Download Genomic alterations in human epidermal growth factor receptor 2

CASE REPORT
Genomic alterations in human epidermal growth factor receptor 2 (HER2/ERBB2) in
head and neck squamous cell carcinoma
Christine H. Chung, MD,1,2,3* Alexis Germain, BS,4 Rathan M. Subramaniam, MD, PhD,5 Andreas M. Heilmann, PhD,4 Kyle Fedorchak, BS,4
Siraj M. Ali, MD, PhD,4 Vincent A. Miller, MD,4 Robert A. Palermo, MD,6 Carole Fakhry, MD, MPH2
1
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 2Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins
University School of Medicine, Baltimore, Maryland, 3Department of Head and Neck–Endocrine Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, 4Foundation
Medicine, Cambridge, Massachusetts, 5Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 6Department of Pathology, Greater Baltimore Medical Center, Baltimore, Maryland.
Accepted 5 August 2016
Published online 21 September 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24587
ABSTRACT: Background. Despite recent advances, survival outcomes
for those with metastatic or recurrent head and neck squamous cell carcinoma (HNSCC) have remained poor. Novel approaches should be
investigated to improve outcomes.
Methods. A retrospective chart review was performed of a patient
who presented with a TNM classification III HNSCC of the oropharynx,
positive for human papillomavirus (HPV) who had a complete
response to a human epidermal growth factor receptor 2 (HER2)-targeted therapy. Amplification rates of HER2 in the HNSCC Cancer Genome
Atlas Network (TCGA) dataset and the FoundationOne genomic profiling
dataset were evaluated.
INTRODUCTION
Head and neck squamous cell carcinoma (HNSCC) arises
from heterogeneous anatomic mucosal sites, including the
oral cavity, pharynx, and larynx. HNSCC is the sixth
most common malignancy globally, with an annual incidence of over half a million cases.1 Risk factors include
tobacco, alcohol use, and oral human papillomavirus
(HPV) infection, particularly in the oropharynx.2,3 Prognosis for HNSCC is dependent upon anatomic site and
stage, but tends to be poor in the setting of recurrent/metastatic HNSCC.4 Despite recent advances, the 2-year survival rate for patients with recurrent or metastatic
HNSCC has not improved significantly, remaining
between 28% and 55%.4,5 The current standard of care
*Corresponding author: C. H. Chung, Department of Head and Neck–
Endocrine Oncology, Moffitt Cancer Center and Research Institute, 12902
Magnolia Drive FOB-2, Suite #5.2106, Tampa, FL 33612. E-mail: christine.
[email protected]
Conflict of Interest: A.G., A.H., K.F., S.M.A., and V.A.M. are employees of
Foundation Medicine. C.H.C. received research funding from Boehringer
Ingelheim for preclinical research and honoraria from Bristol-Myers Squibb
and Lilly Oncology for serving in scientific advisory boards. All other authors
have no conflict of interest to declare.
Results. Comprehensive genomic profiling of the tumor obtained from
the dermal metastasis identified amplification of HER2. Data from TCGA
and FoundationOne showed that the frequency of HER2 alteration was
not observed to vary significantly with HPV tumor status.
