Skip to main content
NCBI home page
The Oncologist logoLink to The Oncologist
. 2014 Dec 5;20(1):7–12. doi: 10.1634/theoncologist.2014-0234

Oncogenic Alterations in ERBB2/HER2 Represent Potential Therapeutic Targets Across Tumors From Diverse Anatomic Sites of Origin

Juliann Chmielecki a,*,✉, Jeffrey S Ross a,b,*, Kai Wang a, Garrett M Frampton a, Gary A Palmer a, Siraj M Ali a, Norma Palma a, Deborah Morosini a, Vincent A Miller a, Roman Yelensky a, Doron Lipson a, Philip J Stephens a,✉
PMCID: PMC4294606  PMID: 25480824

The authors explored activating ERBB2 alterations in solid tumor specimens that underwent comprehensive genomic profiling using next-generation sequencing. Results showed that activating events in ERBB2/HER2 occurred across a wide variety of tumors. Additionally, standard slide-based tests for overexpression or amplification of ERBB2 would fail to detect the majority of activating mutations that occur overwhelmingly in the absence of copy number changes. Comprehensive genomic profiling of a more diverse set of tumor types may identify more patients likely to benefit from ERBB2-targeted therapy.

Keywords: High-throughput nucleotide sequencing, Mutation, Antibodies, Monoclonal, Humanized, Trastuzumab, Lapatinib, Pertuzumab

Abstract

Background.

Targeted ERBB2/HER2 inhibitors are approved by the U.S. Food and Drug Administration for the treatment of breast, gastric, and esophageal cancers that overexpress or amplify HER2/ERBB2, as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Activating mutations in ERBB2 have also been reported and are predicted to confer sensitivity to these targeted agents. Testing for these mutations is not performed routinely, and FISH and IHC are not applied outside of these approved indications.

Materials and Methods.

We explored the spectrum of activating ERBB2 alterations across a collection of ∼7,300 solid tumor specimens that underwent comprehensive genomic profiling using next-generation sequencing. Results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes.

Results.

Known oncogenic ERBB2 alterations were identified in tumors derived from 27 tissues, and ERBB2 amplification in breast, gastric, and gastroesophageal cancers accounted for only 30% of these alterations. Activating mutations in ERBB2 were identified in 131 samples (32.5%); amplification was observed in 246 samples (61%). Two samples (0.5%) harbored an ERBB2 rearrangement. Ten samples (2.5%) harbored multiple ERBB2 mutations, yet mutations and amplifications were mutually exclusive in 91% of mutated cases.

Conclusion.

Standard slide-based tests for overexpression or amplification of ERBB2 would fail to detect the majority of activating mutations that occur overwhelmingly in the absence of copy number changes. Compared with current clinical standards, comprehensive genomic profiling of a more diverse set of tumor types may identify ∼3.5 times the number of patients who may benefit from ERBB2-targeted therapy.

Implications for Practice:

Tumors with amplification or overexpression of ERBB2/HER2 have a high likelihood of being sensitive to ERBB2/HER2 inhibitors, based on evidence from published studies. Current clinical practice investigates amplification or overexpression of ERBB2/HER2 in breast, gastric, and gastroesophageal cancers. However, recent studies suggest that mutations can also activate this gene, and these alterations may be similarly sensitive to ERBB2/HER2 inhibitors. Our data identified activation of ERBB2/HER2 (either amplification or activating mutation) in 27 different tumor types. Consequently, more comprehensive molecular profiling of multiple tumor types has the potential to identify additional patients who may derive clinical benefit from ERBB2/HER2 inhibitors.

Introduction

The treatment of cancer is moving toward personalized therapies that target driver lesions within a tumor but spare normal tissues [1]. Critical to this effort is the reliable identification of driver alterations and therapeutics that can effectively inhibit their activity. Genomic profiling efforts, such as the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), continue to identify novel cancer genes responsible for tumorigenesis, therapeutic sensitivity, and drug resistance. Despite the fact that many drugs are approved for specific tumor types, many genomic alterations appear to be disease agnostic, and the same alteration can drive tumors from diverse origins [2]. In this paper, we present data detailing the spectrum of known oncogenic genomic changes in an established cancer gene, ERBB2, across a vast variety of tumors. These alterations may sensitize tumors to multiple targeted therapies, both approved and in clinical development.

