Research ArticleExperimental Studies

Changes in Serum Trace Element Concentrations Before and After Surgery in Resectable Breast Cancer

ERIKO TAKAHASHI, KAZUHIRO IMAI, MAYUKO FUKUYAMA, KAORI TERATA, HIROSHI NANJO, KOICHI ISHIYAMA, YUKO HIROSHIMA, MISAKO YATSUYANAGI, CHIAKI KUDO, AOI MORISHITA, AKIYUKI WAKITA, SHINOGU TAKASHIMA, YUSUKE SATO, KYOKO NOMURA and YOSHIHIRO MINAMIYA
Anticancer Research November 2022, 42 (11) 5323-5334; DOI: https://doi.org/10.21873/anticanres.16039

Abstract

Background/Aim: Minerals and trace elements (TEs) play vital roles in normal biological functions and in all cancers. Breast carcinoma is the most commonly occurring cancer in women. The aim of this study was to evaluate changes in TE levels before and after breast cancer surgery and the clinical utility and reliability of TE levels assayed using inductively coupled plasma mass spectrometry (ICP-MS). Patients and Methods: Thirteen patients with ductal carcinoma in situ (DCIS) and 34 with invasive ductal carcinoma (IDC) treated with planned surgery were enrolled between August 2017 and February 2019. Blood samples were collected before and the day after resection of the primary tumor. All enrolled patients received mastectomy or quadrantectomy and axillary lymph node dissection/biopsy. Serum TE concentrations were determined using ICP-MS. Results: Changes in boron, titanium, vanadium, chromium, copper, zinc, and selenium levels from before to after surgery differed between IDC and DCIS patients. Boron and copper levels before surgery and changes in titanium, vanadium, and chromium before and after surgery are potential predictors distinguishing DCIS from IDC. Subset analysis showed that chromium is a potential biomarker for luminal subtype, while titanium and chromium are potential biomarkers for pathological staging. Conclusion: Changes in serum TEs before and after surgery may help with diagnosis and staging of breast cancer and in establishing TE supplementation protocols.

Key Words:

Breast cancer is the most commonly occurring cancer in women worldwide. Traditional breast cancer classification, mainly based on clinicopathological features and assessment of routine biomarkers, may not capture the varied clinical courses of individual breast cancers (1). Although typical tumor markers in breast cancer are CEA, CA15-3 and NCC-ST439, these may also be high in patients with benign tumors or other cancers as well as in aged individuals and those who smoke (2-3). Moreover, positivity rates for tumor markers in early-stage breast cancer are very low and are currently limited to assisting in assessing the effect treatment after recurrence (3). To address these limitations, an increasing number of studies have focused on the relation between nutrition and breast cancer and tumor progression biomarkers (4-8).

Minerals and trace elements (TEs) play pivotal roles in the biological functions of all organisms (9). Inductively coupled plasma mass spectrometry (ICP-MS) is the most effective and widely used technique for analyzing TEs in biological samples. For instance, iron (Fe), copper (Cu), zinc (Zn) and selenium (Se) serve as cofactors for diverse enzymes essential for a wide variety of cellular activities (10-12). In addition, the levels of arsenic (As), Cu, cobalt (Co), nickel (Ni), magnesium (Mg) and lead (Pb) are reported to be high in several cancers and are believed to contribute to their development, including breast cancer (13-14). TE abnormalities can cause instability within the genome and contribute to the pathogenesis and progression of breast cancer (15). For that reason, accurate determination of TE levels and detection of changes in those levels after breast cancer surgery is of great significance.

The most common type of breast cancer is ductal carcinoma, which presents in two forms: invasive ductal carcinoma (IDC), characterized by infiltration and abnormal proliferation by malignant cells, and ductal carcinoma in situ (DCIS), a noninvasive, premalignant lesion in which neoplastic epithelial cells are restricted to the ducts. The biological progression from DCIS to IDC has yet to be elucidated, and there are still no histopathological or immunological markers that are accurately predictive of progression from DCIS to IDC (16-17).

In the present study, we focused on differences in serum TE concentrations between DCIS and IDC and the changes before and after (before/after) breast cancer surgery. Our aim was to evaluate changes in TE levels before/after breast cancer surgery and the clinical utility and reliability of assaying serum TE levels using ICP-MS.

