|Year : 2016 | Volume
| Issue : 4 | Page : 505-511
Human epidermal growth factor receptor 2 expression in gastric carcinoma and its association with histopathological parameters in Indian population
P Gupta1, S Rao2, S Bhalla2
1 Department of Pathology, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Histopathology, Sir Ganga Ram Hospital, New Delhi, India
|Date of Web Publication||21-Apr-2017|
Department of Pathology, Sir Ganga Ram Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Introduction: Gastric carcinoma is a leading cause of death worldwide with a five year survival of 10-15% even after curative resection. Trastuzumab has emerged as a potential targeted therapy in treatment of Her 2 positive gastric cancer. Her2 positivity ranges from 7-34% in studies across the world. There is a paucity of Indian studies hence a need for determination of Her2 expression in Indian population for better patient management. This study was carried out to determine the frequency of Her 2 expression in gastric carcinoma by immunohistochemistry (IHC) technique and to evaluate its association with histopathological parameters. Material and Methods: A total of 110 cases of gastric adenocarcinoma diagnosed on histopathological examination from July 2013 to June 2015 were included. Of these, 40 cases were resection specimens and 70 were biopsies. Histological typing of gastric carcinoma was done on the basis of Lauren classification. IHC for Her2 was done in all 110 cases. Her 2 expression was correlated with various histopathological parameters. Results: Positive Her 2 expression (IHC 3+) was seen in 24.5% cases of gastric carcinoma. Patients in older age group(> 60 years) showed higher Her 2 positivity rate as compared to middle age (40-60 years) and younger population (<40 years). Higher percentage of Her 2 positivity was noted in male patients as compared to female patients. Her 2 positivity was seen more commonly in intestinal type of tumor as compared to diffuse and mixed types. Her 2 positivity was seen more in well differentiated carcinoma and higher stage tumors (pT3 and pT4). However, out of all, a statistically significant association of Her2 expression was found only with (intestinal) type of tumors (p= 0.005) and no significant association was seen with age, gender, site of tumor, tumor stage, lymph node status, lymphovascular, perineural and perinodal invasion or survival. Conclusion: Inspired by promising results of Trastuzumab therapy in Her 2 positive gastric carcinoma worldwide, it is recommended to routinely test all cases of gastric carcinoma for Her 2 expression and to use the targeted therapy with curative intentions in Indian population.
Keywords: Gastric carcinoma, histopathological parameters, human epidermal growth factor receptor 2 expression
|How to cite this article:|
Gupta P, Rao S, Bhalla S. Human epidermal growth factor receptor 2 expression in gastric carcinoma and its association with histopathological parameters in Indian population. Indian J Cancer 2016;53:505-11
|How to cite this URL:|
Gupta P, Rao S, Bhalla S. Human epidermal growth factor receptor 2 expression in gastric carcinoma and its association with histopathological parameters in Indian population. Indian J Cancer [serial online] 2016 [cited 2019 Aug 23];53:505-11. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/505/204773
| » Introduction|| |
Gastric carcinoma is a substantial health-care problem worldwide, with over 6.8% of total new cancer diagnoses and 8.8% of total cancer-related deaths annually. It is the third leading cause of cancer mortality in the world. Incidence is highest in Japan, Eastern Asia, South America, and Eastern Europe; whereas Canada, Northern Europe, Africa, and the United States of America have the lowest incidences. Gastric cancer is the second most common cause of cancer deaths in Indian population.
Among the causative and risk factors for carcinogenesis, Helicobacter pylori infection and dietary factors have been proven to play an important role., Less common causes include chronic atrophic gastritis, hypertrophic gastropathy (Menetrier's disease), gastric polyps, low socioeconomic status, and obesity. Dominant hereditary predisposition for gastric cancer is reported in familial adenomatous polyposis, Lynch syndrome, Li–Fraumeni syndrome, and germline mutation of E-cadherin gene.
Surgery is the mainstay of treatment but the majority of patients present with advanced, inoperable disease, where treatment is palliative and median survival is just 3 months with supportive care alone. Chemotherapy improves survival in patients with advanced gastric cancer, and combination regimens are superior in this respect to monotherapy. While there is no globally accepted standard first-line regimen, a platinum-fluoropyrimidine doublet, with or without epirubicin  or docetaxel, is most commonly used. However, even with optimal combination chemotherapy, the median survival in Western studies remains <1 year. Although modest increments in survival may be possible from further refinements of first- and second-line chemotherapy regimens, attention has turned to potential molecular targets in gastric cancer.
