Digital Whole Slide Image Analysis of Elevated Stromal Content and Extracellular Matrix Protein Expression Predicts Adverse Prognosis in Triple-Negative Breast Cancer
Abstract
:1. Introduction
2. Results
2.1. Clinicopathological Characteristics of Patients
2.2. Variability and Categorization of TSR and OSR on H&E-Stained WSIs
2.3. Association of the TSR and the OSR with the Clinicopathological Factors
2.4. Impact of TSR and OSR on Survival
2.5. Variability and Categorization of Type-I Collagen, Type-III Collagen, and Fibrillin-1 Expression and Stromal Content on TMAs
2.6. The Effect of Type-I Collagen, Type-III Collagen, and Fibrillin-1 Expression on Survival
3. Discussion
3.1. Discussion of Study Results
3.2. Limitations of This Study
4. Materials and Methods
4.1. Patients
4.2. Study Design
4.3. Evaluation Methods
4.4. Comparison with Independent Cohorts
4.5. Statistics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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All | Visual TSR | Visual OSR | |||||
---|---|---|---|---|---|---|---|
n = 99 | Stroma-High (>65) | Stroma-Low (≤65) | t-Test/Log-Rank (p *) | Stroma-High (≥35) | Stroma-Low (<35) | t-Test/Log-Rank (p *) | |
Age (n = 99) | |||||||
<48 years | 17 | 5 | 12 | t = 1.8 (0.07) | 3 | 14 | t = 3.5 (<0.001 **) |
≥48 years | 82 | 41 | 41 | 48 | 34 | ||
pT category (n = 97) | |||||||
pT1b-pT1c | 54 | 21 | 33 | t = 0.83 (0.41) | 27 | 27 | t = 0.03 (0.97) |
pT2-pT3 | 43 | 23 | 20 | 23 | 20 | ||
pN category (n = 85) | |||||||
pN0-pN1mi | 55 | 20 | 35 | t = 3.3 (0.002 **) | 25 | 30 | t = 2.5 (0.013 *) |
pN1-pN3a | 30 | 19 | 11 | 20 | 10 | ||
Stromal tumor-infiltrating lymphocyte (n = 99) | |||||||
≤20 | 50 | 27 | 23 | t = 1.4 (0.15) | 32 | 18 | t = 3.0 (0.004 **) |
>20 | 49 | 19 | 30 | 19 | 30 | ||
Mitotic index (n = 85) | |||||||
<25 | 36 | 24 | 12 | t = 3.0 (0.003 **) | 25 | 11 | t = 3.7 (0.001 **) |
≥25 | 49 | 15 | 34 | 20 | 29 | ||
Overall survival (n = 99) | |||||||
Alive | 62 | 28 | 34 | pLR = 0.49 | 27 | 35 | pLR = 0.017 * |
Dead | 37 | 18 | 19 | 24 | 13 | ||
Progression-free survival (n = 99) | |||||||
No progression | 63 | 27 | 36 | pLR = 0.35 | 29 | 34 | pLR = 0.19 |
Progression | 36 | 19 | 17 | 21 | 15 |
A | ||||||
Spearman Correlation | Visual TSR Obs. 1/1 | Visual TSR Obs. 1/2 | Visual TSR Obs. 2 | DIA TSR Obs. 1/1 | DIA TSR Obs. 1/2 | DIA TSR Obs. 2 |
Visual TSR Obs. 1/1 | 1 | 0.979 ** | 0.865 ** | 0.943 ** | 0.946 ** | 0.930 ** |
Visual TSR Obs. 1/2 | 0.979 ** | 1 | 0.866 ** | 0.928 ** | 0.943 ** | 0.911 ** |
Visual TSR Obs. 2 | 0.865 ** | 0.866 ** | 1 | 0.876 ** | 0.879 ** | 0.888 ** |
DIA TSR Obs. 1/1 | 0.943 ** | 0.928 ** | 0.876 ** | 1 | 0.961 ** | 0.964 ** |
DIA TSR Obs. 1/2 | 0.946 ** | 0.943 ** | 0.879 ** | 0.961 ** | 1 | 0.962 ** |
B | ||||||
Pearson Correlation | Visual OSR | DIA OSR Obs. 1/1 | DIA OSR Obs. 1/2 | DIA OSR Obs. 2 | ||
Visual OSR | 1 | 0.833 ** | 0.833 ** | 0.843 ** | ||
DIA OSR Obs. 1/1 | 0.833 ** | 1 | 0.911 ** | 0.920 ** | ||
DIA OSR 2 Obs. 1/2 | 0.833 ** | 0.911 ** | 1 | 0.918 ** |
PFS | Univariate HR | CI | p | Multivariate HR | CI | p |
DIA OSR (continuous) | 1.012 | 0.996–1.034 | 0.113 | 1.007 | 0.984–1.031 | 0.540 |
DIA OSR categorical (≤39.34% vs. above) | 1.907 | 0.979–3.715 | 0.058 | |||
Number of positive lymph nodes | 1.220 | 1.107–1.345 | <0.001 ** | 1.179 | 1.065–1.306 | 0.002 ** |
Presence of fibrotic foci | 2.119 | 1.007–4.458 | 0.048 * | 2.043 | 0.894–4.670 | 0.090 |
sTIL categorical (≤20% vs. above) | 0.498 | 0.252–0.985 | 0.045 * | |||
OS | Univariate HR | CI | p | Multivariate HR | CI | p |
DIA OSR (continuous) | 1.023 | 1.003–1.044 | 0.023 * | 1.037 | 1.007–1.041 | 0.028 * |
DIA OSR categorical (≤39.34% vs. above) | 1.955 | 1.004–3.808 | 0.045 * | |||
Age | 1.039 | 1.009–1.069 | 0.01 * | 1.023 | 0.989–1.059 | 0.188 |
