CoChat
Sign Up
Cited by 2HER2/EGFR in Cancer ResearchColorectal Cancer Treatments and StudiesLung Cancer Treatments and Mutations

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Novel ERBB2 Variant Potentially Associated with Resistance against Anti-HER2 Monoclonal Antibody–Based Therapy in ERBB2 -Amplified Metastatic Colorectal Cancer

Open access
Iida, Naoko, Imai, Mitsuho, Okamoto, Wataru, Kato, Takeshi, Esaki, Taito, Kato, Ken, Komatsu, Yoshito, Yuki, Satoshi, Masuishi, Toshiki, Nishina, Tomohiro, Ebi, Hiromichi, Taniguchi, Hiroya, Nonomura, Norio, Sunakawa, Yu, Shiozawa, Manabu, Yamazaki, Kentaro, Boku, Shogen, Bando, Hideaki, Shiraishi, Yuichi, Kobayashi, Maki, Goto, Hiroki, Sato, Akihiro, Fujii, Satoshi, Yoshino, Takayuki, Nakamura, Yoshiaki·2024·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-24-1023PMC PMC11393546

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Purpose: HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data. Experimental Design: We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC. Results: In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant. Conclusions: This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/1078-0432.ccr-24-1023

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1. Therapy efficacy and gene alterations in 155 patients with ERBB2-amplified cancer treated with HER2-targeted therapy in SCRUM-Japan GOZILA/MONSTAR-SCREEN. A, Overall response of HER2-targeted therapy. Patients were grouped by drug class and ERBB2 genomic status. B, Kaplan–Meier plots of PFS for patients with tumors harboring ERBB2 wild-type, VUS, and pathogenic variants. The log-rank test P-value was 0.098. C, PFS, best overall response, and HER2 genomic status of 93 patients with ERBB2 amplification treated with HER2-targeted therapy in the SCRUM-Japan project. BoR, best overall response; CR, complete response; PD, progressive disease; PR, partial response.
Figure 1. Therapy efficacy and gene alterations in 155 patients with ERBB2-amplified cancer treated with HER2-targeted therapy in SCRUM-Japan GOZILA/MONSTAR-SCREEN. A, Overall response of HER2-targeted therapy. Patients were grouped by drug class and ERBB2 genomic status. B, Kaplan–Meier plots of PFS for patients with tumors harboring ERBB2 wild-type, VUS, and pathogenic variants. The log-rank test P-value was 0.098. C, PFS, best overall response, and HER2 genomic status of 93 patients with ERBB2 amplification treated with HER2-targeted therapy in the SCRUM-Japan project. BoR, best overall response; CR, complete response; PD, progressive disease; PR, partial response.CC BY-NC-ND · PubMed Central
Figure 2. Study overview. A, Experimental design. Fourteen patients enrolled in the TRIUMPH project had ERBB2-amplified metastatic colon cancer. The patients were treated by pertuzumab and trastuzumab. We obtained fresh tumor tissues pretreatment and postprogression and ctDNA pretreatment, 3 weeks after the start of treatment, and postprogression. B, Best overall response (BoR) and change in tumor size in response to treatment. Waterfall plot showing the change in the sum of the longest diameters of lesions from the baseline to the best postbaseline investigator assessment. The x-axis indicates the TRIUMPH IDs; green font indicates the presence of clinical benefit. C, Overview of the results of HER2 IHC, ERBB2 copy number (CNV), and transcription (TPM) for tissue samples. Tiles marked with slashes indicate the absence of data. WES data of pre- and post-treatment are available for 12 and 4 patients, respectively. WTS data of pre- and post-treatment are available for 13 and 5 patients, respectively. Therefore, paired pre- and post-treatment data sets of WES and WTS are available for four and six patients, respectively. D, Relationship between TPM and IHC score (left) and TPM and CN (right). The symbols represent the presence (triangle) and absence (circle) of clinical benefit.
Figure 2. Study overview. A, Experimental design. Fourteen patients enrolled in the TRIUMPH project had ERBB2-amplified metastatic colon cancer. The patients were treated by pertuzumab and trastuzumab. We obtained fresh tumor tissues pretreatment and postprogression and ctDNA pretreatment, 3 weeks after the start of treatment, and postprogression. B, Best overall response (BoR) and change in tumor size in response to treatment. Waterfall plot showing the change in the sum of the longest diameters of lesions from the baseline to the best postbaseline investigator assessment. The x-axis indicates the TRIUMPH IDs; green font indicates the presence of clinical benefit. C, Overview of the results of HER2 IHC, ERBB2 copy number (CNV), and transcription (TPM) for tissue samples. Tiles marked with slashes indicate the absence of data. WES data of pre- and post-treatment are available for 12 and 4 patients, respectively. WTS data of pre- and post-treatment are available for 13 and 5 patients, respectively. Therefore, paired pre- and post-treatment data sets of WES and WTS are available for four and six patients, respectively. D, Relationship between TPM and IHC score (left) and TPM and CN (right). The symbols represent the presence (triangle) and absence (circle) of clinical benefit.CC BY-NC-ND · PubMed Central
