ERBB2 Amplification as a Predictive and Prognostic Biomarker in Upper Tract Urothelial Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Population and Clinicopathological Data Assessment
2.2. Construction of Tissue Microarrays (TMAs)
2.3. IHC
2.4. FISH
2.5. Statistical Analysis
3. Results
3.1. Tumor and Patients Characteristics
3.2. Morphological Evaluation (H&E Stains)
3.3. Determination of ERBB2 Status
3.3.1. ERBB2 Immunoscoring
3.3.2. ERBB2 FISH Analysis
3.3.3. Quality Parameters and Correlation Analyses
3.4. Survival Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Number of Patients | 157 | |
Age and gender n (%) | Mean 70.14 yrs, range 34.99–94.19 yrs 99 (63.1) males, 58 females (36.9) | |
Localization n (%) Total n = 160 | Renal pelvis Ureter Renal pelvis and ureter | 99 (62.7) 34 (21.5) 25 (15.8) |
WHO grading n (%) Total n = 160 | G1 G2 G3 | 17 (10.6) 60 (37.5) 83 (51.9) |
Tumor size (mm) | Mean ± SD Range | 44.23 ± 32.93 1–230 |
pT n (%) Total n = 160 | a 1 2 3 4 is | 31 (19.4) 36 (22.5) 17 (10.6) 50 (31.3) 25 (15.6) 1 (0.6) |
pN n (%) Total n = 114 | 0 1 2 | 82 (71.9) 6 (5.3) 26 (22.8) |
cM n (%) Total n = 106 | 0 1 | 91 (85.8) 15 (14.2) |
L n (%) Total n = 141 | 0 1 | 87 (61.7) 54 (38.3) |
V n (%) Total n = 142 | 0 1 2 | 92 (64.8) 48 (33.8) 2 (1.4) |
Pn n (%) Total n = 69 | 0 1 | 50 (72.5) 19 (27.5) |
Residual status n (%) Total n = 152 | 0 1 2 | 119 (78.3) 23 (15.1) 10 (6.6) * |
Growth pattern n (%) Total n = 160 | Papillary Papillary-solid/inverted Solid Mixed pattern Micropapillary Sarcomatoid Cis | 49 (30.6) 25 (15.6) 28 (17.5) 52 (32.5) 2 (1.3) 3 (1.9) 1 (0.6) |
Necrosis n (%) Total n = 128 | Absent Present (>10%) | 65 (50.8) 63 (49.2) |
Chronic lymphofollicular inflammation n (%) Total n = 128 | Absent Present | 115 (85.8) 19 (14.2) |
ERBB2 Immunoscore | Immunoscoring (According to ASCO/CAP 2018 Guidelines for ERBB2/HER2 Testing in BC) | Immunoscoring (According to ASCO/CAP 2017 Guidelines for ERBB2/HER2 Testing in GC) | Number of Amplified ERBB2 Cases |
---|---|---|---|
n (%) | n (%) | n (%) | |
0 | 59 (36.9) | 59 (36.9) | 0 |
1+ | 72 (45.0) | 26 (16.3) | 1 (6.7) |
2+ | 5 (3.1) | 43 (26.9) | 6 (40.0) |
3+ | 10 (6.3) | 18 (11.3) | 7 (46.7) |
n.a. | 14 (8.8) | 14 (8.8) | 1 (6.7) |
Total n | 160 (100) | 160 (100) | 15 (100) |
Patients and Tumor Properties | ERBB2-Immunoscoring According to Guidelines for Breast Cancer | ERBB2-Immunoscoring According to Guidelines for Gastric Adenocarcinoma | ERBB2 Amplification or Gain |
---|---|---|---|
p-Value | p-Value | p-Value | |
Gender (male, female) | 0.994 | 0.537 | 0.557 |
Age ≤ 60 yrs, >60 yrs | 0.041 | 0.820 | 1.000 |
Survival | 0.939 | 0.906 | 0.939 |
Progression | 0.195 | 0.028 | 0.549 |
Morphology (papillary, papillary-solid/inverted, solid, mixed pattern, micropapillary, sarcomatoid, cis) | 0.945 | 0.805 | 0.057 |
Necrosis | 0.204 | 0.146 | 0.048 |
Lymphofollicular inflammation | 0.578 | 0.680 | 0.356 |
WHO grading (G1, G2, G3) | 0.012 | 0.077 | <0.001 |
Invasion, pTa or T1–4 | 0.257 | 0.359 | 0.003 |
Stage | 0.701 | 0.226 | 0.014 |
pN | 0.180 | 0.145 | 0.005 |
cM | 0.547 | 0.878 | 0.064 |
L | 0.496 | 0.676 | 0.005 |
V | 0.893 | 0.389 | 0.065 |
Pn | 0.773 | 0.862 | 0.005 |
