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Validation of HER2 Amplification as a Predictive Biomarker for Anti–Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer
Abstract
Purpose: HER2 amplification has been implicated in resistance to therapy with anti–epidermal growth factor receptor antibodies (anti-EGFRabs) in metastatic colorectal cancer (mCRC). The purpose of the study was to validate the predictive impact of HER2 amplification in mCRC. Patients and Methods: We analyzed patients with RAS/BRAF wild-type mCRC across two distinct cohorts. In cohort 1 (n = 98), HER2 amplification was tested in tumor tissue using dual in situ hybridization ( HER2 amplification: HER2/CEP17 ratio, 2.0 or greater). Cohort 2 (n = 70) included 16 patients with HER2 amplification and 54 HER2 nonamplified controls identified by next-generation sequencing ( HER2 amplification: four or more copies) who had received prior anti-EGFRabs. The primary end point was progression-free survival (PFS) on treatment with anti-EGFRab therapy, which was estimated and compared using the Kaplan-Meier method and log-rank test. Results: Median PFS in cohort 1 on anti-EGFRab–based therapy was significantly shorter in patients with HER2 amplification compared with HER2 nonamplified patients (2.8 v 8.1 months, respectively; hazard ratio [HR], 7.05; 95% CI, 3.4 to 14.9; P < .001). These findings were validated in cohort 2 (median PFS for HER2 amplified v nonamplified: 2.8 v 9.3 months, respectively; HR, 10.66; 95% CI, 4.5 to 25.1; P < .001). The median PFS on therapy without anti-EGFRabs was similar among HER2-amplified and nonamplified patients in both cohort 1 (9.7 v 11.1 months, respectively; HR, 1.01; 95% CI, 0.4 to 2.4; P = .97) and cohort 2 (9.6 v 11.3 months, respectively; HR, 1.21; 95% CI, 0.5 to 3.1; P = .66). In multivariable analyses, HER2 amplification emerged as a single independent predictor of poor PFS on anti-EGFRab therapy in both cohort 1 (HR, 6.48; 95% CI, 3.1 to 13.6; P < .001) and cohort 2 (HR, 10.1; 95% CI, 4.3 to 23.9; P < .001). Conclusion: HER2 amplification in RAS/RAF wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy. Screening patients with RAS/BRAF wild-type mCRC for HER2 amplification should be considered before anti-EGFRab treatment to guide therapy and to identify patients for early referral to clinical trials.
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“the prognostic relevance of ERBB2 amplification itself in mCRC remains controversial.42 43 45”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [43]
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Cites
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455
Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2004088 · Cited by 15,160
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11252 · Cited by 8,499
Bang, Y.-J., Van Cutsem, E., Feyereislova, A., Chung, H. C., Shen, L., Sawaki, A., Lordick, F., Ohtsu, A., Omuro, Y., Satoh, T., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)61121-x · Cited by 7,302
Wolff, A. C., Hammond, M. E. H., Hicks, D. G., Dowsett, M., McShane, L. M., Allison, K. H., Allred, D. C., Bartlett, J. M. S., Bilous, M., Fitzgibbons, P. L., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.50.9984 · Cited by 4,080
Trastuzumab emtansine for HER2-positive advanced breast cancer
Verma, S., Miles, D., Gianni, L., Krop, I. E., Welslau, M., Baselga, J., Pegram, M., Oh, D.-Y., Diéras, V., Guardino, E., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1209124 · Cited by 3,834
Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer
Geyer, C. E., Forster, J. K., Lindquist, D. L., Chan, S. Y. T., Romieu, C. G., Pieńkowski, T., Jagiełło-Gruszfeld, A., Crown, J. P., Chan, A., Kaufman, B., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa064320 · Cited by 3,458
Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer
Douillard, J.-Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M., Humblet, Y., Bodoky, G., Cunningham, D., Jassem, J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1305275 · Cited by 2,263
Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer
Swain, S. M., Baselga, J., Kim, S.-B., Ro, J., Semiglazov, V., Campone, M., Ciruelos, E., Ferrero, J.-M., Schneeweiss, A., Heeson, S., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1413513 · Cited by 2,164
Frampton, G. M., Fichtenholtz, A., Otto, G. A., Wang, K., Downing, S. R., He, J., Schnall-Levin, M., White, J., Sanford, E. M., An, P., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2696 · Cited by 2,157
Sartore-Bianchi, A., Trusolino, L., Martino, C., Bencardino, K., Lonardi, S., Bergamo, F., Zagonel, V., Leone, F., Depetris, I., Martinelli, E., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)00150-9 · Cited by 1,016
Bertotti, A., Migliardi, G., Galimi, F., Sassi, F., Torti, D., Isella, C., Corà, D., Di Nicolantonio, F., Buscarino, M., Petti, C., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0109 · Cited by 939
Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab
Yonesaka, K., Zejnullahu, K., Okamoto, I., Satoh, T., Cappuzzo, F., Souglakos, J., Ercan, D., Rogers, A., Roncalli, M., Takeda, M., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002442 · Cited by 663
Biomarker: Predictive or Prognostic?
