Breast Cancer Treatment Decreases Serum Levels of TGF-β1, VEGFR2, and TIMP-2 Compared to Healthy Volunteers: Significance for Therapeutic Outcomes?
Abstract
:1. Introduction
2. Materials and Methods
2.1. Experimental Design
2.1.1. Inclusion Criteria
2.1.2. Exclusion Criteria
2.2. Clinical Assessment
2.3. Assessment of the Serum Levels of TGF-β1, VEGF-R2, and TIMP-2 Molecules
2.4. Upper Limb Lymphoscintigraphy
2.5. Statistical Analysis
3. Results
3.1. Clinical Evaluation of Patients
3.2. TGF-β1, VEGFR-2, and TIMP-2 Serum Levels
3.3. Correlation Analysis of the Level of Fibrosis Molecules
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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Group Characteristics of Patients | Patients after Breast Cancer Treatment n = 67 | Healthy n = 25 |
---|---|---|
Age (years) | 47.0 [44; 49] | 42.0 [38; 47] |
Years since treatment | 3.0 [2; 5] | - |
Number of patients TNM stage | ||
I (T1N0M0) | 8 (12%) | - |
II A (T2N1M0) | 46 (68%) | - |
II B (T3N1M0) | 3 (5%) | - |
III A (T3N2M0) | 2 (3%) | - |
III B (T4N2M0) | 8 (12%) | - |
Types of breast cancer | ||
Ductal carcinoma in situ (DCIS) | 7 (11%) | - |
Invasive ductal carcinoma (IDC) | 49 (73%) | - |
Invasive lobular carcinoma (ILC) | 11 (16%) | - |
Breast cancer hormone receptor status | ||
Hormone receptor-positive (HR+) | 55 (72%) | - |
Hormone receptor-negative (HR−) | 12 (18%) | - |
Major pathological grades of breast cancer | ||
Grade 1 | 10 (15%) | - |
Grade 2 | 35 (52%) | - |
Grade 3 | 22 (33%) | - |
Treatment of breast cancer | ||
Complex treatment (surgical treatment, radiotherapy, chemotherapy) | 37 (55%) | - |
Combination of surgical treatment and chemotherapy | 18 (27%) | - |
Combination of surgical treatment and radiotherapy | 7 (10%) | - |
Only surgical treatment | 5 (7%) | - |
Type of surgical treatment | ||
Modified unilateral mastectomy Madden | 53 (79%) | - |
Sector mastectomy | 14 (21%) | - |
Hormonal therapy (tamoxifen vs. GH-LH analogues) | ||
Do not take the medicine | 12 (18%) | |
Take the medicine | 50 (75%) | |
Completed the course | 5 (7%) |
Clinical Characteristics | Number of Patients (N, %) |
---|---|
Restriction of movement in the shoulder | 37 (55%) |
Lymphedema of the arm | 27 (40%) |
Change Type | Number of Patients (N, %) |
---|---|
Dermal backflow | 36 (53%) |
Compensatory changes | 31 (47%) |
Dermal backflow without clinical lymphedema | 10 (15%) |
Clinical lymphedema without dermal backflow | 8 (12%) |
Fibrosis Molecules | Patients (n = 67) | Healthy (n = 25) | Mann–Whitney U-Test | Significance (p) |
---|---|---|---|---|
TGF-β1 | 6356 [551; 11,706] | 17,374 [8802; 17,152] | 666 | <0.001 * |
VEGFR2 | 17,750 [6865; 30,200] | 20,850 [10,137; 35,402] | 1345 | 0.082 |
TIMP-2 | 85 [74; 95] | 100 [92; 113] | 637 | <0.001 * |
Sign of Separation | Characteristic of the Sign | Number of Patients (and Age) | TGF-β1 | Kruskal–Wallis Test | p | VEGFR2 | Kruskal–Wallis Test | p | TIMP-2 | Kruskal–Wallis Test | p |
---|---|---|---|---|---|---|---|---|---|---|---|
Presence of lymphedema (LE) | yes | 27 (42.0 [40; 46]) | 6087 [1065; 1008] | 32.231 | <0.001 * | 16,328 [8224; 21,223] | 3.127 | 0.209 | 82 [75; 92] | 30.749 | <0.001 * |