Human epidermal growth factor receptor 2 (Her2) gene amplification and protein overexpression have emerged as a potential molecular target likened to breast carcinoma. Up to 30% of breast cancers overexpress Her2 and its positivity is associated with significantly worse outcomes than Her2-negative breast cancer. Trastuzumab has revolutionized the treatment of Her2-positive breast cancer and improved its outcomes. Taking the cue from breast cancer, large numbers of studies on Her2 positivity in gastric cancer have been published from Western part of the world, relating it to important clinicopathological characteristics and survival. Percentage positivity ranges from 7% to 34% in most of the studies.
Evidence of improved survival on addition of trastuzumab to chemotherapy has been seen in patients with Her2-positive gastric carcinoma in trastuzumab for gastric cancer (ToGA) trial. Median overall survival was significantly improved with trastuzumab plus chemotherapy compared to chemotherapy alone: 13.8 (12–16) versus 11.1 (10–13) months, respectively (P = 0.0046).
Only a handful of studies related to Her2 expression in gastric cancer in Indian population is available. Therefore, this study was conducted to evaluate the percentage positivity of Her2 in gastric carcinoma in Indian population and to correlate Her2 overexpression with clinicopathological parameters and overall survival.
| » Materials and Methods|| |
It was a prospective study where a total of 110 cases of gastric carcinoma diagnosed on biopsy and resection specimens received in our department over a time span of 2 years (July 2013 to June 2015) were included in the study. There were forty resection specimens including total/partial gastrectomy and esophagogastrectomy specimens and seventy endoscopic biopsies from the stomach and gastroesophageal junction (GEJ).
Cases with inadequate sample or extensive necrosis having an insufficient number of viable tumor cells for accurate evaluation of the immunohistochemistry (IHC) results were not included in this study.
The cases where resection specimen was received subsequent to biopsy were grouped in resection specimen category. Clinical data, including patient's age, gender, and surgical findings, were recorded. Resection specimens were examined, and site and size of tumor were noted. Representative sections were taken from the specimens and processed including all the lymph nodes isolated. Hematoxylin and eosin stained sections were examined. Tumor morphology, extent of invasion, and other morphological features, namely, lymphovascular invasion, perineural invasion, lymph node infiltration, and perinodal infiltration by tumor were noted. Tumors were classified according to Lauren classification.
Her2 overexpression was determined by IHC for which 3 μ thick sections were taken on coated slides, and prediluted rabbit monoclonal antibody (Biogenex, clone – EP1045Y) was used in all cases in an automated stainer operator.
For determination of Her2 expression, a semiquantitative scoring criteria proposed by Hofmann et al. [Table 1] and [Figure 1]a,[Figure 1]b,[Figure 1]c,[Figure 1]d was applied in sections from resection specimens. Score of 3+ was taken as positive. Score values of 1+ and 0 were taken as negative. Confirmation of cases reported as equivocal (IHC Her2 score 2+) by fluorescence in situ hybridization (FISH) could not be done due to financial constraints. Therefore, score 2+ was also included as negative for all practical purposes. For biopsy specimens, the criteria of 10% cells showing reactivity were not applied, and scoring was done on the basis of intensity of staining as proposed by Hofmann et al. Strong membranous, complete, basolateral, or lateral Her2 expression in “any number of cells” were taken as positive in these cases. Overall Her2 overexpression in gastric cancer was evaluated and was further correlated with various clinicopathological features. Impact of trastuzumab on survival in Her2-positive cases was not studied.