Deregulation of ERBB family members (EGFR, ERBB2/HER2, ERBB3, and ERBB4) by mutation or genomic amplification is frequently oncogenic and has been observed in multiple cancer types. Because cancer cells can become “addicted” to the aberrant signaling emanating from these proteins, they are attractive therapeutic targets; this concept has yielded dramatic clinical responses [3]. Activating mutations in the kinase domain of EGFR, for example, are observed in ∼20% of non-small cell lung cancers (NSCLCs) and confer sensitivity to the tyrosine kinase inhibitors erlotinib (Tarceva; OSI Pharmaceuticals, Northbrook, IL, https://www.astellas.us), gefitinib (Iressa; AstraZeneca, London, U.K., http://www.astrazeneca-us.com), and afatinib (Gilotrif; Boehringer Ingelheim Pharmaceuticals, Ingelheim am Rhein, Rhineland-Palatinate, Germany, http://www.boehringer-ingelheim.com); these agents have demonstrated superior clinical efficacy versus chemotherapy in this subset of selected patients [4–6].

Amplification of wild-type (nonmutated) ERBB2 (HER2) is observed in ∼20% of breast carcinomas and a similar proportion of gastric and gastroesophageal (GE) junction adenocarcinomas [7]. This observation led to the development of antibodies against this receptor, including trastuzumab (Herceptin; Genentech, South San Francisco, CA, http://www.gene.com), pertuzumab (Perjeta; Genentech), and ado-trasuzumab emtansine (Kadcyla; Genentech), and to ERBB2-selective small molecule inhibitors, such as lapatinib (Tykerb; GlaxoSmithKline, Brentford, U.K., http://www.gsk.com). Trastuzumab is approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of early stage and metastatic ERBB2/HER2-positive breast cancers and metastatic gastric/GE junction cancers that either overexpress ERBB2 or amplify the gene encoding this protein [8–11]. Lapatinib is FDA approved for the treatment of metastatic ERBB2/HER2-positive breast cancers [12]. Afatinib, which is FDA approved for the treatment of EGFR mutant NSCLC, and the investigational agent neratinib have also demonstrated clinical activity against tumors driven by HER2/ERBB2 [13, 14]. Genomic amplification of ERBB2 is highly correlated to protein overexpression in both diseases [15, 16]. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to test for ERBB2 amplification and expression, respectively, are performed routinely as part of standard clinical care for breast and upper gastrointestinal tract adenocarcinomas [17] to identify patients for whom anti-ERBB2 therapy is predicted to be most beneficial.

Recent studies have also implicated ERBB2 mutations in tumorigenesis. Insertions and mutations within the kinase domain of ERBB2, for example, have been observed in ∼2% of lung cancers [18–20]. Similarly, activating ERBB2 mutations have also been found in ∼2% of breast cancer and are enriched 10-fold in invasive lobular carcinomas that harbor concurrent CDH1 mutations [21, 22]. Finally, activating extracellular domain mutations have been observed in ∼40% of micropapillary urothelial carcinomas [23]. Extensive preclinical studies have demonstrated that these mutations are oncogenic and sensitive to ERBB2 inhibitors in vitro [24–26]. Furthermore, multiple lines of clinical evidence are emerging that support the efficacy of EBB2 inhibitors against this class of alterations [14, 27–29].

Given this evolving data in the literature, we hypothesized that ERBB2 amplification and point mutations may be present across a broad spectrum of cancers. To investigate this possibility, we mined data from ∼7,300 patients diagnosed with solid tumors that were profiled by a targeted next-generation sequencing (NGS)-based assay for genomic alterations in human cancer genes. Interestingly, we discovered activating events in ERBB2, including point mutations, insertions/deletions (indels), and amplifications in tumors arising from 27 different tissues of origin, of which less than one-third were amplifications in breast, gastric, or GE junction cancers. These data suggest that additional patients may benefit from therapies that target ERBB2.

