Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 6  |  Page : 684-689  

Comparison of the influence of human epidermal growth factor receptor 2/neu on the markers of aggression in gastric adenocarcinomas and ductal carcinoma breast


Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication16-Nov-2016

Correspondence Address:
Arijit Sen
Department of Pathology, Armed Forces Medical College, Solapur Road, Pune - 411 040, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.194182

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  Abstract 

Background: Human epidermal growth factor receptor 2/neu (HER2/neu) assessment is carried out in gastric adenocarcinomas (GAC) and invasive ductal carcinoma (IDC) breast to decide upon of trastuzumab targeted therapy. The study the only of its kind which has compared the influence of HER2/neu expression to markers of tumor aggression in these two malignancies in similar target population. Material and Methods: HER2/neu evaluation was conducted by immunohistochemistry (IHC) using the guidelines of Trastuzumab for Gastric Cancer trial for GAC and ASCO-CAP 2013 for IDC breast. The study correlated HER2/neu expression with markers of tumor aggression. Aims: The present retrospective study compares the disease influence of HER2/neu over expression on markers of disease aggression like age at presentation, grade of tumor and lymph node metastasis in GAC and IDC. Results: We have compared 82 cases of GAC with 113 cases of IDC. HER2/neu expression was seen in 23.2% and 36.3% of GACs and IDCs respectively. The mean age of HER2/neu positive GACs was found to be 3.47 years greater than their negative counterpart but the pattern was reversed in cases of IDC breast where the mean age of HER2/neu positive tumors was 6.09 years less than their negative counterpart. Though no correlation was found between grade of tumor and HER2neu status in GACs (P = 0.2930), however in IDC breast a significant correlation HER2neu positivity was found with higher grade (P = 0.0002). Similarly though we did not find any correlation of HER2neu status with nodal metastasis in GACs (P 0.0511) but in IDCs a significant correlation was found of nodal metastasis with HER2/neu positivity (P = 0.0001). Conclusion: We conclude that HER2/neu expression is more frequent in IDC breast and is significantly associated with markers of aggression in contrast to its influence on the same markers in GACs.

Keywords: Comparison, ductal carcinoma breast, gastric adenocarcinoma, human epidermal growth factor receptor 2/neu


How to cite this article:
Kulkarni A, Sen A, Menon M. Comparison of the influence of human epidermal growth factor receptor 2/neu on the markers of aggression in gastric adenocarcinomas and ductal carcinoma breast. Med J DY Patil Univ 2016;9:684-9

How to cite this URL:
Kulkarni A, Sen A, Menon M. Comparison of the influence of human epidermal growth factor receptor 2/neu on the markers of aggression in gastric adenocarcinomas and ductal carcinoma breast. Med J DY Patil Univ [serial online] 2016 [cited 2024 Mar 28];9:684-9. Available from: https://journals.lww.com/mjdy/pages/default.aspx/text.asp?2016/9/6/684/194182


  Introduction Top


Human epidermal growth factor receptor 2/neu (HER2/neu) is a transmembrane tyrosine kinase receptor coded by ERBB2/HER2 oncogene located on the chromosome 17q21. It belongs to the epidermal growth factor receptor family. This oncogene is overexpressed in 20%-30% of breast cancers [1] and 6%-23% of gastric cancers, [2],[3] respectively, and is associated with aggressive behavior. Use of trastuzumab targeted therapy has made HER2/neu evaluation a must for both these carcinomas. Evaluation of HER2/neu expression by immunohistochemistry (IHC) is different in gastric adenocarcinoma (GAC) as compared with invasive ductal carcinoma (IDC). [4],[5] HER2/neu overexpression is taken as the second poorest prognostic variable after lymph node metastasis in GAC. [6] The present study proposes to study the expression of HER2/neu by IHC in GAC and IDC breast cases. The study also aims to compare these two malignancies, the influence of HER2/neu overexpression on markers of aggression such as age at presentation, grade of tumor, and lymph node metastasis. On review of literature, no studies of similar nature were found in the Indian population.


