Evaluation of the Prognostic Value of Obesity, Vitamin D Concentrations, and Systemic Inflammatory Response Indexes (SIRI, SII, PIV) in Patients With Breast Cancer Scheduled for Neoadjuvant Treatment

Abstract

Introduction:

The purpose of this study was to determine the prognostic utility of vitamin D concentrations and BMI (body mass index) values and the systemic immune-inflammation index (SII), the systemic inflammation response index (SIRI) and the pan-immune-inflammation value (PIV) to predict the achievement of a complete response to neoadjuvant treatment (NAT) in patients with breast cancer. The correlations between systemic inflammatory response indices and vitamin D concentrations and BMI values were also analysed.

Material and Methods:

The study included 96 patients with breast cancer, prior to the start of NAT, of which 51 patients were diagnosed with triple-negative breast cancer (TNBC) and 45 patients with human epidermal growth factor receptor type 2 (HER2)-positive type.

Results:

The SIRI and PIV indices were shown to be significantly higher in patients with TNBC (P = .001; P = .001) than in patients with HER2. There were no statistical differences in SII, SIRI, PIV, BMI, and vitamin D, according to the response to NAT treatment (pCR vs non-pCR). In the HER2+ group without pCR after NAT, there was a positive correlation of the SII coefficient with BMI values (R = .41; P = .045). Furthermore, in the entire HER2+ group (irrespective of the NAT response), SII values were negatively correlated with vitamin D levels (R = −0.39; P = .008).

Conclusions:

In patients with breast cancer, high SIRI and PIV values may indicate the biological subtype of TNBC. In the HER2+ group, higher SII values were associated with low vitamin D concentrations and elevated BMI.

Introduction

Neoadjuvant treatment (NAT) was introduced at the end of the 20th century and is dedicated to a specific group of patients with malignancies with different primary tumour locations. Breast cancer is a cancer in which neoadjuvant treatment (NAT) is used for early and locally advanced disease. The therapeutic effect of the use of NAT is evaluable in postoperative material and should lead to a complete pathomorphological response (pCR). Obtaining a pCR in NAT has been shown to be of particular importance in patients with triple-negative breast cancer (TNBC) or with the presence of the human epidermal growth factor receptor type 2 (HER2), as pCR ranks as a favourable prognostic factor for progression-free time and overall survival (OS). ¹ A known factor promoting neoplastic transformation and the course of the disease is inflammation that accompanies tumours, in which infiltrating immune cells have been shown to be a prognostic factor. There are various indicators of tumour progression or biochemical markers in the blood such as lactate dehydrogenase and the immunological markers such as cytokines.^2,3 In clinical practice, the assessment of inflammation is mainly based on blood counts, in which the number of neutrophils (N), monocytes (M), lymphocytes (L), and platelets (P) expresses the degree of activity of this process. These cell populations were used to create indexes of the inflammatory process, such as NLR (neutrophils/lymphocytes), LMR (lymphocytes/monocytes), and PLR (platelets/lymphocytes). Evaluation of the first binary indexes, such as NLR, suggests their usefulness in predicting the course of the disease, including in systemically treated patients with breast cancer.^{4 -8}

It appears that recent indexes showing the configuration of the 3 cell populations activated by inflammation, that is, SII, the systemic immune-inflammation index (platelets, neutrophils and lymphocytes; P × N/L), and SIRI, the systemic inflammation response index (neutrophils, monocytes and lymphocytes; N × M/L) or PIV (pan-immune-inflammation value – PIV = N × P × M/L), may be better predictors than NLR. These new prognostic factors, which are not related to tumour biology but affect processes related to cancer development, allow the prediction of treatment outcomes. However, studies that indicate their prognostic value of disease-free survival (DFS) and OS, in relation to response to neoadjuvant treatment, in patients with breast cancer are described in few articles and need to be confirmed.^{9 -12}