|Table 1: Human epidermal growth factor receptor 2 immunohistochemistry scoring as per criteria defined by Hofmann et al.|
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|Figure 1: Human epidermal growth factor receptor 2 expression on immunohistochemistry: 3+ (strong, complete, basolateral, or lateral membranous reactivity in ≥10% of tumor cells) (a) 2+ (weak to moderate, complete, basolateral, or lateral membranous reactivity in ≥10% of tumor cells) (b) 1+ (faint or barely perceptible reactivity in ≥10% of tumor cells; cells are reactive only in part of their membrane) (c) 0 (no reactivity or membranous reactivity in <10% of tumor cells) (d) (×400)|
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Statistical analysis was done with SPSS version 19.0 (Armonk NY, IBM Corp) software. Categorical variables were expressed as frequencies and percentages. Nominal categorical data between the groups were compared using Chi-square test. Survival analysis was done using Kaplan–Meier (log-rank tests) survival curves. For all statistical tests, a P< 0.05 was taken to indicate a significant difference.
| » Results|| |
A total of 110 cases were included out of which 70 were gastric biopsies and 40 were resection specimens (total/partial gastrectomy). Eight out of forty resection cases also had previous biopsies done in our center; these cases were included only in the resection specimen group. The age range of patients varied from 28 to 82 years. Peak tumor incidence was between 40 and 60 years. The mean age of presentation was 57.1 years. Of the total 110 patients, 77 were male and 33 were female. The male to female ratio was 2:1. On histological examination, there were 57 intestinal, 47 diffuse, and 6 mixed tumors subtypes using Lauren's classification for gastric tumors. Diffuse type of tumors was observed more frequently in younger age (64.3% in <40 years group) as compared to older patients (34.8% in >60 years group). In older patients, there was a higher incidence of intestinal type of tumors (63.0%). Middle-aged patients (40–60 years) had an almost equal incidence of diffuse and intestinal types of tumor, 44% and 48%, respectively. Mixed type of tumors showed no age predilection.
In 103 cases, site of tumor was known. Of these, 56 tumors were in the proximal stomach which included GEJ tumors (39), tumors in cardia (4), and fundus (13) of the stomach. Distal tumors (47) included those in body and antrum of the stomach. On histological subtyping of tumors according to the site of involvement, proximal stomach tumors were predominantly of intestinal type as compared to diffuse type (64.3% vs. 28.6%). While distal tumors had no apparent predilection for any histological type, a higher rate of occurrence of intestinal type of tumors at the proximal location was found to be statistically significant (P = 0.023).
Her2 overexpression of 3+ was considered as positive; whereas score values of 2+, 1+, and 0 were taken as negative. Of the total 110 cases, Her2 was positive in 27 cases (24.5%). Of the total positive cases, 6 were resection specimens (15%) and 21 were gastric biopsies (30%).
Patients in older age group (>60 years) showed higher Her2 positivity rate (32.6%) as compared to a younger population (22% positivity in 40–60 years and 7.1% in <40 years of age). Her2 was positive in 23 out of 77 male patients (29.9%) and in 4 of 33 female patients (12.1%).
Her2 positivity of tumors with respect to localization in proximal or distal stomach was analyzed. Tumor location was known in 103 cases. Proximal tumors showed slightly higher Her2 expression as compared to distal tumors (30.4% vs. 19. %). However, no significant correlation was found between Her2 positivity and localization of tumor.
Intestinal type of tumor showed 36.8% Her2 positivity. As against this, only 10.6% of diffuse type of tumor showed Her2 overexpression. One case of the mixed type of tumor showed differential Her2 positivity. The intestinal component showed 3+ positivity, while diffuse component was negative for Her2 (0). Intestinal component comprised >10% of total tumor; hence, a score of 3+ was given. The correlation of Her2 positivity with type of tumor was found to be highly significant with a P = 0.005 [Figure 2].
|Figure 2: Human epidermal growth factor receptor 2 expression in relation to type of tumor|
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Of the 57 intestinal tumors, 13 were well differentiated, 35 moderately differentiated, and 9 were poorly differentiated. Her2 positivity was higher in well-differentiated intestinal tumors as compared to those of moderate differentiation (53.8% vs. 40%). None of the poorly differentiated tumors showed Her2 positivity. Despite this trend of Her2 positivity in better differentiated intestinal tumors, the association was not statistically significant (P = 0.125). Lymphovascular, perineural/intraneural infiltration, pathological stage, lymph node involvement, and perinodal tumor invasion were studied in forty resection specimens. Association of Her2 positivity with these prognostic factors was not found to be significant. Comparison of various clinicopathological features with Her2 expression is tabulated in [Table 2].
