Lung Cancer That Harbors an HER2 Mutation: Epidemiologic Characteristics and Therapeutic Perspectives
Abstract
Purpose: HER2 mutations are identified in approximately 2%of non–small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC. Patients and Methods: We retrospectively identified 65 NSCLC, diagnosed with a HER2 in-frame insertion in exon 20. We collected clinicopathologic characteristics, patients' outcomes, and treatments. Results: HER2 mutation was identified in 65 (1.7%) of 3,800 patients tested and was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. Our population presented with a median age of 60 years (range, 31 to 86 years), a high proportion of women (45 women v 20 men; 69%), and a high proportion of never-smokers (n= 34; 52.3%). All tumors were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti–human epidermal growth factor receptor 2 (HER2) treatments were administered after conventional chemotherapy in 16 patients. Subsequently, four patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate, 50%; disease control rate [DCR], 82%). Specifically, we observed a DCR of 93% for trastuzumab-based therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no response to other HER2-targeted drugs (n = 3). Progression-free survival for patients with HER2 therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively. Conclusion: This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Exon 20 of EGFR and HER2 contains two major regions, the α-C helix and the loop following it.
“Exon 20 of EGFR and HER2 contains two major regions, the α-C helix (residues 762–766 in EGFR and 770–774 in HER2) and the loop following the α-C helix (residues 767–774 in EGFR and 775–783 in HER2)16,19,20,27.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [20]
Cites
Travis, W. D., Brambilla, E. M., Noguchi, M., Nicholson, A. G., Geisinger, K. R., Yatabe, Y., Beer, D. G., Powell, C. A., Riely, G. J., Schil, P. E. V., et al. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318206a221 · Cited by 4,780 · see citing works
Goldstraw, P., Crowley, J., Chansky, K., Giroux, D. J., Groome, P. A., Rami-Porta, R., Postmus, P. E., Rusch, V., & Sobin, L. (2007) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e31812f3c1a · Cited by 3,655 · see citing works
Treatment of HER2-positive breast cancer: current status and future perspectives
Arteaga, C. L., Sliwkowski, M. X., Osborne, C. K., Perez, E. A., Puglisi, F., & Gianni, L. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2011.177 · Cited by 860 · see citing works
Intragenic ERBB2 kinase mutations in tumours
Stephens, P., Hunter, C., Bignell, G., Edkins, S., Davies, H., Teague, J., Stevens, C., O'Meara, S., Smith, R., Parker, A., et al. (2004) · Nature · doi:10.1038/431525b · Cited by 802 · see citing works
Somatic Mutations of the <i>HER2</i> Kinase Domain in Lung Adenocarcinomas
Shigematsu, H., Takahashi, T., Nomura, M., Majmudar, K., Suzuki, M., Lee, H., Wistuba, I. I., Fong, K. M., Toyooka, S., Shimizu, N., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4235 · Cited by 678 · see citing works
Arcila, M. E., Chaft, J. E., Nafa, K., Roy-Chowdhuri, S., Lau, C., Zaidinski, M., Paik, P. K., Zakowski, M. F., Kris, M. G., & Ladanyi, M. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0912 · Cited by 505 · see citing works
Spector, N. L., & Blackwell, K. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.22.1507 · Cited by 497 · see citing works
Gatzemeier, U., Groth, G., Butts, C. A., van Zandwijk, N., Shepherd, F. A., Ardizzoni, A., Barton, C. M., Ghahramani, P., & Hirsh, V. (2003) · Annals of Oncology · doi:10.1093/annonc/mdh031 · Cited by 388 · see citing works
Grève, J. D., Teugels, E., Geers, C., Decoster, L., Galdermans, D., Mey, J. D., Everaert, H., Umelo, I. A., Veld, P. I. '., & Schallier, D. C. C. (2012) · Lung Cancer · doi:10.1016/j.lungcan.2012.01.008 · Cited by 272 · see citing works
HER2Mutation and Response to Trastuzumab Therapy in Non–Small-Cell Lung Cancer
Cappuzzo, F., Bemis, L., & Varella‐Garcia, M. (2006) · New England Journal of Medicine · doi:10.1056/nejmc060020 · Cited by 216 · see citing works
Chipping away at the lung cancer genome
Pao, W. J., & Hutchinson, K. E. (2012) · Nature Medicine · doi:10.1038/nm.2697 · Cited by 192 · see citing works
