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Abstract

BACKGROUND:

Cancer cells can defend themselves against apoptosis by activating NF-κB. Nuclear factor-kappa B (NF-κB) activity has also been associated with chemotherapy resistance.

OBJECTIVE:

We aimed to investigate the relationship between NF-κB expression and intrinsic subtypes and anthracycline-based neoadjuvant chemotherapy responses in patients with locally advanced breast cancer.

METHODS:

This prospective cohort study examined NF-κB expression and intrinsic subtypes of breast cancer tissue using immunohistochemistry (IHC). We conducted descriptive statistical analyses as well as survival analyses.

RESULTS:

The study sample was 63 patients, of which 21 cases (33.33%) were responsive to neoadjuvant chemotherapy, and 42 cases (66.7%) were non-responsive. There is a significant relationship between negative ER, negative PR, grading, and high Ki67 expression with NF-κB overexpression (p < 0.05). No significant relationship was found between intrinsic subtypes and HER2 with NF-κB expression (p > 0.05). A significant relationship was found between NF-κB expression and responsive chemotherapy results (p < 0.01).

CONCLUSION:

In locally advanced breast cancer, there is a correlation between NF-B expression and response to anthracycline-based neoadjuvant chemotherapy. Patients who express NF-KB have a better response to chemotherapy than those who overexpress NF-kB.

Keywords

NF-κB breast cancer neoadjuvant chemotherapy anthracyclines

1. Introduction

Breast cancer (BC) is the most frequently diagnosed type of cancer in women and the leading cause of cancer death in women globally, with an incidence of 18.1 million new cases and a mortality rate of 9.6 in 2018. Based on the Global Cancer Observatory data, Indonesia has the highest rate of new breast cancer diagnoses worldwide, with as many as 58,256 new cases (16.7%) in 2018 [1]. The majority of BC patients in Indonesia start treatment at an advanced stage of the disease, with 63% at stages III and IV when diagnosed [2,3].

Chemotherapy is critical in the locally advanced stage of breast cancer. Chemotherapy, on the other hand, has a disadvantage in that it can result in chemotherapy resistance. Numerous studies have demonstrated that cancer cells can protect themselves from apoptosis by activating NF-κB [4]. NF-κB (nuclear factor kappa light chain enhancer of activated B cells) is a transcription factor that can affect numerous aspects of tumorigenesis, including growth without exogenous growth stimuli (self-sufficiency in growth signals); resistance to anti-growth signals; decreased apoptosis; unrestricted proliferation; and increased angiogenesis, invasion, and metastasis, resulting in tumorigenesis [5].

In a previous study, a correlation was revealed between the expression obtained by NF-κB with a Bcl-2 and Bax ratio, in which the signaling pathway of NF-κB/Bcl2 was associated with an inadequate response to neoadjuvant chemotherapy based on doxorubicin [6]. The administration of SN38 and doxorubicin topoisomerase enzymes mediate DNA damage and activate NF-κB via the functional pathway of the IKK complex, causing phosphorylation of IκB-α and degradation of NF-κB, thus activating antiapoptotic gene transcription [7]. Chemoprevention NF-B expression is associated with chemotherapy resistance in patients with locally advanced breast cancer [8].

NF-κB complex activity involves several signal paths and crosstalk connections [9]. In breast cancer tissue, NF-κB activity has been found to increase at negative ER, especially with HER2 amplification [10]. A breast cancer cell culture study showed that IKKα plays an important role in controlling the ability of HER2 to activate NF-κB via the canonical pathway (phosphorylation of IkBα, RelA/p65, IKK activation, and regulation of target gene expression). IKKα controls cell invasion by HER2, and the PI3K pathway contributes to the Activation of NF-κB [11].

Breast cancer has been identified genetically and clinically as a heterogeneous disease. For the management of BC to be uniform, several BC classification systems have been designed based on molecular biology. This classification is used as a standard for the management of BC while simultaneously predicting the prognosis of the disease. Based on the gene expression profile, or immunohistochemistry, breast cancer has been divided into several subtypes, such as Luminal A, Luminal B, HER2, and triple-negative (TNBC). Each subtype demonstrates a different aggressiveness and response to systemic treatment. At the 12th St Gallen International Breast Cancer Conference in 2011, an expert panel agreed that BC subtypes affected their chemotherapy response [12].