|Table 2: Comparison of clinicopathological features with Her2 expression|
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Follow-up information was available in 37 cases which included 13 Her2-positive and 24 Her2-negative patients. The mean follow-up period was 12 months. The median survival time of patients with Her2-positive cancer was 12 months as compared to 19 months in Her2-negative cancer. There were eight tumor-related deaths (events) in Her2-positive group and nine in Her2-negative group. Her2 expression was not significantly associated with carcinoma-specific survival in patients with gastric carcinoma (P = 0.135) [Figure 3].
|Figure 3: Kaplan–Meier survival curves of 37 patients with human epidermal growth factor receptor 2 positive (n = 13) and human epidermal growth factor receptor 2 negative (n = 24) gastric carcinoma|
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| » Discussion|| |
Gastric carcinoma is a leading cause of cancer mortality all over the world and nationally the second most common cause of cancer-related deaths. The overall 5-year survival rate of patients with gastric cancer ranges from 10% to 30% in the studies done worldwide.
Gastric carcinoma has been managed with different treatment strategies around the world. Surgery is the mainstay of treatment for nonmetastatic disease. Adjuvant chemotherapy is recommended to prevent recurrences after curative resections. Majorities of patients with gastric carcinoma in clinical practice have advanced or metastatic disease, where chemotherapy is considered standard treatment to provide palliation and to prolong survival; however, prognosis remains poor. A great interest in targeted therapies has emerged in recent past, and several molecular targeting agents are being tested.
Her2 expression in gastric carcinoma is known for >20 years. Efficacy of trastuzumab in patients with breast cancer has led to emerging interest in its antitumor activity in patients with Her2-positive gastric carcinoma. Many studies have been carried out along with a large multicentric trial (ToGA trial) to investigate the role of trastuzumab in the management of gastric cancer. In the studies published till date, Her2 positivity in gastric carcinoma ranges from as low as 4% to as high as 53%., In a literature analysis by Maresch et al., median Her2 positivity of 20.2% was observed in studies involving >8000 patients. In our study, Her2 overexpression was observed in 24.5% cases of gastric carcinoma. This commensurate with results of ToGA trial and falls close to range of Her2 positivity by IHC observed in most of the studies across the world. Higher Her2 expression was seen in older age and in males; however, the correlation was not statistically significant. A strong association of Her2 positivity with intestinal type (36.8%) of tumors as compared to diffuse type (10.6%) and mixed type (16.7%) was observed (P = 0.005). This has been consistently proven in other studies as well.,, Preferential Her2 expression in intestinal type of tumors as opposed to diffuse type can be attributed to specific tumor characteristics, similar to breast carcinoma. In breast cancers, invasive ductal carcinoma expresses Her2 in much higher percentage as compared to lobular carcinoma which shows loss of E-cadherin gene function. Diffuse carcinomas of the stomach also show loss of E-cadherin gene. An inverse relation between Her2 expression and E-cadherin loss has also been proven in gastric tumors.
A trend toward reduced Her2 expression with loss of differentiation in intestinal type of tumors was seen. Shan et al. study with a larger sample size found a correlation; however, we did not find a significant correlation in this study.
Conflicting results have been reported regarding tumor location and Her2 expression. Many authors did not report any significant association between site of tumor and Her2 positivity. In contrast, the study by Fan et al. reported a significant association of Her2 positivity with proximal tumors. We found a higher Her2 positivity (30.4%) in proximal as compared to distal tumors (19.1%); however, the association was not statistically significant.
No correlation was found between Her2 overexpression and tumor stage, lymph node metastasis, lymphovascular, and perineural invasion in the present study. This can be due to a relatively lower Her2 positivity seen in resection specimens in which the above-mentioned factors could be noted. The reason for this discrepant Her2 positivity in resection and biopsy specimens may possibly be due to different scoring criteria applied for the two types of specimens. Resection specimens require >10% cells showing strong positivity for 3+ score in contrast to biopsy specimens where any number of cells showing definite expression is considered positive.