no | 40 (48.0 [46; 50]) | 6498 [292; 11,229] | 19,050 [6086; 31,110] | 88 [72; 99] | |||||||
Limitation of movement in the shoulder joint (LSh) | yes | 37 (47.5 [43.5; 49]) | 8277 [3502; 9223] | 22.589 | <0.001 * | 9223 [7559; 12,122] | 2.328 | 0.312 | 91 [77; 101] | 22.589 | <0.001 * |
no | 30 (44.6 [41; 46.5]) | 6932 [1823; 8993] | 16,468 [8014; 25,183] | 81 [74; 97] | |||||||
Hormone receptor status of breast cancer (HRS) | HR+ | 55 (42.0 [39; 47.4]) | 6356 [512; 10,133] | 21.62 | <0.001 * | 18,250 [6749; 28,800] | 4.344 | 0.227 | 86 [75; 96] | 24.397 | <0.001 * |
HR− | 12 (47.4 [44; 49]) | 6230 [1950; 1284] | 13,355 [9022; 29,200] | 81 [71; 101] | |||||||
Major pathological grades of breast cancer (G) | G1 | 10 (48.0 [43; 49]) | 6041 [627; 8749] | 34.061 | <0.001 * | 22,750 [12,248; 36,509] | 4.274 | 0.233 | 73 [69; 82] | 43.015 | <0.001 * |
G2 | 35 (47.0 [44; 48]) | 6340 [870; 9628] | 17,450 [6321; 24,950] | 91 [82; 101] | |||||||
G3 | 22 (46.0 [42; 49]) | 4811 [864; 12,505] | 15,132 [10,096; 20,100] | 81 [72; 87] | |||||||
Treatment history | Only surgical treatment (OS) | 5 (45.0 [43; 48.7]) | 7941 [7437; 14,676] | 37.287 | <0.001 * | 6086 [4373; 23,050] | 2.261 | 0.262 | 93 [85; 102] | 36.643 | <0.001 * |
Surgical treatment and radiotherapy (S + R) | 7 (46.5 [44; 48]) | 8868 [7604; 11,705] | 3574 [3508; 13,612] | 91 [84; 101] | |||||||
Surgical treatment and chemotherapy (S + Ch) | 18 (46.0 [43.8; 49]) | 5725 [959; 8307] | 14,391 [6787; 30,200] | 81 [68; 94] | |||||||
Complex treatment (CT) | 37 (47.0 [44; 49)] | 18,250 [9022; 31,995] | 18,250 [9022; 31,995] | 87 [73; 96] | |||||||
Operation type | Modified unilateral mastectomy Madden (M) | 53 (45.3 [42.5; 47]) | 6940 [870; 12,568] | 36.297 | <0.001 * | 18,050 [7255; 27,550] | 4.221 | 0.239 | 87 [75; 98] | 31.876 | <0.001 * |
Sector mastectomy (SM) | 14 (47,8 [44.8; 49)] | 7437 [5460; 11,251] | 21,450 [9207; 27,150] | 82 [72; 95] | |||||||
Lymphoscintigraphy changes | Dermal backflow (DB) | 36 (48.0 [45; 49]) | 4876 [704; 9787] | 22.526 | <0.001 * | 19,650 [8392; 31,529] | 4.029 | 0.258 | 82 [73; 94] | 22.757 | <0.001 * |
Compensatory changes (CCh) | 31 (46.3 [43.3; 47]) | 6624 [704; 12,381] | 15,058 [5930; 23,350] | 83 [74; 101] | |||||||
Changes in lymphoscintigraphy with clinic | Dermal backflow without clinical lymphedema (DB without LY) | 10 (44.0 [42; 46]) | 2412 [152; 6349] | 21.152 | <0.001 * | 28,880 [7657; 42,449] | 3.567 | 0.312 | 89 [75; 95] | 23.784 | <0.001 * |
Clinical lymphedema without dermal backflow (LY without DB) | 8 (47.0 [44; 49)] | 6024 [777; 9707] | 15,132 [9121; 19,145] | 85 [78; 91] |
Sign of Separation | (I) Criterion | (J) Criterion | Mean Difference (I-J) | Std. Error | p | 95% Confidence Interval (CI) | |
---|---|---|---|---|---|---|---|
Lower Bound | Upper Bound | ||||||
LY | Healthy | Yes | 7076 | 1528 | <0.001 * | 3405 | 10,075 |
Healthy | No | 6979 | 1530 | <0.001 * | 3309 | 10,650 | |
Yes | No | −96 | 1487 | 1 | −3669 | 3576 | |
LSh | Healthy | Yes | 7705 | 1668 | <0.001 * | 3670 | 9293 |
Healthy | No | 6668 | 1445 | <0.001 * | 3205 | 9223 | |