In the recent literature on breast cancer, researchers have highlighted the association of obesity in patients with prognosis. High values (greater than 30 or more) of body mass index (BMI) have been suggested to negatively affect prognosis in BC.^13,14 This may be a result of the fact that obesity is associated with increased serum levels of leptin, insulin, oestrogen hormones and other growth factors, resulting in increased tumour mass and stimulation of metastatic cells that cause resistance to chemotherapy. It has been speculated that chemotherapeutics can diffuse into adipose tissue, thus decreasing the amount of chemotherapeutics that need to penetrate tumour tissue, which may be more commonly observed in obese patients.^{13 -15} A deficiency of fat-soluble vitamin D, which plays a key role in calcium phosphate metabolism, is often associated with obesity, but extrinsic effects have also been described: for example, in adipocyte physiology and glucose metabolism, altered in obese patients. Furthermore, it is now recognized that vitamin D also affects cell proliferation, differentiation, and adhesion processes, potentially leading to carcinogenesis. Recent studies indicate a potential link between vitamin D levels and cancer, and lower vitamin D levels have been linked to a higher risk of developing various cancers, including breast cancer. ¹⁶ In many cancer cells of various types of tumours, the vitamin D receptor (VDR) is elevated, which binds the active form of vitamin D (calcitriol) and regulates gene expression. This affects the functioning of the immune system. Vitamin D has a significant effect on the regulation of inflammation, especially in the tumour microenvironment (TME). Signalling can be activated or inhibited through 2 main pathways: MAP kinase phosphatase 5 (MKP5) and NF-κB. Vitamin D can increase MKP5 expression in cancer cells, causing MAPK inhibition and subsequently reducing IL-6 production, and can inhibit the activity of NF-κB as a precursor to the production of another pro-inflammatory cytokine, IL-8. In addition, the binding of NF-κB to DNA can be disrupted in the presence of vitamin D. ¹⁷ The high BMI index associated with inflammation results from the ability of macrophages infiltrating adipose tissue to release interleukin 6 (IL-6) and TNF-α, which stimulate the production of C-reactive protein. Leptin and adiponectin produced in adipocytes have inflammatory mediator properties. ¹⁸ As fast-growing immune and cancer cells use the same pathways and genes to control proliferation, differentiation, and apoptosis, it is not surprising that vitamin D signalling alters these processes in cancer cells as well. Thus, the anticancer effects of vitamin D may be due to the management of immune growth and differentiation.^19,20

The purpose of our study was to determine the prognostic utility of the SII, SIRI, and PIV indices to predict the achievement of a complete response to neoadjuvant treatment in patients with breast cancer with subtypes TNBC and HER2+, and to test whether there is a relationship between the SII, SIRI, and PIV indices and vitamin D concentrations and BMI values, that is, factors that can modulate immune cell activity.

Material and Methods

Patients

The study included 96 patients with breast cancer, treated in Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. All patients were prior to neoadjuvant treatment, of whom 51 patients were diagnosed with triple-negative cancer and 45 patients were confirmed to have the HER2 receptor. The median age was 43 years. Informed written consent was obtained from patients to participate in the study.

In the TNBC group, most patients (N = 37; 73%) were treated with neoadjuvant therapy (NAT) according to a 4xAC regimen (doxorubicin + cyclophosphamide) + 12PCL (paclitaxel) and the remaining patients (N = 14; 27%) received a 4xAC + 12PCL regimen with carboplatin. Complete response (pCR) was achieved in 23 patients and residual disease (RBC) was present in 26 patients. On the contrary, in the group with a diagnosis of HER2-positive breast cancer, therapy with the TCH regimen (docetaxel, carboplatin, trastuzumab) was administered to 39 (87%) patients and to 6 (13%) patients the 4xAC + 12PCL sequence with trastuzumab. A complete response to treatment was achieved in this group in 21 patients and 24 had residual disease (RBC). The study was conducted over 5 years, from 2018 to 2023.

Inclusion and exclusion criteria

Inclusion criteria were female sex, age ⩾ 18 years, histologically confirmed localized breast cancer and eligibility for neoadjuvant chemotherapy. Exclusion criteria were to contraindications due to the use of low-intensity electrical current during body composition testing and included patients with a cardiac defibrillator, metal implants, epilepsy, and pregnant women.