Clinical oncology is urged to enter an era where detection, diagnosis, and therapy are increasingly guided by molecular markers obtained through tumor biology analyses that influence tumor behavior [13]. In addition to its role in the survival of cancer cells, NF-κB activity has also been identified as playing a key role in chemotherapy resistance; therefore, knowing the molecular markers of NF-κB, as well as the signaling and crosstalk pathways that influence it, are promising targets to discover solutions to chemotherapy resistance [9]. We conducted a correlation between NF-κB expression and intrinsic subtypes with anthracycline-based neoadjuvant chemotherapy responses in locally advanced BC patients in Makassar, Indonesia.

2. Methods

2.1. Setting and subjects

This study was an observational study that was carried out using a prospective cohort study method. Examination of NF-κB expression and intrinsic subtypes (ER, PR, HER2, and Ki-67) of breast cancer tissue was carried out in our pathology anatomy laboratory. The ethical approval of this study was granted by the Ethical Committee, Faculty of Medicine, Hasanuddin University Makassar, Indonesia. The period of research was from November 2017 until May 2018. Inclusion criteria included the following: female patients with locally advanced BC, histopathological type of invasive ductal carcinoma mammae, underwent neoadjuvant chemotherapy with CAF regimens.

2.2. Immunohistochemistry (IHC)

The immunohistochemistry staining technique was examined by NF-κB p65 antibody-ChIP Grade with Catalog No. ab7970 purchased from Abcam, Cambridge, MA, USA [14]. The results of NF-κB staining were interpreted semiquantitatively by examining the percentage of colored cell groups and the staining intensity. The percentage was calculated by adding all positive cells within the field of view of the tumor preparation examined under a light microscope.

2.3. Interpretation of the IHC results

In the current study, the immunohistochemistry distribution of NF-κB/p65 was classified as focal (10%) value 1, regional (11–50%) value 2, and diffuse (>50%) value 3, while the staining intensity was classified as weak value 1, medium value 2, and strong value 3. When the intensity and extent of the staining distribution in the nucleus and cytoplasm give a strong-diffuse value of 6, a strong-regional value of 5, and a moderate-diffuse value of 5, the results are considered to be positively expressed. Additionally, if the value is 5, the overexpression will be determined, and the expression will be determined if the value is greater than 5.

2.4. Statistical analysis

SPSS version 22 (IBM Corp., 2013) was used to analyze the data. Version 22.0 of IBM SPSS Statistics for Windows. IBM Corporation, Armonk, New York). The frequency distribution and Chi-Square statistical tests are used as statistical methods. The Chi-Square test is used to determine whether two categorical variables are correlated (nominal or ordinal scale). If the study’s findings indicated that more than two variables were significantly related, a multivariate analysis using the logistic regression test was conducted. If the p-value of the test was 0.05, the results were statistically significant.

3. Results

From November 2017 to May 2018, 63 breast cancer patients with neoadjuvant chemotherapy regimen CAF (cyclophosphamide-anthracycline-5FU) fulfilled criteria samples, of which 21 cases (33.33%) were responsive to neoadjuvant chemotherapy and as many as 42 cases (66.7%) were non-responsive. The youngest patient was 26 years old, and the oldest was 66 years old, with most of the 33 cases (52.4%) being from patients under 50 years of age. Based on tumor grading, 28 cases were a moderate grade (44.4%), 28 cases were a high grade (44.4%), and 7 cases were a low grade (11.1%).

In the patients with immunohistochemical panels, a positive receptor estrogen status (ER+) was obtained in 19 cases (30.2%), while negative estrogen receptors (ER−) were gathered in 40 cases (69.8%). Progesterone status was positive in 19 cases (30.2%) and negative in 44 cases (69.8%). Based on HER2 status, 25 cases (39.7%) were HER2 positive, while 38 cases (60.3%) were HER2 negative. Based on the morphological characteristics of tumor grading, low grade comprised 11.1% of the sample, the moderate grade was 44.4%, and high grade was 44.4%. In the examination of the Ki67 expression, the high expression observed in 54 cases (85.7%), and the low expression was in 9 cases (14.3). For the NF-κB examination, high expression was found in 43 cases (68.3%) and low expression in 20 cases (31.7%). Most intrinsic subtypes were found in the Luminal B subtype in 22 cases (34.9%), followed by the triple-negative breast cancer (TNBC) subtype and HER2 subtype in 18 cases each (28.6%), and the Luminal A subtype in 5 cases (7.9%). Based on the response to anthracycline-based neoadjuvant chemotherapy (CAF), there were 21 responsive cases (33.3%), while 42 cases (66.7%) were non-responsive. Characteristics of samples in breast cancer patients can be seen in Table 1.

