Hunan Cancer Hospital, and the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha 410013, China; Department of Breast Cancer Medical Oncology, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China; Central Laboratory, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China.
Hunan Cancer Hospital, and the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China; Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha 410013, China; Department of Breast Cancer Medical Oncology, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha 410013, China.
EBioMedicine. 2018 Jun;32:111-118. doi: 10.1016/j.ebiom.2018.05.015. Epub 2018 May 26.
In cancer patients, tumor gene mutations contribute to drug resistance and treatment failure. In patients with metastatic breast cancer (MBC), these mutations increase after multiline treatment, thereby decreasing treatment efficiency. The aim of this study was to evaluate gene mutation patterns in MBC patients to predict drug resistance and disease progression.
A total of 68 MBC patients who had received multiline treatment were recruited. Circulating tumor DNA (ctDNA) mutations were evaluated and compared among hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) subgroups.
The baseline gene mutation pattern (at the time of recruitment) varied among HR/HER2 subtypes. BRCA1 and MED12 were frequently mutated in triple negative breast cancer (TNBC) patients, PIK3CA and FAT1 mutations were frequent in HR+ patients, and PIK3CA and ERBB2 mutations were frequent in HER2+ patients. Gene mutation patterns also varied in patients who progressed within either 3 months or 3-6 months of chemotherapy treatment. For example, in HR+ patients who progressed within 3 months of treatment, the frequency of TERT mutations significantly increased. Other related mutations included FAT1 and NOTCH4. In HR+ patients who progressed within 3-6 months, PIK3CA, TP53, MLL3, ERBB2, NOTCH2, and ERS1 were the candidate mutations. This suggests that different mechanisms underlie disease progression at different times after treatment initiation. In the COX model, the ctDNA TP53 + PIK3CA gene mutation pattern successfully predicted progression within 6 months.
ctDNA gene mutation profiles differed among HR/HER2 subtypes of MBC patients. By identifying mutations associated with treatment resistance, we hope to improve therapy selection for MBC patients who received multiline treatment.
在癌症患者中，肿瘤基因突变导致药物耐药和治疗失败。在转移性乳腺癌（MBC）患者中，这些突变在多线治疗后增加，从而降低了治疗效率。本研究旨在评估 MBC 患者的基因突变模式，以预测药物耐药和疾病进展。
共招募了 68 名接受多线治疗的 MBC 患者。评估并比较了激素受体（HR）/人表皮生长因子受体 2（HER2）亚组之间的循环肿瘤 DNA（ctDNA）突变。
HR/HER2 亚型的基线基因突变模式（在招募时）存在差异。BRCA1 和 MED12 在三阴性乳腺癌（TNBC）患者中频繁突变，PIK3CA 和 FAT1 突变在 HR+患者中常见，PIK3CA 和 ERBB2 突变在 HER2+患者中常见。在化疗治疗 3 个月或 3-6 个月内进展的患者中，基因突变模式也存在差异。例如，在治疗 3 个月内进展的 HR+患者中，TERT 突变的频率显著增加。其他相关突变包括 FAT1 和 NOTCH4。在治疗 3-6 个月内进展的 HR+患者中，PIK3CA、TP53、MLL3、ERBB2、NOTCH2 和 ERS1 是候选突变。这表明不同的机制导致治疗开始后不同时间的疾病进展。在 COX 模型中，ctDNA TP53+PIK3CA 基因突变模式成功预测了 6 个月内的进展。
MBC 患者的 HR/HER2 亚型的 ctDNA 基因突变谱存在差异。通过鉴定与治疗耐药相关的突变，我们希望改善接受多线治疗的 MBC 患者的治疗选择。
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