Materials and Methods

Comprehensive Genomic Profiling

Local site permissions to use clinical samples were obtained for this study. All samples were submitted to a Clinical Laboratory Improvement Amendments-certified, New York State- and College of American Pathologists-accredited laboratory (Foundation Medicine, Cambridge MA) for NGS-based genomic profiling, as described previously [30, 31]. Samples were from predominantly late-stage patients, and diagnoses were confirmed by an independent pathology review at Foundation Medicine. Extracted DNA was adaptor ligated, and capture was performed for all coding exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer (earlier version of the test) (supplemental online Table 1) or all coding exons from 236 cancer-related genes and 47 introns of 19 genes frequently rearranged in cancer (current version of the test) (supplemental online Table 2). Captured libraries were sequenced to a median exon coverage depth of >600×, and resultant sequences were analyzed for base substitutions, insertions, deletions, copy number alterations (focal amplifications and homozygous deletions), and select gene fusions, as described previously [30, 31]. Previous validation studies demonstrated the high accuracy and sensitivity of this approach and high concordance with established assays (e.g., FISH and IHC) [30].

Results

From our collection of ∼7,300 solid tumors, we identified 403 tumors from 27 different tissues that harbored at least one alteration in ERBB2 (Fig. 1). We focused on ERBB2 alterations that have been previously reported and characterized as somatic and/or associated with increased ERBB2 activity, drug sensitivity, or drug resistance [21, 24, 26, 32–34]. There were 131 samples (32.5%) that harbored a known ERBB2 mutation (including indels), 246 samples that exhibited ERBB2 amplification (61%), and 2 samples (0.5%) that harbored a rearrangement involving ERBB2. In addition, 10 samples (2.5%) harbored multiple ERBB2 mutations, and 14 samples (3.5%) had concurrent ERBB2 mutation and amplification. Across the collection of tumors, peritoneal carcinomas had the highest proportion of ERBB2 alterations (31% of all peritoneal tumors in this data set) (Fig. 1), followed closely by duodenal adenocarcinomas (29% of all duodenal tumors in this data set) (Fig. 1). ERBB2 alterations were also observed in >15% of GE junction and bile duct adenocarcinomas and urothelial carcinomas of the bladder (Fig. 1). Consistent with previously published reports [7], ∼15%–20% of the breast and gastric cancers in this set exhibited ERBB2 amplification (Fig. 1). The complete spectra of genomic alterations in the five most commonly mutated tumor types (excluding unknown primaries) are outlined in supplemental online Figs. 1–5.

Figure 1.

Figure 1.

Open in a new tab

Distribution of ERBB2 alterations across diseases. Mutations, amplifications, and rearrangements involving ERBB2 were identified in 403 tumors across 27 disease types. Data are expressed as a percentage compared with the total number of tumors within that subtype in our data set.

Abbreviations: cholangio, cholangiocarcinoma; GE, gastroesophageal.

Mutations in ERBB2 were clustered within the extracellular and kinase domains (Fig. 2). In total, 165 mutations were identified in 155 samples (38.5% of ERBB2 alterations). The most common mutation in ERBB2 was S310F (n = 39); we also observed similar recurrent S310Y mutations (n = 5) at this residue. These mutations were followed in frequency by the A775_G776insYVMA kinase domain insertion within exon 20 (n = 31). Collectively, we observed 11 unique insertions in exon 20 (Table 1; supplemental online Table 3) that were all predicted to be activating based on their location and similarity to other reported insertions in this region. Other highly recurrent mutations (n ≥ 10) included R678Q (n = 16), L755S (n = 15), and V842I (n = 11). With the exception of 14 alterations (G309A, N319D, T733I, I767M, D769H, Y772_773insLMAY, A775_G776insSVMA, A775_G776insV, G776 > VC, G776_G777 > AVGSVG, G776_G777 > AVGCV, G776_G777 > AVCV, V777_G778insC, G778S) that were identified in a single sample, all other mutations were recurrent. Of the samples that harbored multiple mutations, we observed recurrent co-mutation of L755S with V842I (n = 3) and S310F with R678Q (n = 2). Amplification of ERBB2 was observed concurrently with S310F (n = 4), A775_G776insYVMA (n = 3), L755S (n = 2) and D769Y (n = 2).

Figure 2.

Figure 2.

Open in a new tab

Schematic diagram of mutations observed in ERBB2. Mutation frequency at each residue is depicted by vertical red bars. All exon 20 insertions (ex20ins) are graphed in red; however, only the most frequent site is labeled (A775_G776insYVMA). For a complete list of exon 20 alterations and the diseases in which they occur, see supplemental online Table 3.

