World J Oncol

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

Review

Volume 16, Number 2, April 2025, pages 143-151

Tumor Necrosis Factor-Alpha and Its Association With Breast Cancer: A Systematic Review

Figure 1. PRISMA flowchart. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

**Table 1.** Eligibility Criteria for This Review
Criteria	Inclusion	Exclusion
TNF-α: tumor necrosis factor-alpha.
Study design	Observational studies (cross-sectional, case-control, cohort)	Non-observational studies (e.g., reviews, editorials, case reports)
Language	Published in English or Indonesian	Published in other languages without an available translation
Population	Human studies including breast cancer patients and healthy controls with matched age and relevant demographics	Non-human studies or studies without a well-defined control group/matched population
Outcome reporting	Studies that directly assess TNF-α levels about breast cancer with sufficient data	Studies lacking TNF-α measurements or missing relevant data

Table 1. Eligibility Criteria for This Review

Criteria

Inclusion

Exclusion

TNF-α: tumor necrosis factor-alpha.

Study design

Observational studies (cross-sectional, case-control, cohort)

Non-observational studies (e.g., reviews, editorials, case reports)

Language

Published in English or Indonesian

Published in other languages without an available translation

Population

Human studies including breast cancer patients and healthy controls with matched age and relevant demographics

Non-human studies or studies without a well-defined control group/matched population

Outcome reporting

Studies that directly assess TNF-α levels about breast cancer with sufficient data

Studies lacking TNF-α measurements or missing relevant data

**Table 2.** Risk of Bias Assessment Using Revised Risk of Bias Assessment Tool for Nonrandomized Studies of Interventions (RoBANS 2)
No.	Domain	Study index number
1	Comparability of the target group	Low	Low	Low	Unclear	Low	Low	Low	Unclear	High
2	Target group selection	High	Low	Low	Low	Low	High	Low	Unclear	Low
3	Confounders	Low	Low	Low	Unclear	Unclear	Low	Low	Low	Unclear
4	Measurement of exposure	Low	Low	Low	Low	Low	Low	Low	Low	Low
5	Blinding of assessors	Low	Low	Low	Low	Low	Low	Low	Low	Low
6	Outcome assessment	Low	Low	Low	Low	Low	Low	Low	Low	Low
7	Incomplete outcome data	Low	Low	Low	Low	Low	Low	Low	Low	Low
8	Selective outcome reporting	Low	Low	Low	Low	Low	Low	Low	Low	Low
Overall results	High	Low	Low	Some concern	Some concern	High	Low	Some concern	High

Table 2. Risk of Bias Assessment Using Revised Risk of Bias Assessment Tool for Nonrandomized Studies of Interventions (RoBANS 2)

No.

