Updates in HER2 Testing in Gastric Cancer

Sofia Taboada¹ and Christa L Whitney-Miller^2*

¹North Shore-LIJ Health System, NY, USA

²University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Box 626, Rochester, NY 14642, USA

*Corresponding Author:

Christa L Whitney-Miller
University of Rochester Medical Center, School of Medicine and Dentistry
601 Elmwood Ave, Box 626, Rochester, NY 14642, USA
Tel: (585) 275-8762
E-mail: Christa_Whitney-miller@URMC.Rochester.edu

Received date: July 31, 2013; Accepted date: August 08, 2013; Published date: August 11, 2013

Citation: Taboada S, Whitney-Miller CL (2013) Updates in HER2 Testing in Gastric Cancer. J Gastroint Dig Syst 3:131. doi: 10.4172/2161-069X.1000131

Copyright: © 2013 Taboada S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Introduction

Gastric adenocarcinoma is a major cause of morbidity and mortality in the world with median overall survival being less than a year [1-4]. Advanced gastric adenocarcinoma is associated with a dismal prognosis, and increasing survival time, even by a few months, can be significant in this patient population [3,5,6]. Recently there was a major breakthrough in the treatment of gastric cancer, which arose by studying a therapy currently used for treatment of another solid tumor, HER2 positive breast carcinoma. Trastuzumab, a monoclonal antibody that targets the extracellular domain of the HER2 receptor, has become standard first-line treatment in this classification of breast carcinomas [7-10]. A recent clinical trial (ToGA) using trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2- positive advanced gastric or gastro-esophageal junction cancer showed an increase in overall survival in advanced (inoperable locally advanced, recurrent, or metastatic) gastric cancer treated with chemotherapy plus trastuzumab versus chemotherapy alone [1]. This was the first time a biological therapeutic was proven to increase survival in gastric cancer. Critical to the ToGA trial was determining which patients would be eligible for randomization - i.e. which patients had tumors that over-expressed HER2. Therefore, not only was trastuzumab shown to prolong survival in patients with advanced gastric cancer, but a protocol was proposed for HER2 testing in gastric cancer in a corollary study [11]. HER2 interpretation in gastric cancer is similar to, but slightly different than interpretation in breast cancer. Hofmann put forth an initial proposal, which was subsequently validated with minor clarifications added by Ruschoff [11,12]. The modifications in gastric cancer HER2 interpretation are related to heterogeneity (percentage of cells positive and different criteria in biopsies versus resections) and physiology (pattern of staining - basolateral/lateral versus complete circumferential staining). The ToGA study established trastuzumab as a viable treatment option in advanced gastric cancer and led to approval by the Food and Drug Administration (FDA) and the European Union for its use in combination with chemotherapy in that setting [13,14]. The most recent National Comprehensive Cancer Network (NCCN) Guidelines recommend trastuzumab with chemotherapy for patients with advanced or metastatic cancer, if the tumor is HER2 positive as confirmed by immunohistochemistry (IHC 3+) or fluorescence in situ hybridization (FISH score ≥ 2 for IHC 2+ tumors).

HER2 Testing

Correlating amplification and overexpression

There is a high degree of concordance between HER2 overexpression detected by immunohistochemistry and by fluorescence in situ hybridization (FISH) in breast cancer [15]. Multiple studies have demonstrated a similar high concordance in gastric cancer cases between immunohistochemical overexpression (IHC3+) and fluorescence in situ hybridization amplification [11,12,14,16,17]. As expected, concordance between HER2 IHC2+ and amplification is more variable. The subset of cases showing IHC/FISH discordant results may be due to heterogenous HER2 protein expression [16]. Concordance improves when the immunoscoring modifications recommended by Hofmann are applied (basolateral versus complete staining, lower percentage cells positive in resections, cluster of positive cells in a biopsy - see Table 1).

Table 1: HER2 Testing Scoring Criterion: Breast versus Gastric cancer.

Given the degree of tumor heterogeneity in gastric cancer, modified methods for HER2 fluorescence in situ hybridization (FISH) and silver in situ hybridization (SISH) should be considered. ISH should be directed based on the corresponding IHC-stained slide [14,18]. The clinical relevance of intratumoral heterogeneity is yet to be determined. One recent study showed evidence to suggest prognostic differences between cases showing heterogeneous versus homogenous HER2 gene amplification [14,17].