Table 1
Characteristics of patients

Variable n % P

Age <50 years old 33 52.4

≥50 years 30 47.6

ER 0.019

Positive 19 30.2

Negative 44 69.8

PR 0.019

Positive 19 30.2

Negative 44 69.8

HER2 0.284

Positive 25 39.7

Negative 38 60.3

Grading 0.008

Low grade 7 11.1

Moderate grade 28 44.4

High grade 28 44.4

Ki67 expression 0.003

Low 9 14.3

High 54 85.7

NF-κB expression Expression 20 31.7

Overexpression 43 68.3

Intrinsic subtype Luminal A 5 7.9

Luminal B 22 34.9

TNBC 18 28.6

HER2 type 18 28.6

Chemotherapy Responsive 21 33.3

response Non-Responsive 42 66.7

Variable		n	%	P
Age	<50 years old	33	52.4
	≥50 years	30	47.6
ER				0.019
	Positive	19	30.2
	Negative	44	69.8
PR				0.019
	Positive	19	30.2
	Negative	44	69.8
HER2				0.284
	Positive	25	39.7
	Negative	38	60.3
Grading				0.008
	Low grade	7	11.1
	Moderate grade	28	44.4
	High grade	28	44.4
Ki67 expression				0.003
	Low	9	14.3
	High	54	85.7
NF-κB expression	Expression	20	31.7
	Overexpression	43	68.3
Intrinsic subtype	Luminal A	5	7.9
	Luminal B	22	34.9
	TNBC	18	28.6
	HER2 type	18	28.6
Chemotherapy	Responsive	21	33.3
response	Non-Responsive	42	66.7

Table 2

Logistic regression analysis results

						95% CI
Variable step	el	B	Wald	p	OR	Lower	Upper
Step 1	ER	0.45	0.35	0.556	1.6	0. 35	7.02
	Grading		2.62	0.270
	Grading (1)	1.24	1.39	0.239	3.4	0.44	27.04
	Grading (2)	1.95	2.60	0.107	7.0	0.66	74.57
	KI67	1.93	4.30	0.038	6.9	1.11	42.66
Step 2	Grading		5.12	0.077
	Grading (1)	1.48	2.29	0.130	4.4	0.65	30.17
	Grading (2)	2.32	5.06	0.025	10.2	1.35	77.48
	KI67	1.98	4.50	0.034	7.2	1.16	44.74
Step 3	KI67	2.40	7.75	0.005	11.0	2.04	59.87

OR = Odds Ratio. Note: PR is not included in the analysis because the data are the same as ER.

Table 3

Association expression of NF-κB with CAF neoadjuvant chemotherapy response in locally advanced breast cancer

		Chemotherapy response
NF-KB expression		Responsive	Non-responsive	P	OR (95% CI)
Expression	n	16	4
	%	80.0	20.0
Overexpression	n	5	38	0.001	30.4 (7.2 – 128.1)
	%	11.6	88.4
Total	n	21	42
	%	33.3	66.7

Chi-Square test. CI = Confidence Interval.

There was a significant correlation between negative ER and overexpression of NF-κB (p < 0.05), which found overexpression of NF-κB to be higher in negative ER (77.3%) compared to positive ER (47.4%). No significant correlation was found between HER2 and NF-κB expression (p > 0.05).

There is a significant correlation between grading and NF-kB expression (p < 0.01), in which the overexpression proportion of NF-kB increases with grading. At a low grade, a 28.6% overexpression of NF-κB was found, which increased to 60.7% at a moderate grade and 85.7% at a high grade. There is a significant correlation between high Ki67 expression and NF-κB overexpression (p < 0.01), in which NF-κB overexpression (75.9%) was found to be higher in high Ki67 expression compared to low Ki67 expression (22.2%).

Based on the analysis, a significant correlation was found between ER, PR, grading, and Ki67 with NF-κB expression. A logistic regression test was carried out to find the most significant variable. Based on step 3 (Table 2), the Ki67 expression was the most significantly related to NF-κB expression (p < 0.01). Based on the OR value, subjects with high Ki67 expression have an 11 times greater risk for NF-κB overexpression than subjects with low Ki67 expression. Bivariate analysis was used to determine whether NF-κB expression is related to the anthracycline-based neoadjuvant chemotherapy response (CAF) in breast cancer, as shown in Table 3.

