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
© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Cancer medicine - 11(2022), 14 vom: 07. Juli, Seite 2767-2778 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Binliang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.07.2022 Date Revised 15.09.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/cam4.4652 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM339234733 |
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| 041 | |a eng | ||
| 100 | 1 | |a Liu, Binliang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 25.07.2022 | ||
| 500 | |a Date Revised 15.09.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a TP53 | |
| 650 | 4 | |a anti-HER2 treatment | |
| 650 | 4 | |a breast neoplasms | |
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| 650 | 4 | |a mutation | |
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| 650 | 7 | |a Circulating Tumor DNA |2 NLM | |
| 650 | 7 | |a TP53 protein, human |2 NLM | |
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| 650 | 7 | |a Receptor, ErbB-2 |2 NLM | |
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| 700 | 1 | |a Guan, Yanfang |e verfasserin |4 aut | |
| 700 | 1 | |a Ouyang, Quchang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chunxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Xiuwen |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Lixi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhai, Jingtong |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Haili |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Binghe |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Yixin |e verfasserin |4 aut | |
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