NSCLC and HER2: between lights and shadows

Ricciardi, Giuseppina Rosaria Rita; Russo, Alessandro; Franchina, Tindara; Ferraro, Giuseppa; Zanghì, Mariangela; Picone, Antonio; Scimone, Antonino; Adamo, Vincenzo

doi:10.1097/jto.0000000000000379

Cited by 78Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Research Studies

NSCLC and HER2: between lights and shadows

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Ricciardi, Giuseppina Rosaria Rita, Russo, Alessandro, Franchina, Tindara, Ferraro, Giuseppa, Zanghì, Mariangela, Picone, Antonio, Scimone, Antonino, Adamo, Vincenzo·2014·Journal of Thoracic Oncology

DOI 10.1097/jto.0000000000000379

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Abstract

The therapeutic landscape of non-small-cell lung cancer (NSCLC) has dramatically changed in the last few years with the introduction of molecularly targeted agents, leading to unprecedented results in lung tumors with a paradigmatic shift from a "one size fits all" approach to an histologic and molecular-based approach. The discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC in 2004 and the marked response to the EGFR tyrosine kinase inhibitor gefitinib, in a small subset of patients harboring these genetic abnormalities, stimulated the study of other kinase mutants involvement in NSCLC. The incredible story of ALK rearranged tumors, with the rapid Food and Drug Administration approval of Crizotinib after only 4 years from the discovery of EML4-ALK translocation in NSCLC, has profoundly influenced the concept of drug development in NSCLC, paving the way to a novel series of molecularly selected studies with specific inhibitors. The identification of these oncogenic drivers has dramatically changed the genetic landscape of NSCLC moving away from the old concept of a large indistinct histological entity to a combination of rare clinically relevant molecular subsets. Recently, a renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time to be associated in NSCLC with different sensitivity to the EGFR tyrosine kinase inhibitors, to have a possible prognostic role and more recently HER2 amplification has been emerged as a possible mechanism in EGFR-mutated tumors of acquired resistance to the EGFR tyrosine kinase inhibitors. In addition, dysregulation of the HER2 pathway, in particular HER2 mutations (mostly, in-frame exon 20 insertions), may represent a possible novel therapeutic target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC patients with HER2 mutations, several targeted agents have been evaluated in HER2-mutated patients, generating a growing interest upon this oncogenic driver, leading to the design of molecularly selected trials with anti-HER2 compounds and the rediscover of hastily thrown out drugs, such as neratinib. The aim of this article is to provide an overview of the role of HER2 dysregulation in NSCLCs, trying to throw a light not only on the strengths but also the weaknesses of the studies conducted so far. It is a long way to the clinical implementation of these biomarkers and probably the increasing use of next generation sequencing techniques, the creation of large multi-institutional molecular testing platforms and the design of rationally based trials can get closer personalized medicine in NSCLC.

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Before EGFR mutations emerged as the major predictive factor, several predictive biomarkers such as EGFR overexpression/amplification and HER2 overexpression/amplification were studied.
“In attempt to identify patients with improved outcome when treated with EGFR TKIs, several predictive biomarkers, such as EGFR overexpression/amplification [59] and HER2 overexpression/amplification [60], were studied before EGFR mutations emerged as the major predictive factor to these targeted agents.”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [60]

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Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors
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
A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives
Russo, A., Franchina, T., Rita Ricciardi, G. R., Picone, A., Ferraro, G., Zanghì, M., Toscano, G., Giordano, A., & Adamo, V. (2015) · Oncotarget · doi:10.18632/oncotarget.4254 · Cited by 173 · see citing works
Self-citation

Authors: Ricciardi, G. R. R., Russo, A., Franchina, T., Ferraro, G., Zanghì, M., Picone, A., Scimone, A., & Adamo, V.
Affiliations: University of Messina (IT)
ORCID: Ricciardi, Giuseppina Rosaria Rita
Russo, Alessandro
Franchina, Tindara
Picone, Antonio
Adamo, Vincenzo
Venue: Journal of Thoracic Oncology
Publisher: Elsevier BV
Published: 2014-12
Volume: 9
Issue: 12
Pages: 1750-1762
ISSN: 1556-0864 (ISSN-L)
DOI: 10.1097/jto.0000000000000379
OpenAlex: W2082664617
Cited by: 78
References: 109
Citations by year: 2026: 3 · 2025: 6 · 2024: 4 · 2023: 8 · 2022: 10 · 2021: 8 · 2020: 12 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 5 · 2015: 5
FWCI: 0.91
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
Locations: Journal of Thoracic Oncology (publishedVersion)
PubMed (publishedVersion)
INFM-OAR (INFN Catania) (submittedVersion, other-oa)
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: non-small cell lung cancer, HER2, HER2 mutation, HER2 amplification, EGFR tyrosine kinase inhibitors, gefitinib, acquired drug resistance, neratinib, targeted therapy, molecular subtyping, biomarkers, ALK rearrangement, crizotinib, EML4-ALK fusion, HER2 exon 20 insertion, predictive biomarkers
MeSH terms: Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Signal Transduction, Erb-b2 Receptor Tyrosine Kinases

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NSCLC and HER2: between lights and shadows

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