Patients and Methods

Patients. The studies involving human participants were reviewed and approved by the Ethics Committee of Akita University (study no. 1777). The patients provided their written informed consent to participate in this study. Patients with breast cancer that was histologically confirmed through core needle biopsy or vacuum-assisted biopsy and was amenable to surgical resection with curative intent were eligible to participate in this study. All participants were radiation-naïve, >20 years of age and received no TEs or mineral supplementation. Patients who had planned breast cancer surgery between August 2017 and February 2019 were consecutively enrolled/eligible in the study (only if the patient gave consent and enough serum sample was available). Exclusion criteria included high general surgical risks, insufficient residual serum, and no consent. The patients’ clinical characteristics are listed in Table I. A diagram of the process by which cases were selected for study is shown in Figure 1.

View this table:
Table I.

Patient characteristics.

Figure 1.
Figure 1.

Flow chart illustrating the subject enrollment protocol.

Sample procedure. Blood samples were collected before and on the first post-operative day after resection of the primary tumor, to avoid the differences of meal content/volume after surgery. All samples were collected at the Central Laboratory, Akita University Hospital; after collection, the serum was separated and immediately stored at −30°C until further analysis. Prior to analysis for TEs, weighed serum samples were placed in Savillex Teflon 7 ml vials, and 1 ml of concentrated HNO3 was added to each sample. The samples were then placed on a metal-free hot plate at 90°C, and 0.1 ml of H2O2 was added to each sample. The samples were then dried at 90-125°C. Once the samples were completely dry, they were cooled down, and 0.36 ml of 7M HNO3 and 4.64 ml of Milli-Q water were added. The final samples consisted of 5 ml of 0.5M HNO3 solution. The samples were then capped and heated at 115°C for least for 5 h.

Surgery. All patients received standard pre- and intraoperative care. Total mastectomy or partial mastectomy was performed following the latest published Clinical Practice Guidelines for Breast Cancer from The Japanese Breast Cancer Society. When performing partial mastectomy, the lateral thickness of the removed healthy gland was at least 1.5 cm from the neoplasm, and the margin status was analyzed on the lateral sides of the specimen. In addition, patients with negative clinical node underwent a sentinel lymph node biopsy entailing administration of technetium99m sulfur colloid (plus blue dye) that was subsequently probed using a gamma ray detector. Patients with positive clinical node or a positive sentinel lymph node underwent a complete axillary node dissection (Level I to II, ALND). All patients received the same peri-operative fluid management.

Determination of trace element concentrations in serum. TE concentrations in serum were determined using quadrupole ICP-MS (Figure 2) (Agilent 7700, Agilent Technologies, Santa Clara, CA, USA). Calibration standards containing 10 ng/g or 100 ng/g TEs were prepared in 0.5 M HNO3 from multi-element standard solutions (ICP-MS-68A; High Purity Standards, Charleston, SC, USA). The Rhodium single element standard (High Purity Standards) was added to both standards and samples as a monitor, although we did not use it as a standard because the density of the resultant solutions differed slightly between the calibration standards and unknown samples. The calibration standards were measured after every 10 unknown samples were analyzed. The certified reference materials such as SLRS-6 (the National Research Council Canada) and CRM-TMDW (High Purity Standards) were analyzed as unknown samples to confirm the accuracy of analysis before the analysis of serum samples. The 5-ml 0.5 M HNO3 final sample solutions were diluted 1:5000 to measure 23Na, 24Mg, 31P, 39K and 43Ca. The concentrations of 9Be, 71Ga, 72Ge, 90Zr, 93Nb, 95Mo, 105Pd, 107Ag, 111Cd, 115In, 125Te, 139La, 140Ce, 141Pr, 146Nd, 147Sm, 153Eu, 157Gd, 159Tb, 163Dy, 165Ho, 166Er, 169Tm, 172Yb, 175Lu, 178Hf, 181Ta, 182W, 185Re, 189Os, 193Ir, 195Pt, 197Au, 205Tl, 207Pb, 209Bi, 232Th and 238U in serum were below the limit of quantitation. Figure 3 shows the 28 elements (7Li, 11B, 23Na, 24Mg, 27Al, 28Si, 31P, 39K, 43Ca, 45Sc, 47Ti, 51V, 53Cr, 55Mn, 56Fe, 59Co, 60Ni, 63Cu, 66Zn, 75As, 78Se, 85Rb, 88Sr, 89Y, 78Sb, 118Sn, 133Cs, 137Ba) analyzed with ICP-MS in this study. The dwell time of each element was 0.51 s. As the instrumental setting for the analysis, each test was repeated 3 times to demonstrate reproducibility of the measurements and the average was calculated.

