World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access |
Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc |
Journal website https://wjon.elmerpub.com |
Original Article
Volume 000, Number 000, April 2025, pages 000-000
Co-expression of HER2/EGFRvIII/CD44 and Claudin 18.2/CD109 as Novel Prognostic Indicators in Stomach Adenocarcinoma
Figures
Tables
Characteristics | Number of patients (%) | Overall survival in years (mean ± SE) | 95% CI | P-value |
---|---|---|---|---|
*Statistically significant. CI: confidence interval; SE: standard error. | ||||
Age | 0.369 | |||
< 60 | 12 (15.4) | 7.0 ± 1.5 | 4.0 - 10.0 | |
≥ 60 | ||||
Gender | 66 (84.6) | 6.3 ± 0.7 | 5.0 - 7.5 | 0.277 |
Male | ||||
Lauren classification | 55 (70.5) | 6.9 ± 0.8 | 5.3 - 8.5 | 0.394 |
Intestinal type | 39 (50.6) | 6.1 ± 0.8 | 4.5 - 7.7 | |
Diffuse type/mixed type | ||||
T-stage | 38 (44.2) | 7.2 ± 0.9 | 5.3 - 9.1 | 0.185 |
T1 + T2 | 39 (50.0) | 7.2 ± 0.8 | 5.6 - 8.9 | |
T3 + T4 | ||||
Grade | 39 (50.0) | 5.2 ± 0.7 | 3.8 - 6.7 | 0.353 |
< G3 | 22 (28.2) | 5.6 ± 1.1 | 3.4 - 7.7 | |
G3 | ||||
Lymph node invasion | 56 (71.8) | 6.7 ± 0.7 | 5.2 - 8.1 | 0.030* |
Absent | 32 (41.0) | 8.4 ± 1.8 | 6.1 - 10.7 | |
Present | ||||
Lymphatic invasion | 46 (59.0) | 5.3 ± 0.7 | 4.0 - 6.7 | 0.575 |
Absent | 32 (41.0) | 6.9 ± 0.9 | 5.1 - 8.6 | |
Present | ||||
Vascular invasion | 46 (59.0) | 6.4 ± 0.9 | 4.4 - 8.3 | 0.057 |
Absent | 57 (73.1) | 7.1 ± 0.8 | 5.6 - 8.6 | |
Present | ||||
Perineural invasion | 21 (26.9) | 4.4 ± 0.8 | 2.9 - 5.9 | 0.019* |
Absent | 50 (64.1) | 7.3 ± 0.8 | 5.9 - 8.8 | |
Present | 28 (35.9) | 3.9 ± 0.7 | 2.5 - 5.3 |
Receptor expression | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Scoring criteria | Wt-EGFR | HER2 | HER3 | HER4 | EGFRvIII | CD44 | CD109 | CLDN18.2 | |||||
Percentage of positive tumor cells, % | |||||||||||||
≥ 5% | 10 (12.8) | 64 (82.1) | 7 (9.0) | 26 (33.3) | 26 (33.3) | 32 (41.0) | 47 (60.3) | 31 (39.7) | |||||
≥ 10% | 6 (7.7) | 60 (76.9) | 4 (5.1) | 19 (24.4) | 17 (21.8) | 31 (39.7) | 44 (56.4) | 24 (30.8) | |||||
≥ 20% | 3 (3.8) | 53 (67.9) | 2 (2.6) | 15 (19.2) | 10 (12.8) | 24 (34.6) | 34 (43.6) | 17 (21.8) | |||||
≥ 50% | 1 (1.3) | 28 (35.9) | 0 | 4 (5.1) | 7 (9.0) | 13 (15.7) | 20 (23.3) | 13 (16.7) | |||||
Intensity | |||||||||||||
1+ | 8 (10.3) | 34 (43.6) | 4 (5.1) | 25 (32.1) | 20 (25.6) | 14 (17.9) | 47 (60.3) | 19 (24.4) | |||||
2+ | 0 | 32 (41.0) | 4 (5.1) | 1 (1.3) | 11 (14.1) | 16 (20.5) | 1 (1.3) | 14 (17.9) | |||||
3+ | 2 (2.6) | 6 (7.7) | 2 (2.6) | 0 | 0 | 14 (17.9) | 0 | 6 (7.7) | |||||
Sub-cellular localization | |||||||||||||
Membranous | 3 (3.8) | 10 (12.8) | 5 (6.4) | 0 | 0 | 32 (41.0) | 17 (19.8) | 31 (39.7) | |||||
Cytoplasmic | 10 (12.8) | 61 (78.2) | 3 (2.8) | 17 (21.8) | 25 (32.1) | 0 | 47 (60.3) | 0 | |||||
