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Published in: Annals of Surgical Oncology 10/2011

01-10-2011 | Gastrointestinal Oncology

Evaluation of HER2 Protein Expression in Gastric Carcinomas: Comparative Analysis of 1414 Cases of Whole-Tissue Sections and 595 Cases of Tissue Microarrays

Authors: Kab Choong Kim, MD, Young Wha Koh, MD, Heung-Moon Chang, MD, Tae Hwan Kim, MD, Jeong Hwan Yook, MD, Byung Sik Kim, MD, Se Jin Jang, MD, Young Soo Park, MD

Published in: Annals of Surgical Oncology | Issue 10/2011

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Abstract

Background

Recent advances in molecular targeted therapy have identified HER2 as an important target for anti-cancer therapy in gastric cancer (GC). Although the clinical relevance and prognostic significance of HER2 in breast cancer has been well acknowledged, it remains controversial in GC.

Methods

HER2 expression was investigated in two independent series of GC by immunohistochemical staining. One series corresponded to 1,414 cases of whole-tissue sections and the other corresponded to 595 cases of tissue microarrays (TMAs). Results were compared and correlated with clinicopathologic parameters.

Results

HER2-positivity was detected in 12.3% of whole-tissue sections and 17% of TMAs. Among samples scored 3+, 90.1% stained ≥50% of the tumor area, but only 40.9% in score 2+ cases stained ≥50% of the tumor area. In whole-tissue sections, HER2-positivity was correlated with age (P = 0.002), histological type (differentiated or intestinal, P < 0.001), lymphovascular invasion (P = 0.005), and lymph node metastasis (P = 0.009). In TMAs, HER2-positivity was correlated only with age (P = 0.003) and histological type (P < 0.001). Multivariate analyses of the differentiated GC subgroup revealed that HER2-positivity was an independent poor prognostic factor (P = 0.042). The cases with HER2-positive in ≥50% of the tumor area showed worse prognosis than those of <50% (P = 0.021).

