Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China.
Geneplus-Beijing Institute, Beijing, 100021, P. R. China.
Cancer Commun (Lond). 2020 Jun;40(6):260-269. doi: 10.1002/cac2.12032. Epub 2020 May 21.
TP53 mutations are common in breast cancer. There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China. The predictive value of TP53 mutations for the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in breast cancer remains controversial. In the present study, we aimed to analyze the clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA (ctDNA) from breast cancer patients in China.
We retrospectively analyzed the clinical data and TP53 mutation features in ctDNA samples from 804 patients with metastatic breast cancer. TP53 mutations were detected by target region capture-based next-generation sequencing. The relationship between TP53 mutation status and disease-free survival (DFS) was analyzed in 444 patients with metastatic breast cancer. Moreover, the relationship between TP53 mutation status and progression-free survival (PFS) was analyzed in 55 HER2-positive patients treated with first-line trastuzumab-based therapy. Kaplan-Meier analysis was performed to estimate the survival curves of the different subgroups, and the log-rank test was used to compare the curves. A Cox regression model was used to estimate multivariable-adjusted hazard ratios and their 95% confidence intervals (CIs) associated with the DFS and PFS.
Among the 804 investigated patients, 431 (53.6%) patients harbored TP53 mutations. TP53 mutations were differentially distributed among different molecular subtypes of breast cancer (P < 0.05). Patients with TP53 mutations had a shorter DFS than those with wild-type TP53 (hazard ratio = 1.32, 95% CI = 1.09-1.61, P = 0.005). TP53 mutations in exons 5-8 were associated with worse outcome (hazard ratio = 1.50, 95% CI = 1.11-2.03, P = 0.009). However, TP53 mutation status was not significantly associated with PFS in HER2-positive patients who received first-line trastuzumab-based therapy (P = 0.966). Interestingly, in the taxane combination group, patients with TP53 mutations exhibited longer PFS than those without TP53 mutations (hazard ratio = 0.08, 95% CI = 0.02-0.30, P < 0.001). However, in the non-taxane combination group, patients with TP53 mutations displayed shorter PFS than those with wild-type TP53 (hazard ratio = 4.84, 95% CI = 1.60-14.66, P = 0.005).
TP53 mutations in exons 5-8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer. TP53 mutations had opposite effects on trastuzumab-treated patients treated with and without taxanes.
TP53 突变在乳腺癌中很常见。目前尚无大规模的队列研究来调查中国乳腺癌患者的 TP53 图谱。TP53 突变对曲妥珠单抗靶向治疗乳腺癌患者疗效的预测价值仍存在争议。本研究旨在分析中国乳腺癌患者循环肿瘤 DNA（ctDNA）中 TP53 突变的临床谱和预后价值。
我们回顾性分析了 804 例转移性乳腺癌患者的临床数据和 ctDNA 样本中的 TP53 突变特征。通过基于靶向区域捕获的下一代测序检测 TP53 突变。在 444 例转移性乳腺癌患者中分析了 TP53 突变状态与无病生存期（DFS）的关系。此外，在 55 例接受一线曲妥珠单抗治疗的 HER2 阳性患者中分析了 TP53 突变状态与无进展生存期（PFS）的关系。Kaplan-Meier 分析用于估计不同亚组的生存曲线，对数秩检验用于比较曲线。Cox 回归模型用于估计与 DFS 和 PFS 相关的多变量调整后的风险比及其 95%置信区间（CI）。
在所研究的 804 例患者中，431（53.6%）例患者存在 TP53 突变。TP53 突变在不同的乳腺癌分子亚型中分布不同（P<0.05）。与野生型 TP53 相比，携带 TP53 突变的患者 DFS 更短（风险比=1.32，95%CI=1.09-1.61，P=0.005）。外显子 5-8 中的 TP53 突变与较差的预后相关（风险比=1.50，95%CI=1.11-2.03，P=0.009）。然而，TP53 突变状态与接受一线曲妥珠单抗治疗的 HER2 阳性患者的 PFS 无显著相关性（P=0.966）。有趣的是，在紫杉醇联合组中，携带 TP53 突变的患者的 PFS 长于不携带 TP53 突变的患者（风险比=0.08，95%CI=0.02-0.30，P<0.001）。然而，在非紫杉醇联合组中，携带 TP53 突变的患者的 PFS 短于野生型 TP53 的患者（风险比=4.84，95%CI=1.60-14.66，P=0.005）。
外显子 5-8 中的 TP53 突变可能是转移性乳腺癌患者 DFS 较短的独立预后标志物。TP53 突变对接受曲妥珠单抗治疗的患者的影响与是否接受紫杉醇治疗有关。
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