Figure 3. Genomic variants identified in ERBB2. A, Heatmap of variants. Short nucleotide variants were analyzed in tissue samples pretreatment (left) and postprogression (right). We extracted variants in genes associated with cancer (listed in the Cancer Gene Census). Pathogenic variants reported in Clinvar and OncoKB are indicated in red. On the x-axis, green font indicates clinical benefit. B, Variants detected in ERBB2. The illustration was downloaded from the PDB database (https://pdb101.rcsb.org/motm/268). Labels denoting protein or cDNA changes based on transcriptional consequences of NM_004448 transcript. Variants in exons are described as labels of a reference amino acid, a position in a protein sequence, and alternative amino acid. For a variant in intron c.644-66_-2del, the label indicates the deletion from -66th to -2nd base position against the 644th base position in the cDNA. For a variant in deep intron c.902-1277G>C, the label indicates the base substitution of G to C at -1277 base position against the 902nd base position in the cDNA. Red font indicates pathogenic variants reported in OncoKB. CT, C-terminal; ECD, extracellular domain; KD, kinase domain.
Figure 3. Genomic variants identified in ERBB2. A, Heatmap of variants. Short nucleotide variants were analyzed in tissue samples pretreatment (left) and postprogression (right). We extracted variants in genes associated with cancer (listed in the Cancer Gene Census). Pathogenic variants reported in Clinvar and OncoKB are indicated in red. On the x-axis, green font indicates clinical benefit. B, Variants detected in ERBB2. The illustration was downloaded from the PDB database (https://pdb101.rcsb.org/motm/268). Labels denoting protein or cDNA changes based on transcriptional consequences of NM_004448 transcript. Variants in exons are described as labels of a reference amino acid, a position in a protein sequence, and alternative amino acid. For a variant in intron c.644-66_-2del, the label indicates the deletion from -66th to -2nd base position against the 644th base position in the cDNA. For a variant in deep intron c.902-1277G>C, the label indicates the base substitution of G to C at -1277 base position against the 902nd base position in the cDNA. Red font indicates pathogenic variants reported in OncoKB. CT, C-terminal; ECD, extracellular domain; KD, kinase domain.CC BY-NC-ND · PubMed Central
Figure 4. Novel splicing-associated variants. A, Alignment status of around c.644-66_-2del in ERBB2 shown by Integrative Genomics Viewer for ERBB2 for WES of patient t0001. B, Sashimi plot for patient t0001 pretreatment liver (without c.644-66_-2del, top) and postprogression pelvic mass (with c.644-66_-2del, bottom) using WTS. c.644-66_-2del resulted in in-frame skipping of exons 6 and 7. The red circle presents the position of the variant. C, Three-dimensional structure of HER2. Protein structures were predicted using the amino acid sequences of the wild-type sequence (left) and the variant with exons 6 and 7 skipping with leucine at 215 replaced with histidine and deletion of the amino sequences from the 216th to 301st position (right) by AlphaFold2. The pink region is around the extracellular domain II (190th to 343rd position in the amino acid sequence). The color coding is based on the Local Distance Difference Test scores, which assess the accuracy of predictions. A higher score with cooler colors indicates greater accuracy.
Figure 4. Novel splicing-associated variants. A, Alignment status of around c.644-66_-2del in ERBB2 shown by Integrative Genomics Viewer for ERBB2 for WES of patient t0001. B, Sashimi plot for patient t0001 pretreatment liver (without c.644-66_-2del, top) and postprogression pelvic mass (with c.644-66_-2del, bottom) using WTS. c.644-66_-2del resulted in in-frame skipping of exons 6 and 7. The red circle presents the position of the variant. C, Three-dimensional structure of HER2. Protein structures were predicted using the amino acid sequences of the wild-type sequence (left) and the variant with exons 6 and 7 skipping with leucine at 215 replaced with histidine and deletion of the amino sequences from the 216th to 301st position (right) by AlphaFold2. The pink region is around the extracellular domain II (190th to 343rd position in the amino acid sequence). The color coding is based on the Local Distance Difference Test scores, which assess the accuracy of predictions. A higher score with cooler colors indicates greater accuracy.CC BY-NC-ND · PubMed Central
Figure 5. Dynamics of ERBB2 status throughout treatment. A, CT images reveal the change in tumor size in patient t0001 in the liver (top) and pelvic mass (bottom) before (left) and after (right) treatment. The orange circles indicate tumors. B, Detection of variants in tissue and ctDNA. The red color indicates the detection of variants in tissue and at sampling timing. Pre, pretreatment; 3W, 3rd week after starting treatment; and Post, after disease progression. C, ctDNA analysis. Relative variant frequency (VAF) and copy number (CN) of ERBB2 in ctDNA. D and E, CN (D) and the length (E) of amplified region containing ERBB2 locus in the pretreatment liver, postprogression liver, and postprogression pelvic mass of patient t0001.
Figure 5. Dynamics of ERBB2 status throughout treatment. A, CT images reveal the change in tumor size in patient t0001 in the liver (top) and pelvic mass (bottom) before (left) and after (right) treatment. The orange circles indicate tumors. B, Detection of variants in tissue and ctDNA. The red color indicates the detection of variants in tissue and at sampling timing. Pre, pretreatment; 3W, 3rd week after starting treatment; and Post, after disease progression. C, ctDNA analysis. Relative variant frequency (VAF) and copy number (CN) of ERBB2 in ctDNA. D and E, CN (D) and the length (E) of amplified region containing ERBB2 locus in the pretreatment liver, postprogression liver, and postprogression pelvic mass of patient t0001.CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Research works printed but not linked: 27