Ballman, K. V. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.63.3651 · Cited by 520
Resistance to anti-EGFR therapy in colorectal cancer: From heterogeneity to convergent evolution
Misale, S., Di Nicolantonio, F., Sartore-Bianchi, A., Siena, S., & Bardelli, A. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0462 · Cited by 513
Predictive biomarkers: a paradigm shift towards personalized cancer medicine
Thangue, N. B. L., & Kerr, D. J. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2011.121 · Cited by 340
Assessment of a HER2 scoring system for colorectal cancer: results from a validation study
Valtorta, E., Martino, C., Bianchi, A. S., Penault-Llorca, F. M., Viale, G., Risio, M., Rugge, M., Grigioni, W., Bencardino, K. B., Lonardi, S., et al. (2015) · Modern Pathology · doi:10.1038/modpathol.2015.98 · Cited by 320
HER2 Activating Mutations Are Targets for Colorectal Cancer Treatment
Kavuri, S. M., Jain, N., Galimi, F., Cottino, F., Leto, S. M., Migliardi, G., Searleman, A. C., Shen, W., Monsey, J., Trusolino, L., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-1211 · Cited by 302
Allegra, C. J., Rumble, R. B., Hamilton, S. R., Mangu, P. B., Roach, N., Hantel, A., & Schilsky, R. L. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.63.9674 · Cited by 267
Richman, S. D., Southward, K., Chambers, P., Cross, D., Barrett, J., Hemmings, G., Taylor, M., Wood, H., Hutchins, G., Foster, J. M., et al. (2016) · The Journal of Pathology · doi:10.1002/path.4679 · Cited by 241
Pietrantonio, F., Vernieri, C., Siravegna, G., Mennitto, A., Berenato, R., Perrone, F., Gloghini, A., Tamborini, E., Lonardi, S., Morano, F., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1863 · Cited by 182
Martin, V, Landi, L., Molinari, F., Fountzilas, G., Geva, R., Riva, A., Saletti, P., De Dosso, S., Spitale, A., Tejpar, S., et al. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.4 · Cited by 156
Next-Generation Assessment of Human Epidermal Growth Factor Receptor 2 (ERBB2) Amplification Status
Ross, D. S., Zehir, A., Cheng, D. T., Benayed, R., Nafa, K., Hechtman, J. F., Janjigian, Y. Y., Weigelt, B., Razavi, P., Hyman, D. M., et al. (2016) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2016.09.010 · Cited by 134
Wulfkuhle, J. D., Berg, D., Wolff, C., Langer, R., Tran, K., Illi, J., Espina, V. A., Pierobon, M., Deng, J., DeMichele, A. M., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0452 · Cited by 122
Chemotherapy Usage Patterns in a US-Wide Cohort of Patients With Metastatic Colorectal Cancer
Abrams, T. A., Meyer, G. E., Schrag, D., Meyerhardt, J. A., Moloney, J., & Fuchs, C. S. (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt371 · Cited by 110
Clinical Actionability Enhanced through Deep Targeted Sequencing of Solid Tumors
Chen, K., Meric‐Bernstam, F., Zhao, H., Zhang, Q. C., Ezzeddine, N., Tang, L.-Y., Qi, Y., Mao, Y., Chen, T., Chong, Z., et al. (2015) · Clinical Chemistry · doi:10.1373/clinchem.2014.231100 · Cited by 97
Self-citationRaghav, K. P. S., Morris, V. K., Tang, C. Z., Morelli, P., Amin, H. M., Chen, K., Manyam, G. C., Broom, B. M., Overman, M. J., Shaw, K. R. M., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.10559 · Cited by 76
Self-citationHER2Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma
Bartley, A. N., Washington, M. K., Ventura, C. B., Ismaila, N., Colasacco, C., Benson, A. B., Carrato, A., Gulley, M. L., Jain, D., Kakar, S., et al. (2016) · American Journal of Clinical Pathology · doi:10.1093/ajcp/aqw206 · Cited by 72
Jeong, J. H., Kim, J., Hong, Y. S., Kim, D., Kim, J. E., Kim, S. Y., Kim, K., Yoon, Y., Kim, D., Chun, S., et al. (2017) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2017.01.005 · Cited by 43
Hurwitz, H. I., Raghav, K. P. S., Burris, H. A., Kurzrock, R., Sweeney, C. J., Meric‐Bernstam, F., Vanderwalde, A. M., Spigel, D. R., Bose, R., Fakih, M., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.35.4_suppl.676 · Cited by 38
Self-citationOverman, M. J., Morris, V. K., Kee, B. K., Fogelman, D. R., Xiao, L., Eng, C., Dasari, A. N., Shroff, R. T., Mazard, T., Shaw, K. R. M., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw073 · Cited by 26
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Research works printed but not linked: 2
- Gabriel S, 2009, ., 2, Unit 2.12
- Wulfkuhle JD, 2018, Precis Oncol, 1
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Ciardiello, F., Ciardiello, D., Martini, G., Napolitano, S., Tabernero, J. M., & Cervantes, A. M. R. (2022) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21728 · Cited by 556
Siena, S., Bartolomeo, M. D., Raghav, K. P. S., Masuishi, T., Loupakis, F., Kawakami, H., Yamaguchi, K., Nishina, T., Fakih, M., Élez, E., et al. (2021) · The Lancet Oncology · doi:10.1016/s1470-2045(21)00086-3 · Cited by 436
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Sveen, A., Kopetz, S., & Lothe, R. A. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0241-1 · Cited by 320
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Metadata
- Authors
- Raghav, K., Loree, J. M., Morris, J. S., Overman, M. J., Yu, R., Meric-Bernstam, F., Menter, D., Korphaisarn, K., Kee, B., Muranyi, A., Singh, S., Routbort, M., Chen, K., Shaw, K. R. M., Katkhuda, R., Shanmugam, K., Maru, D., Fakih, M., & Kopetz, S.
- Affiliations
- City Of Hope National Medical Center (US)
- Kanwal Raghav, Jonathan M. Loree, Jeffrey S. Morris, Michael J. Overman, Ruoxi Yu, Funda Meric-Bernstam, David Menter, Krittiya Korphaisarn, Brian Kee, Mark Routbort, Ken Chen, Kenna R.M. Shaw, Riham Katkhuda, Dipen Maru, and Scott Kopetz, The University of Texas MD Anderson Cancer Center, Houston, TX; Andrea Muranyi, Shalini Singh, and Kandavel Shanmugam, Ventana Medical Systems, Tucson, AZ; and Marwan Fakih, City of Hope Comprehensive Cancer Center, Duarte, CA.
- ORCID
- Venue
- JCO Precision Oncology
- Published
- 2019-12
- Volume
- 3
- Issue
- 3
- Pages
- 1-13
- ISSN
- 2473-4284 (ISSN-L)
- OpenAlex
- W2912216712
- Cited by
- 132
- References
- 31
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 24 · 2023: 20 · 2022: 20 · 2021: 9 · 2020: 8 · 2019: 15
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JCO Precision Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- HER2 amplification, metastatic colorectal cancer, anti-EGFR antibody therapy, predictive biomarkers, progression-free survival, RAS/BRAF wild-type, treatment resistance, HER2/CEP17 ratio, next-generation sequencing, anti-EGFR therapy, biomarker validation, prognostic factors
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