Domain

Study index number

Comparability of the target group

Low

Unclear

Low

Unclear

High

Target group selection

High

Low

High

Low

Unclear

Low

Confounders

Low

Unclear

Low

Unclear

Measurement of exposure

Low

Blinding of assessors

Low

Outcome assessment

Low

Incomplete outcome data

Low

Selective outcome reporting

Low

Overall results

High

Low

Some concern

High

Low

Some concern

High

**Table 3.** Summary of Included Studies
No.	Study details	Subject characteristics	Results
TNF-α: tumor necrosis factor-alpha; IQR: interquartile range; AUC: area under the curve; CI: confidence interval; OR: odds ratio; SD: standard deviation.
1	Moaiedi et al, 2021 [30], Iran, cross-sectional	N = 50 (32 women with breast cancer, 18 healthy control)	The mRNA expression of TNF-α was high in breast cancer patients without surgery in comparison to healthy controls, but not significant (P > 0.05), whereas, its mRNA expression of TNF-α was low in patients with surgery in comparison to healthy controls, but not significant (P > 0.05).
		Median age was 42 years (28 - 60 years) in the breast cancer group and 45 years (36 - 53 years) in the control group.
2	Gharib et al, 2022 [29], Saudi Arabia, case-control	N = 200 (100 women with early or locally advanced breast cancer and 100 healthy women) from 20 to 80 years.	TNF-α was significantly higher in breast cancer patients compared to healthy controls.
			The mean TNF-α level was 42.15 ± 18.76 pg/mL in the patient group compared to 5.54 ± 2.32 pg/mL in the control group (t = 19.26, P < 0.0001).
3	Papadopoulou et al, 2010 [28], Greece, case-control	N = 101 (56 women with primary breast cancer and 45 healthy women).	The serum levels of TNF-α were significantly higher in patients with primary breast cancer than in the control group (19.18 pg/mL, IQR: 12.04 - 32.51 pg/mL vs. 7.92 pg/mL, IQR: 4.41 - 12.14 pg/mL, P < 0.001).
		The mean age was 61.3 years (33 - 88 years) in the breast cancer group and 57.2 years (31 - 82 years) in the control group.	The AUC’s diagnostic significance of TNF-α in breast cancer was 0.848 (95% CI: 0.774 - 0.923, P < 0.001).
			Statistically significantly elevated levels of TNF-α were found in larger tumors (P = 0.038), poorly differentiated tumors (P = 0.011), and in patients with more than three positive lymph nodes (P = 0.046).
			A marginal trend towards higher values of TNF-α was found in invasive tumors (P = 0.069) and in advanced-stage carcinomas (P = 0.062).
			The mean survival time was 44 ± 2 months (95% CI: 39 - 48 months) in patients with low levels of TNF-α (≤ 21.55 pg/mL; n = 31) and 35 ± 4 months (95% CI: 28 - 42 months) in patients with high levels of TNF-α (> 21.55 pg/mL; n = 25).
4	Berberoglu et al, 2004 [27], Turkey, case-control	N = 32 (20 women with locally advanced breast cancer and 12 healthy women).	TNF-α in breast cancer patients was higher than healthy group (15.9 ± 0.9 pg/mL vs. 5.8 ± 1.7 pg/mL, P < 0.0001).
		Median age was 45 years (30 - 75 years) in the breast cancer group and 43 years (37 - 66 years) in the control group.	TNF-α was reduced significantly after chemotherapy both in partial and complete response.
			There was a significant correlation between the type of response and the relative change in TNF-α values (r = -0.62, P = 0.004).
5	Adrian et al, 2023 [23], Indonesia, cross-sectional	N = 38 women with breast cancer who received anthracycline-based neoadjuvant chemotherapy and never received chemotherapy before (20 participants were < 50 years old).	Most participants with high TNF-α levels had a negative response to chemotherapy, while those with low TNF-α levels had a positive response (P < 0.001).
			The statical analysis showed a significant association between TNF-α levels and the clinical response to chemotherapy, which showed r = -0.606 and P < 0.001.
6	Efendi et al, 2022 [24], Indonesia, cross-sectional	N = 50 women with breast cancer	There is a statistically significant association between serum TNF-α levels and the incidence of breast cancer metastases (P = 0.009)
		The mean age was 48.8 years (29 - 65 years).
7	Fontvieille et al, 2022 [26], France, case-control	N = 906 (453 women with breast cancer and 453 control from the general population).	In the fully adjusted model, TNF-α was positively associated with breast cancer risk (OR per SD increment = 1.32 (1.11 - 1.58); OR Q4 vs. Q1= 2.03 (1.26 - 3.26), P= 0.006).
		The case and control groups have a mean age of 38.7 years
8	Ma et al, 2017 [25], China, case-control	N = 140 (110 women with breast cancer and 30 healthy women).	The serum TNF-α levels of stage III carcinoma patients were significantly higher than those in the healthy controls (P < 0.001).
		Age range from 35 to 65 years in the breast cancer group and 28 to 57 years in the healthy group.	Serum TNF-α levels also correlated with clinical tumor stage and lymph node metastasis (P < 0.001).
9	Mohammed et al, 2022 [31], Iraq, case-control	N = 90 (59 women with breast cancer and 31 healthy women).	Individuals with ductal carcinoma showed significant differences (P < 0.001) in the mean levels of the TNF-α compared with healthy groups
		The mean age was 37.4 years in the breast cancer group and 34.7 years in the control group (25 - 61 years).	There is a significantly increased level of TNF-α in lymph node metastasis compared to healthy groups.
			There is no significant difference in the levels of TNF-α between the non-metastasis and metastasis groups.

Table 3. Summary of Included Studies

No.

Study details

Subject characteristics

Results

TNF-α: tumor necrosis factor-alpha; IQR: interquartile range; AUC: area under the curve; CI: confidence interval; OR: odds ratio; SD: standard deviation.

Moaiedi et al, 2021 [30], Iran, cross-sectional

N = 50 (32 women with breast cancer, 18 healthy control)

The mRNA expression of TNF-α was high in breast cancer patients without surgery in comparison to healthy controls, but not significant (P > 0.05), whereas, its mRNA expression of TNF-α was low in patients with surgery in comparison to healthy controls, but not significant (P > 0.05).