  1. Sawada, 2018, Prognostic and predictive value of HER2 amplification in patients with metastatic colorectal cancer, Clin Colorectal Cancer, 17, 198, 10.1016/j.clcc.2018.05.006 · DOI
  2. Ross, 2018, Targeting HER2 in colorectal cancer: the landscape of amplification and short variant mutations in ERBB2 and ERBB3, Cancer, 124, 1358, 10.1002/cncr.31125 · DOI
  3. Strickler, 2022, Diagnosis and treatment of ERBB2-positive metastatic colorectal cancer: a review, JAMA Oncol, 8, 760, 10.1001/jamaoncol.2021.8196 · DOI
  4. Siena, 2021, Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial, Lancet Oncol, 22, 779, 10.1016/S1470-2045(21)00086-3 · DOI
  5. Meric-Bernstam, 2019, Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study, Lancet Oncol, 20, 518, 10.1016/S1470-2045(18)30904-5 · DOI · Paper page
  6. Nakamura, 2021, Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial, Nat Med, 27, 1899, 10.1038/s41591-021-01553-w · DOI · Paper page
  7. Meric-Bernstam, 2022, Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study, Lancet Oncol, 23, 1558, 10.1016/S1470-2045(22)00621-0 · DOI
  8. Connolly, 2024, Trastuzumab and pertuzumab in patients with non-breast/gastroesophageal HER2-amplified tumors: results from the NCI–MATCH ECOG–ACRIN trial (EAY131) subprotocol J, Clin Cancer Res, 30, 1273, 10.1158/1078-0432.CCR-23-0633 · DOI
  9. Vaghi, 2023, The predictive role of ERBB2 point mutations in metastatic colorectal cancer: a systematic review, Cancer Treat Rev, 112, 102488, 10.1016/j.ctrv.2022.102488 · DOI
  10. Yaeger, 2018, Clinical sequencing defines the genomic landscape of metastatic colorectal cancer, Cancer Cell, 33, 125, 10.1016/j.ccell.2017.12.004 · DOI · Paper page
  11. Cancer Genome Atlas Network, 2012, Comprehensive molecular characterization of human colon and rectal cancer, Nat [Internet], 487, 330, 10.1038/nature11252 · DOI · Paper page
  12. Nakamura, 2021, SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN: path to the realization of biomarker-guided precision oncology in advanced solid tumors, Cancer Sci, 112, 4425, 10.1111/cas.15132 · DOI
  13. Fujii, 2020, International harmonization of provisional diagnostic criteria for ERBB2-amplified metastatic colorectal cancer allowing for screening by next-generation sequencing panel, JCO Precis Oncol, 4, 6, 10.1200/PO.19.00154 · DOI
  14. McKenna, 2010, The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data, Genome Res, 20, 1297, 10.1101/gr.107524.110 · DOI · Paper page
  15. McLaren, 2016, The ensembl variant effect predictor, Genome Biol, 17, 122, 10.1186/s13059-016-0974-4 · DOI · Paper page
  16. Talevich, 2016, CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing, PLoS Comput Biol, 12, e1004873, 10.1371/journal.pcbi.1004873 · DOI
  17. Tate, 2019, COSMIC: the catalogue of somatic mutations in cancer, Nucleic Acids Res, 47, D941, 10.1093/nar/gky1015 · DOI · Paper page
  18. Dobin, 2013, STAR: ultrafast universal RNA-seq aligner, Bioinformatics, 29, 15, 10.1093/bioinformatics/bts635 · DOI · Paper page
  19. Liao, 2014, featureCounts: an efficient general purpose program for assigning sequence reads to genomic features, Bioinformatics, 30, 923, 10.1093/bioinformatics/btt656 · DOI · Paper page
  20. Garrido-Martín, 2018, ggsashimi: Sashimi plot revised for browser- and annotation-independent splicing visualization, PLoS Comput Biol, 14, e1006360, 10.1371/journal.pcbi.1006360 · DOI
  21. Shiraishi, 2018, A comprehensive characterization of cis-acting splicing-associated variants in human cancer, Genome Res, 28, 1111, 10.1101/gr.231951.117 · DOI
  22. Smith, 2020, An ErbB2 splice variant lacking exon 16 drives lung carcinoma, Proc Natl Acad Sci U S A, 117, 20139, 10.1073/pnas.2007474117 · DOI
  23. Siena, 2021, 386O Exploratory biomarker analysis of DESTINY-CRC01, a phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd, DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC), Ann Oncol, 32, S532, 10.1016/j.annonc.2021.08.908 · DOI
  24. Siravegna, 2018, Radiologic and genomic evolution of individual metastases during HER2 blockade in colorectal cancer, Cancer Cell, 34, 148, 10.1016/j.ccell.2018.06.004 · DOI
  25. Hart, 2021, HER2-PI9 and HER2-I12: two novel and functionally active splice variants of the oncogene HER2 in breast cancer, J Cancer Res Clin Oncol, 147, 2893, 10.1007/s00432-021-03689-1 · DOI
  26. Silipo, 2017, How is Herstatin, a tumor suppressor splice variant of the oncogene HER2, regulated?, RNA Biol, 14, 536, 10.1080/15476286.2016.1267074 · DOI
  27. Jiao, 2021, HER2 splice site mutation c.1899-1G>A as the potential acquired resistance to trastuzumab in a patient with HER2-positive gastric adenocarcinoma, Oncologist, 26, 717, 10.1002/onco.13799 · DOI

