Gastric carcinoma is one of the most common tumors in the world. An estimate made by the National Cancer Institute of the Brazilian Health Ministry (INCA) for 2016 was 12,920 new cases in men and 7,600 in women, occupying the fourth position for men and fifth for women [
The epithelial growth factor receptors (EGFR: HER1, HER2, HER3, and HER4) are cellular membrane structures expressed in several healthy tissues and in various tumors, particularly in those of epithelial origin, and their activation apparently has an important relationship with the genesis of these tumors, due to the stimulation of cellular proliferation stimulus and the inhibition of apoptosis [
Over the last few years, diverse medications having an effect on EGFR have been developed. One specific group, which has presented promising results [
The primary objective of this study was to evaluate the positivity of the HER2 expression in gastric adenocarcinomas in the Brazilian population that had undergone surgery. Secondly, we investigated the relationship between this receptor and the patient characteristics and their possible influence on the prognosis.
A retrospective analysis was made based on prospectively acquired data, collected from a specific protocol filled in every gastrectomy due to gastric adenocarcinoma performed with curative intent at the Hospital of Santa Casa of São Paulo Medical School from January 2008 to July 2012. All were submitted to surgery with curative potential (free margins, negative cytology, and adequate lymphadenectomy), independent of the stage, histological type or any other variable. The follow-up time was at least 3 years or until death. Perioperative deaths were excluded.
Right after the resection, the specimens were fixed in 10% neutral buffered formalin for a period not less than 18 h or more than 24 h, as recommended by the Pathology Department of our institution, as well as the reagents’ manufacturer. The tissues then were sliced and conserved in paraffin. The paraffin blocks that presented the best tumor representation were analyzed on slides stained with hematoxylin-eosin. Once the block had been chosen, the material was sliced into new sections measuring 3 to 5
The processes of deparaffinization and hydration were performed at room temperature in xylene and alcohol baths, finishing in a distilled water bath. Antigenic recovery was then performed making use of a solution supplied in the kit and an endogenous peroxidase blocker (incubation in a humid chamber for 5 minutes with 100
All of the slides, both hematoxylin-eosin and immunohistochemical, were evaluated by a very capable pathologist (Dr. L. Claro). Following well-established protocols [ Score 0: absence of color or reaction in less than 10% of neoplastic cells; interpretation = negative; Score 1: weak and/or incomplete coloring of the membrane in more than 10% of the neoplastic cells; interpretation = positive 1+; Score 2: moderate and/or incomplete coloring of membrane in more than 10% of the neoplastic cells; interpretation = positive 2+; Score 3: strong and complete and/or incomplete of the membrane in more than 10% of the neoplastic cells; interpretation = positive 3+.
Following what is already widely accepted in the literature, we stratified the results obtained in this manner: score 0 and 1+ defined as absent HER2; score 2+ defined as indeterminate HER2; and score 3+ considered positive HER2.
There was no follow-up loss and the histopathological results were analyzed by both the author and the same pathologist. The adopted classification for the tumor invasion (T), lymph node involvement (N), and final staging was that of the
In order to determine the association between the presence, indetermination, or absence of the HER2 protein and the studied characteristics, the Chi-square or Fisher’s exact tests were used, fixing the rejection level of the null hypothesis at 0.05 or 5%, or in other words, with
This study was analyzed and approved by the Ethics Committee of the Education and Research Institute at the Santa Casa of São Paulo Medical School (registry number 44942013.0.00005479). There was no sponsorship whatsoever by any medical companies and the whole of the study followed the most rigid protocols for research using human beings (Helsinki Declaration).
During the period of January 2008 to July 2012, 222 patients with gastric adenocarcinoma were treated by the Stomach and Obesity Surgery Department of Santa Casa of São Paulo Medical School. However, only 121 (54.5%) were submitted to surgery with a curative potential and thus being considered eligible for the study. Tables
Characteristics of patients and their relationship with the expression of HER2.
Characteristic | HER2 |
| ||||
---|---|---|---|---|---|---|
Absent |
Indeterminate |
Present |
Total |
HER2 present % | ||
Sex | ||||||
Male | 59 (48.7) | 5 (4.1) | 2 (1.6) | 66 (54.5) | 3.1 | 0. |
Female | 52 (42.9) | 1 (0.8) | 2 (1.6) | 55 (45.5) | 3.6 | |
Tumor site | ||||||
Proximal | 40 (33.1) | 0 (0.0) | 1 (0.8) | 41 (33.9) | 2.4 | 0. |
