Translational Genomics and Targeted Therapies in Solid Tumors group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.
Cancer. 2024 Aug 15;130(16):2746-2762. doi: 10.1002/cncr.35323. Epub 2024 May 16.
Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset.
Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05.
Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS.
In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.
携带 BRCA1/2 基因种系致病性变异（PVs）的年轻（≤40 岁）女性乳腺癌（BC）较为少见，但常具有侵袭性特征。人表皮生长因子受体 2（HER2）低表达 BC 最近成为一个新的治疗靶点，但在这种罕见的患者亚组中尚未得到描述。
本研究回顾性纳入了来自全球 78 个医疗中心的 3547 名新诊断为早期 HER2 阴性（HER2-0 和 HER2-低）且携带种系 BRCA1/2 PVs 的年轻（≤40 岁）女性 BC 患者。采用卡方检验和学生 t 检验描述 HER2-0 和 HER2-低之间的变量分布。采用逻辑回归评估与 HER2-低状态的相关性。采用 Kaplan-Meier 法和 Cox 回归分析评估无病生存期（DFS）和总生存期。p 值≤0.05 为差异有统计学意义。
在纳入的 3547 例患者中，32.3%的患者存在 HER2-低 BC，占激素受体阳性患者的 46.3%，三阴性（TN）患者的 21.3%。与 HER2-0 BC 相比，HER2-低 BC 更常为分级 1/2（p<0.001）、激素受体阳性（p<0.001）和淋巴结阳性（p=0.003）。BRCA2 PVs 与 HER2-低的相关性强于 BRCA1 PVs（p<0.001）。在总体人群中，HER2-低与 HER2-0 相比，DFS 更好（风险比 [HR]，0.86；95%置信区间 [CI]，0.76-0.97），在 TN 亚组中，DFS 更有利（HR，0.78；95%CI，0.64-0.95）和总生存期（HR，0.65；95%CI，0.46-0.93）。HER2-低的管腔 A 样肿瘤（p=0.014）和 TN 和管腔 A 样肿瘤的 HER2-0（p=0.019）的 DFS 最差。
在携带 HER2 阴性和种系 BRCA1/2 PVs 的年轻 BC 患者中，HER2-低疾病的发生率低于预期，且更常与 BRCA2 PVs 相关，并与管腔样疾病相关。HER2-低状态与预后略有改善相关。