Biochemical measurement methods

In the study group, BMI (body weight [kg]/height [m²]) was determined before the start of treatment and total levels of vitamin D 25(OH)D were determined in serum with Roche kits on a Cobas E-601 system. On the basis of the morphology of the blood determined on Sysmex XN1000, Japan, the number of platelets was also determined, as well as the number of lymphocytes, neutrophils and monocytes. The indicators studied were calculated on this basis. The SII and SIRI inflammatory indexes were determined according to the formulae:

$$\mathrm{SII}=\mathrm{platelet}\mathrm{count}x\mathrm{neutrophil}\mathrm{count}/\mathrm{lymphocyte}\mathrm{count},$$

$$\begin{array}{l}\mathrm{SIRI}\mathrm{=}\mathrm{number}\mathrm{of}\mathrm{neutrophils}\mathrm{x}\mathrm{number}\mathrm{of}\mathrm{monocytes}\mathrm{/}\\ \mathrm{number}\mathrm{of}\mathrm{lymphocytes}\end{array}$$

$$\begin{array}{l}\mathrm{PIV}=\mathrm{number}\mathrm{of}\mathrm{neutrophils}\times \mathrm{number}\mathrm{of}\mathrm{platelets}\times \\ \mathrm{number}\mathrm{of}\mathrm{monocytes}/\mathrm{number}\mathrm{of}\mathrm{lymphocytes}.\end{array}$$

Blood for the study was collected from the patients during the visit before the start of NAT, that is, on the day of administration of the first dose of the drug, approximately 2 weeks after diagnosis.

Statistical methods

The Mann-Whitney test and the Spearman rank correlation of the Statistica PL programme (StatSoft) were used for statistical calculations. The diagnostic power of the parameters determined was analysed using the MedCalc program. The receiver operating characteristic (ROC) analysis was applied to determine our own cutoff points for the parameters tested depending on the pCR versus non-pCR after NAT. Nonparametric pairwise comparisons of neighbouring area under the curve (AUCs) were performed using the Wilcoxon signed rank test.

Results

The characteristics of the patients are shown in Table 1.

Table 1.

Characteristics of the breast cancer patient groups studied.

Parameters	TNBC (N-51)	HER2+ (N-45)
	Number of patients (%)
Hormonal status:
Premenopausal	39 (76%)	29 (64%)
Postmenopausal	12 (24%)	16 (35%)
Tumour size (T)
T1	7 (14%)	12 (27%)
T2	34 (67%)	30 (67%)
T3	8 (15%)	2 (4%)
T4	2 (4%)	1 (2%)
Lymph node status (N)
N0	23 (45%)	25 (55%)
N1-N2	28 (55%)	20 (45%)
Distance metastasis status (M)
M0	51 (100%)	45 (100%)
Tumour grade (G)
G1	0	7 (15%)
G2	25 (49%)	22 (49%)
G3	26 (51%)	16 (36%)
Response to treatment
pCR	23 (45%)	21 (47%)
Non-pCR/RCB	28 (55%)	24 (53%)
RCB stage
I	12 (43%)	11 (46%)
II	10 (36%)	11 (46%)
III	6 (21%)	2 (8%)
	median (range)
Age, y	42 (26-67)	44 (23-70)
BMI	25.8 (17.5-37.8)	25.5 (16.1-36.2)
Vitamin 25(OH)D total ng/mL	21 (7.0-52.3)	23 (9.0-61.0)
SII	610 (215-2894)	544 (160-6232)
SIRI	1.33 (0.26-13.51)	0.60 (0.1-7.44)
PIV	321 (87-5406)	152 (23-1526)

The values of systemic inflammatory response indices and BMI and vitamin D levels were analysed in 2 groups of patients with breast cancer: group I TNBC and group II positive for the HER2 receptor (HER2+). Comparing the parameters values of the studied showed significantly higher SIRI and PIV indices in patients with TNBC (P = .001; P = .001) compared with their values in HER2+ patients (Figure 1).

Figure 1.

Medians and ranges of PIV and SIRI values in patients with breast cancer according to molecular type.

