TY - JOUR
AU - Birner, P
AB - Abstract Background Some 10–15 per cent of patients with oesophageal cancer overexpress human epidermal growth factor receptor (HER) 2 at the primary tumour site, leading to the hope that specific targeted systemic therapy might favourably influence clinical and subclinical disease at locoregional and distant sites. This approach is based on primary tumour characteristics, without knowledge of expression patterns at metastatic sites. In oesophageal cancer, concordance between HER-2 status at the primary tumour and other sites is unknown. Methods The HER-2 status of primary tumours and corresponding metastatic sites (lymph node and distant) and local recurrence were evaluated in a series of patients with oesophageal cancer, using immunohistochemistry and dual colorimetric in situ hybridization. Results There were 97 adenocarcinomas (ACs) and 79 squamous cell carcinomas (SCCs). Some 14 per cent of primary ACs and 1 per cent of primary SCCs were staged as HER-2-positive. The HER-2 status was identical in the primary tumour and lymph node metastases in 95 per cent of ACs and 99 per cent of SCCs respectively (P = 0·375, sign test). Nineteen of 22 distant metastases from AC and all from SCC had identical HER-2 status to the primary tumour. In two of 22 patients with AC the primary tumour was classed as negative but distant metastases were HER-2-positive. Conclusion With over 85 per cent concordance in HER-2 status between primary tumours and distant metastases in oesophageal cancer, routine HER-2 testing of metastases to confirm HER-2 positivity is not warranted. Assessment of HER-2 status at metastatic sites may be worthwhile in some patients with easily accessible metastases and negative HER-2 status at the primary tumour, or if adequate material cannot be obtained from the primary site. Introduction Oesophageal cancer is the ninth most frequent cancer worldwide and the incidence of oesophageal adenocarcinoma (AC) is rising dramatically1. Improvements in survival rates in recent years remain modest2. Systemic therapies in the context of attempted curative therapies, and as palliative treatments, have improved the outcome of only small subsets of patients. A recent study demonstrated better outcome for patients with locally advanced or metastatic oesophagogastric cancer treated with the antibody trastuzumab, which targets human epidermal growth factor receptor (HER) 23. Patients with strong protein overexpression (HER-2 + + +) on immunohistochemistry (IHC), or moderate expression (HER-2 + +) on IHC in combination with HER-2 gene amplification, specifically benefited from this targeted therapy. HER-2 is overexpressed in about 15 per cent of patients with oesophageal AC and 4 per cent of those with squamous cell carcinoma (SCC), indicating a group of patients who might benefit from HER-2-targeted therapies4. In the majority of patients, systemic targeted therapy is based on the primary tumour without knowing expression patterns at other sites. Although a few studies have examined consistency in HER-2 expression at various sites in breast cancer5,6, there are no such data for oesophagogastric cancer. This study compared HER-2 status in primary oesophageal tumours and their corresponding lymph node and distant metastases as well as local recurrence from a series of patients with oesophagogastric cancer using IHC and dual colorimetric in situ hybridization (CISH). Methods From a prospectively collected database of patients with oesophageal cancer, who had undergone radical surgery at the University Hospital of Vienna between 1992 and 2009, all those with sufficient tumour for analysis from the primary tumour and lymph node or distant metastases were selected. Tissues from