Clinical and molecular characterization of HER2amplified-pancreatic cancer
- Angela Chou†1, 2, 3,
- Nicola Waddell†6,
- Mark J Cowley†1, 3,
- Anthony J Gill1, 4, 5,
- David K Chang1, 12, 13,
- Ann-Marie Patch6,
- Katia Nones6,
- Jianmin Wu1, 3,
- Mark Pinese1, 3,
- Amber L Johns1,
- David K Miller6,
- Karin S Kassahn6,
- Adnan M Nagrial1, 3,
- Harpreet Wasan7,
- David Goldstein8,
- Christopher W Toon4, 5, 9,
- Venessa Chin1, 3,
- Lorraine Chantrill1, 3, 10,
- Jeremy Humphris1,
- R Scott Mead1, 2, 3,
- Ilse Rooman1, 3,
- Jaswinder S Samra11,
- Marina Pajic1, 3,
- Elizabeth A Musgrove1, 12,
- John V Pearson6,
- Adrienne L Morey2Email author,
- Sean M Grimmond6, 12Email author and
- Andrew V Biankin1, 12, 13Email author
© Chou et al.; licensee BioMed Central Ltd. 2013
Received: 11 June 2013
Accepted: 23 August 2013
Published: 31 August 2013
Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.
HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).
An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.
HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.
Pancreatic cancer is the fourth leading cause of cancer death in western societies, with a 5-year survival rate of less than 5% . Systemic therapies are only modestly effective; however, there is emerging evidence that small groups of patients may respond well to specific treatments [2, 3]. Current therapeutic development is focused on targeting molecular mechanisms, and this has resulted in significant improvements in outcome for several cancer types (for example, crizotinib for EML4-ALK fusion-positive non-small cell lung cancer (NSCLC)). This approach is shifting the traditional organ-based classification of cancer towards a new molecular taxonomy, and creating opportunities to apply therapeutics for the treatment of cancers originating in other organs that harbour similar molecular anomalies. Such indications for extension of existing therapeutics is attractive; however, specific molecular phenotypes and diagnostic characteristics are complex and usually inadequately defined [4, 5]. The target population for cancers of organs, apart from where the therapeutic strategy was initially developed, often occur at low frequency, further adding to the challenge.
Emerging data from cancer sequencing initiatives such as the International Cancer Genome Consortium (ICGC)  and The Cancer Genome Atlas (TCGA)  are unveiling a vast heterogeneity of molecular aberrations in cancer. Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, is particularly heterogeneous, and apart from a few notable exceptions, which have not been successfully targeted, most genetic aberrations have a frequency of 2% or less [8–10].
Trastuzumab, a monoclonal antibody that targets the HER2 receptor, is an effective therapy for HER2-amplified breast cancer, and was recently extended to the treatment of HER2-amplified gastric cancer . In addition, borderline signals have been seen in clinical trials of semi-selected patients with NSCLC , and case reports describe exceptional responses to trastuzumab in other cancers with HER2 amplification, such as cholangiocarcinoma . Defining HER2 amplification as a biomarker of trastuzumab responsiveness is integral to targeting appropriate populations for therapy. Although HER2 overexpression and amplification has been assessed in PDAC (see Additional file 1), standardized diagnostic assays have on the whole not been applied, and the roles of emerging diagnostic approaches such as genomic sequencing are yet to be explored. As a consequence, the diagnostic criteria and prevalence of HER2 amplification in PDAC remain unclear. Although preclinical studies support potential efficacy of trastuzumab in PDAC [13, 14], clinical trials have been hampered by non-standardized assays and a consequent lack of focus on appropriate subgroups [15, 16]. With the current poor survival, low therapeutic responsiveness, and vast molecular heterogeneity of PDAC, even if a relatively low proportion were found to be HER2-amplified, targeting by HER2 amplification represents an attractive potential therapy.
In this study, we identified HER2 amplification in diagnostic specimens of PDAC using single nucleotide polymorphism (SNP) arrays and whole genome sequencing. We defined the characteristics and prevalence (2.1%) of HER2 amplification in a large cohort of patients with resected PDAC using standardized reference laboratory assays. We found that HER2-amplified PDAC has an atypical pattern of metastatic spread with a predilection for lung metastasis and local recurrence, rather than liver metastases. Assessment of HER2 amplification across 16 cancer types suggested a prevalence of at least 22,000 cases per annum in the USA (excluding breast and gastric cancer), suggesting that a molecular recruitment strategy may make it feasible to test anti-HER2 therapies in less common cancer types.