Nuclear | 0 | 0 | 0 | 22 (28.2) | 2 (2.6) | 0 | 0 | 0 | |||||
Co-expression | |||||||||||||
Markers | ≥ 5% cut-off | ≥ 10% cut-off | ≥ 20% cut-off | ≥ 50% cut-off | |||||||||
CD: cluster of differentiation; CLDN18.2: claudin 18.2; EGFRvIII: epidermal growth factor receptor variant III; HER2: human epidermal growth factor receptor 2; wt: wild-type. | |||||||||||||
Wt-EGFR/HER2 | 7 (9.0) | 4 (5.1) | 1 (1.3) | 0 | |||||||||
Wt-EGFR/CD109 | 8 (10.3) | 6 (7.7) | 3 (3.8) | 1 (1.3) | |||||||||
HER2/HER4 | 21 (26.9) | 14 (17.9) | 11 (14.1) | 1 (1.3) | |||||||||
HER2/EGFRvIII | 22 (28.2) | 12 (15.4) | 4 (5.1) | 0 | |||||||||
HER2/CD44 | 26 (33.3) | 21 (26.9) | 16 (20.5) | 4 (5.1) | |||||||||
HER2/CD109 | 38 (48.7) | 34 (43.6) | 24 (30.8) | 10 (12.8) | |||||||||
HER2/CLDN18.2 | 25 (32.1) | 19 (24.4) | 13 (16.7) | 4 (5.1) | |||||||||
HER2/EGFRvIII/CD44 | 9 (11.5) | 4 (5.1) | 4 (5.1) | 0 | |||||||||
HER2/EGFRvIII/CD109 | 13 (16.7) | 5 (6.4) | 1 (1.3) | 0 | |||||||||
HER2/CD44/CD109 | 20 (25.6) | 16 (20.5) | 10 (12.8) | 3 (3.8) | |||||||||
HER2/CD44/CLDN18.2 | 13 (16.7) | 9 (11.5) | 3 (3.8) | 0 | |||||||||
HER2/CD44/CD109/CLDN18.2 | 12 (15.4) | 9 (11.5) | 2 (2.6) | 0 | |||||||||
HER2/ CD109/CLDN18.2 | 20 (25.6) | 16 (20.5) | 9 (11.5) | 2 (2.6) | |||||||||
HER4/EGFRvIII | 7 (9.0) | 1 (1.3) | 0 | 0 | |||||||||
HER4/CD44 | 15 (19.2) | 8 (10.3) | 7 (9.0) | 0 | |||||||||
HER4/CD109 | 19 (24.4) | 16 (20.5) | 8 (10.3) | 1 (1.3) | |||||||||
HER4/CLDN18.2 | 13 (16.7) | 8 (10.3) | 4 (5.1) | 0 | |||||||||
HER4/CD44/CD109 | 11 (14.1) | 7 (9.0) | 5 (6.4) | 0 | |||||||||
HER4/CD44/CLDN18.2 | 8 (10.3) | 3 (3.8) | 0 | 0 | |||||||||
HER4/CD109/CLDN18.2 | 13 (16.7) | 8 (10.3) | 3 (3.8) | 0 | |||||||||
HER4/CD44/CD109/CLDN18.2 | 8 (10.3) | 3 (3.6) | 0 | 0 | |||||||||
EGFRvIII/CD44 | 10 (12.8) | 4 (5.1) | 4 (5.1) | 1 (1.3) | |||||||||
EGFRvIII/CD109 | 14 (17.9) | 6 (7.7) | 2 (2.6) | 0 | |||||||||
EGFRvIII/CLDN18.2 | 10 (12.8) | 2 (2.6) | 0 | 0 | |||||||||
EGFRvIII/CD44/CD109 | 8 (10.3) | 3 (3.8) | 1 (1.3) | 0 | |||||||||
EGFRvIII/CD109/CLDN18.2 | 7 (9.0) | 2 (2.6) | 0 | 0 | |||||||||
CD44/CD109 | 24 (30.8) | 20 (25.6) | 13 (16.7) | 5 (6.4) | |||||||||
CD44/CLDN18.2 | 15 (19.2) | 11 (14.1) | 3 (3.8) | 2 (2.6) | |||||||||
CD44/CD109/CLDN18.2 | 14 (17.9) | 10 (12.8) | 2 (2.6) | 1 (1.3) | |||||||||
CD109/CLDN18.2 | 25 (32.1) | 21 (26.0) | 12 (15.4) | (6.4) |
Receptor (sub-categories) | Clinicopathological parameters | Chi-square test (FET) | |
---|---|---|---|
Number of patients with receptor expression | |||
CD: cluster of differentiation; CLDN18.2: claudin 18.2; EGFRvIII: epidermal growth factor receptor variant III; FET: Fisher’s exact t-test; HER2: human epidermal growth factor receptor 2; wt: wild-type. | |||
Age | |||
< 60 | ≥ 60 | ||
HER2/CLDN18.2 (≥ 5%) | 0 | 25 | 0.010 (0.007) |