Conclusions

Despite discrepancies in the results from whole-tissue sections and TMAs, HER2 overexpression was positively correlated with aggressive biological behavior and was an independent poor prognostic factor for recurrence in differentiated GCs. Therefore, HER2-positive GCs should be considered for adjuvant trastuzumab therapy.
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Literature
1.
go back to reference Kamangar F, Dores GM, Anderson WF. 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. 2006;24:2137–50.PubMedCrossRef Kamangar F, Dores GM, Anderson WF. 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. 2006;24:2137–50.PubMedCrossRef
2.
go back to reference Jackson C, Cunningham D, Oliveira J. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(Suppl 4):34–6.PubMed Jackson C, Cunningham D, Oliveira J. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(Suppl 4):34–6.PubMed
3.
go back to reference Javle M, Hsueh CT. Updates in gastrointestinal oncology: insights from the 2008 44th annual meeting of the American Society of Clinical Oncology. J Hematol Oncol. 2009;2:9.PubMedCrossRef Javle M, Hsueh CT. Updates in gastrointestinal oncology: insights from the 2008 44th annual meeting of the American Society of Clinical Oncology. J Hematol Oncol. 2009;2:9.PubMedCrossRef
4.
go back to reference Wagner AD, Moehler M. Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era. Curr Opin Oncol. 2009;21:381–5.PubMedCrossRef Wagner AD, Moehler M. Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era. Curr Opin Oncol. 2009;21:381–5.PubMedCrossRef
5.
go back to reference Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.PubMedCrossRef Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.PubMedCrossRef
6.
7.
go back to reference Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.PubMedCrossRef Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.PubMedCrossRef
8.
go back to reference Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.PubMedCrossRef Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.PubMedCrossRef
9.
go back to reference Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, et al. 2-Year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369:29–36.PubMedCrossRef Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, et al. 2-Year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369:29–36.PubMedCrossRef
10.
go back to reference Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, 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;376:687–97.PubMedCrossRef Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, 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;376:687–97.PubMedCrossRef
11.
go back to reference Tanner M, Hollmen M, Junttila TT, Kapanen AI, Tommola S, Soini Y, Helin H, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase II alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005;16:273–8.PubMedCrossRef Tanner M, Hollmen M, Junttila TT, Kapanen AI, Tommola S, Soini Y, Helin H, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase II alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005;16:273–8.PubMedCrossRef
12.
go back to reference Hofmann M, Stoss O, Shi D, Buttner R, van de Vijver M, Kim W, Ochiai A, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805.PubMedCrossRef Hofmann M, Stoss O, Shi D, Buttner R, van de Vijver M, Kim W, Ochiai A, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805.PubMedCrossRef
13.
go back to reference Grabsch H, Sivakumar S, Gray S, Gabbert HE, Muller W. HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic value: conclusions from 924 cases of two independent series. Cell Oncol. 2010;32:57–65.PubMed Grabsch H, Sivakumar S, Gray S, Gabbert HE, Muller W. HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic value: conclusions from 924 cases of two independent series. Cell Oncol. 2010;32:57–65.PubMed
14.
go back to reference Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, Cho YK, Sohn CI, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 2006;51:1371–9.PubMedCrossRef Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, Cho YK, Sohn CI, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 2006;51:1371–9.PubMedCrossRef
15.
go back to reference Ruschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, Chenard MP, et al. HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299–307.PubMedCrossRef Ruschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, Chenard MP, et al. HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299–307.PubMedCrossRef
16.
go back to reference Lee EY, Cibull ML, Strodel WE, Haley JV. Expression of HER-2/neu oncoprotein and epidermal growth factor receptor and prognosis in gastric carcinoma. Arch Pathol Lab Med. 1994;118:235–9.PubMed Lee EY, Cibull ML, Strodel WE, Haley JV. Expression of HER-2/neu oncoprotein and epidermal growth factor receptor and prognosis in gastric carcinoma. Arch Pathol Lab Med. 1994;118:235–9.PubMed
17.
go back to reference Kim MA, Jung EJ, Lee HS, Lee HE, Jeon YK, Yang HK, Kim WH. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol. 2007;38:1386–93.PubMedCrossRef Kim MA, Jung EJ, Lee HS, Lee HE, Jeon YK, Yang HK, Kim WH. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol. 2007;38:1386–93.PubMedCrossRef
18.
go back to reference Marx AH, Tharun L, Muth J, Dancau AM, Simon R, Yekebas E, Kaifi JT, et al. HER-2 amplification is highly homogenous in gastric cancer. Hum Pathol. 2009;40:769–77.PubMedCrossRef Marx AH, Tharun L, Muth J, Dancau AM, Simon R, Yekebas E, Kaifi JT, et al. HER-2 amplification is highly homogenous in gastric cancer. Hum Pathol. 2009;40:769–77.PubMedCrossRef
19.
go back to reference Yano T, Doi T, Ohtsu A, Boku N, Hashizume K, Nakanishi M, Ochiai A. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep. 2006;15:65–71.PubMed Yano T, Doi T, Ohtsu A, Boku N, Hashizume K, Nakanishi M, Ochiai A. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep. 2006;15:65–71.PubMed