  Methods Top


The study was performed at an Indian tertiary care center. It is a retrospective observational study. The cases included in the present study are restricted to a 4-year period of June 2010-May 2014. All endoscopic biopsies confirmed as GAC (where subsequent gastrectomy specimens had not been received) and all gastrectomies performed for GAC were included in the study. For IDC breast, all modified radical mastectomies and breast conservation surgeries with axillary node dissection were included in the study. The age and sex of the cases were noted. Sections from the primary tumor were reviewed to confirm the presence of GAC and IDC breast cases, respectively. All these cases of both tumors were assigned a histological grade. The WHO grading system of 2000 [7] was used for grading GAC into well, moderately, and poorly differentiated tumors. The cases of IDC breast were graded based on the Elston's modification of Bloom-Richardson grading system into Grades I, II, and III tumors. [8] Suitable sections from the primary tumor were selected for performing the HER2/neu by IHC. IHC staining for HER2/neu was performed using ready to use mouse monoclonal antibody: Novocastra (Leica) (Product code RTU-CB11) CB11 clone for 30 min. Controls used for each protocol include IDC breast cases (HER2-0, 1+, 2+, and 3+). For GAC, the IHC slides were scored according to scoring system used in Trastuzumab for Gastric Cancer trial. [5],[9] The cases of IDC breast were evaluated for IHC, HER2/neu expression using the ASCO-CAP 2013 [10] guidelines. Cases with score 3+ were considered positive and 2+ were taken as equivocal and asked to undergo fluorescent in situ hybridization (FISH) from an external agency and were considered positive only on confirmation as positive by FISH. The prevalence of positive HER2/neu expression was noted in both gastric and breast carcinomas. The HER2/neu status of the tumor in both types was correlated with histological grade of the tumor and lymph node metastatic status. For correlation with histological grade, the cases were grouped into low and high grade. Well and moderately differentiated GAC and Grades I and II IDC breast were placed into low-grade group. Poorly differentiated GAC and Grade III IDC breast were placed into high-grade group. The sections of the lymph node (where nodal dissection had been done) were reviewed to confirm nodal status for metastasis in both kinds of tumor. The tumor histology, grade, nodal status, and HER2/neu scoring were undertaken. The data were analyzed on SPSS version 20 (IBM software). The categorical variables were assessed using Fisher's exact test. For assessment, P = 0.05 or less was considered statistically significant. Ethical clearance was taken for this retrospective study from the tertiary care institution (the place of study) ethical committee with co-opted members of the society. No extra testing of any kind was performed on the patient samples since HER2/neu testing in both these tumors is routinely performed and falls within the purview of implied consent for therapy.


  Results Top


The total number of adequate biopsies received as GAC during the period of the study was 82. Out of these 21 cases were upper gastrointestinal endoscopic biopsies which did not follow up with a gastrectomy; hence these could not be evaluated for nodal involvement. The remaining 61 cases were gastrectomy specimens with nodal resection and thus were available for nodal evaluation. As far as the cases of IDC breast are concerned, we received 113 cases satisfying the inclusion criteria. The histopathological diagnosis in all these cases was confirmed not only for the tumor but also for the grade using the criteria as mentioned under methods above. The 82 cases of GAC consisted of 25 females (30.5%) and 57 males (69.5%). As far as the IDC breast is concerned, all the 113 cases which fitted the inclusion criteria were females. The age group of GAC and IDC breast cases ranged from 30 to 72 years and 35-87 years, respectively. Scoring criteria for HER2/neu differ for breast carcinoma, endoscopic biopsy specimens for GAC, and finally tumor tissue in gastrectomy specimens. Sixty-three (76.8%) out of the 82 case of GAC included in the present study were HER2/neu negative and rest 19 (23.2%) were positive [Table 1]. The mean age of HER2/neu negative and positive GAC cases was 58.87 and 62.33 years, respectively [Table 1]. As far as IDC breast is concerned, 72 (63.7%) out of 113 cases were HER2/neu negative and rest 41 (36.3%) were positive [Table 1]. The mean age of HER2/neu negative and positive cases of IDC was 56.61 years and 50.52 years, respectively [Table 1]. The cases as per the proposal of the study were grouped into low- and high-grade lesion (refer methods). For GAC, out of the 63 (63/82) (76.8%) cases which were HER2/neu negative, 26 (41.27%) were found to be low-grade lesion and 37 (58.73%) were high-grade lesion. Whereas among the 19 (19/82) (23.2%) HER2/neu positive cases, 11/19 (57.89%) were low-grade lesion and 8/19 (42.11%) were high grade lesion [Table 2]. [Figure 1] depicts various grades of GAC and IDC. [Figure 2] depicts HER2/neu scoring in GAC and IDC. The Fisher's exact test revealed a two-tailed P = 0.2930. Thus, no significant correlation was found between HER2/neu status and grade in GAC. As far as IDC breast is concerned, out of the 72/113 (63.72%) cases which were HER2/neu negative, 67/72 (93.05%) were low-grade lesion and 5/72 (6.95%) were high-grade lesion. Among the 41/113 (36.28%) HER2/neu positive cases, 26/41 (63.41%) were low-grade lesion and 15/41 (36.59%) were high-grade lesion [Table 2]. The Fisher's exact test revealed the two-tailed P = 0.0002. Thus, a significant correlation was found between HER2/neu positive status and higher grade in cases of IDC breast. Sixty-one out of the 82 cases of GAC were gastrectomy specimens, where nodal status could be evaluated for the presence of metastasis. Fifty (81.97%) out of these 61 cases were HER2/neu negative and 11 (18.03%) were positive. The nodes were positive for metastasis in 35 out of the fifty HER2/neu negative cases, whereas 15 were negative for nodal metastasis. As far as the 11 HER2/neu positive cases are concerned, all were positive for nodal metastasis [Table 3]. The Fisher's exact test revealed the two-tailed P = 0.0511. Thus, no significant correlation was found between HER2/neu status and nodal metastasis in cases of GAC. For IDC breast, 47 (65.28%) out of the 72 cases which were HER2/neu negative did not have nodal metastasis, whereas 25 (34.72%) were positive [Table 3]. Whereas out of the 41 cases which were HER2/neu positive 31 (75.61%) cases had nodal metastasis while 10 (24.39%) did not [Table 3]. The Fisher's exact test revealed the two-tailed P = 0.0001. Thus, a significant correlation was found between HER2/neu status and nodal metastasis in cases of IDC breast. A comparative data of GAC and IDC breast cases for immunoexpression of HER2/neu and its correlation with markers of aggression is tabulated in [Table 4].
Figure 1: (a) Well-differentiated gastric adenocarcinoma, gastrectomy specimen. (b) Moderately differentiated gastric adenocarcinoma, endoscopic biopsy. (c) Poorly differentiated gastric adenocarcinoma, gastrectomy specimen. (d) Grade I invasive ductal carcinoma breast. (e) Grade II invasive ductal carcinoma breast. (f) Grade III invasive ductal carcinoma breast (all H and E stain at × 400)