Abbreviation: CRC, colorectal cancer.

Table 1.

Frequency of ERBB2 mutations

graphic file with name theoncologist_14234t1.jpg

Open in a new tab

Finally, we investigated our data for the presence of ERBB2 rearrangements that occurred in the absence of amplification. We identified an ERBB2-GRB7 rearrangement in a bladder cancer and a breast cancer, both of which have been described previously [22, 23, 35]; these fusions were mutually exclusive with other ERBB2 alterations. However, it is unknown if this genomic rearrangement produces an in-frame fusion event, and the functional significance of ERBB2-GRB7 has yet to be established.

Discussion

ERBB2 amplification and/or overexpression have been observed clinically in a subset of breast, gastric, and GE junction cancers; preclinical data have confirmed a causative role for these events in tumorigenesis. These findings led to the development and eventual FDA approval of the ERBB2 inhibitors trastuzumab, pertuzumab, ado-trastuzumab emtansine, and lapatinib for treatment of these diseases [36–38]. Slide-based FISH and IHC assays to test for ERBB2 amplification and ERBB2 overexpression, respectively, are performed routinely as part of standard clinical care for these patients to identify tumors that are likely to benefit from ERBB2-targeted agents [17]. Recent studies have also identified rare ERBB2 oncogenic mutations in a subset of breast, lung, colorectal, gastric, and bladder cancers [18, 19, 21–23, 39, 40]; however, these mutations are not currently tested for as part of routine clinical care.

Based on the identification of rare activating point mutations in these small cohorts, we hypothesized that their existence may be more widespread across multiple cancer types. In this expanded study, we investigated the frequency of ERBB2 alterations across ∼7,300 tumors and identified oncogenic amplifications and mutations in tumors derived from 27 distinct tissues (Fig. 1). This analysis included only ERBB2 alterations that have been previously reported and characterized as somatic and/or associated with increased ERBB2 activity, drug sensitivity, or drug resistance [21, 24, 26, 32–34]. As expected, the mutations identified in this study clustered within the extracellular and kinase domains of ERBB2 (Fig. 2). Many of these mutations (G309A, S310F/Y, D769Y/H, V777L, V842I, T862A) lead to constitutive kinase activity and oncogenic transformation of normal cells [21, 24, 26, 32]. Based on previous work characterizing A771_Y772insYVMA and P780_Y781insGSP as activating [21, 33, 34], we hypothesize that the additional insertions within similar regions that were identified in this study (Fig. 2A; supplemental online Table 3) are also oncogenic. Five mutations (N319D, n = 1; R678Q, n = 16; T733I, n = 1; L755S, n = 15; and I767M, n = 1) have been characterized previously as nontransforming or weakly transforming in preclinical systems [21, 24, 32]. Eight of the 34 samples harboring these mutations also contained additional activating events in ERBB2, whereas one sample harbored concurrent R678Q and L755S mutations, suggesting that additional alterations may facilitate oncogenesis in these cases. Interestingly, both T733I and L755S mutations are associated with resistance to the ERBB2 inhibitor lapatinib in vitro [21, 26, 32]. It is unknown if any of these patients had received tyrosine kinase inhibitor therapy prior to their samples undergoing genomic profiling.

A search for somatic ERBB2 mutations within the Catalog of Somatic Mutations in Cancer (COSMIC) database [41] also identified multiple ERBB2 alterations across cancers arising from 16 different tissues (COSMIC, January 2014), suggesting that this finding is not unique to our data set (Table 1). These included multiple similar mutations associated with receptor hyperactivation and therapeutic resistance. In addition, analysis of samples included within the TCGA for which both copy number and mutation data were available identified somatic ERBB2 alterations in 17 cancer types [42, 43] (supplemental online Fig. 6). In non-small cell lung cancer, activating mutations in the related family member EGFR frequently co-occur with amplification [44]. In contrast, of the 155 samples in our data set that harbored at least one mutation in ERBB2, 91% (n = 141) lacked amplification of the gene; this observation is consistent with other findings from smaller studies investigating ERBB2 mutations [21]. Within the TCGA data set, mutations were mutually exclusive, with amplification in 96% of cases (supplemental online Fig. 6).