20.
go back to reference Gulmann C, Butler D, Kay E, Grace A, Leader M. Biopsy of a biopsy: validation of immunoprofiling in gastric cancer biopsy tissue microarrays. Histopathology. 2003;42:70–6.PubMedCrossRef Gulmann C, Butler D, Kay E, Grace A, Leader M. Biopsy of a biopsy: validation of immunoprofiling in gastric cancer biopsy tissue microarrays. Histopathology. 2003;42:70–6.PubMedCrossRef
21.
go back to reference Yan B, Yau EX, Bte Omar SS, Ong CW, Pang B, Yeoh KG, Salto-Tellez M. A study of HER2 gene amplification and protein expression in gastric cancer. J Clin Pathol. 2010;63:839–42.PubMedCrossRef Yan B, Yau EX, Bte Omar SS, Ong CW, Pang B, Yeoh KG, Salto-Tellez M. A study of HER2 gene amplification and protein expression in gastric cancer. J Clin Pathol. 2010;63:839–42.PubMedCrossRef
22.
go back to reference Allgayer H, Babic R, Gruetzner KU, Tarabichi A, Schildberg FW, Heiss MM. 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. 2000;18:2201–9.PubMed Allgayer H, Babic R, Gruetzner KU, Tarabichi A, Schildberg FW, Heiss MM. 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. 2000;18:2201–9.PubMed
23.
go back to reference Lee HR, Kim JH, Uhm HD, Ahn JB, Rha SY, Cho JY, Lee JI, et al. Overexpression of c-ErbB-2 protein in gastric cancer by immunohistochemical stain. Oncology. 1996;53:192–7.PubMedCrossRef Lee HR, Kim JH, Uhm HD, Ahn JB, Rha SY, Cho JY, Lee JI, et al. Overexpression of c-ErbB-2 protein in gastric cancer by immunohistochemical stain. Oncology. 1996;53:192–7.PubMedCrossRef
24.
go back to reference Pinto-de-Sousa J, David L, Almeida R, Leitao D, Preto JR, Seixas M, Pimenta A. c-erb B-2 expression is associated with tumor location and venous invasion and influences survival of patients with gastric carcinoma. Int J Surg Pathol. 2002;10:247–56.PubMedCrossRef Pinto-de-Sousa J, David L, Almeida R, Leitao D, Preto JR, Seixas M, Pimenta A. c-erb B-2 expression is associated with tumor location and venous invasion and influences survival of patients with gastric carcinoma. Int J Surg Pathol. 2002;10:247–56.PubMedCrossRef
25.
go back to reference Shun CT, Wu MS, Lin JT, Chen SY, Wang HP, Lee WJ, Wang TH, et al. Relationship of p53 and c-erbB-2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. Hepatogastroenterology. 1997;44:604–9.PubMed Shun CT, Wu MS, Lin JT, Chen SY, Wang HP, Lee WJ, Wang TH, et al. Relationship of p53 and c-erbB-2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. Hepatogastroenterology. 1997;44:604–9.PubMed
26.
go back to reference Uchino S, Tsuda H, Maruyama K, Kinoshita T, Sasako M, Saito T, Kobayashi M, et al. Overexpression of c-erbB-2 protein in gastric cancer. Its correlation with long-term survival of patients. Cancer. 1993;72:3179–84.PubMedCrossRef Uchino S, Tsuda H, Maruyama K, Kinoshita T, Sasako M, Saito T, Kobayashi M, et al. Overexpression of c-erbB-2 protein in gastric cancer. Its correlation with long-term survival of patients. Cancer. 1993;72:3179–84.PubMedCrossRef
27.
go back to reference Yonemura Y, Ninomiya I, Yamaguchi A, Fushida S, Kimura H, Ohoyama S, Miyazaki I, et al. Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res. 1991;51:1034–8.PubMed Yonemura Y, Ninomiya I, Yamaguchi A, Fushida S, Kimura H, Ohoyama S, Miyazaki I, et al. Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res. 1991;51:1034–8.PubMed
28.
go back to reference Zhang XL, Yang YS, Xu DP, Qu JH, Guo MZ, Gong Y, Huang J. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg. 2009;33:2112–8.PubMedCrossRef Zhang XL, Yang YS, Xu DP, Qu JH, Guo MZ, Gong Y, Huang J. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg. 2009;33:2112–8.PubMedCrossRef
29.
go back to reference Barros-Silva JD, Leitao D, Afonso L, Vieira J, Dinis-Ribeiro M, Fragoso M, Bento MJ, et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer. 2009;100:487–93.PubMedCrossRef Barros-Silva JD, Leitao D, Afonso L, Vieira J, Dinis-Ribeiro M, Fragoso M, Bento MJ, et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer. 2009;100:487–93.PubMedCrossRef
30.
go back to reference Sasano H, Date F, Imatani A, Asaki S, Nagura H. Double immunostaining for c-erbB-2 and p53 in human stomach cancer cells. Hum Pathol. 1993;24:584–9.PubMedCrossRef Sasano H, Date F, Imatani A, Asaki S, Nagura H. Double immunostaining for c-erbB-2 and p53 in human stomach cancer cells. Hum Pathol. 1993;24:584–9.PubMedCrossRef
31.
go back to reference Tateishi M, Toda T, Minamisono Y, Nagasaki S. Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. J Surg Oncol. 1992;49:209–12.PubMedCrossRef Tateishi M, Toda T, Minamisono Y, Nagasaki S. Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. J Surg Oncol. 1992;49:209–12.PubMedCrossRef
32.
go back to reference Yonemura Y, Ninomiya I, Ohoyama S, Fushida S, Kimura H, Tsugawa K, Kamata T, et al. Correlation of c-erbB-2 protein expression and lymph node status in early gastric cancer. Oncology. 1992;49:363–7.PubMedCrossRef Yonemura Y, Ninomiya I, Ohoyama S, Fushida S, Kimura H, Tsugawa K, Kamata T, et al. Correlation of c-erbB-2 protein expression and lymph node status in early gastric cancer. Oncology. 1992;49:363–7.PubMedCrossRef
Metadata
Title
Evaluation of HER2 Protein Expression in Gastric Carcinomas: Comparative Analysis of 1414 Cases of Whole-Tissue Sections and 595 Cases of Tissue Microarrays
Authors
Kab Choong Kim, MD
Young Wha Koh, MD
Heung-Moon Chang, MD
Tae Hwan Kim, MD
Jeong Hwan Yook, MD
Byung Sik Kim, MD
Se Jin Jang, MD
Young Soo Park, MD
Publication date
01-10-2011
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 10/2011
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-011-1695-2

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