Ethics approval for acquisition of data and biological material was obtained from the human research ethics committee at each participating institution, conducted in accordance with the National Statement on Ethical Conduct in Human Research 2007 and the Declaration of Helsinki. Consent was obtained from prospectively recruited patients for genomic sequencing through the Australian Pancreatic Cancer Genome Initiative (APGI) as part of the ICGC. Consent was waived by Human Research Ethics Committees for retrospectively acquired data and material under an approved protocol (see Additional file 2).
Genomic sequencing, copy number, and mRNA expression analysis
Patients were prospectively recruited to the APGI  for genomic sequencing as part of the ICGC, and details of sample acquisition and processing have been described previously . Briefly, samples focused on primary operable non-pretreated PDAC. Tissue was prepared by either full face frozen sectioning or the ends being excised and processed in formalin, then representative sections were reviewed by at least one pathologist to verify presence of carcinoma in the sample to be sequenced, and to estimate the percentage of malignant epithelial nuclei in the sample relative to stromal nuclei. Nucleic acids were extracted from fresh frozen tumour and normal tissue pairs, and whole genome and exome sequencing was performed using a combination of long mate pair and paired-end approaches. DNA copy number was assessed using specific microarrays (HumanOmni1-Quad BeadChip, Illumina Inc., San Diego, CA, USA). Primary tumour mRNA expression was assayed using human microarrays (HT-12 V4; Illumina) (GEO accession GSE36924). Gene expression profiles were classified into intrinsic breast cancer subtypes using the PAM50 classifier .
Defining prevalence and diagnostic criteria for HER2amplification
Formalin-fixed, paraffin wax-embedded diagnostic material from a cohort of 469 patients who had undergone operative resection for PDAC was accrued from 12 institutions associated with the APGI between 1990 and 2012. Subsets of this cohort have previously been published [19, 20], and detailed characteristics are presented (see Additional file 3: Table S2).
IHC and FISH scoring for the detection of HER2 amplification a
Her2 IHC score
(n = 469)
Positive, n = 10
Negative, n = 459
aThe criteria used for scoring HER2 by immunohistochemistry and in situ hybridization in PDAC were as follows. Her2 IHC score criteria (modified from Hofmann et al): 0, no staining of any pattern or intensity; 1+. weak discernable membrane staining; 2+, mild to moderate complete or basolateral membrane staining; 3+, strong, complete, or basolateral membrane staining. HER2 ISH criteria: non-amplified, Her2 count <4 and Her2:cep17 ratio <2; amplified, Her2 count ≥4 and Her2:cep17 ratio ≥2.
Genomic characteristics of HER2-amplified pancreatic ductal adenocarcinoma
Whole genome and exome sequencing identified several classes of mutation including single nucleotide variants, small insertions and deletions (indels), and chromosomal rearrangements (see Additional file 5). Chromosomal rearrangements included a region of loss on chromosome 18 containing the MAPK4, DCC, SMAD4, and ELAC1 genes, and three complex amplification regions: an inverted amplification of a region of chromosome 17, spanning HER2 and truncating MED1 and TOP2A at either end (chr17:37,565,271-38,554,848) (Figure 1B), and two overlapping fold back inversion events on chromosome 9: a 1.5 Mb event within a 1.9 Mb event, disrupting UBAP2. Exome sequencing identified 23 somatic mutations affecting 21 genes, including KRASp.G12V and TP53p.Q317, and 2 mutations in both TOP2A and RYR2 (Figure 1C).
We performed gene set enrichment analysis using all genes affected by mutation, amplification, copy number alterations (GISTIC2.0 peaks P < 0.25), and disruptions caused by structural rearrangements (see Additional file 6). There were three strong biological themes: 1) genes from the HER2-amplicon (13 genes; P<1 × 10-7); 2) a broad cancer theme driven by KRAS, TP53, and EPHA5 (13 gene sets; P<0.001); and 3) an immune signature, driven by type I interferons, IFNA2, INFA6, INFA13 (7 gene sets; P < 0.001), which are involved in recognition of viral infection and neoplasia (see Additional file 7).
Intrinsic subtype analysis using expression microarray data from the APGI cohort (n = 90)  classified each PDAC sample using the PAM50 classifier, which captures five breast cancer subtypes: HER2-amplified, luminal A, luminal B, basal, and normal-like . The HER2-amplified patient with PDAC identified above clustered with the HER2-amplified intrinsic subtype, with a confidence of 93%. This was driven by high expression of HER2, GRB7, and FOXA1, and low expression of KRT17 and MIA (see Additional file 8).