Conclusion. This case demonstrates the application of genomic profiling
to guide treatments in a patient with HNSCC with advanced metastatic
C 2016 Wiley Periodidisease refractory to standard of care therapies. V
cals, Inc. Head Neck 39: E15–E19, 2017
KEY WORDS: head and neck squamous cell carcinoma, human epidermal growth factor receptor 2 (HER2), genomic profiling, trastuzumab, biomarker
for patients with metastatic HNSCC is palliative chemotherapy and/or cetuximab with supportive care.5,6
The observation that epidermal growth factor receptor
(EGFR) is overexpressed in 80% to 90% of patients with
HNSCC prompted initial investigations into utilizing
EGFR-targeted therapy in this disease.7,8 To date, the antiEGFR monoclonal antibody, cetuximab, is the only Food
and Drug Administration-approved targeted agent in the
management of recurrent HNSCC that has been shown to
improve overall survival when given with platinum and 5fluorouracil.5 However, genomic alterations, such as gainof-function EGFR mutations are extremely rare, and EGFR
amplification, although identified more frequently, has not
been associated with increased response or survival in
patients treated with cetuximab and other EGFR-targeted
agents.9–11 To build upon the experience gained from successful development of cetuximab and continued attempts
to identify predictive biomarkers of clinical benefit for
EGFR inhibitors, we need to further investigate potential
oncogenic drivers and utilize the genomic data to identify
targeted agents in HNSCC. In this study, we report on the
case of a patient with amplification of known oncogene,
human epidermal growth factor receptor 2 (HER2/ERBB2),
detected through comprehensive genomic profiling, that
responded to an HER2-targeted therapy in combination
with chemotherapy.
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CASE REPORT
A 52-year-old man with an 8 pack-year smoking history
presented with a left tonsillar squamous cell carcinoma, T
classification 3, N classification 1, M classification 0, and
positive for HPV type 16 by in situ hybridization. The
patient was treated with cisplatin, 5-fluorouracil, and radiotherapy as standard of care.12 However, 2 years after the
completion of the primary chemoradiation regimen, he
experienced a local recurrence involving the ipsilateral tonsil, which was treated with a radical tonsillectomy. Negative margins were achieved. Six months later, the patient
had a regional recurrence. He underwent a neck dissection
of levels I to IV. A single node in level II was positive for
squamous cell carcinoma with extracapsular extension. Four
months later, he was found to have a solitary lung metastasis, which was treated with thoracotomy and wedge resection. Approximately 8 months later, he developed another
neck recurrence in the left level IV. Subsequent neck dissection identified 5 malignant lymph nodes with extracapsular extension, perineural invasion, and lymphovascular
invasion. He received postoperative carboplatin, paclitaxel,
and radiation concurrently. However, within 8 months, he
developed recurrence involving subcarinal and hilar lymph
nodes. The patient participated in a phase I melanoma antigen E-A3 and HPV16-specific vaccine trial13 but the disease continued to progress. Five months after completion of
this trial, he developed a dermal metastasis with extension
into the parotid gland and underwent local resection, reconstruction, and brachytherapy. Within a month, he developed
new dermal metastatic nodules along the surgical scar. The
patient was experiencing pain and fatigue and assessed as
having an Eastern Cooperative Oncology Group performance status of 1. At this point, a dermal metastasis was
submitted for comprehensive genomic profiling.
An excision of a dermal metastasis was submitted for histopathology as well as comprehensive genomic profiling
using the FoundationOne assay (Foundation Medicine, Cambridge, MA). Hybridization capture of 3734 exons from 236
cancer-related genes and 47 introns of 19 genes commonly
rearranged in cancer was applied to 50 ng of DNA
extracted from the formalin-fixed paraffin-embedded tumor
and sequenced to a median coverage depth of 3639.14
Comprehensive genomic profiling of the dermal metastasis identified HER2 amplification (13 copies), RICTOR
amplification, MLL2 E766*, and FGF10 amplification.
The HER2 amplification and corresponding overexpression
were confirmed with immunohistochemistry (Her2-neu,
clone 4B5 rabbit monoclonal antibody; Figure 1A) and
fluorescent in situ hybridization (karyotype: nuc
ish 17cen[D17Z1 3 1–4], 17q11.2[HER-2 3 2–17]20;
Figure 1B) although concordance between FoundationOne
and fluorescent in situ hybridization has been established.14
The patient was treated with trastuzumab and paclitaxel
and achieved complete response confirmed by positron
emission tomography (PET) and CT scans (Figure 1C and
1D). Approximately 8 months after initiation of the palliative regimen, the patient’s disease progressed (Figure 1E).