patients with local recurrence were analysed where available. Local institutional review board approval was obtained for this study. All patients were staged according to the International Union Against Cancer tumour node metastasis (TNM) system, seventh edition7. Immunohistochemistry HER-2 protein expression was detected with the Food and Drug Administration-approved monoclonal rabbit antibody PATHWAY® 4B5, used in conjunction with a BenchMark Ultra immunostainer (Roche Diagnostics, Basle, Switzerland). The analysis of IHC was performed as described by Hofmann and colleagues8. In brief, in a surgical specimen, at least 10 per cent of tumour cells had to show moderate to strong complete or basolateral staining, whereas a cluster of at least five positive cells in a biopsy was required for HER-2 + + + positivity by IHC. HER-2 + + was assigned if weak to moderate complete or basolateral membranous reactivity was observed in more than 10 per cent of tumour cells. Dual colorimetric in situ hybridization HER-2 gene amplification was investigated in all patients who were HER-2 + + on IHC, and selected patients where there was a discrepancy between the primary tumour and corresponding metastases on IHC. Bright-field double-signal dual-colour single-hapten in situ hybridization (INFORM™ HER2 DNA and chromosome 17 probe; Roche Diagnostics) was used, with the BenchMark Ultra immunostainer, according to the testing algorithm outlined by Hofmann and colleagues8. A ratio of more than 2 between HER-2 gene signals and chromosome 17 signals assessed in 20 cells was considered as gene amplification. Definition of HER-2 positivity All tumours showing HER-2 + + +, or HER-2 + + on IHC in combination with amplification of the HER-2 gene on CISH, were considered as positive with regard to HER-2 status. Statistical analysis The sign test was used as appropriate for paired samples. Two-tailed P < 0·050 was considered statistically significant. SPSS® version 17.0 (SPSS, Chicago, Illinois, USA) was used for all statistical calculations. Results The mean observation time was 57 months for ACs and 44 months for SCCs. Formalin-fixed, paraffin-embedded specimens from 176 patients with primary oesophageal cancer (97 AC, 79 SCC) were included. Histopathological and clinical data are summarized in Table 1. Table 1 Clinical data . Adenocarcinoma (n = 97) . Squamous cell carcinoma (n = 79) . Mean(s.d.) age (years) 63·9(10·4) 60·4(9·7) Tumour stage  pT0 (biopsy used) 1 (1) 0 (0)  pT1a 0 (0) 1 (1)  pT1b 4 (4) 5 (6)  pT2 28 (29) 21 (27)  pT3 59 (61) 50 (63)  pT4 5 (5) 2 (3) Lymph node status  pNx 8 (8) 3 (4)  pN0 3 (3) 8 (10)  pN1 19 (20) 41 (52)  pN2 29 (30) 17 (22)  pN3 38 (39) 10 (13) Histological grade  G1 1 (1) 5 (6)  G2 29 (30) 54 (68)  G3 67 (69) 20 (25) . Adenocarcinoma (n = 97) . Squamous cell carcinoma (n = 79) . Mean(s.d.) age (years) 63·9(10·4) 60·4(9·7) Tumour stage  pT0 (biopsy used) 1 (1) 0 (0)  pT1a 0 (0) 1 (1)  pT1b 4 (4) 5 (6)  pT2 28 (29) 21 (27)  pT3 59 (61) 50 (63)  pT4 5 (5) 2 (3) Lymph node status  pNx 8 (8) 3 (4)  pN0 3 (3) 8 (10)  pN1 19 (20) 41 (52)  pN2 29 (30) 17 (22)  pN3 38 (39) 10 (13) Histological grade  G1 1 (1) 5 (6)  G2 29 (30) 54 (68)  G3 67 (69) 20 (25) Values in parentheses are percentages. pT, pathological tumour category; pN, pathological node category. Open in new tab Table 1 Clinical data . Adenocarcinoma (n = 97) . Squamous cell carcinoma (n = 79) . Mean(s.d.) age (years) 63·9(10·4) 60·4(9·7) Tumour stage  pT0 (biopsy used) 1 (1) 0 (0)  pT1a 0 (0) 1 (1)  pT1b 4 (4) 5 (6)  pT2 28 (29) 21 (27)  pT3 59 (61) 50 (63)  pT4 5 (5) 2 (3) Lymph node status  pNx 8 (8) 3 (4)  pN0 3 (3) 8 (10)  pN1 19 (20) 41 (52)  pN2 29 (30) 17 (22)  pN3 38 (39) 10 (13) Histological grade  G1 1 (1) 5 (6)  G2 29 (30) 54 (68)  G3 67 (69) 20 (25) . Adenocarcinoma (n = 97) . Squamous cell carcinoma (n = 79) . Mean(s.d.) age (years) 63·9(10·4) 60·4(9·7) Tumour stage  pT0 (biopsy used) 1 (1) 0 (0)  pT1a 0 (0) 1 (1)  pT1b 4 (4) 5 (6)  pT2 28 (29) 21 (27)  pT3 59 (61) 50 (63)  pT4 5 (5) 2 (3) Lymph node status  pNx 8 (8) 3 (4)  pN0 3 (3) 8 (10)  pN1 19 (20) 41 (52)  pN2 29 (30) 17 (22)  pN3 38 (39) 10 (13) Histological grade  G1 1 (1) 5 (6)  G2 29 (30) 54 (68)  G3 67 (69) 20 (25) Values in parentheses are percentages. pT, pathological tumour category; pN, pathological node category. Open in new tab Tissues from corresponding lymph node metastases were available for 85 ACs and 70 SCCs, and from distant metastases for 22 ACs and 13 SCCs. In seven patients (3 AC, 4 SCC) the distant metastases were synchronous, and in the other 28 patients they developed between 1 and 6 years after primary surgery. Tissue from local recurrences was available from 15 patients (8 AC, 7 SCC). In 18 patients (12 AC, 6 SCC), tissues from both lymph nodes and distant metastases were available. In six patients (all AC) tissue was available from lymph node metastases and sites of local recurrence. HER-2 status in primary and metastatic oesophageal tumours On IHC, 11 (11 per cent) of 97 of primary ACs and no SCCs revealed HER-2 overexpression (HER-2 + + +). The rate of HER-2 overexpression in metastatic and recurrent tumours of patients with AC was: nine (11 per cent) of 85 lymph node metastases, five (23 per cent) of 22 distant metastases and one (12 per cent) of eight local recurrences. Typical examples of HER-2 expression in AC and metastases from AC are shown in Fig. 1. None of the metastatic tumours from SCCs showed HER-2 protein overexpression. Fig. 1 Open in new tabDownload slide Immunohistochemistry (IHC) showing a adenocarcinoma (AC) with strong basolateral membranous expression of human epidermal growth factor receptor (HER) 2 (HER-2 + + +), b lymph node metastasis from AC with strong HER-2 protein expression (HER-2 + + +) and c liver metastasis from AC with strong membranous HER-2 expression (HER-2 + + +) (all original magnification × 400). d Dual colorimetric in situ hybridization (CISH) of AC without HER-2 gene amplification (original magnification × 600) Some 14 (14 per cent) of 97 primary ACs and one (1 per cent) of 79 primary SCCs were considered HER-2-positive (HER-2 + + +, or HER-2 + + plus HER gene amplification). In metastatic disease from AC the HER-2 status was graded positive in ten (12 per cent) of 85 lymph node metastases, five (23 per cent) of 22 distant metastases and one (12 per cent) of eight local recurrences (Table 2). Table 2 HER-2 protein expression and HER-2 status in primary and metastatic tumours . Primary tumour . Lymph node metastasis . Distant metastasis . Local recurrence . . AC (n = 97) . SCC (n = 79) . AC (n = 85) . SCC (n = 70) . AC (n = 22) . SCC (n = 13) . AC (n = 8) . SCC (n = 7) . IHC score  0 78 (80) 75 (95) 64 (75) 69 (99) 15 (68) 13 (100) 4 (50) 6 (86)  + 5 (5) 1 (1) 11 (13) 0 (0) 1 (5) 0 (0) 2 (25) 0 (0)  + + 3 (3) 3 (4) 1 (1) 1 (1) 1 (5) 0 (0) 1 (12) 1 (14)  + + with HER-2 gene amplified 3 (3) 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)  + + + 11 (11) 0 (0) 9 (11) 0 (0) 5 (23) 0 (0) 1 (12) 0 (0) HER-2 status  + 14 (14) 1 (1) 10 (12) 0 (0) 5 (23) 0 (0) 1 (12) 0 (0)  − 83 (86) 78 (99) 75 (88) 70 (100) 17 (77) 13 (100) 7 (88) 7 (100) . Primary tumour . Lymph node metastasis . Distant metastasis . Local recurrence . . AC (n = 97) . SCC (n = 79) . AC (n = 85) . SCC (n = 70) . AC (n = 22) . SCC (n = 13) . AC (n = 8) . SCC (n = 7) . IHC score  0 78 (80) 75 (95) 64 (75) 69 (99) 15 (68) 13 (100) 4 (50) 6 (86)  + 5 (5) 1 (1) 11 (13) 0 (0) 1 (5) 0 (0) 2 (25) 0 (0)  + + 3 (3) 3 (4) 1 (1) 1 (1) 1 (5) 0 (0) 1 (12) 1 (14)  + + with HER-2 gene amplified 3 (3) 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)  + + + 11 (11) 0 (0) 9 (11) 0 (0) 5 (23) 0 (0) 1 (12) 0 (0) HER-2 status  + 14 (14) 1 (1) 10 (12) 0 (0) 5 (23) 0 (0) 1 (12) 0 (0)  − 83 (86) 78 (99) 75 (88) 70 (100) 17 (77) 13 (100) 7 (88) 7 (100) Values in parentheses are percentages. AC, oesophageal adenocarcinoma; SCC, oesophageal squamous cell carcinoma; IHC immunohistochemistry; HER, human epidermal growth factor receptor. Open in new tab Table 2 HER-2 protein expression and HER-2 status in primary and metastatic tumours . Primary tumour . Lymph node metastasis . Distant metastasis . Local recurrence . . AC (n = 97) . SCC (n = 79) . AC (n = 85) . SCC (n = 70) . AC (n = 22) . SCC (n = 13) . AC (n = 8) . SCC (n = 7) . IHC score  0 78 (80) 75 (95) 64 (75) 69 (99) 15 (68) 13 (100) 4 (50) 6 (86)  + 5 (5) 1 (1) 11 (13) 0 (0) 1 (5) 0 (0) 2 (25) 0 (0)  + + 3 (3) 3 (4) 1 (1) 1 (1) 1 (5) 0 (0) 1 (12) 1 (14)  + + with HER-2 gene amplified 3 (3) 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)  + + + 11 (11) 0 (0) 9 (11) 0 (0) 5 (23) 0 (0) 1 (12) 0 (0) HER-2 status  + 14 (14) 1 (1) 10 (12) 0 (0) 5 (23) 0 (0) 1 (12) 0 (0)  − 83 (86) 78 (99) 75 (88) 70 (100) 17 (77) 13 (100) 7 (88) 7 (100) . Primary tumour . Lymph node metastasis . Distant metastasis . Local recurrence . . AC (n = 97) . SCC (n = 79) . AC (n = 85) . SCC (n = 70) . AC (n = 22) . SCC (n = 13) . AC (n = 8) . SCC (n = 7) . IHC score  0 78 (80) 75 (95) 64 (75) 69 (99) 15 (68) 13 (100) 4 (50) 6 (86)  + 5 (5) 1 (1) 11 (13) 0 (0) 1 (5) 0 (0) 2 (25) 0 (0)  + + 3 (3) 3 (4) 1 (1) 1 (1) 1 (5) 0 (0) 1 (12) 1 (14)  + + with HER-2 gene amplified 3 (3) 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)  + + + 11 (11) 0 (0) 9 (11) 0 (0) 5 (23) 0 (0) 1 (12) 0 (0) HER-2 status  + 14 (14) 1 (1) 10 (12) 0 (0) 5 (23) 0 (0) 1 (12) 0 (0)  − 83 (86) 78 (99) 75 (88) 70 (100) 17 (77) 13 (100) 7 (88) 7 (100) Values in parentheses are percentages. AC, oesophageal adenocarcinoma; SCC, oesophageal squamous cell carcinoma; IHC immunohistochemistry; HER, human epidermal growth factor receptor. Open in new tab Discordance in HER-2 status between primary tumours and metastases Eighty-five patients (88 per cent) with AC and 70 (89 per cent) with SCC had involved lymph nodes. In 95 and 99 per cent of these patients respectively the HER-2 status was identical in the primary tumour and lymph node metastases (P = 0·375, sign test) (Table 3). In four patients with AC, there was discordance between the primary tumour and lymph node metastases. In three the primary tumour was HER-2-positive and the lymph node metastases were negative, whereas in one patient with a HER-2-negative primary tumour the lymph node metastases were positive. In one patient with HER-2-positive primary SCC, the lymph node metastases were negative. Table 3 Correlation of HER-2 status between primary tumours and recurrences/metastases . Primary AC (n = 97) . Primary SCC (n = 79) . HER-2 status . − . + . − . + . Lymph node metastasis  − 72 (85) 3 (4) 69 (99) 1 (1)  + 1 (1) 9 (11) 0 (0) 0 (0) Distant metastasis  − 16 (73) 1 (5) 13 (100) 0 (0)  + 2 (9) 3 (14) 0 (0) 0 (0) Local recurrence  − 7 (88) 0 (0) 7 (100) 0 (0)  + 0 (0) 1 (12) 0 (0) 0 (0) . Primary AC (n = 97) . Primary SCC (n = 79) . HER-2 status . − . + . − . + . Lymph node metastasis  − 72 (85) 3 (4) 69 (99) 1 (1)  + 1 (1) 9 (11) 0 (0) 0 (0) Distant metastasis  − 16 (73) 1 (5) 13 (100) 0 (0)  + 2 (9) 3 (14) 0 (0) 0 (0) Local recurrence  − 7 (88) 0 (0) 7 (100) 0 (0)  + 0 (0) 1 (12) 0 (0) 0 (0) Values in parentheses are percentages. Human epidermal growth factor receptor (HER) 2-positive status defined as HER-2 + + + on immunohistochemistry, or HER-2 + + with gene amplification. AC, oesophageal