Table 4

Correlation of intrinsic subtype with chemotherapy response

		Chemotherapy response
Intrinsic subtype		Responsive	Non-responsive	p*
Luminal A	n	4	1
	%	80.0	20.0
Luminal B	n	7	15
	%	31.8	68.2
TNBC	n	3	15	0.060
	%	16.7	83.3
HER2 type	n	7	11
	%	38.9	61.1
Total	n	21	42
	%	33.3	66.7

*Fisher Exact test.

Table 5

Correlation of intrinsic subtype with NF-κB expression with chemotherapy response

			Chemotherapy response
Intrinsic subtype	NF-κB expression		Responsive	Non-responsive	p	OR (95% CI)
Luminal A	Expression	n	3	0
		%	100.0	0.0	0.400	*
	Overexpression	n	1	1
		%	50.0	50.0

Luminal B	Expression	n	4	3
		%	57.1	42.9	0.145	5.3 (0.8 – 37.9)
	Overexpression	n	3	12
		%	20.0	80.0

TNBC	Expression	n	3	1
		%	75.0	25.0	0.005	*
	Overexpression	n	0	14
		%	0.0	100.0

HER2 type	Expression	n	6	0
		%	100.0	0.0	0.001	*
	Overexpression	n	1	11
		%	8.3	91.7

Fisher Exact test. *OR cannot be calculated because there is a value of 0.

A significant correlation was found between NF-κB expression and the responsive chemotherapy results (p < 0.01). In this study, the proportion of responsive subjects was significantly higher in NF-κB expression than overexpression. OR calculation results show that subjects with NF-κB expression have a 30.4-time greater responsiveness than subjects with NF-κB overexpression. There was no significant correlation found between intrinsic subtype and chemotherapy response (p > 0.05). However, the highest proportion of responsive subjects was seen in the Luminal A subtype (80.0%), and the lowest was observed in the TNBC subtype (16.7%) (Table 4). Based on the analysis above, it is seen that in addition to NF-κB expression, which showed a significant correlation, the intrinsic subtypes showed no significant correlation with response to chemotherapy. We performed a logistic regression test to determine which variables were the most significant concerning the chemotherapy responses.

In the TNBC subtype and HER2 type, there was a significant correlation between NF-κB expression and responsive chemotherapy (p < 0.01). In TNBC, the proportion of responsive subjects was higher in the NF-κB expression (75.0%) than in overexpression (0.0%). However, in the HER2 type, a 100% response rate to NF-kB expression was found, with only one subject (8.3%) being responsive to NF-κB overexpression. In the Luminal subtypes A and B, there was no significant correlation found between NF-κB expression and chemotherapeutic response (Table 5).

4. Discussion

The purpose of this study is to determine the correlation between NF-κB expression and anthracycline-based neoadjuvant chemotherapy (CAF) response in patients with locally advanced breast cancer using a prospective cohort design. This study collected 75 samples of locally advanced breast cancer from November 2017 to May 2018. A total of 63 samples met the study’s criteria, and 12 samples were discarded. Our findings indicate that patient age varies considerably, with the youngest patient being 26 years old and the oldest being 66 years old, and the most frequently reported age distribution of samples being from patients under the age of 50. According to the American Cancer Society, there were 231,840 new cases of invasive breast cancer in women in the United States in 2015, resulting in 59,990 cases in that age bracket [15]. Breast cancer patients in Asia, according to the literature, are younger than those in Western countries such as Australia and New Zealand. In Europe and America, the majority of breast cancer patients are postmenopausal, whereas, in Asia, the highest incidence occurs during the premenopausal period. This difference may be due to lifestyle, education, or certain genes associated with race that affects an individual’s prognosis of breast cancer at a certain age [16].

Recent studies have confirmed the importance of tumor grading as a predictive and prognostic factor in breast cancer. In a study that observed breast cancer patients during the first five years, grades 2 and 3 had a worse prognosis compared with grade 1 patients [17]. Another study found that among locally advanced breast cancer patients who received chemotherapy, there were significant relationships between histopathological grading and pathological response, disease-free survival (DFS), and overall survival (OS), demonstrating how histopathological grading could be a predictor of chemotherapy response [18].