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Figure 2: (a) Gastrectomy specimen showing barely perceptible focal wall HER2 staining in 5% tumor cells (score 1). (b) Gastrectomy specimen showing moderate lateral wall HER2 staining in 20% tumor cells (score 2). (c) Gastrectomy specimen showing strong complete wall HER2 staining in 90% tumor cells (score 3). (d) MRM specimen-weak and incomplete membrane staining in 5% of tumor cells (score 1). (e) MRM specimen-complete intermediate membrane staining in 15% tumor cells (score2). (f) MRM specimen -Complete intense membrane staining in 95% of tumor cells (score 3). (All IHC with DAB chromogen at 400 X)

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Table 1: Human epidermal growth factor receptor 2/neu status and age of cases gastric adenocarcinoma and ductal carcinoma breast


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Table 2: Correlation of human epidermal growth factor receptor 2/neu status and grade of carcinoma


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Table 3: Correlation of human epidermal growth factor receptor 2/ neu status and nodal metastasis


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Table 4: Comparative data of the human epidermal growth factor receptor 2/neu positive gastric adenocarcinoma and invasive ductal carcinoma breast for markers of aggression


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  Discussion Top


The present study evaluated 82 cases of GAC. Fifty-seven were males and 25 were females in a ratio of 2.28:1. Usually, the ratio varies from 2 to 4:1. [11] The age ranged from 30 to 72 years. Forty-seven out of these 82 cases were between 61 and 70 years of age. The mean age was 59.65 years. Theuer et al. [12] and Nakamura et al. [13] mentioned the peak incidence of gastric cancer to be in the age group of 60-80 years with very low incidence in patients younger than 30. Yeole. [14] and Jemal et al. [15] mentioned that in India, the incidence was found to be more in 45-55 years in the North and 35-55 years in the South. The mean age of HER2/neu negative (63 cases) and positive (19 cases) GAC cases was 58.87 years and 62.33 years, respectively [Table 1]. We observed that the mean age of HER2/neu negative tumors was higher by 3.46 years than those which overexpressed HER2/neu. In previous studies, Tanner et al. [16] did not find any correlation of HER2/neu status and age of onset or gender. All our 113 cases of IDC breast were females. The age ranged from 35 to 87 years. The mean age of 113 cases was 54.42 years. The maximum number of cases was between 51 and 60 years (32 cases out of 113). In India, around 50% of the breast carcinomas in females occur below the age of 50 years (premenopausal). [17] Nearly, half (48%) of female breast cancers in the UK, on the other hand, occur a decade later in 50-69 age group. [18] In the present study, the mean age of 72 HER2/neu negative cases of IDC breast was 56.61 years, whereas for 41 HER2/neu positive tumors, it was 50.52 years, almost 6 years earlier than HER2/neu negative tumors [Table 1]. However, Siadati et al., [19] and Prati et al., [20] respectively, in their study did not find any correlation of age with HER2/neu status. Thus, in our study, we found a reversal of mean age pattern between GAC and IDC breast cases as far as HER2/neu expression was concerned. Influence of HER2/neu on marker of aggression (early age of onset) hence seems to be more in IDC as compared to GAC since our study showed a 6-year early mean age of onset in HER2/neu positive IDCs as compared to negative cases. Similar pattern, however, was not observed in GAC. Instead HER2/neu positive tumors had 3.46 years more mean age of onset. However, here the HER2/neu positive cases of GAC were only 19. 