adenocarcinoma; SCC, oesophageal squamous cell carcinoma. Open in new tab Table 3 Correlation of HER-2 status between primary tumours and recurrences/metastases . Primary AC (n = 97) . Primary SCC (n = 79) . HER-2 status . − . + . − . + . Lymph node metastasis  − 72 (85) 3 (4) 69 (99) 1 (1)  + 1 (1) 9 (11) 0 (0) 0 (0) Distant metastasis  − 16 (73) 1 (5) 13 (100) 0 (0)  + 2 (9) 3 (14) 0 (0) 0 (0) Local recurrence  − 7 (88) 0 (0) 7 (100) 0 (0)  + 0 (0) 1 (12) 0 (0) 0 (0) . Primary AC (n = 97) . Primary SCC (n = 79) . HER-2 status . − . + . − . + . Lymph node metastasis  − 72 (85) 3 (4) 69 (99) 1 (1)  + 1 (1) 9 (11) 0 (0) 0 (0) Distant metastasis  − 16 (73) 1 (5) 13 (100) 0 (0)  + 2 (9) 3 (14) 0 (0) 0 (0) Local recurrence  − 7 (88) 0 (0) 7 (100) 0 (0)  + 0 (0) 1 (12) 0 (0) 0 (0) Values in parentheses are percentages. Human epidermal growth factor receptor (HER) 2-positive status defined as HER-2 + + + on immunohistochemistry, or HER-2 + + with gene amplification. AC, oesophageal adenocarcinoma; SCC, oesophageal squamous cell carcinoma. Open in new tab Among patients with AC, the distant metastases had identical HER-2 status to the primary tumour in 19 (86 per cent) of 22 patients. In two patients with AC the primary tumour was negative with positive distant metastases, and in one patient the reverse applied. The HER-2 status of all primary SCCs was concordant with that of distant metastases. In all patients, HER-2 status was identical in local recurrence and primary tumour (Fig. 2). Fig. 2 Open in new tabDownload slide Percentage concordance of human epidermal growth factor receptor (HER) 2 status between primary oesophageal tumours and various metastatic sites. AC, adenocarcinoma; SCC, squamous cell carcinoma; LN, lymph node None of the patients with discordant HER-2 status between primary and metastatic tumours had received adjuvant chemotherapy after resection of the primary tumour. Comparison of HER-2 status at multiple metastatic sites in the same patient Tissue from positive lymph nodes and distant metastases was available for 12 patients with AC and six with SCC. The HER-2 status of the primary tumour, lymph nodes and metastases was identical in all patients (AC: negative in 10, positive in 2; SCC: negative in all 6). Six patients with AC presented with lymph node metastases and local recurrences. In five the primary tumour, lymph node metastases and local recurrence were all negative for HER-2. In the other patient the primary tumour was HER-2-positive (15 per cent of tumour cells positive with weak basolateral membrane staining, scored as HER-2 + +, and gene amplification), whereas in the lymph node 80 per cent of tumour cells showed only partial membranous staining with moderate intensity, scored as HER-2 +. Gene amplification was also found in the lymph node metastases. A biopsy from the local recurrence had basolateral staining in 5 per cent of tumour cells, with a cluster of more than five positive cells, so was scored as HER-2 + + +. Gene amplification was also found in the local recurrence. Discussion HER-2 is a 185-kDa tyrosine kinase receptor and product of the c-erbB-2/neu oncogene9. As a member of the epidermal growth factor receptor family, downstream effects include cell proliferation, differentiation, adhesion, migration and apoptosis10. Amplification of erbB-2/neu in gastric cancer cell lines was first described in 1986, indicating a potential role in oncogenesis11. This was followed by various publications describing HER-2 amplification and HER-2 protein overexpression in gastric and oesophageal cancers. Since then, overexpression/amplification rates from less than 10 to 70 per cent have been reported in these cancers12–14. Applying a standardized scoring