Residual status | 0.682 | 0.883 | 0.006 |
ERBB2 amplification or gain | <0.001 | <0.001 | - |
Overall Survival | Univariable Analyses | Multivariable Analysis | ||||
---|---|---|---|---|---|---|
Parameter | p-Value | 95% CI | HR | p-Value | 95% CI | Adj HR |
Age > 60 yrs vs. * ≤ 60 yrs | 0.081 | 0.940–2.925 | 1.658 | - | - | - |
Sex m vs. * f | 0.615 | 0.736–1.678 | 1.112 | - | - | - |
Progression vs. * no progression | 0.008 | 1.178–3.001 | 1.880 | 0.451 | 0.324–12.674 | 2.025 |
Pelvic localization vs. ureter vs. * both | 0.711 | 0.818–1.344 | 1.048 | - | - | - |
Growth patterns: * Papillary vs. papillary-inverted/solid * Papillary vs. solid * Papillary vs. mixed type * Papillary vs. micropapillary * Papillary vs. sarcomatoid | 0.007 0.961 0.010 0.160 0.077 <0.001 | 0.504–1.919 1.214–4.066 0.864–2.432 0.868–15.725 2.899–35.123 | 0.983 2.222 1.449 3.694 10.09 | 0.002 0.049 0.763 0.209 0.579 <0.001 | 0.032–0.990 0.175–10.757 0.556–14.580 0.078–109.66 7.614–1364.9 | 0.178 1.373 2.846 2.826 101.942 |
Necrosis vs. * no necrosis | 0.004 | 1.230–3.046 | 1.936 | 0.149 | 0.752–6.505 | 2.212 |
Chronic lymphofollicular inflammation vs. * no inflammation | 0.983 | 0.558–1.771 | 0.994 | - | - | - |
ERBB2 score ** 0 vs. 1+ vs. 2+ vs. * 3+ | 0.193 | 0.937–1.380 | 1.137 | - | - | - |
ERBB2 amplification vs. * ERBB2 <2.0 | 0.176 | 0.827–2.822 | 1.528 | - | - | |
ERBB2 gain or amplification vs. * no ERBB2 gain or amplification | 0.057 | 0.986–2.485 | 1.565 | 0.114 | 0.623–83.766 | 7.222 |
Platin vs. * no platin-based therapy | 0.005 | 1.243–3.316 | 2.031 | 0.043 | 0.003–0.914 | 0.049 |
ERBB2 status and CT | 0.006 | 0.020 | ||||
ERBB2 negative and CT vs. * ERBB2 negative and no CT | 0.009 | 1.227–4.223 | 2.276 | 0.003 | 0.009–0.377 | 0.059 |
ERBB2 positive and CT vs. * ERBB2 negative and no CT | 0.620 | 0.504–3.160 | 1.262 | 0.021 | 0.003–0.624 | 0.046 |
ERBB2 positive and no CT vs. * ERBB2 negative and no CT | 0.003 | 1.341–4.028 | 2.324 | 0.086 | 0.003–1.458 | 0.071 |
Grading | <0.001 | 0.071 | ||||
G2 vs. * G1 | 0.125 | 0.828–4.709 | 1.974 | 0.738 | 0.169–3.522 | 0.772 |
G3 vs. * G1 | 0.001 | 1.692–9.185 | 3.942 | 0.027 | 0.001–0.663 | 0.026 |
pT | <0.001 | 0.004 | ||||
pT1 vs. * pTa | 0.060 | 0.970–4.310 | 2.045 | 0.003 | 2.409–68.305 | 12.827 |
pT2 vs. * pTa | 0.040 | 1.044–5.859 | 2.474 | 0.019 | 1.711–415-792 | 26.674 |
T3 vs. * pTa | <0.001 | 1.673–6.410 | 3.274 | 0.012 | 2.346–1021.94 | 48.959 |
pT4 vs. * pTa | <0.001 | 5.006–23.279 | 10.795 | <0.001 | 11.761–8238.9 | 311.28 |
pN1 or pN2 vs. * pN0 | <0.001 | 1.921–5.125 | 3.138 | 0.678 | 1.189–4.677 | 2.358 |
cM10 vs. * cM0 | <0.001 | 2.910–10.993 | 5.656 | 0.384 | 0.346–15.830 | 2.340 |
Lymphatic invasion (L1 vs. * L0) | <0.001 | 1.525–3.602 | 2.344 | <0.001 | 4.130–71.603 | 17.196 |
Venous invasion (V1 or V2 vs. * V0) | <0.001 | 1.483–3.465 | 2.267 | 0.090 | 0.095–1.187 | 0.335 |
Perineural invasion (Pn1 vs. * Pn0) | <0.001 | 1.105–12.198 | 3.6718 | 0.442 | 0.229–1.903 | 0.660 |
Residual status (R1 or R2 vs. * R0) | <0.001 | 2.917–7.280 | 4.608 | <0.001 | 4.116–76.914 | 17.793 |
Progression-Free Survival | Univariable Analyses | Multivariable Analysis | ||||
---|---|---|---|---|---|---|
Parameter | p-Value | 95% CI | HR | p-Value | 95% CI | Adj HR |