These findings have important and immediate clinical implications. The efficacy of trastuzumab and lapatinib against ERBB2-amplified breast, gastric, and GE junction cancers has been well established [8–12] and led to FDA approval of ERBB2 inhibitors in these diseases. Aside from these tumors, sensitivity to trastuzumab has been reported in a salivary gland carcinoma with ERBB2 overexpression [27]. Clinical case studies have also documented sensitivity to the ERBB2 inhibitors trastuzumab and afatinib in lung tumors harboring ERBB2 kinase domain mutations [14, 28]. An inflammatory breast carcinoma harboring two ERBB2 mutations (S310F and V777L) was also sensitive to treatment with lapatinib in combination with chemotherapy [29]. Recently, a widely metastatic cutaneous adnexal carcinoma with extramammary Paget’s disease harboring an extracellular ERBB2 S310F mutation responded to capecitabine and lapatinib [45]. These anecdotal clinical reports provide a rationale for the use of ERBB2 inhibitors against a spectrum of ERBB2 alterations in multiple tumor types. Based on compelling preclinical data, multiple ongoing clinical trials of second-generation ERBB2 inhibitors require ERBB2 mutation for enrollment (ClinicalTrials.gov identifiers NCT01670877, NCT01827267, and NCT01953926).

Our data also suggest that the majority of ERBB2 alterations would not be detected by routine slide based tests, such as FISH and IHC, which assess only gene amplification or protein overexpression, respectively. Furthermore, we identify high-level amplification of ERBB2 in multiple tumor types without known driver alterations (Fig. 1; supplemental online Figs. 1–5) for which routine slide-based testing for ERBB2 levels is not the standard of care.

Conclusion

More comprehensive genomic profiling that encompasses copy number and mutational events in ERBB2 applied to a broad range of tumors may significantly increase the number of patients who derive benefit from ERBB2 targeted therapy.

See http://www.TheOncologist.com for supplemental material available online.

Supplementary Material

Supplemental Data
supp_20_1_7__index.html (837B, html)

Footnotes

For Further Reading: Douglas B. Johnson, Kimberly H. Dahlman, Jared Knol et al. Enabling a Genetically Informed Approach to Cancer Medicine: A Retrospective Evaluation of the Impact of Comprehensive Tumor Profiling Using a Targeted Next-Generation Sequencing Panel. The Oncologist 2014;19:616–622.

Implications for Practice: Targeted next-generation sequencing (NGS) identifies genetic alterations that may confer sensitivity to approved and experimental targeted therapies in advanced cancer. The authors reviewed their experience with a targeted NGS assay and identified potentially actionable genetic alterations in 83% of tumors, with 21% of these patients receiving genotype-directed therapy. This study highlights the promise of targeted NGS for identifying actionable genetic alterations, facilitating clinical trial enrollment.

Author Contributions

Conception/Design: Juliann Chmielecki, Jeffrey S. Ross, Gary A. Palmer, Vincent A. Miller, Philip J. Stephens

Collection and/or assembly of data: Juliann Chmielecki, Kai Wang, Garrett M. Frampton, Siraj M. Ali, Norma Palma, Deborah Morosini, Roman Yelensky, Doron Lipson

Data analysis and interpretation: Juliann Chmielecki, Garrett M. Frampton

Manuscript writing: Juliann Chmielecki

Final approval of manuscript: Juliann Chmielecki, Jeffrey S. Ross, Kai Wang, Garrett M. Frampton, Gary A. Palmer, Siraj M. Ali, Norma Palma, Deborah Morosini, Vincent A. Miller, Roman Yelensky, Doron Lipson, Philip J. Stephens

Disclosures

Vincent A. Miller: Foundation Medicine (E, OI); Norma Palma: Foundation Medicine (E, OI); Siraj M. Ali: Foundation Medicine (E, OI); Gary A. Palmer: Foundation Medicine (E, OI); Kai Wang: Foundation Medicine (E, OI); Juliann Chmielecki: Foundation Medicine (E, OI); Deborah Morosini: Foundation Medicine (E, OI); Jeffrey S. Ross: Foundation Medicine (RF, E, OI); Genentech, Inc. (H); Philip J. Stephens: Foundation Medicine (E, OI, IP); Doron Lipson: Foundation Medicine (E, OI, IP); Roman Yelensky: Foundation Medicine (E, OI, IP); Garret M. Frampton: Foundation Medicine (E, OI, IP).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