Other practical issues in HER2 testing

Practical issues in HER2 testing are related to the biology of HER2 (i.e. tumor heterogeneity) as well as our current testing methods (preanalytic variables, differences in commercially available IHC assays). As in breast cancer HER2 testing protocols, strict guidelines for preanalytic tissue handling should be followed [18,19]. Standardized preanalytic tissue handling will also enable further studies to characterize the reason for discordant IHC/FISH results. Despite tumor heterogeneity, studies have shown good correlation between biopsy and surgical resections. The use of biopsy tissue, which is immediately put into a fixative after removal from the patient, allows for standardized fixation and reduces error [18]. Yet, the diagnostic material provided in a biopsy is markedly variable and exhaustion of biopsy material may lead to other problematic issues. Current immunohistochemical methods (HercepTest and 4B5) should also be reviewed, considering that differences in sensitivity for detecting HER2 amplification were noted in the Rüschoff et al. guideline validation paper [12].

HER2 Biology in Gastric Cancer

Predictive, not prognosticating

Despite the advance in gastric cancer treatment offered by the ToGA trial, it also left many questions unanswered. While treating patients with HER2 positive tumors lengthens survival, there is significant controversy in the literature about whether or not HER2 itself is an independent prognostic factor. Some studies have shown an association with poor prognosis [20-30] while other studies have shown no association between HER2 status and outcome in patients with gastric cancer [31,32]. Another recent study of patients with metastatic (Stage IV) gastric cancer who received chemotherapy without trastuzumab [13] showed HER2 status had no impact on overall survival or progression free survival. This suggests that HER2 overexpression may not be associated with more aggressive disease or resistance to chemotherapy in metastatic cancer. The study did show an association between HER2 positive status and Lauren’s intestinal histology and liver metastases. Recently published data from the United Kingdom Medical Research Council’s TransMagic study showed that HER2 status is not a prognostic indicator in early cancer; it also showed HER2 cannot be used to select patients for epirubicin, cisplatin and infused 5-fluorouracil (ECF) chemotherapy [16]. All of this is in contrast to breast cancer, where HER2 has been shown repeatedly to be a poor prognostic indicator [33]. Some of this discrepancy may be related to the absence of a standardized definition of “HER2 positive” in gastric cancer prior to Hofmann [11]. Pre-analytic variables may also play a role. And of course, it is possible that breast and gastric cancers have different biology. Nonetheless, even though HER2 may not be an effective prognosticator, determination of HER2 status is critical if use of trastuzumab is being considered.

Clinicopathologic factors

Isolating the clinicopathologic factors that are associated with HER2 overexpression may help identify patients that might benefit from treatment with trastuzumab. Reported rates of HER2 overexpression and/or amplification range from 7% up to 34% in advanced disease, depending on the study group, with most cases in the range of 15-25% [1,11-13,24,27,29,34,35]. The rate of HER2 positivity seems to be lower in early gastric cancer, ranging from 10.4% to 13.6% [16,32]. Despite the variability in overexpression rates, most studies support a strong association between HER2 positive status and Lauren’s intestinal-type adenocarcinomas [1,11-13,29]. Interestingly, this correlates with the significant differences noted in the epidemiological and molecular characteristics between these two histologic subtypes (intestinal and diffuse type gastric adenocarcinomas). As stated previously, HER2 overexpression is associated with liver metastases [13]. Further examination of these associations may provide insight into targeted testing and treatment.

Current clinical studies on trastuzumab

Multiple Phase II and III clinical trials are underway to further examine trastuzumab in combination with different chemotherapy regimens, including Capecitabine and Oxaliplatin, in advanced gastric cancer; one of these studies includes chemoradiotherapy (TOXAG study). Given the results of the ToGA trial, other targets related to HER2 are under investigation, including trastuzumab in combination with poziotinib (a pan-HER inhibitor), pertuzumab (HER dimerization inhibitor), lapatinib (which inhibits HER2 and EGFR), bevacizumab (VEGF-A inhibitor) (http://www.clinicaltrials.gov/ct2/results?term=tr astuzumab+gastric+cancer&pg=1 accessed 6/21/2013).

Conclusion

Advanced gastric cancer is a major cause of morbidity and mortality worldwide. The ToGA trial was the first to show improved survival in patients whose tumors overexpress HER2 when they were treated with transtuzumab + chemotherapy versus chemotherapy alone. Treatment with trastuzumab requires assessment of tissue samples for HER2 overexpression and requires pathologists to keep abreast of current testing and interpretation guidelines. The role of HER2 in gastric carcinogenesis is under investigation, as is its role in other human cancers. Also under investigation is the optimal manner to use trastuzumab in HER2 positive solid tumors.