Age > 60 yrs vs. ≤ * 60 yrs | 0.909 | 0.430–2.579 | 1.054 | - | - | - |
sex m vs. * f | 0.609 | 0.384–1.754 | 0.820 | - | - | - |
Pelvic localization vs. ureter vs. * both | 0.181 | 0.872–2.067 | 1.342 | - | - | - |
Growth patterns: * Papillary vs. papillary-inverted/solid * Papillary vs. solid * Papillary vs. mixed type * Papillary vs. micropapillary * Papillary vs. sarcomatoid | 0.019 0.333 0.944 0.070 0.983 0.004 | 0.099–2.193 0.277–3.963 0.938–5.135 0.000 2.799–246.9 | 0.465 1.048 2.195 0.000 26.29 | 0.869 | 0.583–1.577 | 0.959 |
Necrosis vs. * no necrosis | 0.127 | 0.852–3.620 | 1.756 | - | - | - |
Chronic lymphofollicular inflammation vs. * no inflammation | 0.663 | 0.275–2.274 | 0.791 | - | - | - |
ERBB2 score ** 1+ vs. 2+ vs. * 3+ vs. * 0 | 0.003 | 1.2132.517 | 1.748 | 0.176 | 0.839–2.613 | 1.480 |
ERBB2 amplification vs. * no amplification | 0.040 | 1.042–6.445 | 2.592 | 0.032 | 1.112–11.089 | 3.511 |
Platin vs. * no platin-based therapy | <0.001 | 3.865–16.851 | 8.192 | <0.001 | 4.596–45.811 | 14.510 |
ERBB2 status and CT | <0.001 | 0.296 | 0.419–1.303 | 0.739 | ||
ERBB2 negative and CT vs. * ERBB2 negative and no CT | 0.859 | 0.271–2.968 | 0.898 | |||
ERBB2 positive and CT vs. * ERBB2 negative and no CT | 0.014 | 0.052–0.717 | 0.194 | |||
ERBB2 positive and no CT vs. * ERBB2 negative and no CT | <0.001 | 0.056–0.338 | 0.137 | |||
Grading | 0.154 | - | - | - | ||
G2 vs. * G1 | 0.450 | 0.396–8.083 | 1.789 | |||
G3 vs. * G1 | 0.125 | 0.727–13.78 | 3.166 | |||
pT | 0.037 | 0.791 | 0.546–1.587 | 0.930 | ||
pT1 vs. * pTa | 0.665 | 0.359–4.988 | 1.337 | |||
pT2 vs. * pTa | 0.491 | 0.378–7.611 | 1.696 | |||
pT3 vs. * pTa | 0.059 | 0.958–9.096 | 2.951 | |||
pT4 vs. * pTa | 0.006 | 1.690–24.657 | 6.456 | |||
pN1 or pN2 vs. * pN0 | 0.015 | 1.234–7.247 | 2.991 | 0.070 | 0.082–1.101 | 0.300 |
cM10 vs. * cM0 | 0.001 | 2.274–28.137 | 8.000 | 0.147 | 0.629–22.304 | 3.745 |
Lymphatic invasion (L1 vs. * L0) | 0.121 | 0.852–3.975 | 1.840 | - | - | |
Venous invasion (V1 or V2 vs. * V0) | 0.172 | 0.790–3.738 | 1.718 | - | - | - |
Perineural invasion (Pn1 vs. * Pn0) | 0.288 | 0.538–8.083 | 2.085 | - | - | - |
Residual status (R1 or R2 vs. * R0) | 0.018 | 1.201–6.833 | 2.865 | 0.581 | 0.139–3.023 | 0.648 |
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Zimpfer, A.; Kdimati, S.; Mosig, M.; Rudolf, H.; Zettl, H.; Erbersdobler, A.; Hakenberg, O.W.; Maruschke, M.; Schneider, B. ERBB2 Amplification as a Predictive and Prognostic Biomarker in Upper Tract Urothelial Carcinoma. Cancers 2023, 15, 2414. https://doi.org/10.3390/cancers15092414
Zimpfer A, Kdimati S, Mosig M, Rudolf H, Zettl H, Erbersdobler A, Hakenberg OW, Maruschke M, Schneider B. ERBB2 Amplification as a Predictive and Prognostic Biomarker in Upper Tract Urothelial Carcinoma. Cancers. 2023; 15(9):2414. https://doi.org/10.3390/cancers15092414
Chicago/Turabian StyleZimpfer, Annette, Said Kdimati, Melanie Mosig, Henrik Rudolf, Heike Zettl, Andreas Erbersdobler, Oliver W. Hakenberg, Matthias Maruschke, and Björn Schneider. 2023. "ERBB2 Amplification as a Predictive and Prognostic Biomarker in Upper Tract Urothelial Carcinoma" Cancers 15, no. 9: 2414. https://doi.org/10.3390/cancers15092414