DISCUSSION
This case demonstrates the use of trastuzumab to
achieve a complete response in a patient with advanced
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metastatic disease, demonstrating efficacy of anti-HER2
targeted therapy in HER2-amplified HPV-positive
HNSCC. HPV positivity defines a subset of patients with
HNSCC with a more favorable outcome than HPVnegative patients independent of clinical prognostic factors, with better overall survival and reduced likelihood
of recurrence.15–17 This has been attributed to increased
response to chemoradiation and the lack of field cancerization seen in generally tobacco-induced HPV-negative
HNSCC.18 Recent genomic data supports the differentiation of HNSCC as 2 clinically distinct entities stratified
by the HPV tumor status, which inherently has implications for use of targeted therapy.9,19,20
HER2 (ERBB2), a member of the ErbB/EGFR family,
encodes the receptor tyrosine kinase, HER2. Overexpression of HER2 has been observed in 7% to 39% of
patients with HNSCC, a wide range likely, in part, due to
variations in immunohistochemical methodology.21
The variations in the quantification of protein expression
levels depending on the sample fixation and processing,
specificity and sensitivity of the antibodies, immunohistochemical staining methods, interpretative errors, etc., have
been identified as major problems in biomarker development.22–25 Studies indicate that patients with HNSCC
with HER2 alterations exhibit shorter overall survival and
increased likelihood of recurrence.26 Despite frequent
overexpression of HER2, genomic alterations of this gene
are uncommon.9 In the HNSCC Cancer Genome Atlas
Network dataset of 279 patients, putative high-level
amplification of HER2 was reported in 2.2% of samples,
and mutation in 1.8% (cBioPortal, August 2015).12 Data
from FoundationOne genomic profiling of 619 HNSCC
cases was also analyzed to compare the frequency of
HER2 amplification and mutation between HPV-positive
and HPV-negative cases (Table 1). The frequency of
HER2 alteration was not observed to vary significantly
with HPV tumor status (p 5 .91), and was not statistically different from the The Cancer Genome Atlas (TCGA)
dataset in either amplifications (p 5 .45) or mutations (p
5 .28). The relationship between primary site and HPV
status was additionally evaluated (Table 2). Consistent
with other reports, HPV positivity was strongly associated
with HNSCC tumors arising from oropharyngeal primary
sites compared with those from other regions of the head
and neck (p < .00001).15,27
Trastuzumab is a monoclonal antibody that targets the
extracellular domain of HER2. It has most commonly
been used to treat gastric and breast cancers, although
successful cases of its use in other HER2-amplified cancers have been reported.28–31 Some have postulated that
HER2 may be a potential target in HNSCC in general
due to its frequent overexpression, but an early study that
treated patients with a combination of trastuzumab, platinum, and paclitaxel showed no increase in response rate
with the addition of trastuzumab to a platinum-based chemotherapy regimen. None of the patients involved in this
trial had alteration or amplification of HER2, and so the
lack of response is not surprising.32 HER2 amplification
has been shown to be the most reliable predictor of
response to trastuzumab.33
The impressive response to trastuzumab in this patient
highlights the significance of genomic profiling in
HER2
ALTERATIONS IN
HNSCC
FIGURE 1. (A) ERBB2 (human epidermal
growth factor receptor 2 [HER2]) immunohistochemical 21, (B) ERBB2 (HER2)
fluorescence in situ hybridization
amplified, (C) positron emission tomography (PET) scan before trastuzumab
and paclitaxel treatment, (D) PET scan
after 9 weeks of trastuzumab and paclitaxel treatment, and (E) PET scan at
8 months after initiating trastuzumab
and paclitaxel treatment.
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TABLE 1. Frequency of ERBB2 amplifications and mutations in 619 head and neck squamous cell carcinoma from FoundationOne genomic profiling
sorted by primary sites and human papillomavirus status.