Perera, S. A., Li, D., Shimamura, T., Raso, M. G., Ji, H., Chen, L., Borgman, C. L., Zaghlul, S., Brandstetter, K. A., Kubo, S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808930106 · Cited by 185 · see citing works
Heinmöller, P., Groß, C., Beyser, K., Schmidtgen, C., Maass, G., Pedrocchi, M., & Rüschoff, J. (2003) · PubMed · Cited by 182 · see citing works
Buttitta, F., Barassi, F., Fresu, G., Felicioni, L., Chella, A., Paolizzi, D., Lattanzio, G., Salvatore, S., Camplese, P. P., Rosini, S., et al. (2006) · International Journal of Cancer · doi:10.1002/ijc.22143 · Cited by 180 · see citing works
Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers
Tomizawa, K., Suda, K., Onozato, R., Kosaka, T., Endoh, H., Sekido, Y., Shigematsu, H., Kuwano, H., Yatabe, Y., & Mitsudomi, T. (2011) · Lung Cancer · doi:10.1016/j.lungcan.2011.01.014 · Cited by 151 · see citing works
Ménard, S., Casalini, P., Campiglio, M., Pupa, S. M., Agresti, R., & Tagliabue, E. (2001) · Annals of Oncology · doi:10.1093/annonc/12.suppl_1.s15 · Cited by 149 · see citing works
Liu, L., Shao, X., Gao, W., Bai, J., Wang, R., Huang, P., Yin, Y., Liu, P., & Shu, Y. (2010) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181f26266 · Cited by 140 · see citing works
Shimamura, T., Ji, H., Minami, Y., Thomas, R. K., Lowell, A. M., Shah, K., Greulich, H. E., Glatt, K. A., Meyerson, M. M., Shapiro, G. I., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0971 · Cited by 135 · see citing works
Ross, H. J., Blumenschein, G. R., Aisner, J., Damjanov, N., Dowlati, A., Garst, J. L., Rigas, J. R., Smylie, M., Hassani, H., Allen, K. E., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-3328 · Cited by 121 · see citing works
Lara, P. N., Laptalo, L., Longmate, J., et al. (2004) · Clinical Lung Cancer · doi:10.3816/clc.2004.n.004 · Cited by 111 · see citing works
Pellegrini, C., Falleni, M., Marchetti, A., Cassani, B., Miozzo, M. R., Buttitta, F., Roncalli, M. G., Coggi, G., & Bòsari, S. (2003) · PubMed · Cited by 109 · see citing works
Li, C., Sun, Y., Fang, R., Han, X., Luo, X., Wang, R., Pan, Y., Hu, H., Zhang, Y., Pao, W. J., et al. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318234f0a2 · Cited by 95 · see citing works
Characteristics of lung cancer in women: Importance of hormonal and growth factors
Rouquette, I., Lauwers‐Cancès, V., Allera-Moreau, C., Brouchet, L., Milia, J., Nicaise, Y., Laurent, J., Delisle, M., Favre, G., Didier, A. P., et al. (2011) · Lung Cancer · doi:10.1016/j.lungcan.2011.11.023 · Cited by 53 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
The biology and management of non-small cell lung cancer
Herbst, R. S., Morgensztern, D., & Boshoff, C. (2018) · Nature · doi:10.1038/nature25183 · Cited by 4,891 · see citing works
Cell death-based treatment of lung adenocarcinoma
Denisenko, T. V., Budkevich, I. N., & Zhivotovsky, B. (2018) · Cell Death & Disease · doi:10.1038/s41419-017-0063-y · Cited by 768 · see citing works
Meric-Bernstam, F., Hurwitz, H., Raghav, K. P. S., McWilliams, R. R., Fakih, M., VanderWalde, A., Swanton, C., Kurzrock, R., Burris, H., Sweeney, C., et al. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30904-5 · Cited by 573 · see citing works
Robichaux, J. P., Elamin, Y. Y., Tan, Z., Carter, B. W., Zhang, S., Liu, S., Li, S., Chen, T., Poteete, A., Estrada-Bernal, A., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0007-9 · Cited by 468 · see citing works
Kris, M. G., Camidge, D. R., Giaccone, G., Hida, T., Li, B. T., O'Connell, J., Taylor, I., Zhang, H., Arcila, M. E., Goldberg, Z., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv186 · Cited by 334 · see citing works
HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers
Li, B. T., Ross, D. S., Aisner, D. L., Chaft, J. E., Hsu, M., Kako, S. L., Kris, M. G., Varella-Garcia, M., & Arcila, M. E. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2015.10.025 · Cited by 286 · see citing works
Molecular pathways and therapeutic targets in lung cancer
Shtivelman, E., Hensing, T., Simon, G. R., Dennis, P. A., Otterson, G. A., Bueno, R., & Salgia, R. (2014) · Oncotarget · doi:10.18632/oncotarget.1891 · Cited by 220 · see citing works
“Responses were observed with trastuzumab and afatinib [102, 107] but not with other EGFR-family-targeted drugs such as gefitinib or lapatinib [108, 109].”
