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. 2020 Jun;40(6):260-269.
doi: 10.1002/cac2.12032. Epub 2020 May 21.

Clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA from breast cancer patients in China

Zongbi Yi  1 , Fei Ma  1 , Guohua Rong  1 , Yanfang Guan  2 , Chunxiao Li  3 , Binghe Xu  1
Affiliations

Clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA from breast cancer patients in China

Zongbi Yi et al. Cancer Commun (Lond). 2020 Jun.

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: Chinese; TP53 mutation; breast cancer; circulating tumor DNA; next-generation sequencing; prognosis; taxanes; trastuzumab.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
Frequencies of TP53 mutations in different molecular subtypes of breast cancer. A. Proportion of patients with TP53 mutations according to molecular subtype. B. Comparison of TP53 mutation frequencies between our data and the MSK‐IMPACT data. Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor
FIGURE 2
FIGURE 2
Kaplan‐Meier analyses of DFS in 444 patients with metastatic breast cancer. Abbreviations: DFS, disease‐free survival; CI, confidence interval
FIGURE 3
FIGURE 3
Impact of TP53 mutation on the response to trastuzumab‐based first‐line therapy. A. PFS of patients underwent trastuzumab‐based first‐line treatment based on the presence of TP53 mutation. B. PFS of patients in the taxane combination group based on the presence of TP53 mutation. C. PFS of patients in the non‐taxane combination group based on the presence of TP53 mutation. Abbreviations: PFS, progression‐free survival; CI, confidence interval
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