Diagnostic usefulness for inflammatory index values was assessed using ROC curves, in relation to response to neoadjuvant treatment. Receiver operating characteristic curves were determined for the parameters studied in patients with pCR versus patients with no complete response (non-pCR). In both studied patient groups, the areas under the AUCs for SII, SIRI, and PIV were similar and did not represent a significant diagnostic value. The largest area under the AUC was observed for the PIV index in HER + patients (AUC = 0.592).

The relationships of the parameters studied with the response to NAT were also analysed in both groups of patients. There were no statistical differences in SII, SIRI, PIV and BMI scores, and vitamin D concentrations, according to the response to NAT treatment (pCR vs non-PCR), in both TNBC and HER2+ patients and in the entire study group (Table 2). In patients with the TNBC subtype, without complete response to treatment (non-pCR), a higher percentage of patients with vitamin D deficiency below 20 ng/mL (54%) was observed than in patients with pCR (35%). Similarly, a BMI above 30 was observed more frequently in non-pCR patients (21%) than in pCR patients (17%).

Table 2.

Comparison of variables relative to the response achieved to NAT treatment in patients with type TNBC (2a), HER2+ (2b) breast cancer.

Parameters	pCR (N = 23)	Non-pCR (N = 28)
	Median (range)		P value
Age, y	38 (29-67)	28 (26-67)		.792
BMI	25.2 (17.5-32.7)	26.7 (17.5-37.8)	.615
Vitamin 25(OH)D total ng/mL	23 (7.0-52.3)	17.5 (8.0-44.0)	.184
SII	620 (215-2014)	575 (222-8316)	.449
SIRI	1.09 (0.26-4.65)	1.35 (0.41-13.51)	.733
PIV	304 (87-15 730)	324 (99-5406)	.903

2b Patients HER2+
Parameters	pCR (N = 21)	Non-pCR (N = 24)
	P value	Median (range)
Age, y		44 (23-67)	46 (25-70)	.171
BMI	24.4 (16.1-33.1)	25.7 (20.9-36.2)	.118
Vitamin 25(OH)D total ng/mL	23 (9.0-49.0)	26 (9.0-61.0)	.601
SII	476 (160-1599)	543 (160-2833)	.226
SIRI	0.62 (0.12-7.44)	0.58 (0.11-1.28)	.439
PIV	168 (27-612)	125 (23-374)	.295

In the next step, a correlation analysis of the SII, SIRI, and PIV indexes studied with BMI and vitamin D concentrations was performed. In group II as a whole (HER2+), SII values were negatively correlated with vitamin D concentrations; patients with low vitamin D values were more likely to have higher SII values (R = −0.39; P = .008) (Figure 2). A similar correlation was observed in patients who responded to NAT treatment (R = −0.53; P = .013). On the contrary, in patients who did not respond completely to treatment, SII was positively correlated with BMI, the higher the BMI, the higher the SII (R = .41; P = .045) (Figure 3). In group I (TNBC), there were no significant correlations between the parameters studied.

Figure 2.

Correlation of total vitamin D 25(OH)D concentrations with SII values in patients with HER+ breast cancer.

Figure 3.

Correlation of BMI concentrations with SII index values in patients with HER+ breast cancer who partially responded to NAT treatment.

Discussion

During the past 2 decades, the relationship between chronic inflammation and cancer has interested many researchers and both the diagnostic and therapeutic value of inflammatory markers has been widely studied. ²¹ The authors of the articles agreed that inflammation promotes the initiation and progression of cancer. The demonstration of the effect of lymphocytes, neutrophils, and platelets on tumour cells contributed to the growing interest in the pool of easily measurable cells determined by blood counts and the creation of dual or triple markers such as NLR, SII suggesting their usefulness in predicting the course of the disease, including in systemically treated patients with breast cancer.^{22 -24}