Number of positive lymph nodes | 1.14 | 1.039–1.250 | 0.006 ** | 1.083 | 0.96–1.223 | 0.195 |
Presence of necrosis | 2.739 | 1.043–7.191 | 0.041 * | |||
sTIL categorical (≤20 vs. above) | 0.499 | 0.256–0.972 | 0.041 * | 0.995 | 0.973–1.017 | 0.631 |
Mitotic index (MI) | 1.017 | 0.097–1.038 | 0.096 | 1.040 | 1.040–1.015 | 0.002 ** |
Characteristics of the TMAs (n) | H&E (86) | Type-I Collagen (84) | Type-III Collagen (83) | Fibrillin-1 (85) |
---|---|---|---|---|
Median percentage of positivity (range) | 37.5 (5–80) | 41.8 (5.3–85) | 27.8 (1.7–85.4) | 30 (2–71.6) |
Cut-offs used for further calculations * (number or cases below; above) | OS, PFS: 45% (46; 35) | OS: 30% (37; 43) PFS: 45% (58; 22) | OS, PFS: 20% (32; 50) | |
Median intensity (range) | 198 (126–270) | 191 (143–261) | ||
Median DQ * PQ (range) | 5507 (309–18,444) | 5050 (372–18,687) | ||
Median type-I collagen rate (range) | 0.76 (0.05–2.58) | 0.64 (0.18–1.56) |
Pearson’s Correlation | Stromal Ratio (H&E TMA) | Type-I Collagen | Type-III Collagen | Fibrillin-1 |
---|---|---|---|---|
Stromal ratio (H&E TMA) | 1 | 0.864 ** | 0.718 ** | 0.727 ** |
Type-I collagen | 0.864 ** | 1 | 0.811 ** | 0.809 ** |
Type-III collagen | 0.718 ** | 0.811 ** | 1 | 0.793 ** |
Fibrillin-1 | 0.727 ** | 0.809 ** | 0.793 ** | 1 |
OSR (WSI) | 0.551 ** | 0.627 ** | 0.603 ** | 0.590 ** |
OS | Univariate HR | CI | p | Multivariate HR | CI | p |
DIA type-I collagen categorical (≤45% vs. above) | 2.826 | 1.340–5.961 | 0.006 ** | 3.075 | 1.309–7.228 | 0.01 * |
DIA type-III collagen (continuous) | 1.022 | 1.004–1.040 | 0.017 * | 1.030 | 1.008–1.054 | 0.008 ** |
DIA type-III collagen categorical (≤30% vs. above) | 2.697 | 1.269–5.729 | 0.01 * | 3.467 | 1.411–8.522 | 0.007 ** |
DIA fibrillin-1 (continuous) | 1.031 | 1.007–1.056 | 0.011 * | 1.040 | 1.009–1.071 | 0.01 * |
DIA fibrillin-1 categorical (≤20% vs. above) | 3.129 | 1.331–7.354 | 0.009 ** | 3.439 | 1.248–9.479 | 0.017 * |
PFS | Univariate HR | CI | p | Multivariate HR | CI | p |
DIA type-I collagen categorical (≤45% vs. above) | 2.255 | 1.068–4.760 | 0.033 * | 2.725 | 1.197–2.725 | 0.017 * |
DIA type-III collagen (continuous) | 1.018 | 1.001–1.036 | 0.037 * | 1.033 | 1.009–1.058 | 0.008 ** |
DIA type-III collagen categorical (≤30% vs. above) | 2.280 | 1.087–4.785 | 0.029 * | 3.825 | 1.364–10.731 | 0.011 * |
DIA fibrillin-1 (continuous) | 1.030 | 1.007–1.054 | 0.012 * | 1.045 | 1.013–1.077 | 0.005 ** |
DIA fibrillin-1 categorical (≤20% vs. above) | 3.388 | 1.372–8.368 | 0.008 ** | 3.815 | 1.275–11.574 | 0.018 * |
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Karancsi, Z.; Gregus, B.; Krenács, T.; Cserni, G.; Nagy, Á.; Szőcs-Trinfa, K.F.; Kulka, J.; Tőkés, A.M. Digital Whole Slide Image Analysis of Elevated Stromal Content and Extracellular Matrix Protein Expression Predicts Adverse Prognosis in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2024, 25, 9445. https://doi.org/10.3390/ijms25179445
Karancsi Z, Gregus B, Krenács T, Cserni G, Nagy Á, Szőcs-Trinfa KF, Kulka J, Tőkés AM. Digital Whole Slide Image Analysis of Elevated Stromal Content and Extracellular Matrix Protein Expression Predicts Adverse Prognosis in Triple-Negative Breast Cancer. International Journal of Molecular Sciences. 2024; 25(17):9445. https://doi.org/10.3390/ijms25179445
Chicago/Turabian StyleKarancsi, Zsófia, Barbara Gregus, Tibor Krenács, Gábor Cserni, Ágnes Nagy, Klementina Fruzsina Szőcs-Trinfa, Janina Kulka, and Anna Mária Tőkés. 2024. "Digital Whole Slide Image Analysis of Elevated Stromal Content and Extracellular Matrix Protein Expression Predicts Adverse Prognosis in Triple-Negative Breast Cancer" International Journal of Molecular Sciences 25, no. 17: 9445. https://doi.org/10.3390/ijms25179445