ctDNA dynamics : a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy
BACKGROUND: Most studies utilizing circulating tumor DNA (ctDNA) to monitor disease interrogated only one or a few genes and failed to develop workable criteria to inform clinical practice. We evaluated the feasibility of detecting resistance to anti-HER2 therapy by serial gene-panel ctDNA sequencing.
RESULTS: Primary therapeutic resistance was identified in 6 out of 14 patients with events of progressive disease. For this subset comparison of pre- and post-treatment ctDNA assay results revealed that HER2 amplification concurred with disease progression (4/6, 66.7%). Mutations in TP53 (3/6, 50.0%) and genes implicated in the PI3K/mTOR pathway (3/6, 50.0%) were also dominant markers of resistance. Together, resistance to HER2 blockade should be indicated during treatment if any of the following situations applies: 1) recurrence or persistence of HER2 amplification in the blood; 2) emergence or ≥20% increase in the fraction of mutations in any of these resistance-related genes including TP53/PIK3CA/MTOR/PTEN. Compared with CT scans, dynamic ctDNA profiling utilizing pre-defined criteria was sensitive in identifying drug resistance (sensitivity 85.7%, specificity 55.0%), with a concordance rate up to 82.1%. Besides, the ctDNA criteria had a discriminating role in the prognosis of HER2-positive metastatic breast cancer.
METHODS: 52 plasma samples were prospectively collected from 18 patients with HER2-positive metastatic breast cancer who were treated with an oral anti-HER1/HER2 tyrosine kinase inhibitor (ClinicalTrials.gov NCT01937689). ctDNA was assayed by gene-panel target-capture next-generation sequencing.
CONCLUSIONS: Longitudinal gene-panel ctDNA sequencing could be exploited to determine resistance and guide the precise administration of anti-HER2 targeted therapy in the metastatic setting.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2016 |
|---|---|
| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
|---|---|
| Enthalten in: |
Oncotarget - 7(2016), 40 vom: 04. Okt., Seite 66020-66031 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ma, Fei [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 12.03.2018 Date Revised 04.12.2021 published: Print ClinicalTrials.gov: NCT01937689 Citation Status MEDLINE |
|---|
| doi: |
10.18632/oncotarget.11791 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM264119037 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM264119037 | ||
| 003 | DE-627 | ||
| 005 | 20231224205406.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2016 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.18632/oncotarget.11791 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0880.xml |
| 035 | |a (DE-627)NLM264119037 | ||
| 035 | |a (NLM)27602761 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ma, Fei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a ctDNA dynamics |b a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy |
| 264 | 1 | |c 2016 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.03.2018 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT01937689 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Most studies utilizing circulating tumor DNA (ctDNA) to monitor disease interrogated only one or a few genes and failed to develop workable criteria to inform clinical practice. We evaluated the feasibility of detecting resistance to anti-HER2 therapy by serial gene-panel ctDNA sequencing | ||
| 520 | |a RESULTS: Primary therapeutic resistance was identified in 6 out of 14 patients with events of progressive disease. For this subset comparison of pre- and post-treatment ctDNA assay results revealed that HER2 amplification concurred with disease progression (4/6, 66.7%). Mutations in TP53 (3/6, 50.0%) and genes implicated in the PI3K/mTOR pathway (3/6, 50.0%) were also dominant markers of resistance. Together, resistance to HER2 blockade should be indicated during treatment if any of the following situations applies: 1) recurrence or persistence of HER2 amplification in the blood; 2) emergence or ≥20% increase in the fraction of mutations in any of these resistance-related genes including TP53/PIK3CA/MTOR/PTEN. Compared with CT scans, dynamic ctDNA profiling utilizing pre-defined criteria was sensitive in identifying drug resistance (sensitivity 85.7%, specificity 55.0%), with a concordance rate up to 82.1%. Besides, the ctDNA criteria had a discriminating role in the prognosis of HER2-positive metastatic breast cancer | ||
| 520 | |a METHODS: 52 plasma samples were prospectively collected from 18 patients with HER2-positive metastatic breast cancer who were treated with an oral anti-HER1/HER2 tyrosine kinase inhibitor (ClinicalTrials.gov NCT01937689). ctDNA was assayed by gene-panel target-capture next-generation sequencing | ||
| 520 | |a CONCLUSIONS: Longitudinal gene-panel ctDNA sequencing could be exploited to determine resistance and guide the precise administration of anti-HER2 targeted therapy in the metastatic setting | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a anti-HER2 therapy | |
| 650 | 4 | |a circulating tumor DNA | |
| 650 | 4 | |a dynamics | |
| 650 | 4 | |a metastatic breast cancer | |
| 650 | 4 | |a progression | |
| 650 | 7 | |a Acrylamides |2 NLM | |
| 650 | 7 | |a Aminoquinolines |2 NLM | |
| 650 | 7 | |a Biomarkers, Tumor |2 NLM | |
| 650 | 7 | |a Circulating Tumor DNA |2 NLM | |
| 650 | 7 | |a DNA, Neoplasm |2 NLM | |
| 650 | 7 | |a pyrotinib |2 NLM | |
| 650 | 7 | |a Class I Phosphatidylinositol 3-Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.1.137 |2 NLM | |
| 650 | 7 | |a PIK3CA protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.1.137 |2 NLM | |
| 650 | 7 | |a ERBB2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Receptor, ErbB-2 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a TOR Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a PTEN Phosphohydrolase |2 NLM | |
| 650 | 7 | |a EC 3.1.3.67 |2 NLM | |
| 650 | 7 | |a PTEN protein, human |2 NLM | |
| 650 | 7 | |a EC 3.1.3.67 |2 NLM | |
| 700 | 1 | |a Zhu, Wenjie |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Yanfang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Xuefeng |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shanshan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Qiao |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Xiuwen |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Zongbi |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Haili |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Binghe |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Oncotarget |d 2010 |g 7(2016), 40 vom: 04. Okt., Seite 66020-66031 |w (DE-627)NLM199620113 |x 1949-2553 |7 nnns |
| 773 | 1 | 8 | |g volume:7 |g year:2016 |g number:40 |g day:04 |g month:10 |g pages:66020-66031 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.18632/oncotarget.11791 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 7 |j 2016 |e 40 |b 04 |c 10 |h 66020-66031 | ||