References

  • 1.National Research Council (U.S.) Committee on A Framework for Developing a New Taxonomy of Disease. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. Washington, D.C.: National Academies Press; 2011. [PubMed] [Google Scholar]
  • 2.Chmielecki J, Meyerson M. DNA sequencing of cancer: What have we learned? Annu Rev Med. 2014;65:63–79. doi: 10.1146/annurev-med-060712-200152. [DOI] [PubMed] [Google Scholar]
  • 3.Weinstein IB. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science. 2002;297:63–64. doi: 10.1126/science.1073096. [DOI] [PubMed] [Google Scholar]
  • 4.Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334. doi: 10.1200/JCO.2012.44.2806. [DOI] [PubMed] [Google Scholar]
  • 5.Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957. doi: 10.1056/NEJMoa0810699. [DOI] [PubMed] [Google Scholar]
  • 6.Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958–967. doi: 10.1056/NEJMoa0904554. [DOI] [PubMed] [Google Scholar]
  • 7.Stern HM. Improving treatment of HER2-positive cancers Opportunities and challenges. Sci Transl Med 2012;4127rv2. 10.1126/scitranslmed.3001539 [DOI] [PubMed]
  • 8.Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–1672. doi: 10.1056/NEJMoa052306. [DOI] [PubMed] [Google Scholar]
  • 9.Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–1684. doi: 10.1056/NEJMoa052122. [DOI] [PubMed] [Google Scholar]
  • 10.Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792. doi: 10.1056/NEJM200103153441101. [DOI] [PubMed] [Google Scholar]
  • 11.Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–697. doi: 10.1016/S0140-6736(10)61121-X. [DOI] [PubMed] [Google Scholar]
  • 12.Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–2743. doi: 10.1056/NEJMoa064320. [DOI] [PubMed] [Google Scholar]
  • 13.Awada A, Dirix L, Manso Sanchez L, et al. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol. 2013;24:109–116. doi: 10.1093/annonc/mds284. [DOI] [PubMed] [Google Scholar]
  • 14.Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: Epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31:1997–2003. doi: 10.1200/JCO.2012.45.6095. [DOI] [PubMed] [Google Scholar]
  • 15.Hicks DG, Kulkarni S. Trastuzumab as adjuvant therapy for early breast cancer: The importance of accurate human epidermal growth factor receptor 2 testing. Arch Pathol Lab Med. 2008;132:1008–1015. doi: 10.5858/2008-132-1008-TAATFE. [DOI] [PubMed] [Google Scholar]
  • 16.Rüschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299–307. doi: 10.1007/s00428-010-0952-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Gutierrez C, Schiff R. HER2: Biology, detection, and clinical implications. Arch Pathol Lab Med. 2011;135:55–62. doi: 10.1043/2010-0454-RAR.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Stephens P, Hunter C, Bignell G, et al. Lung cancer: Intragenic ERBB2 kinase mutations in tumours. Nature. 2004;431:525–526. doi: 10.1038/431525b. [DOI] [PubMed] [Google Scholar]
  • 19.Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 2005;65:1642–1646. doi: 10.1158/0008-5472.CAN-04-4235. [DOI] [PubMed] [Google Scholar]
  • 20.Buttitta F, Barassi F, Fresu G, et al. Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: Mutations are mainly present in adenocarcinomas with bronchioloalveolar features. Int J Cancer. 2006;119:2586–2591. doi: 10.1002/ijc.22143. [DOI] [PubMed] [Google Scholar]
  • 21.Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3:224–237. doi: 10.1158/2159-8290.CD-12-0349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Ross JS, Wang K, Sheehan CE, et al. Relapsed classic E-cadherin (CDH1)-mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations. Clin Cancer Res. 2013;19:2668–2676. doi: 10.1158/1078-0432.CCR-13-0295. [DOI] [PubMed] [Google Scholar]
  • 23.Ross JS, Wang K, Gay LM, et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res. 2014;20:68–75. doi: 10.1158/1078-0432.CCR-13-1992. [DOI] [PubMed] [Google Scholar]