Yes | No | −288 | 4102 | 0.78 | −4799 | 2727 | |
HRS | Healthy | HR+ | 7315 | 1379 | <0.001 * | 4077 | 10,553 |
Healthy | HR− | 5455 | 2600 | 0.13 | −1392 | 12,303 | |
HR+ | HR− | −1860 | 2472 | 0.74 | −8540 | 4819 | |
G | Healthy | G1 | 8013 | 1923 | 0.005 * | 2380 | 9223 |
Healthy | G2 | 7368 | 1235 | <0.001 * | 4128 | 9223 | |
Healthy | G3 | 6836 | 1647 | 0.001 * | 2394 | 9223 | |
G1 | G2 | −644, | 1976 | 0.98 | −6363 | 5073 | |
G1 | G3 | −1177 | 2257 | 0.95 | −7465 | 5111 | |
G2 | G3 | −532 | 1709 | 0.98 | −5123 | 4058 | |
Treatment history | Healthy | OS | 2083 | 3160 | 0.96 | −10,928 | 15,095 |
Healthy | S + R | 1648 | 2576 | 0.96 | −13,882 | 17,128 | |
Healthy | S + Ch | 5597 | 1567 | 0.01 * | 1053 | 10,141 | |
Healthy | CT | 3828 | 1474 | 0.04 * | −517 | 7973 | |
OS | S + R | −435 | 3883 | 1 | −15,068 | 14,196 | |
OS | S + Ch | 3513 | 3300 | 0.82 | −9210 | 16,237 | |
OS | CT | 1745 | 3227 | 0.98 | −11,034 | 1 | |
S + R | S + Ch | 3949.23 | 2747.39 | 0.65 | −9768.73 | 17,667.19 | |
S + R | CT | 2180.70 | 2695.26 | 0.91 | −11,926.71 | 16,288.11 | |
S + Ch | CT | −1768.53 | 1756.00 | 0.85 | −6802.28 | 3265.23 | |
Operation type | Healthy | SM | 6464.78 | 1293.53 | <0.001 * | 3069.14 | 9860.43 |
Healthy | M | 5664.95 | 1825.40 | 0.03 * | 417.75 | 10,912.15 | |
M | Healthy | −799.83 | 1920.63 | 0.98 | −6218.37 | 4618.70 | |
Lymphoscintigraphy changes | Healthy | DB | 7485.27 | 1548.83 | <0.001 * | 3397.93 | 11,572.61 |
Healthy | CCh | 6453.91 | 1587.79 | <0.001 * | 2253.70 | 10,654.11 | |
DB | Cch | 1031.36 | 1566.33 | 0.91 | −3117.97 | 5180.69 | |
Changes in lymphoscintigraphy with clinic | Healthy | DB without LY | 9164.26 | 2095.13 | <0.001 * | 3198.09 | 15,130.44 |
Healthy | LY without DB | 7742.97 | 2136.88 | 0.02 * | 1455.36 | 14,030.58 | |
DB without LY | LY without DB | −1421.30 | 2547.40 | 0.94 | −8728.40 | 5885.80 |
Sign of Separation | (I) Criterion | (J) Criterion | Mean Difference (I-J) | Std. Error | p | 95% Confidence Interval (CI) | |
---|---|---|---|---|---|---|---|
Lower Bound | Upper Bound | ||||||
LY | Healthy | Yes | 17.52 | 4.64 | <0.001 * | 6.38 | 28.67 |
Healthy | No | 17.01 | 4.13 | <0.001 * | 7.11 | 26.92 | |
Yes | No | −0.51 | 4.48 | 0.99 | −11.30 | 10.28 | |
LSh | Healthy | Yes | 16.58 | 5.61 | 0.02 * | 2.89 | 30.27 |
Healthy | No | 17.61 | 3.81 | <0.001 * | 8.46 | 26.75 | |
Yes | No | 1.03 | 5.25 | 0.98 | −11.90 | 13.96 | |
HRS | Healthy | HR+ | 16.70 | 3.87 | <0.001 * | 7.44 | 25.96 |
Healthy | HR− | 20.24 | 6.48 | 0.02 * | 3.35 | 37.13 | |
HR+ | HR− | 3.54 | 6.20 | 0.84 | −12.94 | 20.03 | |
G | Healthy | G1 | 31.24 | 3.98 | <0.001 * | 20.22 | 42.27 |
Healthy | G2 | 13.67 | 3.86 | 0.004 * | 3.53 | 23.80 | |
Healthy | G3 | 23.29 | 4.29 | <0.001 * | 11.84 | 34.74 | |
G1 | G2 | −17.58 | 4.28 | 0.002 * | −29.29 | −5.86 | |
G1 | G3 | −7.95 | 4.67 | 0.341 | −20.72 | 4.81 | |
G2 | G3 | 9.62 | 4.56 | 0.165 | −2.53 | 21.78 | |
Treatment history | Healthy | OS | 10.97 | 5.80 | 0.41 | −11.10 | 33.04 |
Healthy | S + R | 9.40 | 10.13 | 0.87 | −59.65 | 78.45 | |
Healthy | S + Ch | 20.57 | 4.60 | <0.001 * | 7.12 | 34.02 | |