HER2/CLDN18.2 (≥ 10%) | 0 | 19 | 0.033 (0.032) |
HER2/CD109/CLDN18.2 (≥ 5%) | 0 | 20 | 0.027 (0.030) |
Lauren classification | |||
Intestinal type | Diffuse/mixed type | ||
HER2/CD44/CLDN18.2 (≥ 5%) | 3 | 10 | 0.026 (0.034) |
T-stage | |||
T1 + T2 | T3 + T4 | ||
HER2 (intensity 1+) | 12 | 22 | 0.022 (0.039) |
EGFRvIII (≥ 5%) | 6 | 20 | 0.0008 (0.002) |
EGFRvIII (cytoplasmic) | 6 | 19 | 0.002 (0.003) |
EGFRvIII (intensity 1+) | 5 | 15 | 0.010 (0.018) |
HER2/HER4 (≥ 5%) | 15 | 6 | 0.022 (0.040) |
HER2/EGFRvIII (≥ 5%) | 6 | 16 | 0.012 (0.022) |
Vascular invasion | |||
Absent | Present | ||
Wt-EGFR (≥ 10%) | 1 | 5 | 0.001 (0.005) |
Wt-EGFR (membranous) | 0 | 3 | 0.004 (0.017) |
EGFRvIII (cytoplasmic) | 14 | 11 | 0.020 (0.029) |
EGFRvIII (intensity 1+) | 11 | 9 | 0.035 (0.044) |
Wt-EGFR/CD109 (≥ 5%) | 3 | 5 | 0.017 (0.029) |
Wt-EGFR/CD109 (≥ 10%) | 1 | 5 | 0.001 (0.005) |
Lymphatic invasion | |||
Absent | Present | ||
Wt-EGFR (≥ 5%) | 0 | 10 | 0.005 (0.004) |
Wt-EGFR (cytoplasmic) | 0 | 10 | 0.005 (0.004) |
Wt-EGFR (intensity 1+) | 0 | 8 | 0.013 (0.018) |
EGFRvIII (≥ 5%) | 5 | 21 | 0.006 (0.007) |
EGFRvIII (cytoplasmic) | 5 | 20 | 0.010 (0.013) |
EGFRvIII (intensity 1+) | 3 | 17 | 0.006 (0.008) |
Wt-EGFR/HER2 (≥ 5%) | 0 | 7 | 0.021 (0.037) |
Wt-EGFR/CD109 (≥ 5%) | 0 | 8 | 0.013 (0.018) |
HER2/EGFRvIII (≥ 5%) | 4 | 18 | 0.010 (0.011) |
HER4/EGFRvIII (≥ 5%) | 0 | 7 | 0.021 (0.037) |
Perineural invasion | |||
Absent | Present | ||
CLDN18.2 (≥ 20%) | 7 | 10 | 0.026 (0.043) |
Grade | |||
< G3 | G3 | ||
HER2 (membranous) | 7 | 3 | 0.002 (0.004) |
HER2 (intensity 1+) | 5 | 29 | 0.020 (0.024) |
CD109 (≥ 10%) | 17 | 27 | 0.020 (0.024) |
CD109 (membranous) | 10 | 7 | 0.002 (0.004) |
HER2/CD109 (≥ 5%) | 16 | 22 | 0.008 (0.011) |
HER2/CD109 (≥ 10%) | 16 | 18 | 0.001 (0.002) |
Expression | Univariate | Multivariate | ||||
---|---|---|---|---|---|---|
Hazard ratio | 95% CI | P-value | Hazard ratio | 95% CI | P-value | |
CD: cluster of differentiation; CI: confidence interval; CLDN18.2: claudin 18.2; EGFRvIII: epidermal growth factor receptor variant III; HER2: human epidermal growth factor receptor 2; NS: non-significant. | ||||||
EGFRvIII intensity 1+ | NS | NS | ||||
CD109 membranous | 2.04 | 1.02 - 4.07 | 0.042 | 2.27 | 1.06 - 3.87 | 0.022 |
CLDN18.2 intensity 3+ | 2.36 | 0.90 - 5.65 | 0.050 | 2.62 | 1.09 - 3.87 | 0.031 |
HER2/EGFRvIII ≥ 5% | 1.89 | 1.02 - 3.49 | 0.041 | 1.96 | 1.06 - 3.65 | 0.031 |
HER2/EGFRvIII ≥ 10% | 2.24 | 1.06 - 4.73 | 0.033 | 2.45 | 1.15 - 5.21 | 0.020 |
EGFRvIII/CD44 ≥ 5% | 2.97 | 1.33 - 6.61 | 0.008 | 2.97 | 1.33 - 6.61 | 0.008 |
CD109/CLDN18.2 ≥ 20% | 2.16 | 1.05 - 4.43 | 0.035 | 2.06 | 1.00 - 4.25 | 0.048 |
HER2/EGFRvIII/CD44 ≥ 5% | 2.68 | 1.16 - 6.20 | 0.021 | 2.68 | 1.16 - 6.20 | 0.021 |
EGFRvIII/CD44/CD109 ≥ 5% | 4.21 | 1.79 - 9.98 | 0.0009 | 4.21 | 1.79 - 9.98 | 0.0009 |