HER2amplification in pancreatic ductal adenocarcinoma
Clinical features of HER2-amplified pancreatic ductal adenocarcinoma
Clinicopathological characteristics of HER2-amplified PDAC
Her2 IHC score
Overall survival (months)
Cause of death
Pattern of recurrence
Laparotomy showed peritoneal and local recurrence
CT at 43 months showed no recurrence
Ascites/pleural effusions, no liver metastases on CT
Site not documented
No liver metastases on CT; peritoneal recurrence
No liver metastases on CT
No liver metastases on CT
No liver metastases on CT
Clinicopathological characteristics of HER2 amplified and HER2 non-amplified cases
Total cohort, n = 469
Amplified, n = 10
Non-amplified, n = 459
Sex, n (%)
28 to 88
47 to 73
28 to 87
AJCC stage, n (%)
T stage, n
N stage, n
AJCC grade, n
1 (well differentiated)
2 (moderately differentiated)
3 (poorly differentiated)
Tumour size, mm
Vascular invasion, n
Perineural invasion, n
Tumour location, n
0.03 to 240
5.0 to 43.6
0.03 to 240
Median follow-up, months
Lost to follow-up
Cancer-specific survival, mean ± SD
20 ± 19.43
28 ± 19.65
20 ± 19.55
Pattern of recurrence, n (% of total n)
Lung without liver metastasis
22 (8.4% of 261)
4 (50% of 8)
18 (7.1% of 253)
Any recurrence without liver metastasis
127 (49% of 261)
8 (100% of 8)
119 (47% of 253)
Adjuvant therapy, n
Since the completion of this study, we have begun prospectively screening patients with PDAC for HER2 amplification using this diagnostic approach, and identified a further two individuals (of eleven) with HER2 amplification. The first was a primary resected cancer with no evidence of recurrent disease to date at 6 months. Subsequently, whole genome sequence analysis on this patient’s tumour confirmed mutation in KRAS p.G12V . The second patient had an atypical pattern of metastatic disease at diagnosis, with a small primary pancreatic tumour on imaging, histologically confirmed peritoneal disease in the pelvis, and nodules in the lungs. Because of the unusual pattern of disease, PDAC was verified using a targeted exome panel of tissue from this patient’s peritoneal disease, which showed mutations in KRAS p.G12V and SMAD4, further supporting the diagnosis of PDAC.
HER2amplification in other cancer types
The low prevalence of HER2 amplification in PDAC and many other cancer types makes clinical trials challenging. Analysis of genomic sequence data for 16 other cancer types (by TCGA, ICGC and other large-scale genomic efforts) identified an incidence of 0.5% to 13%, which equates to over 54,000 new cases of HER2-amplified cancers per year in the USA alone (see Additional file 10). Excluding breast and gastric cancer, we estimate an incidence in excess of 22,000 HER2 amplified cancers per annum. Recruiting patients based on HER2 amplification rather than organ of tumour origin would make trials of anti-HER2 therapies feasible in less common cancer types. In order to identify these 22,000 patients, 740,000 patients would need to be screened using IHC, and of these, all 2+ and 3+ IHC cases (~8%) would require validation using ISH. This approach may circumvent the challenges of previous clinical trials based on organ of origin recruitment, in which there have been mixed results but some efficacy in individuals (see Additional file 11). An orthogonal approach by which a primary molecular classification is used and patients are sub-classified based on organ of origin may be more tractable.
In this study, we found that HER2-amplified PDAC has a prevalence of 2%, is detectable using contemporary genomic approaches, is associated with a clinical phenotype characterized by metastatic spread predominantly to the lungs and peritoneum with local recurrence, and can metastasize to the brain but tends to avoid the liver. It bears molecular similarities to HER2-amplified breast cancer, and is yet to be adequately assessed for potential responsiveness to anti-HER2 therapy. Multiple studies in large cohorts have shown that HER2-amplified breast cancers more commonly metastasize to the lung and the brain . In PDAC, clinical trial data indicate that the first site of distant metastases occurred most commonly in the liver (50%), and occurred in the lung in 9% of the cases . Autopsy studies have reported that 80% of distant metastases are to the liver, which occurred either alone or in combination with peritoneal and or lung metastases, while metastases sparing the liver made up the rest, and occurred in the peritoneum, lung, adrenal glands, and lymph nodes . Cerebral metastases were not found in these studies. In our cohort of 469 patients, the incidence of lung metastases without liver metastases was 8%, comparable to previous studies. We detected only one case with brain metastases (0.2%), although only this single patient was investigated specifically for brain metastases. If we include all 10 HER2-amplified cases with documented metastatic disease, none had evidence of liver metastases (P = 0.0028), and the rate of lung metastases was 50% (P = 0.0022). These data suggest that HER2-amplified PDAC may have a distinct clinical phenotype, and that liver metastases are not determined by physical factors such as portal blood flow, but by the pathophysiology of disease.