23.2% (19 out of 82) of GACs expressed HER2/neu. Studies on GACs by Gravalos and Jimeno. [21] and Park et al. [6] showed HER2/neu overexpression by IHC in 13% (n = 166) and 16% (n = 182) cases, respectively. Indian studies by Rajagopal et al., [22] Sekaran et al., [23] and Patil et al. [24] showed HER2 overexpression by IHC in 22.4% (n = 60), 44.2% (n = 52), and 7% (n = 43) gastric carcinoma cases, respectively. In IDC, positive expression was higher and seen in 36.3% (41 out of 113). In the initial study by Slamon et al. in 1987, a positivity rate of 30% was observed. [25] In a subsequent study by Latta et al., [26] the prevalence was found to 29% in pure IDC, whereas the prevalence was found to be higher in ductal carcinoma in situ (DCIS) with invasive component and cases of pure DCIS. Thus, the prevalence of HER2/neu overexpression differed considerably in the two tumors under comparison of GAC (23.2%) versus IDC breast (36.3%) cases. Refer [Table 1] for tabulated data. In our study, no correlation was found in (P = 0.2930) HER2/neu expression and grade of tumors in GAC [Table 2]. A study by Rajagopal et al. [22] and by Tafe et al., [27] however, showed a significant correlation between HER2 positivity and tumor grade, with P = 0.042 and P = 0.001, respectively. Another study by Shan et al. [28] also showed a significant correlation between HER2 positivity and tumor grade. These studies also observed higher rates of HER2 positivity in well and moderately differentiated carcinomas than poorly differentiated adenocarcinomas. Rajagopal et al. [22] showed HER2 overexpression maximum in moderately differentiated adenocarcinoma. In our study, among the HER2/neu positive cases, the 11/19 were low grade and 8/19 were high grade. No correlation was possibly seen due to a low number of cases in the category HER2/neu positive GAC in this study. The study by Rakhshani et al., [29] however, showed HER2/neu positivity in 46.2% poorly differentiated, 30.7% moderately differentiated, and 23.1% well differentiated gastric carcinomas. The cases of IDC breast showed a significant correlation between high-grade lesion and HER2/neu positivity (P = 0.0002). The distribution of HER2/neu positive and negative cases into low and high grade is tabulated in [Table 2]. In a study by Prati et al. [20] (P < 0.0001) and Siadati et al. [19] (P = 0.003), a significant correlation has been found between HER2/neu positivity and higher grades. In our study, there was a significant increase in the proportion of high-grade lesion in HER2/neu positive tumors as compared to negative tumors [Table 2]. As far as correlation with nodal metastasis is concerned, the 61 cases of GAC which were evaluated 35/50 HER2/neu negative cases and 11/11 HER2/neu positive cases were found to have nodal metastasis [Table 3]. We could not demonstrate a significant correlation between nodal metastasis and HER2/neu positive status (P = 0.0511). In our study, the cases in the HER 2/neu positive category were very few (11). The study with a larger number of cases would have given a more representative data on correlation. In a study of 139 cases of gastric cancer by Son et al. [30] too no correlation (P = 0.789) was found between HER2/neu expression and nodal metastasis in gastric carcinomas. For IDC breast cases, we found a significant correlation of HER2/neu positivity with nodal metastasis (P = 0.0001). Twenty-five out of 72 HER2/neu negative cases and 31 out of 41 HER2/neu positive cases had nodal metastasis. Previous studies by Siadati et al. [19] (P = 0.03) and Tokatli et al., [31] have demonstrated the correlation of HER2/neu positivity and proneness to nodal metastasis.


  Conclusion Top


This comparative study is the first of its kind in the Indian population. IDC and GAC are the two malignancies where trastuzumab targeted therapy against HER2/neu receptor is used. The association of HER2/neu overexpression with markers of tumor aggression like age at presentation, histological grade, and propensity of nodal metastasis differed between GAC and IDC breast. The findings of the study have significance on deciding upon opting for expensive targeted trastuzumab therapy in the third world nation.

Acknowledgments

The authors would like to thank staff members of the Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India.

Financial support and sponsorship

The study was supported by the Tissue blocks and case details Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India.

Conflicts of interest

There are no conflicts of interest.

 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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