Molecular landscape of TP53 mutations in breast cancer and their utility for predicting the response to HER-targeted therapy in HER2 amplification-positive and HER2 mutation-positive amplification-negative patients

被引：16

作者：

Liu, Binliang ^{[1
,2
,3
]}

Yi, Zongbi ^{[1
]}

Guan, Yanfang ^{[4
,5
]}

Ouyang, Quchang ^{[2
,3
]}

Li, Chunxiao ^{[6
]}

Guan, Xiuwen ^{[1
]}

Lv, Dan ^{[1
]}

Li, Lixi ^{[1
]}

Zhai, Jingtong ^{[1
]}

Qian, Haili ^{[6
]}

Xu, Binghe ^{[1
]}

Ma, Fei ^{[1
]}

Zeng, Yixin ^{[7
,8
]}

机构：

[1] Chinese Acad Med Sci & Peking Union Med Coll, Natl Clin Res Ctr Canc, Dept Med Oncol, Natl Canc Ctr,Canc Hosp, Beijing, Peoples R China

[2] Cent South Univ, Hunan Canc Hosp, Dept Breast Canc Med Oncol, Changsha, Hunan, Peoples R China

[3] Cent South Univ, Xiangya Med Sch, Affiliated Canc Hosp, Changsha, Hunan, Peoples R China

[4] Geneplus Beijing Inst, Beijing, Peoples R China

[5] Xi An Jiao Tong Univ, Sch Elect & Informat Engn, Dept Comp Sci & Technol, Xian, Shaanxi, Peoples R China

[6] Chinese Acad Med Sci & Peking Union Med Coll, Natl Clin Res Ctr Canc, State Key Lab Mol Oncol, Natl Canc Ctr,Canc Hosp, Beijing, Peoples R China

[7] Chinese Acad Med Sci & Peking Union Med Coll, Beijing, Peoples R China

[8] Sun Yat Sen Univ, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Canc Ctr, Guangzhou, Peoples R China

来源：

CANCER MEDICINE | 2022年 / 11卷 / 14期

基金：

中国国家自然科学基金;

关键词：

anti-HER2; treatment; breast neoplasms; circulating tumor DNA; mutation; next-generation sequencing; TP53; INHIBITOR; RESISTANT; P53;

D O I：

10.1002/cam4.4652

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose We used targeted capture sequencing to analyze TP53-mutated circulating tumor DNA (ctDNA) in metastatic breast cancer patients and to determine whether TP53 mutation has predictive value for anti-human epidermal growth factor receptor 2 (HER2) treatment for in HER2 amplification-positive patients (HER2+) and HER2 mutation-positive, amplification-negative (HER2-/mut) patients. Patients and Methods TP53 mutation features were analyzed in the Geneplus cohort (n = 1184). The MSK-BREAST cohort was used to explore the value of TP53 mutation in predicting anti-HER-2 antibody efficacy. Sequencing of ctDNA in phase Ib, phase Ic, phase II clinical trials of pyrotinib (HER2+ patients), and an investigator-initiated phase II study of pyrotinib (HER2-/mut patients) were performed to analyze the relationships between TP53 mutation and prognosis for HER2 TKIs. The MSK-BREAST cohort, MutHER, and SUMMIT cohort were used for verification. Results TP53 mutations were detected in 53.1% (629/1184) of patients in the Geneplus cohort. The TP53 mutation rate was higher in HR-negative (p < 0.001) and HER2 amplification-positive (p = 0.015) patients. Among patients receiving anti-HER2 antibody therapy, those whose tumors carried TP53 mutations had a shorter PFS (p = 0.004). However, the value of TP53 mutation in predicting HER2 TKI response was inconsistent. In HER2+ patients, no difference in PFS was observed among patients with different TP53 statuses in the combined analysis of the pyrotinib phase Ib, phase Ic, and phase II clinical trials (p = 1.00) or in the MSK-BREAST cohort (p = 0.62). In HER2-/mut patients, TP53 mutation-positive patients exhibited a trend toward worse prognosis with anti-HER2 TKI treatment than TP53-wild-type patients in our investigator-initiated phase II study (p = 0.15), and this trend was confirmed in the combined analysis of the MutHER and SUMMIT cohorts (p = 0.01). Conclusions TP53 mutation can be used to identify biomarkers of anti-HER2 antibody drug resistance in HER2+ patients and HER2 TKI resistance in HER2-/mut patients.

引用

页码：2767 / 2778

页数：12

共 29 条

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