Figure 2.
Figure 2.

Inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS is a highly sensitive technique that can be used to measure elements at trace levels in biological fluids. Here ICP-MS was used to determine trace element concentrations of serum before/after breast cancer surgery.

Figure 3.
Figure 3.

Determination of trace elements with ICP-MS. We analyzed the levels of 28 elements (7Li, 11B, 23Na, 24Mg, 27Al, 28Si, 31P, 39K, 43Ca, 45Sc, 47Ti, 51V, 53Cr, 55Mn, 56Fe, 59Co, 60Ni, 63Cu, 66Zn, 75As, 78Se, 85Rb, 88Sr, 89Y, 78Sb, 118Sn, 133Cs and 137Ba) in serum from breast cancer patients before and on the day after surgery. In prior analyses with 36 samples, the plasma concentrations of 9Be, 71Ga, 72Ge, 90Zr, 93Nb, 95Mo, 105Pd, 107Ag, 111Cd, 115In, 125Te, 139La, 140Ce, 141Pr, 146Nd, 147Sm, 153Eu, 157Gd, 159Tb, 163Dy, 165Ho, 166Er, 169Tm, 172Yb, 175Lu, 178Hf, 181Ta, 182W, 185Re, 189Os, 193Ir, 195Pt, 197Au, 205Tl, 207Pb, 209Bi, 232Th and 238U were below the detection limit of the assay. 1H, 2He, 6C, 7N, 8O, 9F, 10Ne, 18Ar, 36Kr, 43Tc, 54Xe, 61Pm, 84Po, 85At, 86Rn, 87Fr, 88Ra, 89Ac, 91Pa, 93Np, 94Pu, 95Am, 96Cm, 97Bk, 98Cf, 99Es, 100Fm, 101Md, 102No, 103Lr, 104Rf and 105Ha could not be measured with ICP-MS. 16S, 17Cl, 35Br, 45Rh, 53I and 80Hg could not be measured using this sample processing method. The red box shows measurable trace elements.

Elemental distribution map of breast tissue. Elemental distribution maps of surgical breast tissues were obtained with micro-X-ray Fluorescence (XRF, M4 TORNADO Plus, Bruker, MA, USA). The Rh X-ray tube voltage and current were 50 kV and 600 μA. Scanned areas were acquired with 20 μm of spot size and 10 ms for each pixel.

Pathological evaluation. Expert pathologists evaluated the specimens for this study. All dissected tumors and lymph nodes were sectioned and examined using hematoxylin-eosin staining and immunohistochemistry (IHC). Standard examination of the primary tumor included assessing the histologic type, size, invasiveness, and grade, as well as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)/neu status, and the Ki-67 index. Breast cancers with positive ER or PR staining in ≥1% of examined cancer cells were considered to be positive for the relevant receptor. HER2 status was determined through IHC or fluorescent in situ hybridization (FISH). HER2 positivity was defined as a score of 3+ on IHC or positive results on FISH. A Ki-67 index of ≥20% of examined cancer cells was considered high.

Statistics. Group data are expressed as means±standard deviation. Differences among the groups were compared using the chi-squared test or Fisher’s exact test when applicable. TE changes before/after surgery were analyzed using paired t-tests. Continuous data were compared using unpaired t-tests or the Wilcoxon/Kruskal-Wallis test, while categorical data were compared using the chi-squared test with continuity correction or Fisher’s exact test when applicable. Differences among three groups were compared using Dunnett’s multiple comparison test. p-Values were 2-sided and considered significant if they were below 0.05. Statistical analyses were performed using JMP IN 15.2.0 software (SAS Institute).

Results

ICP-MS analysis was performed with 94 serum samples collected before and the day after surgery from 13 DCIS and 34 IDC patients. Five IDC patients received neoadjuvant chemotherapy. A diagram of the selection process is shown in Figure 1, and the patient characteristics, including pathological stage, are listed in Table I.

Table II shows the changes in the serum concentration of each TE before/after surgery in the 13 patients with DCIS. Only Fe was significantly increased, while P was significantly decreased before/after surgery (Figure 4A). By contrast, Table III shows that in the 34 patients with IDC, eight TEs (P, B, Ti, V, Cr, Cu, Zn, and Se) were decreased after surgery. As in DCIS patients, only Fe was increased after surgery in the IDC patients (Figure 4B).

