转移性三阴性乳腺癌中同源重组相关基因改变与铂类反应差异：ProfiLER-01试验的亚组分析
Alterations in Homologous Recombination-Related Genes and Distinct Platinum Response in Metastatic Triple-Negative Breast Cancers: A Subgroup Analysis of the ProfiLER-01 Trial.
作者信息
Bonnet Elise, Haddad Véronique, Quesada Stanislas, Baffert Kim-Arthur, Lardy-Cléaud Audrey, Treilleux Isabelle, Pissaloux Daniel, Attignon Valéry, Wang Qing, Buisson Adrien, Heudel Pierre-Etienne, Bachelot Thomas, Dufresne Armelle, Eberst Lauriane, Toussaint Philippe, Bonadona Valérie, Lasset Christine, Viari Alain, Sohier Emilie, Paindavoine Sandrine, Combaret Valérie, Pérol David, Ray-Coquard Isabelle, Blay Jean-Yves, Trédan Olivier
机构信息
Department of Medical Oncology, Centre Léon Bérard, 69008 Lyon, France.
Department of Biopathology, Centre Léon Bérard, 69008 Lyon, France.
出版信息
J Pers Med. 2022 Sep 27;12(10):1595. doi: 10.3390/jpm12101595.
BACKGROUND
a specific subset of metastatic triple-negative breast cancers (mTNBC) is characterized by homologous recombination deficiency (HRD), leading to enhanced sensitivity to platinum-based chemotherapy. Apart from mutations in genes, the evaluation of other HRD-related alterations has been limited to date. As such, we analyzed data from mTNBC patients enrolled in the ProfiLER-01 study to determine the prevalence of alterations in homologous recombination-related (HRR) genes and their association with platinum sensitivity.
METHODS
next-generation sequencing and promoter methylation of and were performed on tumors from patients with mTNBC, using a panel of 19 HRR genes. Tumors were separated into three groups based on their molecular status: mutations in , mutations in other HRR genes ( excluded) or promoter methylation and the absence of molecular alterations in HRR genes (groups A, B and C, respectively). Sensitivity to platinum-based chemotherapy was evaluated through the radiological response.
RESULTS
mutations in were detected in seven (13.5%) patients, while alterations in other HRR genes or hypermethylation in or were reported in 16 (30.7%) patients; furthermore, no alteration was found in the majority of patients ( = 29; 55.8%). Among 27 patients who received platinum-based chemotherapy, the disease control rate was 80%, 55% and 18% (groups A, B and C, respectively; = 0.049). Regarding group B, patients with disease control exhibited mutations in , and the genes or methylation; Conclusion: mutations in HRR genes and epimutations in were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in , a more comprehensive evaluation of HRD should be considered in order to enlarge the selection of patients with mTNBC that could benefit from platinum-based chemotherapy.
背景
转移性三阴性乳腺癌（mTNBC）的一个特定亚群具有同源重组缺陷（HRD）特征，这导致其对铂类化疗药物的敏感性增强。除了基因中的突变外，迄今为止，对其他与HRD相关改变的评估一直有限。因此，我们分析了参与ProfiLER - 01研究的mTNBC患者的数据，以确定同源重组相关（HRR）基因改变的发生率及其与铂敏感性的关联。
方法
使用包含19个HRR基因的检测板，对mTNBC患者的肿瘤进行下一代测序和启动子甲基化检测。根据分子状态将肿瘤分为三组：BRCA1突变、其他HRR基因（不包括BRCA1）突变或BRCA1启动子甲基化且HRR基因无分子改变（分别为A组、B组和C组）。通过放射学反应评估对铂类化疗的敏感性。
结果
在7名（13.5%）患者中检测到BRCA1突变，而在16名（30.7%）患者中报告了其他HRR基因的改变或BRCA1或BRCA2的高甲基化；此外，大多数患者（n = 29；55.8%）未发现改变。在接受铂类化疗的27名患者中，疾病控制率分别为80%、55%和18%（分别为A组、B组和C组；P = 0.049）。关于B组，疾病得到控制的患者表现出BRCA2、PALB2和RAD51基因的突变或BRCA1甲基化；结论：HRR基因的突变和BRCA1的表观突变与铂类化疗的疾病控制相关。因此，除了BRCA1中已明确的改变外，应考虑对HRD进行更全面的评估，以扩大可能从铂类化疗中获益的mTNBC患者的选择范围。
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