HER-2/neu Analysis in Gastroesophageal and Gastric Adenocarcinoma Keith Daniel Bohman, MD Carcinoma of the stomach is the fourth most common cancer and second most frequent cause of cancer-related mortality in the world. 1-8 Surgical intervention, including gastrectomy with lymphadenectomy, is currently the only potential curative therapy in localized disease. 3,5,6,8,9 However, gastric adenocarcinoma is often diagnosed in its late stage, and chemotherapeutic treatment modalities have unfortunately proven relatively ineffective, generally resulting in low survival rates, high recurrence rates, and overall poor prognoses. 1,2,5-8,10-13 Targeted molecular-based therapy capitalizing on genes and gene products harbored in gastric and gastroesophageal adenocarcinomas may provide an additional therapeutic method of intervention in advanced tumors. 5,6,11,14 The oncogene HER2/neu, located on chromosome 17q21, is a member of the Human Epidermal Growth Factor Receptor family, which regulates cellular functions, such as proliferation, differentiation, motility, migration, adhesion, and apoptosis, through a transmembrane protein kinase. 2-7,9,11,12,14 Oncogene amplification and subsequent increased protein expression is thought to mediate cell transformation in the initiation and progression of carcinogenesis and metastasis. 8 HER2/neu amplification occurs in approximately 10% to 30% of breast adenocarcinomas and correlates with a poor prognosis, including shorter survival rates and resistance to adjuvant chemotherapy and endocrine therapy. 4,6-9,11,13,15,16 HER2/neu testing has become the standard of care for invasive adenocarcinoma of the breast, because Herceptin (Trastuzumab), a recombinant humanized IgG1 monoclonal anti-her2 antibody, offers an effective treatment modality for HER2/neu positive tumors. 7,12,15,16 HER2/neu is also amplified in many other solid tumors, including those of the lung, head and neck, salivary gland, endometrium, uterine cervix, ovary, fallopian tube, prostate, urinary bladder, colon, and pancreas. 5-7,9,11,15 In upper gastrointestinal tract adenocarcinomas, the percentages of tumors with HER2/neu ampliflication vary widely, ranging from approximately 2% to 45% of gastroesophageal, 8.2% to 53.4% of gastric, and 11% to 73% of esophageal adenocarcinomas. 1,3,5-11,13-18 The 2009 ToGA (Trastuzumab for Gastric Cancer) trial reported that of locally advanced, recurrent, or metastatic tumors, approximately 33% of gastroesophageal junction and 22.1% of gastric adenocarcinomas were HER2 positive by either immunohistochemical (IHC) study or fluorescence in-situ hybridization (FISH) analysis. 1,4,8,9,12,16 The
ToGA trial further demonstrated high concordance rate of 87.2% between HER2/neu amplification conducted by FISH analysis and overexpression evaluated by IHC study. 1,6,8,11,16 The prognostic relevance of HER2/neu amplification and overexpression in gastric cancer is controversial, but some studies have shown an association with poor outcome, aggressive disease, and shorter survival. 3,5,6,8-12,15,16,18 Compared with standard chemotherapy treatment alone in the ToGA trial, the increased median overall survival with the addition of Trastuzumab in patients who were either IHC(3+) or FISH(+) was only a modest 2.7 months (11.1 months with chemotherapy alone compared to 13.8 months with the addition of Trastuzumab). 2,4,7-9,12,16,17 However, in patients who were IHC(3+) or [IHC(2+) and FISH(+)] (high protein expression) and received chemotherapy plus Trastuzumab, the median overall survival improved by 4.2 months (11.8 months with chemotherapy alone compared to 16 months with the addition of Trastuzumab). 1,2,7-9,11,16,17 Therefore, IHC should be utilized as the initial screening modality in HER2/neu testing, and cases equivocal/2+ for HER2 overexpression can be referred for FISH analysis. 1,4,8,9,16,17 The HER2/neu status assessment algorithm in gastroesophageal and gastric adenocarcinoma, which follows the inclusion criteria of the ToGA trial and was proposed by the European Medicines Agency, is depicted in Figure 1. Figure 1: Proposed algorithm for chemotherapy treatment with the addition of Trastuzumab eligibility in inoperable locally advanced or metastatic gastroesophageal and gastric adenocarcinoma 1,4,9 Test for HER2 protein over-expression by IHC (0) (1+) Equivocal (2+) Positive (3+) Test for HER2/neu gene amplification by FISH (HER2/CEP17 <2) Positive (HER2/CEP17 2) Eligible for Trastuzumab treatment
Studies have demonstrated intratumoral heterogeneity for both HER2 overexpression and HER2/neu amplification in gastroesophageal and gastric adenocarcinomas; and it is not clear how diverging heterogeneity occurs in tumor cells or how this phenomenon is relevant to targeted HER2 monoclonal antibody response. 1,9,10,12 Nonetheless, because intratumoral heterogeneity may result in false-negative results in endoscopic biopsies, multiple biopsies are desirable for HER2/neu status assessment, if feasible. 7,10,13,17 The ToGA trial showed that treatment of HER2/neu-positive advanced gastroesophageal and gastric adenocarcinoma with Trastuzumab, in addition to standard chemotherapy (capecitabine or flurouricil plus cisplatin), improved the response rate, median progression-free survival, and overall survival, providing evidence that these tumors are potential responders to monoclonal antibody-based therapy targeting the HER2 protein. 1,8 Trastuzamab was well tolerated when administered concomitantly with chemotherapeutic agents, and it is the first biological agent to show a survival benefit in advanced gastroesophageal and gastric adenocarcinoma. 2,4,7-9,11,12 The Food and Drug Administration (FDA) has approved Trastuzumab in combination with chemotherapy for metastatic gastric and gastroesophageal adenocarcinoma in patients without prior anticancer treatment. 1 Although, the ToGA trial included tumors that were inoperable, the role of Trastuzumab in the adjuvant setting may be promising. 4,7,12 Many researchers advocate assessment of HER2/neu status as a standard component of routine diagnostic work-up in advanced gastroesophageal and gastric adenocarcinoma to identify patients who would benefit from targeted monoclonal antibody therapy. 2-4,7,9,11,12,17 References 1. Albarello L, Pecciarini L, Doglioni C. HER2 testing in gastric cancer. Adv Anat Pathol. 2011;18(1):53 59. doi: 10.1097/PAP.0b013e3182026d72. 2. 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(9742):687 697. doi: 10.1016/S0140-6736(10)61121-X. 3. Xie SD, Xu CY, Shen JG, Jiang ZN, Wang LB. HER 2/neu protein expression in gastric cancer is associated with poor survival. Mol Med Rep. 2009;2(6):943 946. 4. Okines AF, Cunningham D. Trastuzumab in gastric cancer. Eur J Cancer. 2010;46(11):1949 1959. doi: 10.1016/j.ejca.2010.05.003. 5. Yan SY, Hu Y, Fan JG, et al. Clinicopathologic significance of HER-2/neu protein expression and gene amplification in gastric carcinoma. World J Gastroenterol. 2011;17(11):1501 1506. doi: 10.3748/wjg.v17.i11.1501.
6. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523 1529. doi: 10.1093/annonc/mdn169. 7. Moelans CB, van Diest PJ, Milne AN, Offerhaus GJ. Her-2/neu testing and therapy in gastroesophageal adenocarcinoma. Patholog Res Int. 2010;2011:674182. doi: 10.4061/2011/674182. 8. Croxtall JD, McKeage K. Trastuzumab: in HER2-positive metastatic gastric cancer. Drugs. 2010;70(17):2259 2267. doi: 10.2165/11205900-000000000-00000. 9. De Vita F, Giuliani F, Silverstris N, Catalano G, Ciardiello F, Orditura M. Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new therapeutic target. Cancer Treat Rev. 2010;36 Suppl 3:S11 5. doi: 10.1016/S0305-7372(10)70014-1. 10. Grabsch H, Sivakumar S, Gray S, Gabbert HE, Müller W. HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic value - conclusions from 924 cases of two independent series. Cell Oncol. 2010;32(1-2):57 65. doi: 10.3233/CLO-2009-0497. 11. Jorgensen JT. Targeted HER2 treatment in advanced gastric cancer. Oncology. 2010;78(1):26 33. doi: 10.1159/000288295. 12. Roukos DH. Targeting gastric cancer with trastuzumab: new clinical practice and innovative developments to overcome resistance. Ann Surg Oncol. 2010;17(1):14 17. doi: 10.1245/s10434-009-0766-0. 13. Yan B, Yau, EX, Bte Omar SS, et al. A study of HER2 gene amplification and protein expression in gastric cancer. J Clin Pathol. 2010;63(9):839 842. doi: 10.1136/jcp.2010.076570. 14. Schoppmann SF, Jesch B, Friedrich J, et al. Expression of Her-2 in carcinomas of the esophagus. Am J Surg Pathol. 2010;34(12):1868 1873. doi: 10.1097/PAS.0b013e3181f8be17. 15. Marx AH, Tharun L, Muth J, et al. HER-2 amplification is highly homogenous in gastric cancer. Hum Pathol. 2009;40(6):769 777. doi: 10.1016/j.humpath.2008.11.014. 16. Ruschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010; 457(3):299 307. doi: 10.1007/s00428-010-0952-2. 17. Bouche O, Penault-Llorca F. [HER2 and gastric cancer: a novel therapeutic target for trastuzumab]. Bull Cancer. 2010;97(12):1429 1440. doi: 10.1684/bdc.2010.1224. 18. Thompson SK, Sullivan TR, Davies R, Ruszkiewicz AR. Her-2/neu gene amplification in esophageal adenocarcinoma and its influence on survival. Ann Surg Oncol. 2011;18(7):2010 2017. doi: 10.1245/s10434-011-1554-1.
Suggested Reading 1. Albarello L, Pecciarini L, Doglioni C. HER2 testing in gastric cancer. Adv Anat Pathol. 2011;18(1):53 59. 2. 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(9742):687 697. 3. Croxtall JD, McKeage K. Trastuzumab: in HER2-positive metastatic gastric cancer. Drugs. 2010;70(17): 2259 2267. 4. De Vita F, Giuliani F, Silvestris N, Catalano G, Ciardiello F, Orditura M. Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new therapeutic target. Cancer Treat Rev. 2010. 36 Suppl 3:S11 15. 5. Jorgensen JT. Targeted HER2 treatment in advanced gastric cancer. Oncology. 2010; 78(1):26 33. 6. Okines AF, Cunningham D. Trastuzumab in gastric cancer. Eur J Cancer. 2010;46(11):1949 1959. 7. Moelans CB, van Diest PJ, Milne AN, Offerhaus GJ. Her-2/neu testing and therapy in gastroesophageal adenocarcinoma. Patholog Res Int. 2010;2011:674182. 8. Okines AF, Cunningham D. Trastuzumab in gastric cancer. Eur J Cancer. 2010;46(11):1949 1959.