View this table:
Table II.

The concentration changes of each trace element (TE) in serum before and after surgery in all 13 patients with ductal carcinoma in situ (DCIS).

Figure 4.
Figure 4.

Changes in the concentration of each trace element in serum before and after breast cancer surgery. (A) P and Fe were significantly changed before and after surgery in DCIS patients. (B) Nine trace elements (P, B, Ti, V, Cr, Cu, Zn, Se, and Fe) were significantly changed before and after surgery in IDC patients. Significance was calculated using paired t-test. *p<0.05, **p<0.01 and ***p<0.001.

View this table:
Table III.

The concentration changes of each trace element (TE) in serum before and after surgery in all 34 patients with ductal carcinoma in situ (DCIS).

To investigate the associations of TE levels with DCIS/IDC, disease subtype and pStage, and to evaluate the utility of liquid biopsy for predicting DCIS or IDC, TE levels were measured before (TEbefore) and after surgery (TEafter) and the changes in TE levels (TEchange) were compared. The IDC patients who received neoadjuvant chemotherapy were excluded to avoid its influence on TEs. Bbefore, Cubefore, Tichange, Vchange and Crchange all significantly differed between DCIS and IDC patients. Moreover, subset analysis exploring biomarkers for diagnosis suggested Crafter and Crchange were predictive of luminal subtype, while Tibefore and Tichange are potential biomarkers for pStage I, Crbefore a marker for pStage II, and Crchange a marker for pStage I/II (Figure 5).

Figure 5.
Figure 5.

Changes in the concentration of each trace element and its relation to DCIS/IDC, subtype, and/or pStage. Bbefore, Cubefore, Tichange, Vchange and Crchange significantly differed between DCIS and IDC. Significant changes suggested for Crafter and Crchange are predictive of luminal subtype, Tibefore and Tichange of pStage I, Crbefore of pStage II, and Crchange of pStage I/II. Significant differences were identified using Wilcoxon/Kruskal-Wallis test or Dunnett’s multiple comparison test. *p<0.05 and **p<0.01.

To assess the differences of TE levels with normal/breast cancer surgical tissue, TE levels in the 2 representative IDC (pStage II, luminal A like) tissues were measured using the micro-XRF system and elemental distribution maps were obtained. Figure 6 shows the elemental distribution map of surgical breast tissue. In the 2 IDC tissues, P, Ca, S, Al, and Zn in the invasive cancer area were higher than those in normal tissues. Fe was increased in the bleeding lesion. Only Si and Cl in the cancer area were decreased compared to normal tissue. The changes of P and Zn in the cancer area were in line with those decreased after surgery in serum.

Figure 6.
Figure 6.

Elemental distribution map of surgical breast tissue in a representative IDC patient. The micro-XRF system provided the relative distribution of elemental concentrations between breast cancer and normal tissue. P, Ca, S, Al, and Zn in the invasive cancer area were higher compared to those in normal tissue. Fe was increased in the bleeding lesion. Only Si and Cl in the cancer area were decreased compared to normal tissue.

Discussion

In the present study, we found that there were significant changes in the serum levels of 8 (P, B, Ti, V, Cr, Cu, Zn, and Se) out of the 34 TEs tested before and after IDC surgery. By contrast, only P was decreased after DCIS surgery, and Fe was increased after both surgeries. In addition, Bbefore, Cubefore, Tichange, Vchange and Crchange significantly differed between DCIS and IDC, and are thus potential predictors distinguishing DCIS from IDC.

ICP-MS was developed for life science applications and enables ultra-trace determination and speciation of TEs in diverse biological sample types, including solid samples, as well as isotope fractionation and single-particle and single-cell analysis (18-19). The strengths of ICP-MS include its high dynamic range and utility for analysis of nearly all elements in the periodic table at concentrations in the low ng/l range. In addition, a μ XRF spectrometer allows direct analysis of solids (mass/nodule tumor) with little or no sample preparation and provides clearly mapped images of each TE (19). Importantly, imaging mass spectrometry enables assessments without the need for target-specific reagents, which enables the potential discovery of diagnostic and prognostic markers for different cancer types and for determination of effective therapies (20). The images and TE distribution maps provided by this technique may contribute to a better understanding of the biological processes involved in breast cancer and contribute to improved treatment/diagnostic strategies.