BackgroundResultKim, S.-Y., Kim, S.-M., Lim, S., Lee, J. Y., Choi, S.-J., Yang, S.-D., Yun, M. R., Kim, C. G., Gu, S. R., Park, C., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-5026 · Cited by 151 · see citing works
NSCLC and HER2: between lights and shadows
Ricciardi, G. R. R., Russo, A., Franchina, T., Ferraro, G., Zanghì, M., Picone, A., Scimone, A., & Adamo, V. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000379 · Cited by 78 · see citing works
Han, H., Li, S., Chen, T., Fitzgerald, M., Liu, S., Peng, C., Tang, K. H., Cao, S., Chouitar, J., Wu, J., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-1526 · Cited by 57 · see citing works
Goss, G. D., Felip, E., Cobo, M., Lu, S., Syrigos, K., Lee, K. H., Göker, E., Georgoulias, V., Li, W., Guclu, S., et al. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2018.0775 · Cited by 55 · see citing works
Self-citation
- Authors
- Mazières, J., Peters, S., Lepage, B., Cortot, A. B., Barlesi, F., Beau-Faller, M., Besse, B., Blons, H., Mansuet-Lupo, A., Urban, T., Moro-Sibilot, D., Dansin, E., Chouaid, C., Wislez, M., Diebold, J., Felip, E., Rouquette, I., Milia, J. D., & Gautschi, O.
- Affiliations
- Université Toulouse III - Paul Sabatier (FR)
- Julien Mazières, Julie D. Milia, Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse III (Paul Sabatier); Benoit Lepage, Centre Hospitalier Universitaire Toulouse; Isabelle Rouquette, Hôpital Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse; Alexis B. Cortot, Centre Hospitalier Universitaire de Lille; Eric Dansin, Centre Oscar Lambret, Lille; Fabrice Barlesi, Hôpital Nord, Marseille; Michéle Beau-Falle, Hôpital de Hautepierre, Centre Hospitalier...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2013-06-01
- Volume
- 31
- Issue
- 16
- Pages
- 1997-2003
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2112854176
- Cited by
- 668
- References
- 23
- Citations by year
- 2026: 14 · 2025: 35 · 2024: 40 · 2023: 40 · 2022: 50 · 2021: 62 · 2020: 49 · 2019: 41 · 2018: 52 · 2017: 63 · 2016: 53 · 2015: 86 · 2014: 59 · 2013: 21 · 2012: 1
- FWCI
- 59.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-PHUC-0001)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- HER2 mutation, non-small cell lung cancer, lung adenocarcinoma, HER2 exon 20 insertion, HER2-targeted therapy, trastuzumab, afatinib, progression-free survival, disease control rate, never smokers, KRAS mutation, driver mutations
- MeSH terms
- Trastuzumab, Lapatinib, Afatinib, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, France, Humans, Lung Neoplasms, Male, Middle Aged, Neoplasm Staging, Quinazolines, Retrospective Studies, Spain, Switzerland, Gene Expression Regulation, Neoplastic, Mutagenesis, Insertional, Treatment Outcome, In Situ Hybridization, Fluorescence, Disease-Free Survival, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Kaplan-Meier Estimate, Molecular Targeted Therapy, Antibodies, Monoclonal, Humanized
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