Healthy | CT | 12.07 | 4.43 | 0.04 * | −0.43 | 24.56 | |
OS | S + R | −1.57 | 11.18 | 1.00 | −58.42 | 55.29 | |
OS | S + Ch | 9.60 | 6.60 | 0.61 | −12.63 | 31.83 | |
OS | CT | 1.10 | 6.48 | 1.00 | −20.86 | 23.06 | |
S + R | S + Ch | 11.17 | 10.61 | 0.82 | −50.13 | 72.46 | |
S + R | CT | 2.67 | 10.54 | 1.00 | −59.57 | 64.90 | |
S + Ch | CT | −8.50 | 5.44 | 0.53 | −24.06 | 7.06 | |
Operation type | Healthy | SM | 17.03 | 3.99 | <0.001 * | 6.55 | 27.51 |
Healthy | M | 22.73 | 5.00 | <0.001* | 8.56 | 36.90 | |
M | Healthy | 5.70 | 5.34 | 0.71 | −9.14 | 20.54 | |
Lymphoscintigraphy changes | Healthy | DB | 18.03 | 4.65 | <0.001 * | 5.75 | 30.31 |
Healthy | CCh | 17.32 | 4.36 | <0.001 * | 5.77 | 28.87 | |
DB | Cch | 0.71 | 4.72 | 1.00 | −11.78 | 13.20 | |
Changes in lymphoscintigraphy with clinic | Healthy | DB without LY | 17.14 | 5.97 | 0.04 * | 0.03 | 34.25 |
Healthy | LY without DB | 17.50 | 5.45 | 0.03 * | 1.67 | 33.33 | |
DB without LY | LY without DB | 0.36 | 6.85 | 1.00 | −19.24 | 19.97 |
TGF-β1 | VEGFR2 | TIMP-2 | Age (Years) | Years since Treatment | |
---|---|---|---|---|---|
TGF-β1 | - | ρ = −0.264, p = 0.034 * | ρ = 0.328, p = 0.008 * | ρ = 0.093, p = 0.463 | ρ = 0.09, p = 0.474 |
VEGFR2 | ρ = −0.264, p = 0.034 * | - | ρ = −0.369, p = 0.002 * | ρ = −0.055, p = 0.662 | ρ = 0.105, p = 0.403 |
TIMP-2 | ρ = 0.328, p = 0.008 * | ρ = −0.369, p = 0.002 * | - | ρ = −0.13, p = 0.919 | ρ = −0.317, p = 0.010 * |
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Krasnikova, V.; Pospelova, M.; Fionik, O.; Alekseeva, T.; Samochernykh, K.; Ivanova, N.; Trofimov, N.; Vavilova, T.; Vasilieva, E.; Makhanova, A.; et al. Breast Cancer Treatment Decreases Serum Levels of TGF-β1, VEGFR2, and TIMP-2 Compared to Healthy Volunteers: Significance for Therapeutic Outcomes? Pathophysiology 2022, 29, 537-554. https://doi.org/10.3390/pathophysiology29030042
Krasnikova V, Pospelova M, Fionik O, Alekseeva T, Samochernykh K, Ivanova N, Trofimov N, Vavilova T, Vasilieva E, Makhanova A, et al. Breast Cancer Treatment Decreases Serum Levels of TGF-β1, VEGFR2, and TIMP-2 Compared to Healthy Volunteers: Significance for Therapeutic Outcomes? Pathophysiology. 2022; 29(3):537-554. https://doi.org/10.3390/pathophysiology29030042
Chicago/Turabian StyleKrasnikova, Varvara, Maria Pospelova, Olga Fionik, Tatyana Alekseeva, Konstantin Samochernykh, Nataliya Ivanova, Nikita Trofimov, Tatyana Vavilova, Elena Vasilieva, Albina Makhanova, and et al. 2022. "Breast Cancer Treatment Decreases Serum Levels of TGF-β1, VEGFR2, and TIMP-2 Compared to Healthy Volunteers: Significance for Therapeutic Outcomes?" Pathophysiology 29, no. 3: 537-554. https://doi.org/10.3390/pathophysiology29030042
APA StyleKrasnikova, V., Pospelova, M., Fionik, O., Alekseeva, T., Samochernykh, K., Ivanova, N., Trofimov, N., Vavilova, T., Vasilieva, E., Makhanova, A., Tonyan, S., Nikolaeva, A., Kayumova, E., & Shevtsov, M. (2022). Breast Cancer Treatment Decreases Serum Levels of TGF-β1, VEGFR2, and TIMP-2 Compared to Healthy Volunteers: Significance for Therapeutic Outcomes? Pathophysiology, 29(3), 537-554. https://doi.org/10.3390/pathophysiology29030042