References

1. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, et al. (2010) 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 376: 687-697.
2. Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19: 1893-1907.
3. Kamangar F, Dores GM, Anderson WF (2006) Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24: 2137-2150.
4. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55: 74-108.
5. Cunningham SC, Kamangar F, Kim MP, Hammoud S, Haque R, et al. (2005) Survival after gastric adenocarcinoma resection: eighteen-year experience at a single institution. J Gastrointest Surg 9: 718-725.
6. Horner MJ, Ries LAG, Krapcho M (2009) SEER Cancer Statistics Review, 1975-2006.
7. Hudis CA (2007) Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 357: 39-51.
8. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, et al. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353: 1659-1672.
9. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783-792.
10. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, et al. (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369: 29-36.
11. Hofmann M, Stoss O, Shi D, Büttner R, van de Vijver M, et al. (2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52: 797-805.
12. Rüschoff J, Dietel M, Baretton G, Arbogast S, Walch A, et al. (2010) HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch 457: 299-307.
13. Janjigian YY, Werner D, Pauligk C, Steinmetz K, Kelsen DP, et al. (2012) Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann Oncol 23: 2656-2662.
14. Lee HE, Park KU, Yoo SB, Nam SK, Park do J, et al. (2013) Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. Eur J Cancer 49: 1448-1457.
15. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25: 118-145.
16. Okines AF, Thompson LC, Cunningham D, Wotherspoon A, Reis-Filho JS, et al. (2013) Effect of HER2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the MAGIC trial. Ann Oncol 24: 1253-1261.
17. Yoon HH, Shi Q, Sukov WR, Lewis MA, Sattler CA, et al. (2012) Adverse prognostic impact of intratumor heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma. J Clin Oncol 30: 3932-3938.
18. Rüschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, et al. (2012) HER2 testing in gastric cancer: a practical approach. Mod Pathol 25: 637-650.
19. Hicks DG, Whitney-Miller C (2011) HER2 testing in gastric and gastroesophageal junction cancers: a new therapeutic target and diagnostic challenge. Appl Immunohistochem Mol Morphol 19: 506-508.
20. Albino AP, Jaehne J, Altorki N, Blundell M, Urmacher C, et al. (1995) Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site. Eur J Surg Oncol 21: 56-60.
21. Allgayer H, Babic R, Gruetzner KU, Tarabichi A, Schildberg FW, et al. (2000) c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. J Clin Oncol 18: 2201-2209.
22. Begnami MD, Fukuda E, Fregnani JH, Nonogaki S, Montagnini AL, et al. (2011) Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol 29: 3030-3036.
23. García I, Vizoso F, Martín A, Sanz L, Abdel-Lah O, et al. (2003) Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol 10: 234-241.
24. Gravalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19: 1523-1529.
25. Mizutani T, Onda M, Tokunaga A, Yamanaka N, Sugisaki Y (1993) Relationship of C-erbB-2 protein expression and gene amplification to invasion and metastasis in human gastric cancer. Cancer 72: 2083-2088.
26. Nakajima M, Sawada H, Yamada Y, Watanabe A, Tatsumi M, et al. (1999) The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 85: 1894-1902.
27. Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, et al. (2006) HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci 51: 1371-1379.
28. Takehana T, Kunitomo K, Kono K, Kitahara F, Iizuka H, et al. (2002) Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Int J Cancer 98: 833-837.
29. Tanner M, Hollmén M, Junttila TT, Kapanen AI, Tommola S, et al. (2005) Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 16: 273-278.
30. Yonemura Y, Ninomiya I, Yamaguchi A, Fushida S, Kimura H, et al. (1991) Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res 51: 1034-1038.
31. Marx AH, Tharun L, Muth J, Dancau AM, Simon R, et al. (2009) HER-2 amplification is highly homogenous in gastric cancer. Hum Pathol 40: 769-777.
32. Terashima M, Kitada K, Ochiai A, Ichikawa W, Kurahashi I, et al. (2012) Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clin Cancer Res 18: 5992-6000.
33. Hicks DG, Kulkarni S (2008) HER2+ breast cancer: review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol 129: 263-273.
34. Yano T, Doi T, Ohtsu A, Boku N, Hashizume K, et al. (2006) Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep 15: 65-71.
35. Zhang XL, Yang YS, Xu DP, Qu JH, Guo MZ, et al. (2009) Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg 33: 2112-2118.