披露 Disclosure
A. Shatta, None..
D. F. Chamorro, None..
B. E. Nelson, None..
B. Lim, None.