DCIS is widely recognized to be a precursor of IDC and is associated with a better prognosis and different clinical course and treatment strategies (21-22). Breast cancer patients presenting with DCIS are more likely to be younger with a lower tumor grade, are more frequently luminal B/HER2 positive, have a lower incidence of lymph node metastasis and are less likely to receive a mastectomy than IDC patients (23). Although clinical research is essential to explain the biological behavior of IDC and DCIS, the exact drivers and biomarkers, including TEs and the DCIS subtypes that tend to progress to IDC remain to be elucidated. The cellular distribution of Ca, Cu, Fe and Zn in the breast tissue of IDC patients has been examined using microprobe synchrotron radiation X-ray fluorescence (24-25). Those studies revealed average increases in Ca, Cu and Zn levels within areas of malignancy. The average levels of Fe are also reportedly higher, though lower levels in tumor regions were observed in some samples (24). Our data demonstrate that Cu and Zn decrease while Fe increases after surgery only in IDC patients, suggesting IDC may take up these minerals. Characterization of the difference in biometal levels between tumoral and normal tissues may help in selecting treatment strategies for breast cancer once there is an understanding of the changes of TEs before and after cancer surgery. In addition, the effect of TE supplementation has been explored in various illnesses, including pneumonia and septic shock/systemic inflammatory response syndrome (SIRS), and in surgical patients, and a few prospective randomized studies have demonstrated an overall mortality benefit (26). Hence, TE supplementation should not be underappreciated.

The strategy for breast cancer is surgery, followed by loco-regional radiation therapy. The radiation therapy has important toxic effects including dermatitis, asthenia, and breast pain. An early study reported that breast cancer patients had significantly lower pre-radiation therapy concentrations of B, Cu, and Zn, and significantly higher concentrations of Sr than healthy women (27). Their TEs plasma concentrations of pre-radiation therapy were associated with the molecular characteristics of breast cancers such as hormone receptors, epidermal growth factor receptor 2, Ki67 antigen, as well as the main radiation toxicity to radiation. The changes of B, Cu, and Zn which consisted with the changes before/after surgery in the IDC patients tested in the present study may be the candidates to speculate pathological characteristics of the tumors.

Se is involved in various biological processes, and the serum Se concentration has been reported to be associated with breast cancer risk and may be a useful predictor of breast cancer (5). We found that serum Se concentration decreased after surgery in IDC patients but was nearly unchanged in DCIS patients. Nutritional Se supplementation may reduce incidence of breast cancer (28) and has been reported to be inversely associated with breast cancer mortality (29). Interestingly, in a multicenter, double-blind, randomized, placebo-controlled cancer prevention trial, nutritional supplementation with Se (oral administration of 200 μg/day) in cancer-free people with a history of skin cancers was associated with a nearly 50% decrease in overall cancer morbidity and mortality (30). Although the specific mechanism underlying the anticarcinogenic effect of Se is not yet known, Se intake after IDC surgery is seemingly beneficial with the potential to prevent drug resistance and provide protection against toxicity in anticancer drug therapy (31).

Zn is an important component required for processes vital to DNA and RNA synthesis and is essential for proper immune function (32). Zn, along with Cu, is a crucial part of first-line antioxidant enzymes, e.g., superoxide dismutases (33-34). Zn also plays important roles in breast cancer tumorigenesis and progression (8, 35-36). Intracellular Zn overload and reduction in circulating Zn levels affects the activities of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9. It also induces the activation of transforming growth factor β (TGF-β) and vascular endothelial growth factor (VEGF) (8). Collectively, these effects contribute to breast cancer invasion, metastasis, and angiogenesis (35). In addition, Cu plays key roles in tumor progression and has the capacity to activate ERα and induce estrogen-regulated pathways contributing to the development of breast cancer (8, 37). Our study shows that Cu and Zn concentrations are not remarkably changed before and after surgery in IDC and DCIS patients. Nonetheless, several reports have shown that changes Cu/Zn levels are potentially predictive of the efficacy of surgery for advanced breast cancer (8, 35-37).

We found that Fe levels were significantly increased after surgery in both IDC and DCIS patients. Fe deficiency contributes to the high recurrence of breast cancer in premenopausal women, whereas Fe overload may play a role in the onset of breast cancer in postmenopausal women (38-39). Understanding the role of Fe imbalance in breast cancer may benefit patients by decreasing both its incidence and recurrence and increasing overall survival. If Fe deficiency does contribute to enhancing breast cancer angiogenesis and recurrence, supplementing patients with Fe before surgery could potentially lead to a decrease in the angiogenic response, for example through a decline in VEGF expression, and decreased recurrence in the long term (38).

