HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer

Takegawa, Naoki; Yonesaka, Kimio; Sakai, Kazuko; Ueda, Hayato; Watanabe, Satomi; Nonagase, Yoshikane; Okuno, Tatsuya; Takeda, Masayuki; Maenishi, Osamu; Tsurutani, Junji; Satoh, Taroh; Okamoto, Isamu; Nishio, Kazuto; Tamura, Takao; Nakagawa, Kazuhiko

doi:10.18632/oncotarget.6498

Cited by 60 publications

(48 citation statements)

References 26 publications

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“…While ERBB2 amplification and mutation of KRAS, EGFR, and other genes have been identified in ctDNA samples from patients with CRC, this is the first report of an ALK rearrangement in a patient with CRC detected by ctDNA. In this case study, a STRN‐ALK fusion was detected by genomic profiling of ctDNA and later confirmed via tissue testing.…”

Section: Significance Of the Specific Mutation In The Particular Cancermentioning

confidence: 76%

Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA

Lai¹,

Schrock²,

Erlich³

et al. 2017

The Oncologist

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Section: Significance Of the Specific Mutation In The Particular Cancermentioning

confidence: 76%

Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA

Lai¹,

Schrock²,

Erlich³

et al. 2017

The Oncologist

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“…The cut‐off value was defined based on the log2 ratio of the read depth of NGS . We previously reported the detection of copy number gains in HER2 using ddPCR in colorectal cancer patients who were refractory to anti‐EGFR antibody therapy . Thus, ddPCR might have specific features that influence its ability to sensitively detect copy number gains.…”

Section: Discussionmentioning

confidence: 99%

“…20 We previously reported the detection of copy number gains in HER2 using ddPCR in colorectal cancer patients who were refractory to anti-EGFR antibody therapy. 19 mutations are known mechanisms of resistance to EGFR-TKI. 26 In the present study, ERBB4 S341L and EGFR I759M mutations were detected in cfDNA using amplicon sequencing.…”

Section: Discussionmentioning

confidence: 99%

Barcode sequencing identifies resistant mechanisms to epidermal growth factor receptor inhibitors in circulating tumor DNA of lung cancer patients

et al. 2019

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Most patients with epidermal growth factor receptor (EGFR) mutation‐positive non‐small cell lung cancer (NSCLC) will inevitably develop acquired resistance induced by treatment with EGFR tyrosine kinase inhibitors (EGFR‐TKI). The mechanisms of resistance to EGFR‐TKI are multifactorial, and the detection of these mechanisms is critical for treatment choices in patients who have progressed after EGFR‐TKI therapy. We evaluated the feasibility of a molecular barcode method using next‐generation sequencing to detect multifactorial resistance mechanisms in circulating tumor DNA and compared the results with those obtained using other technologies. Plasma samples were collected from 25 EGFR mutation‐positive NSCLC patients after the development of EGFR‐TKI resistance. Somatic mutation profiles of these samples were assessed using two methods of next‐generation sequencing and droplet digital PCR (ddPCR). The positive rate for EGFR‐sensitizing mutations was 18/25 (72.0%) using ddPCR, 17/25 (68.0%) using amplicon sequencing, and 19/25 (76.0%) using molecular barcode sequencing. Rate of the EGFR T790M resistance mutation among patients with EGFR‐sensitizing mutations was shown to be 7/18 (38.9%) using ddPCR, 6/17 (35.3%) using amplicon sequencing, and 8/19 (42.1%) using molecular barcode sequencing. Copy number gain in the MET gene was detected in three cases using ddPCR. PIK3CA, KRAS and TP53 mutations were detected using amplicon sequencing. Molecular barcode sequencing detected PIK3CA, TP53, KRAS, and MAP2K1 mutations. Results of the three assays were comparable; however, in cell‐free DNA, molecular barcode sequencing detected mutations causing multifactorial resistance more sensitively than did the other assays.

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“…After deparaffinization and blocking of endogenous peroxidase, HER2 immunostaining was performed using rabbit anti‐human c‐erbB‐2 primary antibody, diluted 1:100 (Dako Corp., Carpinteria, CA, USA). Primary antibody binding was assessed using the Dako Quick‐Staining, Labeled Streptavidin‐Biotin System (Dako Corp.) and subsequent addition of diaminobenzidine as a chromogen . Scoring was performed according to the clinical practice guideline for breast cancer …”

Section: Methodsmentioning

confidence: 99%

DS‐8201a, a new HER2‐targeting antibody–drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2‐positive gastric cancer T‐DM1 resistance

Takegawa

Nonagase

Yonesaka

et al. 2017

Intl Journal of Cancer

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134

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Anti-HER2 therapies are beneficial for patients with HER2-positive breast or gastric cancer. T-DM1 is a HER2-targeting antibody-drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T-DM1 resistance. DS-8201a is a new ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). DS-8201a has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Owing to these unique characteristics and unlike T-DM1, DS-8201a is effective against cancers with low-HER2 expression. In the present work, T-DM1-resistant cells (N87-TDMR), established using the HER2-positive gastric cancer line NCI-N87 and continuous T-DM1 exposure, were shown to be susceptible to DS-8201a. The ATP-binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87-TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T-DM1 sensitivity. Therefore, resistance to T-DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS-8201a inhibited the growth of N87-TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS-8201a relative to T-DM1 compensates for increased efflux. Notably, N87-TDMR xenograft tumor growth was prevented by DS-8201a. In conclusion, the efficacy of DS-8201a as a treatment for patients with T-DM1-resistant breast or gastric cancer merits investigation.

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HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer

Cited by 60 publications

References 26 publications

Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA

Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA

Barcode sequencing identifies resistant mechanisms to epidermal growth factor receptor inhibitors in circulating tumor DNA of lung cancer patients

DS‐8201a, a new HER2‐targeting antibody–drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2‐positive gastric cancer T‐DM1 resistance

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