Biology and patterns of response to EGFR-inhibition in squamous cell cancers of the lung and head &amp; neck

Juergens, Rosalyn A.; Bratman, Scott V.; Tsao, Ming‐Sound; Laurie, Scott A.; Kuruvilla, M. Sara; Razak, Albiruni R. Abdul; Hansen, Aaron R.

doi:10.1016/j.ctrv.2017.01.003

Cited by 15 publications

(14 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, the combination of radiotherapy with the epidermal growth factor receptor (EGFR) binding antibody cetuximab has shown efficacy and EGFR expression has been associated with poor survival, preferentially in non-accelerated schedules arguing for a role in tumor repopulation (37)(38)(39)(40). The role of EGFR and cellular proliferation in radiotherapy response needs to be further elaborated (41)(42)(43). However proliferation, as determined by the proliferation marker by Starmans et al has been linked to aggressive disease or disease progression in multiple cancer types; unfortunately this was not assessed in HNSCC (44).…”

Section: Introductionmentioning

confidence: 99%

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

View full text Add to dashboard Cite

Purpose: Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. Methods: RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Results: Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 (r = 0.4, p < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8 + T cell abundance and proliferation scores (r = 0.52, 0.56, and 0.6, respectively with p < 0.001). van der Heijden et al. HNSCC Biology Impacting Chemo-Radiotherapy Outcomes Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, p < 0.05) and T-cell infiltration (CD8 + T-cells: HR = 2.2, p < 0.05; CD8 + T-cells/Treg: HR = 2.6, p < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Conclusion: Tumor acute and chronic hypoxia, stem cell-ness, and CD8 + Tcell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC.

show abstract

Section: Introductionmentioning

confidence: 99%

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In HNSCC, cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody therapy, has provided some benefit in the setting of platinum-refractory metastatic and/or recurrent HNSCC, as well as being an addition to radiotherapy for locally or regionally advanced disease (Bonner et al, 2006(Bonner et al, , 2010. However, the activity of EGFR-targeted therapy is modest, predictive biomarkers have not been established, and mortality rates remain high (Juergens et al, 2017). More recently, immune checkpoint inhibitors have shown some promise (Ferris et al, 2016;Seiwert et al, 2016), but only a subset of patients respond, with objective response rates ranging from 11% to 18% (De Meulenaere et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Patient-Derived Xenografts for Prognostication and Personalized Treatment for Head and Neck Squamous Cell Carcinoma

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…EGFR is considered to be an important target for multiple cancer therapies [ 19 , 20 ]. Currently, two different types of EGFR targeted drugs are used in the clinic, therapeutic mAbs which can block the extracellular ligand-binding domain and induce ADCC, and small molecule inhibitors targeting the EGFR signaling cascade [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of 7A7, an anti-mouse EGFR monoclonal antibody proposed to be the mouse equivalent of cetuximab

Cruz

Joseph

et al. 2018

Oncotarget

View full text Add to dashboard Cite

The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer. However, only 15-20% patients benefit from this drug, thus new strategies to improve cetuximab efficiency are required. We aimed to develop a reliable and easy preclinical mouse model to evaluate the efficacy of EGFR-targeted antibodies and examine the immune mechanisms involved in tumour regression. We selected an anti-mouse EGFR mAb, 7A7, which has been reported to be “mouse cetuximab” and to exhibit similar properties to its human counterpart. Unfortunately, we were unable to reproduce previous results obtained with the 7A7 mAb. In our hands, 7A7 failed to recognize mouse EGFR, both in native and reducing conditions. Moreover, in vivo administration of 7A7 in an EGFR-expressing HPV38 tumour model did not have any impact on tumour regression or animal survival. We conclude that 7A7 does not recognize mouse EGFR and therefore cannot be used as the mouse equivalent of cetuximab use in humans. As a number of groups have spent effort and resources with similar issues we feel that publication is a responsible approach.

show abstract

Biology and patterns of response to EGFR-inhibition in squamous cell cancers of the lung and head & neck

Cited by 15 publications

References 106 publications

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Patient-Derived Xenografts for Prognostication and Personalized Treatment for Head and Neck Squamous Cell Carcinoma

Characterization of 7A7, an anti-mouse EGFR monoclonal antibody proposed to be the mouse equivalent of cetuximab

Contact Info

Product

Resources

About