Subset analysis in the present study showed that Crbefore is a potential biomarker for pStage II while Crchange for pStage I/II. In the body, Cr participates in carbohydrate and lipid metabolism and may exert beneficial effects, such as reducing blood pressure in type 2 diabetes mellitus patients (40). On the other hand, reduction of hexavalent to trivalent Cr generates hydroxyl and superoxide radicals and activates signaling pathways that inhibit apoptosis via PI3K/AKT pathways. This inhibition of apoptosis leads to the accumulation of mutations that stimulate cancer progression and recurrence (41-43). Cr supplementation in the perioperative period has the potential to prevent these undesirable microenvironmental changes.

This study has several limitations. First, the clinical utility of serum TE levels using ICP-MS had limited diagnostic value for determining the treatment strategy. Although TEs could potentially serve as serum biomarkers, no control group of healthy volunteers was used to define the baseline TE concentrations, and the cut-off values of the respective TEs have not been determined between DCIS and IDC in the present study. The normal level values are typically referred through the Agency for Toxic Substances and Disease Registry (ATSDR) website (https://www.atsdr.cdc.gov/). An important second limitation is the small sample size and possible selection, allocation, and confounding bias, which are the main pitfalls of the histological tissue comparison studies. The baseline of two groups was inconsistent because IDC was more progressive breast cancer than DCIS. Therefore, these results should be interpreted cautiously. The allocation bias may lead to overestimation of the clinical effects by TEs. Third, although we additionally measured Na, Mg, P, K, Ca as serum minerals in the present study, their change might be affected by perioperative fluid management and the patients’ history of TEs supplementation. Fourth, the survival data was pre-mature. Of all 47 enrolled patients, no patient had events including breast cancer death or recurrence because the follow-up period was short. For a more complete understanding of the changes in TE levels before/after surgery in DCIS and IDC patients, future large-scale research and continuous TEs monitoring will be needed to provide additional data from recurrent/advanced breast cancer or other cancer patients. Breast cancer has always included normal tissues such as skin, lymphatic/vascular vessels, and fat. Micro-XRF system could solve the contamination of normal tissues. However, the TEs influence on serum from the breast cancer tissue was insufficient to demonstrate in the present study.

Conclusion

In summary, we have shown that changes in the levels of B, Ti, V, Cr, Cu, Zn, and Se before and after surgery differ between breast IDC and DCIS. Bbefore, Cubefore, Tichange, Vchange and Crchange appear to be potential markers distinguishing between DCIS and IDC. In addition, Crafter and Crchange may be predictive of luminal subtype, and Tibefore, Tichange, Crbefore, Crchange and Pbefore may be useful for staging. This suggests serum TE levels warrant further prospective investigation into their association with DCIS and IDC. By a better understanding of the biological processes involved in breast cancer, modulation of TEs before/after surgery may help with diagnosis, staging and strategies for TE supplementation in clinical practice.

Acknowledgements

The authors are grateful to Akiteru Goto (Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine) for suggesting pathological diagnoses. We also thank Mr. Manabu Mizuhira (Bruker Japan, Kanagawa, Japan) for the elemental distribution map analyses.

Footnotes

  • Authors’ Contributions

    KI, MF, KT, ET and YM contributed to conception and design of the study. ET organized the database. KN performed the statistical analysis. KI wrote the first draft of the manuscript. All Authors contributed to manuscript revision, read, and approved the submitted version.

  • Conflicts of Interest

    The Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  • Received August 25, 2022.
  • Revision received September 4, 2022.
  • Accepted September 6, 2022.

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Changes in Serum Trace Element Concentrations Before and After Surgery in Resectable Breast Cancer
ERIKO TAKAHASHI, KAZUHIRO IMAI, MAYUKO FUKUYAMA, KAORI TERATA, HIROSHI NANJO, KOICHI ISHIYAMA, YUKO HIROSHIMA, MISAKO YATSUYANAGI, CHIAKI KUDO, AOI MORISHITA, AKIYUKI WAKITA, SHINOGU TAKASHIMA, YUSUKE SATO, KYOKO NOMURA, YOSHIHIRO MINAMIYA
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