The primary objective of our study was to determine the usefulness of the SII, SIRI, and PIV indices to predict the response of the pCR to NAT in patients with breast cancer. In our study, due to differences in patient prognosis depending on the presence of receptors, we decided to create 2 homogeneous groups in terms of cell biology: patients with TNBC and patients with HER2+. In the group of patients with TNBC and HER2+, we did not observe differences in the values of any of the indexes studied depending on the response to NAT. Therefore, we did not demonstrate the usefulness of the indices studied to predict pCR achievement in the 2 cancer subtypes analysed. However, we observed higher values of SIRI and PIV in patients with TNBC compared with HER2+ patients. Therefore, high SIRI and PIV values prior to treatment may indicate a TNBC subtype, the course, and treatment of which is still problematic, which can guide the clinician on the optimal treatment regimen from the outset. In the available literature, the most common studies have included patients with different biological subtypes of breast cancer, thus analysing molecularly heterogeneous patients, increasing their numbers. The authors of these studies show the usefulness of inflammatory markers in predicting the acquisition of pCR and increasing the chance of an effective NAT effect in patients with low SIRI, SII, and PIV indices. Dong et al ⁴ demonstrated the value of the SIRI index as an independent prognostic factor for pCR; SIRI values below the designated cutoff point indicated a 5-fold increase in the chance of pCR. Similarly, Yang et al ¹⁰ and Şahin et al ²⁵ described such a relationship for SII and PIV by determining the ROC curves and cutoff values. As is known, in breast cancer, the molecular definition of the tumour is extremely important, which has a direct impact on the course of the disease and, above all, on the treatment. For this reason, in our analyses we took into account the molecular subtype of the tumour and studied the relationships separately for TNBC and HER2+ patients, so that our study groups were relatively less numerous, although homogeneous, which may have influenced the discrepancy in results. Our study group consisted of patients with confirmed breast cancer, just before the start of treatment, with locally advanced disease, i.e. without distant metastases. Neither cancer cachexia nor sarcopenia were observed in these patients, which, as other researchers have shown, may have a prognostic impact on OS, but in the case of advanced breast cancer with distant metastases.^26,27

In the study group of patients, as well as in both subgroups, we did not show an association between BMI values and vitamin D concentrations with response to NAT treatment. The literature suggests that the prognosis of patients with breast cancer may be negatively affected by obesity.^13,28 Fontanella et al described the association of DFS and OS with patients’ BMI, performing analyses on a very large group. High BMI was associated with worse survival. On the contrary, as in our study, they did not show a correlation of normal patient weight with response to pCR treatment. ²⁸ Zhao et al ²⁹ indicates that high BMI may be associated with HER2 in women younger than 55 years of age and worse progression-free survival. In our study, we did not confirm such an association, but the group sizes were much smaller and overweight patients made up a small percentage of the study population, median BMI 25—the upper limit of normal weight. On the contrary, in a group of HER2+ patients who did not respond to treatment, we showed that BMI was positively correlated with SII. It is interesting to note that the result obtained referred to a group of patients whose median BMI was at the lower end of the range that defines overweight. Adipose tissue, which exhibits metabolic activity in overweight and especially obese individuals, becomes a source of excess active molecules released, including pro-inflammatory cytokines, leading to the appearance of chronic inflammation.^30,31 However, the effect of adipose tissue in an analogous group of TNBC patients was not reflected in the correlation. In our group of patients with TNBC, there was no determinable index of inflammation correlated with BMI.

The association of vitamin D deficiency with obesity and increased cancer risk was the reason for its inclusion in our study in patients with breast cancer. Hormonally active vitamin D binds in a complex to the highly specific common VDR receptor, which influences immune function.^28,29 The expression and activity of VDR has been found to play an important role in both the development, differentiation, and effector function of T lymphocytes, which are of great importance for both immunity and the development of inflammatory diseases.^{32 -34} The decrease in the expression of the VDR in BC cells accelerates primary tumour growth and enables metastatic development, demonstrating a tumour-autonomous effect of vitamin D signalling.^19,35 The occurrence of low vitamin D concentrations in both study groups confirmed both the literature data indicating vitamin D deficiency in patients with newly diagnosed breast cancer and was also consistent with the widespread vitamin D deficiency observed in the Polish population.^36,37 When analysing vitamin D concentrations in relation to inflammatory markers, we expected negative correlations for all markers, but confirmation was obtained only for SII and in HER2+ patients who responded to NAT treatment. In the literature, we found only 1 article in patients with ischaemic heart disease, in which a negative correlation between vitamin D and both analysed SII and SIRI indices was confirmed. ³⁸ The association between vitamin D and inflammatory indices was not present in TNBC patients. Our results in HER2+ patients, in whom we demonstrated a correlation of SII with BMI and vitamin D values, in clinical practice indicate the need to monitor vitamin D and BMI levels during systemic treatment.