The need for standardized processing method and a modified scoring system emerged due to discrepant results in various studies and dissimilarity of gastric cancer to breast cancer in the form of intratumoral heterogeneity and basolateral membrane staining by Her2 antibody. After decades of prevailing lack of consensus regarding the most suitable testing method for Her2 evaluation, IHC and FISH have emerged as most preferred techniques. The European Medicines Agency recommends initial evaluation of Her2 expression by IHC followed by confirmation of gene amplification of equivocal (2+) cases by FISH providing a therapeutic advantage to such patients. Another approach according to the US Food and Drug Administration (FDA), and applied in ToGA trial as well, is to subject all cases to IHC and FISH simultaneously. This provided an added advantage of picking up those gene amplified cases (candidates for trastuzumab therapy) which showed no or 1+ Her2 expression on IHC. In ToGA trial, such cases amounted to only 4% thus rendering the assumed advantage of this approach to be only theoretical.
The pre-ToGA validation study by Hofmann et al. and results of ToGA trial, both of which incorporated IHC and FISH, showed Her2 gene amplification by FISH in one-third of cases with equivocal Her2 score 2+ expression by IHC., The potential weakness of our study was the nonavailability of FISH analysis to determine Her2 amplification in cases with equivocal (2+) Her2 score. If FISH analysis could be done in the equivocal cases in our study, the final percentage of Her2 positivity would have been somewhat higher.
Prognosis in gastric carcinoma varies among patient with similar clinical and histomorphological features. Additional parameters are required to identify biological subsets of this cancer. Her2 expression has emerged as a poor prognostic factor associated with shortened survival., 20, ,, However, in our study, Her2 expression was not significantly associated with poor carcinoma-specific survival in patients with gastric carcinoma (P = 0.135). Failure to demonstrate this association can be attributed to a short follow-up period and a small number of patients.
Research pertaining to Her2 expression in gastric carcinoma is very limited in Indian population despite a significant disease burden. In the few Indian studies done till date, Her2 positivity in gastric carcinoma was found to be variable, ranging from 17% to 44.2%.,, The higher Her2 positivity (44.2%) by Sekaran et al. was attributed to use of highly sensitive streptavidin-biotin elite kit monoclonal antibody and inclusion of both membrane and cytoplasmic staining of Her2. A strict adherence to scoring criteria proposed by Hofmann et al. and applied during ToGA trial is recommended to correctly diagnose true Her2-positive cases.
Based on the results of ToGA trial, the US FDA granted the approval for trastuzumab (Herceptin, Genentech, Inc.) in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) for the treatment of patients with Her2-overexpressing metastatic gastric or GEJ carcinoma, who have not received prior treatment for metastatic disease. Similarly, in Europe, the European Medicines Agency approved trastuzumab in association with chemotherapy for the treatment of metastatic adenocarcinoma of the stomach and GEJ. Indian council of medical research recommends the use of trastuzumab as targeted therapy in Her2-positive advanced gastric cancer only. Post-ToGA trial, a case of pathological complete response has been reported, after neoadjuvant chemotherapy with trastuzumab-containing regimen in a patient with locally advanced gastric cancer-overexpressing HER2.
Many trials employing modified antibodies against Her2 receptors are either completed or underway to improve the efficacy of targeted therapy against Her2-positive gastric carcinoma. Lapatinib, a combined inhibitor of EGFR and Her2, was investigated in two Phase III trials. No significant survival benefit was reported with Lapatinib in LoGIC III trial. While in TyTAN trial, a statistically significant improvements in overall survival and progression-free survival were observed among patients with strong Her2 positivity. The JACOB Phase III study is currently recruiting participants to evaluate the effectiveness of pertuzumab in addition to trastuzumab plus chemotherapy in chemo-naïve patients with Her2-overexpressing advanced gastric cancer.
Effects of use of trastuzumab in Her2-positive cases in relation to disease progression, prognosis, and survival were beyond the scope of our study.
| » Conclusion|| |
Our study highlights the need of further defining the role of Her2 expression in gastric carcinoma in Indian patients. Her2 overexpression, its prognostic implications, and emergence of targeted therapies have been proven to be significance in gastric carcinoma. Routine testing of gastric tumors for Her2 expression is recommended to provide a therapeutic advantage in Indian patients, and standardized criteria for Her2 detection need to be applied for uniformity and accuracy of results.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]