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Original Investigation |

Identification of Targetable ERBB2 Aberrations in Head and Neck Squamous Cell Carcinoma

Andrew C. Birkeland, MD1; Megan Yanik, BS2; Brittny N. Tillman, MD1; Megan V. Scott, BS2; Susan K. Foltin, BS1; Jacqueline E. Mann, BS1; Nicole L. Michmerhuizen, BS1; Megan L. Ludwig, BS1; Morgan M. Sandelski, BS2; Christine M. Komarck, BS1; Thomas E. Carey, PhD1,3; Mark E. P. Prince, MD1,3; Carol R. Bradford, MD1,3; Jonathan B. McHugh, MD4; Matthew E. Spector, MD1,3; J. Chad Brenner, PhD1,3
[+] Author Affiliations
1Department of Otolaryngology–Head and Neck Surgery, University of Michigan Medical School, Ann Arbor
2medical student, University of Michigan Medical School, Ann Arbor
3Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor
4Department of Pathology, University of Michigan Medical School, Ann Arbor
JAMA Otolaryngol Head Neck Surg. 2016;142(6):559-567. doi:10.1001/jamaoto.2016.0335.
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Importance  ERBB2 (formerly HER2) is an important drug target in breast cancer, where anti-ERBB2 therapy has been shown to lead to improvements in disease recurrence and overall survival. ERBB2 status in head and neck squamous cell carcinoma (HNSCC) has not been well studied. Identification of ERBB2-positive tumors and characterization of response to ERBB2 therapy could lead to targeted treatment options in HNSCC.

Objective  To identify ERBB2 aberrations in HNSCCs and investigate the potential for ERBB2-targeted therapy in HNSCCs.

Design, Setting, and Participants  A retrospective case series of patients with laryngeal (42 tumor specimens) and oral cavity (94 tumor specimens) SCC enrolled in the University of Michigan Head and Neck Specialized Program of Research Excellence was conducted. Publicly available sequencing data (The Cancer Genome Atlas), as well as data from other studies, were reviewed to identify additional mutations and overexpression in ERBB2 in HNSCC. Established HNSCC cell lines were used for follow-up in vitro analysis. The study was conducted from October 1, 2014, to August 30, 2015.

Interventions  With the use of targeted, amplicon-based sequencing with the Oncomine Cancer Panel, the copy number and mutation status of commonly altered genes in HNSCCs were assessed. Immunohistochemical staining was performed on tissue microarrays of HNSCCs to assess the expression of ERBB2. Western blotting for HNSCC cell line ERBB2 expression and cell survival assays after treatment with ERBB2 inhibitors were performed.

Main Outcomes and Measures  The prevalence of ERBB2 genetic aberrations and ERBB2 overexpression in laryngeal and oral cavity SCCs, prevalence of ERBB2 aberrations in HNSCC in The Cancer Genome Atlas, ERBB2 protein expression in HNSCC cell lines, and response of HNSCC cell lines to targeted ERBB2 inhibitors.

Results  Of the 42 laryngeal SCC samples screened by targeted sequencing, 4 (10%) were positive for ERBB2 amplification. Two of these samples showed ERBB2 overexpression on immunohistochemistry. Two of the 94 oral cavity SCC samples (2%) were positive for ERBB2 on immunohistochemistry. Analysis of 288 patients from publicly available HNSCC sequencing data revealed 9 amplifications (3%) in ERBB2. Protein expression was variable across HNSCC cell lines, and a subset of these cell lines showed responsiveness to anti-ERBB2 therapy.

Conclusions and Relevance  ERBB2 aberrations were identified in a subset of HNSCCs. These tumors may be responsive to targeted therapy against ERBB2. Screening for ERBB2 aberrations and applying targeted therapy in ERBB2-positive patients may be useful in personalized therapy trials, particularly in patients who are refractory to current treatment paradigms.

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Figure 1.
Copy Number Analysis of ERBB2-Positive Laryngeal Cancer Samples

Genes from the comprehensive Oncomine Cancer Panel were assessed for relative copy number by Ion Torrent sequencing. Genes are plotted along the x-axis beginning with chromosome 1 and ending with the X chromosome. Each color represents probe sets for an individual gene, and each point represents an individual probe. Only statistically differential genes are highlighted, with amplified genes in green text and depleted genes in purple text. CN indicates copy number.

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Figure 2.
ERBB2 Immunohistochemistry Demonstrates Protein Overexpression in Head and Neck Squamous Cell Carcinoma (SCC)

ERBB2 overexpression is demonstrated in laryngeal SCC (A) and oral cavity SCC (C) samples. Corresponding stains were performed (hematoxylin-eosin, original magnification ×40) (B and D). Representative images of positive cases were used to demonstrate staining.

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Figure 3.
ERBB2 Expression in The Cancer Genome Atlas (TCGA) Head and Neck Squamous Cell Carcinoma (HNSCC) Data Sets

ERBB2 amplifications are identified in specific HNSCC samples. A, Using the TCGA data, copy number was plotted along on a log scale such that points (each representing individual patients) to the right of the dotted blue line had statistically significant increases in ERBB2 copy number. RNA overexpression of ERBB2 is also identified in these HNSCC samples. B, Using the TCGA data, we stratified patients by disruptive genomic events in each of the 4 ERBB genes. Color represents the type of genomic aberration as indicated. C, Comparison of RNA expression of ERBB2 and EGFR across breast cancer, cervical SCC, and HNSCC. D, Mutations in ERBB2 and other members of the EGFR family are also identified (B and D), and the distribution of mutations in ERBB2 is shown in the schematic. The line across the middle represents the length of the gene. N indicates N terminus; C, C terminus; and TM, transmembrane domain.

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Figure 4.
ERBB2 Protein Expression in Head and Neck Squamous Cell Carcinoma (SCC) Cell Lines

ERBB2 and EGFR levels across multiple oral cavity SCC (UM-SCC-1, -2, -14A, -23, -49, -59, -92, -97, -103, -108, and -110) and laryngeal SCC (UM-SCC-23) cell lines. Overexpression of ERBB2 was seen in UM-SCC-1 in comparison with the remaining cell lines. β-Actin was used to demonstrate overall protein level normalization.

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Figure 5.
Response of Head and Neck Squamous Cell Carcinoma (SCC) Cell Lines to ERBB2 Inhibitors

A-D, A subset of University of Michigan (UM)-SCC cell lines demonstrated sensitivity to ERBB2 tyrosine kinase inhibitors. In our panel of cell lines, UM-SCC-1, UM-SCC-110, and, to a lesser extent, UM-SCC-23 demonstrated sensitivity to ERBB2 inhibitors currently in clinical trials. CP724714 (C) is a ERBB2-specific inhibitor; the remaining inhibitors have some combination inhibition of EGFR as well. UM-SCC-1 showed significantly higher ERBB2 expression and appeared to be the most responsive of the UM-SCC cell lines.

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