In this study, a positive estrogen receptor (ER) status was observed in 30.2% of the samples. There was a significant correlation between negative ER with high expression of NF-κB compared with positive ER. These data are similar to other studies in which the most prominent expression of the target NF-κB gene in breast cancer samples had a low ER expression [19]. Another study found that breast cancer NF-κB activity increased in negative ER, especially with HER2 amplification [10]. In this study, the positive status of HER2 (human epidermal growth factor receptor 2) was 39.7%, and no significant correlation was found between HER2 and NF-κB. The HER2 gene consists of 4 transmembrane protein kinase receptors, which play a role in mediating cell growth, differentiation, and survival. Amplification or overexpression of the HER2 gene occurs in about 18–20% of breast cancer cases associated with tumor aggressiveness, which is associated with high rates of recurrence and death [20]. Research on breast cancer by Pathmanathan et al., who worked in the pathology anatomy laboratories of several countries in the Asia-Pacific region, determined that the percentage of HER2 expression in Asia averaged around 23.5%, with a range from 19.7% to 44.2%. This study concluded that the breast cancer population in Asia, compared to Western countries, tends to be younger with high histopathological grading and greater HER2 overexpression [21].

Based on the molecular characteristics of NF-κB in this study, a high expression of NF-κB was found in 68.5% of the breast cancer samples. NF-κB as a transcription factor acts as a target gene transcription catalyst that can affect every aspect of tumorigenesis, which is a trait signifying that something can grow without requiring exogenous growth stimuli (self-sufficiency in growth signals); it is also defined by a lack of sensitivity to anti-growth signals, decreased apoptosis, unlimited proliferation, angiogenesis, invasion, and metastasis, thus resulting in the hallmarks of cancer [5]. By promoting these genes, NF-κB directs its function against chemotherapy resistance [22]. Several studies have examined the relationship between NF-κB and breast cancer, one of which found an increase in NF-κB expression in breast cancer cell cultures [23]. Montagut et al. noted a 45.9% increase in NF-κB expression in locally advanced breast cancer, and NF-κB activation was found to be a predictor of chemotherapy resistance in breast cancer [8]. There is a significant relationship between grading with NF-κB expression (p < 0.01), where the proportion of NF-κB overexpression is directly correlated with high grading. At a low grade, 28.6% overexpression of NF-κB was found, which increased to 60.7% at a moderate grade and 85.7% at a high grade. Sarkar et al. conducted a study of breast cancer patients in India and found an association between NF-κB exposure and clinical stage, tumor size, high grade, high NPI (Nottingham prognostic index), negative estrogen receptor status, and HER2 overexpression [24]. In our study, 33.3% was found to be clinically responsive to anthracycline-based neoadjuvant chemotherapy (CAF).

Anthracycline-based regimens are the most commonly used in neoadjuvant chemotherapy for breast cancer, but as only a small proportion of patients can achieve a complete pathological response (pCR), some cases result in resistance [25]. Drug resistance is a major factor that limits the effectiveness of chemotherapy. Tumors can be intrinsically resistant before chemotherapy or initially sensitive but become resistant during treatment [26]. The administration of anthracycline-based neoadjuvant chemotherapy provides benefits when followed by adjuvant chemotherapy in the form of local recurrence and metastasis. Kim et al. administered anthracycline-based neoadjuvant chemotherapy regimens in locally advanced breast cancer, achieving a clinical response of 60%, [27]. Yao et al. examined the predictive factors of HER2 on anthracycline-based neoadjuvant chemotherapy, reporting that breast cancer patients with a positive HER2 status had better responsiveness compared to negative HER2 [25].

A bivariate analysis of the NF-κB expression on anthracycline-based neoadjuvant chemotherapy response (CAF) in locally advanced breast cancer was performed with a Chi-Square test; a significant relationship (p < 0.001) was observed, as the percentage of responsive subjects was higher in negative NF-κB expression (88.4%). In their study of 82 samples of breast cancer patients who received neoadjuvant chemotherapy CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) regimens, Thomas et al. found a correlation between NF-κB and Bcl2-Bax protein expression and activation of the NF-κB/Bcl2 paActivationciated with resistance to chemotherapy [6]. Montagut et al. conducted a study of 51 locally advanced breast cancer patients who received chemotherapy. Samples obtained with NF-κB expression pre-chemotherapy expressed through immunohistochemical staining had a clinical response of 20%, whereas samples that were not expressed achieved a 91% response rate, demonstrating a significant relationship between NF-κB expression and chemotherapy response [8].