Median age was 42 years (28 - 60 years) in the breast cancer group and 45 years (36 - 53 years) in the control group.

Gharib et al, 2022 [29], Saudi Arabia, case-control

N = 200 (100 women with early or locally advanced breast cancer and 100 healthy women) from 20 to 80 years.

TNF-α was significantly higher in breast cancer patients compared to healthy controls.

The mean TNF-α level was 42.15 ± 18.76 pg/mL in the patient group compared to 5.54 ± 2.32 pg/mL in the control group (t = 19.26, P < 0.0001).

Papadopoulou et al, 2010 [28], Greece, case-control

N = 101 (56 women with primary breast cancer and 45 healthy women).

The serum levels of TNF-α were significantly higher in patients with primary breast cancer than in the control group (19.18 pg/mL, IQR: 12.04 - 32.51 pg/mL vs. 7.92 pg/mL, IQR: 4.41 - 12.14 pg/mL, P < 0.001).

The mean age was 61.3 years (33 - 88 years) in the breast cancer group and 57.2 years (31 - 82 years) in the control group.

The AUC’s diagnostic significance of TNF-α in breast cancer was 0.848 (95% CI: 0.774 - 0.923, P < 0.001).

Statistically significantly elevated levels of TNF-α were found in larger tumors (P = 0.038), poorly differentiated tumors (P = 0.011), and in patients with more than three positive lymph nodes (P = 0.046).

A marginal trend towards higher values of TNF-α was found in invasive tumors (P = 0.069) and in advanced-stage carcinomas (P = 0.062).

The mean survival time was 44 ± 2 months (95% CI: 39 - 48 months) in patients with low levels of TNF-α (≤ 21.55 pg/mL; n = 31) and 35 ± 4 months (95% CI: 28 - 42 months) in patients with high levels of TNF-α (> 21.55 pg/mL; n = 25).

Berberoglu et al, 2004 [27], Turkey, case-control

N = 32 (20 women with locally advanced breast cancer and 12 healthy women).

TNF-α in breast cancer patients was higher than healthy group (15.9 ± 0.9 pg/mL vs. 5.8 ± 1.7 pg/mL, P < 0.0001).

Median age was 45 years (30 - 75 years) in the breast cancer group and 43 years (37 - 66 years) in the control group.

TNF-α was reduced significantly after chemotherapy both in partial and complete response.

There was a significant correlation between the type of response and the relative change in TNF-α values (r = -0.62, P = 0.004).

Adrian et al, 2023 [23], Indonesia, cross-sectional

N = 38 women with breast cancer who received anthracycline-based neoadjuvant chemotherapy and never received chemotherapy before (20 participants were < 50 years old).

Most participants with high TNF-α levels had a negative response to chemotherapy, while those with low TNF-α levels had a positive response (P < 0.001).

The statical analysis showed a significant association between TNF-α levels and the clinical response to chemotherapy, which showed r = -0.606 and P < 0.001.

Efendi et al, 2022 [24], Indonesia, cross-sectional

N = 50 women with breast cancer

There is a statistically significant association between serum TNF-α levels and the incidence of breast cancer metastases (P = 0.009)

The mean age was 48.8 years (29 - 65 years).

Fontvieille et al, 2022 [26], France, case-control

N = 906 (453 women with breast cancer and 453 control from the general population).

In the fully adjusted model, TNF-α was positively associated with breast cancer risk (OR per SD increment = 1.32 (1.11 - 1.58); OR Q4 vs. Q1= 2.03 (1.26 - 3.26), P= 0.006).

The case and control groups have a mean age of 38.7 years

Ma et al, 2017 [25], China, case-control

N = 140 (110 women with breast cancer and 30 healthy women).

The serum TNF-α levels of stage III carcinoma patients were significantly higher than those in the healthy controls (P < 0.001).

Age range from 35 to 65 years in the breast cancer group and 28 to 57 years in the healthy group.

Serum TNF-α levels also correlated with clinical tumor stage and lymph node metastasis (P < 0.001).

Mohammed et al, 2022 [31], Iraq, case-control

N = 90 (59 women with breast cancer and 31 healthy women).

Individuals with ductal carcinoma showed significant differences (P < 0.001) in the mean levels of the TNF-α compared with healthy groups

The mean age was 37.4 years in the breast cancer group and 34.7 years in the control group (25 - 61 years).

There is a significantly increased level of TNF-α in lymph node metastasis compared to healthy groups.

There is no significant difference in the levels of TNF-α between the non-metastasis and metastasis groups.