Distal | 71 (58.7) | 6 (4.9) | 3 (2.5) | 80 (66.1) | 3.8 | |
Surgery | ||||||
Gastrectomy subtotal | 92 (76.1) | 6 (4.9) | 4 (3.3) | 102 (84.3) | 3.9 | 0. |
Total gastrectomy | 19 (15.7) | 0 (0.0) | 0 (0.0) | 19 (15.7) | 0.0 | |
Tumor depth | ||||||
T1 | 35 (28.9) | 1 (0.8) | 0 (0.0) | 36 (29.7) | 0.0 | 0. |
T2 | 12 (9.9) | 1 (0.8) | 2 (1.6) | 15 (12.4) | 13.3 | |
T3 | 22 (18.2) | 2 (1.6) | 0 (0,0) | 24 (19.8) | 0.0 | |
T4 | 42 (34.7) | 2 (1.6) | 2 (1.6) | 46 (38.1) | 4.3 | |
Lymph node involvement | ||||||
N0 | 55 (45.4) | 2 (1.6) | 1 (0.8) | 58 (47.9) | 1.7 | 0. |
N1 | 12 (9.9) | 0 (0.0) | 0 (0.0) | 12 (10.7) | 0.0 | |
N2 | 13 (10.7) | 3 (2.5) | 0 (0.0) | 16 (13.2) | 0.0 | |
N3 | 31 (25.6) | 1 (0.8) | 3 (2.5) | 35 (28.9) | 8.6 | |
Stage | ||||||
I | 41 (33.9) | 2 (1.6) | 1 (0.8) | 44 (36.4) | 2.2 | 0. |
II | 20 (16.5) | 0 (0.0) | 0 (0.0) | 20 (16.5) | 0.0 | |
III | 50 (41.3) | 4 (3.3) | 3 (2.5) | 57 (47.1) | 5.2 | |
Histological type | ||||||
Well-differentiated | 18 (14.9) | 1 (0.8) | 0 (0.0) | 19 (15.7) | 0.0 | 0. |
Mod. differentiated | 33 (27.3) | 5 (4.1) | 3 (2.5) | 41 (33.9) | 7.3 | |
Little differentiated | 54 (44.7) | 0 (0.0) | 1 (0.8) | 55 (45.4) | 1.8 | |
Nondifferentiated | 6 (4.9) | 0 (0.0) | 0 (0.0) | 6 (4.9) | 0.0 | |
Angiolymphatic invasion | ||||||
Yes | 61 (50.4) | 5 (4.1) | 4 (3.3) | 70 (57.8) | 5.7 | 0. |
No | 50 (41.3) | 1 (0.8) | 0 (0.0) | 51 (42.1) | 0.0 | |
Perineural invasion | ||||||
Yes | 50 (41.3) | 2 (1.6) | 1 (0.8) | 53 (43.8) | 1.9 | 0. |
No | 61 (50.4) | 4 (3.3) | 3 (2.5) | 68 (56.2) | 4.4 | |
Adjuvant treatment | ||||||
Yes | 50 (41.3) | 2 (1.6) | 3 (2.5) | 55 (45.4) | 5.4 | 0. |
No | 61 (50.4) | 4 (3.3) | 1 (0.8) | 66 (54.6) | 1.5 | |
Relapse | ||||||
Yes | 14 (11.6) | 0 (0.0) | 1 (0.8) | 15 (12.4) | 6.6 | 0. |
No | 97 (80.2) | 6 (4.9) | 3 (2.5) | 106 (87.6) | 2.8 | |
Death | ||||||
Yes | 45 (37.2) | 3 (2.5) | 2 (1.6) | 50 (41.3) | 4.0 | 0. |
No | 66 (54.5) | 3 (2.5) | 2 (1.6) | 71 (58.7) | 2.8 |
Correlation of age, survival time, and lymph node involvement in patients with HER2 expression.
Characteristic | HER2 |
| ||
---|---|---|---|---|
Absent | Indeterminate | Present | ||
Age (years) |
|
|
|
0. |
Min = 26 | Min = 60 | Min = 48 | ||
Max = 83 | Max = 89 | Max = 71 | ||
Median = 61.0 | Median = 89.5 | Median = 56.5 | ||
Average = 60.1 | Average = 71.0 | Average = 58.0 | ||
SD = 12.3 | SD = 9.8 | SD = 10.6 | ||
|
||||
Survival time (months) |
|
|
|
0. |
Min = 1 | Min = 1 | Min = 4 | ||
Max = 82 | Max = 60 | Max = 46 | ||
Median = 42 | Median = 42.5 | Median = 42.5 | ||
Average = 39.3 | Average = 34.3 | Average = 33.8 | ||
SD = 25.0 | SD = 24.7 | SD = 19.9 | ||
|
||||
Positive lymph nodes |
|
|
|
0. |
Min = 0 | Min = 0 | Min = 0 | ||
Max = 64 | Max = 8 | Max = 11 | ||
Median = 1.0 | Median = 4.0 | Median = 8.0 | ||
Average = 5.8 | Average = 3.5 | Average = 6.8 | ||
SD = 10.2 | SD = 3.1 | SD = 4.8 |
The human epithelial growth factor receptors are a family of four structurally similar homologous members (HER1 to HER4), containing an extracellular binder component, a transmembrane hydrophobic segment, and domain with tyrosine-kinase intracellular activity [
As previously stated, in various published studies the intermediate results (2+ reactions) were submitted to a new analysis using fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH), thus obtaining only positive or negative results. In a post hoc analysis of the data obtained in the ToGA Trial [
The real implication of the superexpression of HER2 as a risk factor for a worse prognosis in patients with gastric cancer has not yet been established. In the present study, there was no statistical difference as to the evolution of these patients, even though the low number of positive cases might have influenced such a result. Nonetheless, in a recent revision of meta-analyses, Nagaraja and Eslick analyzed nine large studies [
Even though our study has not shown a statistical difference between the diverse clinical-pathological characteristics and the expression of HER2, the relationship between the lymph node involvement (
In this manner, in light of the similarity with other studies, we found a relatively low HER2 positivity in our gastric carcinoma cohort and we did not find a statistical relationship with the survival or with clinical characteristics. Albeit, when present, HER2 becomes one more treatment option in this disease with so few satisfactory results when in its advanced phase. Studies with new drugs are proving to be more and more promising, especially when combined with already established therapies. It is possible that one might not be able to establish an adequate relationship between prognosis and clinical characteristics specific to the superexpression of HER2, but certainly the research into its expression is very valid. As long as every viable treatment should be offered to the patient, defining if he or she presents with conditions to be submitted to a target treatment seems essential to us.
The authors declare no competing interests.