Oropharynx; HPV-positive
Oropharynx; HPV-negative
Nonoropharynx; HPV-positive
Nonoropharynx; HPV-negative
Total oropharynx
Total nonoropharynx
Total HPV-positive
Total HPV-negative
Total no. of
HNSCC cases
No. of cases with
ERBB2 amplification
No. of cases with an
activating ERBB2 mutation
No. of total cases with
ERBB2 alteration
170
88
35
326
258
361
205
414
3 (1.76%)
1 (1.14%)
0 (0%)
5 (1.53%)
4 (1.55%)
5 (1.38%)
3 (1.46%)
6 (1.45%)
6 (3.53%)
1 (1.14%)
0 (0%)
12 (3.68%)
7 (2.71%)
12 (3.32%)
6 (2.92%)
13 (3.14%)
9 (5.29%)
2 (2.27%)
0 (0%)
17 (5.20%)
11 (4.26%)
17 (4.71%)
9 (4.39%)
19 (4.59%)
Abbreviations: HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus.
advanced metastatic head and neck cancer to identify targetable alterations. Beyond the established agent, trastuzumab, a number of other anti-HER2 targeted therapies
may also have potential for use in patients with HNSCC
with HER2 amplification or activation, such as presented
here. Pertuzumab and lapatinib have been used to target
HER2 in breast cancer, and afatinib has been used in the
lungs. Particularly, the ErbB family inhibitor, afatinib,
has been explored in phase II and III trials in HNSCC
and exhibited improved progression-free survival over
chemotherapy in second-line and antitumor activity comparable to that of cetuximab.34,35 Thus, the identification
of HER2 amplification may be valuable in providing multiple potentially effective therapeutic options. Furthermore, the approach shown here has potential for
application in other forms of head and neck disease. In
particular, HER2 amplification has been observed in as
many as 38.5% of salivary duct carcinomas.36,37 Two separate case studies have shown successful treatment of this
diagnosis using trastuzumab.38,39
However, the limitation of targeted therapies has been
development of resistance even after achieving initial
complete response. This patient developed progression of
disease after approximately 8 months of the trastuzumabcontaining regimen. The exact resistance mechanism is
unclear because the patient was deceased without a repeat
biopsy at the time of progression. One can speculate an
emergence of a resistant clone with oncogenic dependency in the phosphotidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway as the patient’s
tumor exhibited RICTOR amplification. Some studies
have shown alterations within the PI3K/mTOR pathway,
TABLE 2. The number of cases of head and neck squamous cell
carcinoma from FoundationOne genomic profiling sorted by primary
sites and human papillomavirus status.
Oropharynx
Nonoropharynx
No. of HNSCC
cases
No. of
HPV-positive
cases
No. of
HPV-negative
cases
258
361
170 (65.9%)
35 (9.7%)
88 (34.1%)
326 (90.3%)
Abbreviations: HNSCC, head and neck squamous cell carcinoma; HPV, human
papillomavirus.
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such as PIK3CA gain-of-function mutations or phosphatase and tensin homolog loss, to be characteristic of
HPV-positive HNSCC and one of the resistance mechanisms of trastuzumab.19,40,41 Additional possible mechanism of the HER2 inhibitor resistance is shifting the
growth signal to other ErbB/EGFR family members, such
as EGFR, HER3, or HER4. Therefore, a therapeutic
approach to combine the ErbB/EGFR family receptor
inhibitors with PI3K/mTOR inhibitors or completely
block the ErbB/EGFR pathway by combining EGFR and
HER2 inhibitors may be explored.
Although genomic testing is highly promising, clinical
implementation of genomic alteration-based treatment
selection is still in its developmental phase. The main challenges are conducting trials in patients with rare genomic
alterations and relatively uncommon cancers, such as
HER2 in HNSCC and salivary duct carcinoma. This challenge is potentially alleviated by testing the efficacy of
therapeutic agents in multiple tumor types with a common
alteration. Prospective evaluation of clinical trials enrolling
patients based on the genomic alteration rather than organ
sites of the disease is ongoing at Eastern Cooperative
Oncology Group-ACRIN Cancer Research Group
(MATCH, NCT02465060) and the National Cancer Institute (NCT01827384). Support and further development of
such innovative trials must be a priority.
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