  • 24.Greulich H, Kaplan B, Mertins P, et al. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci USA. 2012;109:14476–14481. doi: 10.1073/pnas.1203201109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Shimamura T, Ji H, Minami Y, et al. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res. 2006;66:6487–6491. doi: 10.1158/0008-5472.CAN-06-0971. [DOI] [PubMed] [Google Scholar]
  • 26.Kancha RK, von Bubnoff N, Bartosch N, et al. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS One. 2011;6:e26760. doi: 10.1371/journal.pone.0026760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Kaidar-Person O, Billan S, Kuten A. Targeted therapy with trastuzumab for advanced salivary ductal carcinoma: Case report and literature review. Med Oncol. 2012;29:704–706. doi: 10.1007/s12032-011-9884-1. [DOI] [PubMed] [Google Scholar]
  • 28.Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med. 2006;354:2619–2621. doi: 10.1056/NEJMc060020. [DOI] [PubMed] [Google Scholar]
  • 29.Ali SM, Alpaugh RK, Downing SR, et al. Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2-targeted therapy. J Clin Oncol. 2014;32:e88–e91. doi: 10.1200/JCO.2013.49.0599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31:1023–1031. doi: 10.1038/nbt.2696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18:382–384. doi: 10.1038/nm.2673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Trowe T, Boukouvala S, Calkins K, et al. EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation. Clin Cancer Res. 2008;14:2465–2475. doi: 10.1158/1078-0432.CCR-07-4367. [DOI] [PubMed] [Google Scholar]
  • 33.Minami Y, Shimamura T, Shah K, et al. The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272. Oncogene. 2007;26:5023–5027. doi: 10.1038/sj.onc.1210292. [DOI] [PubMed] [Google Scholar]
  • 34.Wang SE, Narasanna A, Perez-Torres M, et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell. 2006;10:25–38. doi: 10.1016/j.ccr.2006.05.023. [DOI] [PubMed] [Google Scholar]
  • 35.Ross JS, Wang K, Al-Rohil RN et al. Advanced urothelial carcinoma: Next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol 2014;27:271–280. [DOI] [PubMed]
  • 36.Nielsen DL, Kümler I, Palshof JA, et al. Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Breast. 2013;22:1–12. doi: 10.1016/j.breast.2012.09.008. [DOI] [PubMed] [Google Scholar]
  • 37.Murphy CG, Morris PG. Recent advances in novel targeted therapies for HER2-positive breast cancer. Anticancer Drugs. 2012;23:765–776. doi: 10.1097/CAD.0b013e328352d292. [DOI] [PubMed] [Google Scholar]
  • 38.Fornaro L, Lucchesi M, Caparello C, et al. Anti-HER agents in gastric cancer: From bench to bedside. Nat Rev Gastroenterol Hepatol. 2011;8:369–383. doi: 10.1038/nrgastro.2011.81. [DOI] [PubMed] [Google Scholar]
  • 39.Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012;18:4910–4918. doi: 10.1158/1078-0432.CCR-12-0912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Lee JW, Soung YH, Seo SH, et al. Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res. 2006;12:57–61. doi: 10.1158/1078-0432.CCR-05-0976. [DOI] [PubMed] [Google Scholar]
  • 41.Forbes SA, Bindal N, Bamford S, et al. COSMIC: Mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2011;39:D945–D950. doi: 10.1093/nar/gkq929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–404. doi: 10.1158/2159-8290.CD-12-0095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1. doi: 10.1126/scisignal.2004088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Liang Z, Zhang J, Zeng X, et al. Relationship between EGFR expression, copy number and mutation in lung adenocarcinomas. BMC Cancer. 2010;10:376. doi: 10.1186/1471-2407-10-376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Vornicova O, Hershkovitz D, Yablonski-Peretz T, et al. Treatment of metastatic extramammary Paget’s disease associated with adnexal adenocarcinoma, with anti-HER2 drugs based on genomic alteration ERBB2 S310F. The Oncologist. 2014;19:1006–1007. doi: 10.1634/theoncologist.2014-0054. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Data
supp_20_1_7__index.html (837B, html)
supp_the2014-0234_Supplemental_Figures.pdf (1.6MB, pdf)
supp_the2014-0234_Supplemental_Tables.pdf (162.1KB, pdf)

Articles from The Oncologist are provided here courtesy of Oxford University Press

RESOURCES