A bivariate analysis of HER2 expression on anthracycline-based neoadjuvant chemotherapy response (CAF) in locally advanced breast cancer performed with a Chi-Square test did not show a significant correlation (p < 0.060), but it was seen that the highest proportion of responsive subjects corresponded to the Luminal A subtype (80%) and the lowest to the TNBC subtype (16.7%). In the HER2 type subtype, a high percentage was found to be non-responsive (61.1%). These results are similar to those obtained by Zhang et al., who examined the relationship of HER2 with chemotherapy responses in 1625 patients receiving adjuvant chemotherapy with HER2 overexpression that was related to resistance to CMF (Cyclophosphamide-Metrotrexata-5FU) regimens but sensitive to anthracycline or Taxane-based regimens [28].

A multivariate analysis of NF-κB with subtypes intrinsic to Anthracycline-based neoadjuvant chemotherapy response in locally advanced breast cancer of the TNBC subtype and HER2 types showed a significant correlation between the NF-kB expression of chemotherapy responsiveness (p < 0.01). In TNBC, the proportion of non-responsive subjects was higher in high NF-kB expression (100.0%) than in low NF-kB expression (25.0%). However, in the HER2 type, a 100% responsiveness rate was noted to the NF-κB expression, and only one subject (8.3%) was responsive to NF-κB overexpression. In the luminal subtypes A and B, no significant relationship was found between NF-κB expression and chemotherapy response. These results are the same as those reported by Shapochka et al., who found an increase in NF-κB expression with decreased expression of hormonal receptors (ER and PR), referring to an increase in P53 related to HER2 positive and Basal Like types [29]. At present, there have not been many reports of studies looking at the relationship of NF-κB with intrinsic subtypes of breast cancer.

NF-κB crosstalk with other pathways has been reported in breast cancer, which indicates a resistance to chemotherapy. Several studies have examined the role of HER2 expressed in breast cancer by activating NF-κB. Biswas et al. showed that the overexpression of HER2 activates NF-κB, which exerts its influence on the apoptotic response by TNFα through the NF-κB pathway [10]. Grandage et al. [30] demonstrated the activation of NF-κB via the PI3K Activation. The addition of Trastuzumab inhibits the activity of NF-κB through the activation of NEMO, resulting in Activationll cycle progression and proliferation and induction of apoptosis [10].

Several studies have shown a correlation between NF-κB activity and estrogen independence. In breast cell culture, increased levels of NF-κB DNA activity have been observed in negative ER cells compared with positive ER. In addition, rat mammary adenocarcinoma cells with hormone-independent phenotype have demonstrated 2 times increased expression of NF-κB in primary breast tumors [31]. This corresponds with other evidence showing an inverse association between ER and NF-κB cell tumors, in which the status of lower ER displays the activity of higher NF-κB [32]. In addition to the suppression of ER by NF-κB, ER is also able to suppress NF-κB. One mechanism is to increase the transcription of the NF-κB p105 subunit located in the cytoplasm until partially degraded. Activation of the PI3K signaling pathway can also cause NF-κB accumulation in the cytoplasm. Another mechanism is by increasing the interaction with co-repressors and content competencies for coactivators with ER [33].

5. Conclusion

There is a correlation between NF-κB expression and anthracycline-based neoadjuvant chemotherapy response in locally advanced breast cancer. Subjects with NF-KB expression have a greater chemotherapy response than those with NF-kB overexpression.

Footnotes

Acknowledgements

We acknowledge Muhammad Faruk, M.D., for his help in providing us with linguistic assistance for this study.

Consent

Written informed consent was obtained from the patients for publication of this research.

Conflicts of interest

The authors declare no competing interests.

Funding

No funding or sponsorship.

Author contributions

Elridho Sampepajung, William Hamdani, and Prihantono designed the study, wrote the manuscript, designed the tables and figures, and performed the statistical analysis. Elridho Sampepajung and Prihantono assessed the histology and immunohistochemical studies. Elridho Sampepajung, William Hamdani, Daniel Sampepajung, and Prihantono edited the manuscript. All authors collectively approved the final version of this manuscript.

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