Metadata

Authors
Iida, N., Imai, M., Okamoto, W., Kato, T., Esaki, T., Kato, K., Komatsu, Y., Yuki, S., Masuishi, T., Nishina, T., Ebi, H., Taniguchi, H., Nonomura, N., Sunakawa, Y., Shiozawa, M., Yamazaki, K., Boku, S., Bando, H., Shiraishi, Y., Kobayashi, M., Goto, H., Sato, A., Fujii, S., Yoshino, T., & Nakamura, Y.
Affiliations
  • National Cancer Center Hospital East (JP)
  • Hiroshima University Hospital (JP)
  • Osaka National Hospital (JP)
  • National Hospital Organization Kyushu Cancer Center (JP)
  • National Cancer Center Hospital (JP)
  • Hokkaido University Hospital (JP)
  • Aichi Cancer Center (JP)
  • Shikoku Cancer Center (JP)
  • The University of Osaka (JP)
  • St. Marianna University School of Medicine (JP)
  • Kanagawa Cancer Center (JP)
  • Shizuoka Cancer Center (JP)
  • Kansai Medical University Hospital (JP)
  • National Cancer Centre Japan (JP)
  • National Cancer Center Research Institute (JP)
  • Daiichi-Sankyo (Japan) (JP)
Corresponding author
Nakamura, Yoshiaki
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2024-07-17
Volume
30
Issue
18
Pages
4167-4178
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-24-1023
PMC
PMC11393546
OpenAlex
W4401715124
Cited by
2
References
4
Citations by year
2026: 1 · 2025: 1
FWCI
0.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Cancer Research (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
Funders
  • Japan Agency for Medical Research and Development (16lk0201054h0001, 19ck0106445h0002)
  • National Cancer Center Japan (2021-A-06)
  • Daiichi Sankyo Company
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
ERBB2 amplification, metastatic colorectal cancer, HER2-targeted therapy, pertuzumab, circulating tumor DNA, treatment resistance, variants of uncertain significance
MeSH terms
Circulating Tumor DNA, Antineoplastic Agents, Immunological, Adult, Aged, Female, Gene Amplification, Humans, Male, Middle Aged, Neoplasm Metastasis, Biomarkers, Tumor, Colorectal Neoplasms, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review