These findings have significant clinical implications. First, the detection of small lung nodules should not delay the diagnosis of metastatic disease originating in the pancreas or at relapse if the liver and other sites are clear, particularly in known HER2-amplified cases. Second, if an individual is known to have an HER2-amplified PDAC, then monitoring for disease progression in non-traditional sites such as the lung and the brain, with vigilance for neurological symptoms may be prudent. Finally, there is potential for anti-HER2 therapies in this subset of patients.
In situ hybridization studies in our reference laboratory identified HER2 amplification only in PDACs with high protein expression by IHC (score 2+/3+). Therefore, a reasonable and cost-effective approach to universal HER2 screening is to initially test all cases with IHC and then perform secondary ISH testing only on cases with 2+/3+ staining, as was initially performed for breast cancer. Using this approach, 8% of PDAC (2+ and 3+ cancers) will require HER2 ISH assessment, and of these one-quarter will be amplified.
In the current study, in-depth genomic analysis, apart from HER2 amplification, did not reveal any features that are atypical of PDAC, with mutations of KRAS and TP53 and loss of SMAD4 found, although the inherent heterogeneity of PDAC makes it difficult to draw conclusions about the other mutations detected. mRNA expression profiles clustered with HER2-amplified breast cancer, suggesting that HER2 may be an important driver of carcinogenesis in this subgroup of PDAC.
It is interesting to note that all three HER2-amplified cases with available genomic data harboured the KRASp.G12V mutation. This mutation is less common than the p.G12D mutation, and accounts for 32% of KRAS mutations in PDAC versus 40% for p.G12D . Given the small numbers of HER2-amplified cases, further studies of larger cohorts will be required before it can be determined if this association is sufficiently robust to be used diagnostically or targeted therapeutically.
Two clinical trials have assessed targeted trastuzumab therapy in PDAC [15, 16]. Both are single arm phase II trials used in combination with gemcitabine  and capecitabine . Although the latter performed HER2 FISH for 2+ expressing cases, the former did not, and neither verified the 3+ IHC cases by FISH. In addition, these were not standardized assays performed in reference laboratories, and resulted in a HER2 positive rate of over 10%. This likely overestimation underpowered the trials by over 80%, making a negative result uninterpretable.
HER2 amplification occurs in 2.1% of PDAC cases, and is associated with an atypical pattern of metastatic disease. A number of cancers of different organs including NSCLC, ovarian cancer, cholangiocarcinoma, and PDAC have well-defined low-prevalence HER2 amplification. Testing anti-HER2 therapies may not be feasible in organ groups because of this low prevalence and the likely heterogeneous response rates. However, these studies could be approached using novel adaptive clinical trials testing personalized therapeutic strategies (for example,: BATTLE , I-SPY , FOCUS 4  and IMPaCT ), or using a molecular taxonomy or ‘biotype’ that recruits HER2-amplified cancers irrespective of the organ in which the tumour arises (often referred to as ‘basket’ trials) , with specific attention to diagnostic criteria for patient recruitment, particularly as more effective anti-HER2 therapies emerge.
Australian Pancreatic Genome Initiative
Fluorescence in situ hybridization
International Cancer Genome Consortium
In situ hybridization
Non-small cell lung cancer
Pancreatic ductal adenocarcinoma
Single nucleotide polymorphism
The Cancer Genome Atlas.
The work was supported by the National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 535914); Cancer Council NSW (SRP06-01; ICGC09-01; SRP11-01); Australian Government: Department of Innovation, Industry, Science, Research and Tertiary Education (DIISRTE); Australian Cancer Research Foundation (ACRF); Queensland Government (NIRAP); University of Queensland; Cancer Institute NSW (06/ECF/1-24, 09/CDF/2-40, 07/CDF/1-03, 10/CRF/1-01, 08/RSA/1-15, 10/CDF/2-26,10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26); Garvan Institute of Medical Research; Avner Nahmani Pancreatic Cancer Foundation; R.T. Hall Trust; Jane Hemstritch in memory of Philip Hemstritch; Gastroenterological Society of Australia (GESA); Royal Australasian College of Surgeons (RACS); Sydney Catalyst Translational Cancer Centre; Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA) and the St Vincent’s Clinic Foundation.
We thank all the members of the Australian APGI (http://www.pancreaticcancer.net.au/apgi/collaborators) for their continuing support with provision of biospecimens and clinical data. We also thank Mary-Anne Brancato BSc, Michelle Thomas BSc, Sarah Rowe BSc, and Mona Martyn-Smith BSc for maintenance of the APGI database and biospecimen resource.
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