system using IHC and CISH, the authors recently demonstrated HER-2 overexpression in 15·3 per cent of ACs and 3·9 per cent of SCCs of the oesophagus4. Targeted anticancer therapy has always seemed attractive, and with positive results in the ToGA trial there is increasing interest in HER-2-targeted therapy3,15. Evaluation of a marker that might predict response to a specific therapy is generally carried out on the primary tumour, and this approach is used even when the treatment is aimed at patients with metastases or local recurrences after attempted curative treatments. As the benefit of the anti-HER-2 monoclonal antibody trastuzumab is limited to patients with HER-2 overexpression or gene amplification, careful selection of patients is crucial to avoid unnecessary treatment in those who will not benefit. It seems imperative in oesophageal cancer to determine whether HER-2 expression between the primary tumour and metastases is concordant. In the present study, 14 per cent of ACs and 1 per cent of SCCs were HER-2-positive. The rate for AC was similar to the that in the ToGA trial, where about 20 per cent of patients were HER-2-positive3. Among patients with AC, 12 per cent of lymph node metastases, 23 per cent of distant metastases and 13 per cent of local recurrences were considered HER-2-positive. This translated into discordance in HER-2 status between the primary tumour and corresponding lymph node metastases in 5 per cent of patients, and between the primary tumour and distant metastases in 14 per cent. This meant that, overall, 9 per cent of patients would not have received a potentially beneficial targeted therapy if the primary tumours alone had been used to determine HER-2 status. Mechanisms responsible for changes in HER-2 expression between primary tumours and metastatic disease have yet to be completely understood. Differences could result from genetic drift during tumour progression or intratumoral heterogeneity, whereby a clone or clones with more aggressive phenotypes start the metastatic process16. It is also possible that cells that metastasize have different biological properties from those that have the capacity to invade locally17,18. As HER-2 status was concordant in the primary tumour and distant metastases in more than 85 per cent of patients with oesophageal cancer, this study does not support the routine testing of metastases to confirm HER-2 positivity if the primary tumour is already known to be positive. Assessment of HER-2 status at a metastatic site may be worthwhile in some patients with easily accessible metastases and insufficient or absent HER-2 analysis from the primary tumour. Acknowledgements The authors thank Julia Friedrich for her organizational help. The authors declare that the submitted work is their own and that copyright has not been breached in seeking its publication. S.F.S. was supported by an unrestricted research grant from Roche. The authors declare no conflict of interest. References 1 Pera M , Manterola C, Vidal O, Grande L. Epidemiology of esophageal adenocarcinoma . J Surg Oncol 2005 ; 92 : 151 – 159 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Ng T , Dipetrillo T, Purviance J, Safran H. Multimodality treatment of esophageal cancer: a review of the current status and future directions . Curr Oncol Rep 2006 ; 8 : 174 – 182 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Bang YJ , Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki 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 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Schoppmann SF , Jesch B, Friedrich J, Wrba F, Schultheis A, Pluschnig U et al. Expression of HER-2 in carcinomas of the esophagus . Am J Surg Pathol 2010 ; 34 : 1868 – 1873 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Gancberg D , Di Leo A, Cardoso F, Rouas G, Pedrocchi M, Paesmans M et al. Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites . Ann Oncol 2002 ; 13 : 1036 – 1043 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Guarneri V , Giovannelli S, Ficarra G, Bettelli S, Maiorana A, Piacentini F et al. Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management . Oncologist 2008 ; 13 : 838 – 844 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Sobin L , Gospodarowicz M, Wittekind C. TNM Classification of Malignant Tumours . 7th edition. Wiley-Blackwell : Oxford , 2009 ; 66 – 72 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 8 Hofmann M , Stoss O, Shi D, Büttner R, van de Vijver M, Kim W et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study . Histopathology 2008 ; 52 : 797 – 805 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Schechter AL , Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI et al. The neu oncogene: an erb-B-related gene encoding a 185 000-Mr tumour antigen . Nature 1984 ; 312 : 513 – 516 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Sepp-Lorenzino L , Eberhard I, Ma Z, Cho C, Serve H, Liu F et al. Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells . Oncogene 1996 ; 12 : 1679 – 1687 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 11 Yamamoto T , Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N et al. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor . Nature 1986 ; 319 : 230 – 234 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Brien TP , Odze RD, Sheehan CE, McKenna BJ, Ross JS. HER-2/neu gene amplification by FISH predicts poor survival in Barrett's esophagus-associated adenocarcinoma . Hum Pathol 2000 ; 31 : 35 – 39 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Geddert H , Zeriouh M, Wolter M, Heise JW, Gabbert HE, Sarbia M. Gene amplification and protein overexpression of c-erb-b2 in Barrett carcinoma and its precursor lesions . Am J Clin Pathol 2002 ; 118 : 60 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Risio M , De Rosa G, Sarotto I, Casorzo L, Capussotti L, Torchio B et al. HER2 testing in gastric cancer: molecular morphology and storage time-related changes in archival samples . Int J Oncol 2003 ; 23 : 1381 – 1387 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 15 Van Cutsem E , Kang Y, Chung H, Shen L, Sawaki A, Lordick F et al. Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). ASCO annual meeting . J Clin Oncol 2009 ; 27 ( Suppl ): LBA4509 . Google Scholar Crossref Search ADS WorldCat 16 Santinelli A , Pisa E, Stramazzotti D, Fabris G. HER-2 status discrepancy between primary breast cancer and metastatic sites. Impact on target therapy . Int J Cancer 2008 ; 122 : 999 – 1004 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Kedrin D , Wyckoff J, Boimel PJ, Coniglio SJ, Hynes NE, Arteaga CL et al. ERBB1 and ERBB2 have distinct functions in tumor cell invasion and intravasation . Clin Cancer Res 2009 ; 15 : 3733 – 3739 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Schoppmann SF , Tamandl D, Roberts L, Jomrich G, Schoppmann A, Zwrtek R et al. HER2/neu expression correlates with vascular endothelial growth factor-C and lymphangiogenesis in lymph node-positive breast cancer . Ann Oncol 2009 ; 21 : 955 – 960 . Google Scholar Crossref Search ADS PubMed WorldCat Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
TI - HER-2 status in primary oesophageal cancer, lymph nodes and distant metastases
JO - British Journal of Surgery
DO - 10.1002/bjs.7562
DA - 2011-09-02
UR - https://www.deepdyve.com/lp/oxford-university-press/her-2-status-in-primary-oesophageal-cancer-lymph-nodes-and-distant-eUU3MSUDMT
SP - 1408
EP - 1413
VL - 98
IS - 10
DP - DeepDyve
ER -