The results of our study obtained from small-group analyses suggest the need for further studies on significantly larger groups. We plan to continue our studies related to the assessment of the prognostic value of inflammatory markers, vitamin D, and BMI for pCR after NAT in molecularly homogeneous groups of patients with breast cancer, especially TNBC type, due to the difficult course and poor response to treatment. Our study did not take vitamin D supplementation into account, but what is most important in the context of the relationships studied, we checked its actual level in the serum of patients. However, we demonstrated, as in the studies by Araz et al, ³⁹ that vitamin D3 concentrations do not have a direct influence on pCR.

Of particular interest is the determination of the utility of inflammatory indices in pCR patients with breast cancer in relation to the residual cancer burden after neoadjuvant treatment.

A limitation of our study, in assessing the prognostic value of selected inflammatory markers, vitamin D3 and BMI for the occurrence of pCR after neoadjuvant chemotherapy, was the size of the study groups. As this is a single-centre, prospective study, conducted by design with molecularly homogeneous groups, hence the relatively small size of the selected patients (TNBC and HER2 plus). Furthermore, indices based on blood count parameters, although readily available clinically, are unfortunately nonspecific. In addition, in our database, a high BMI indicative of overweight was observed in a small proportion of patients, which may have affected analyses of the relationship between BMI and other parameters, a limitation of this study. Some authors point out that BMI has various drawbacks as a measure of obesity, as it is an indirect measure of body fat compared with more direct methods. ⁴⁰ Factors such as diet, physical activity, or other lifestyle factors that may affect inflammation markers, vitamin D levels, and BMI were not taken into account. Our results, not always similar to those of other investigators, suggest the need for follow-up and validation based on analyses in larger, molecularly homogeneous groups of patients with breast cancer. We plan to continue our studies related to the search for the relationship of selected inflammatory process exponents with objective response to systemic treatment, especially in patients with TNBC due to the difficult course and poor response to the treatment used.

Differences between the SII, SIRI, and PIV inflammatory indices in different molecular subtypes of breast cancer may result from differences in immune cells associated with the TME. The varied expression of different components of the TME indicates its heterogeneity in different molecular subtypes of breast cancer. For example, the HER-2 subtype is rich in tumour-associated macrophages compared with TNBC. Our study showed that SIRI and PIV were higher in patients with TNBC, which may be related to the presence of large numbers of neutrophils or macrophages in the TME. Elevated levels of SIRI and PIV markers in patients with TNBC may be correlated with lymphocyte activation in these patients. ⁴¹ However, the correlation between elevated SII and reduced vitamin D levels in HER2+ patients indicates the anti-inflammatory effect of vitamin D through the reduction of pro-inflammatory cytokine levels and the increase in anti-inflammatory cytokine concentrations. The correlation between elevated SII and elevated BMI in HER2+ patients is linked to the fact that adipocytes produce pro-inflammatory factors such as cytokines (eg, TNF-alpha, IL-6). The SII marker is often cited as an important prognostic factor in patients with obesity and diabetes. It is therefore possible that there is a correlation between SII levels and insulin resistance, which in turn may adversely affect the proliferation of HER2 receptor–dependent cancer cells. ⁴²

To summarize the results of our study presented here, the demonstration, in a group of HER2-positive patients with breast cancer, of a correlation of vitamin D deficiency and higher BMI values with inflammation intensity (expressed by an increase in SII) indicates the need to monitor these parameters during treatment, and the dynamics of their changes may be helpful in assessing treatment response. In the future we plan to expand the study to include 100 new patients and extend the follow-up to 5 years.

Conclusions

In patients with confirmed HER2-positive breast cancer, vitamin D deficiency and higher BMI may be associated with higher SII inflammatory index values; in addition, high SIRI and PIV index values may suggest the biological subtype of TNBC. No significant association was found between inflammatory indices or clinical factors (vitamin D, BMI) and complete pathological response (pCR).