Background
Breast cancer has the highest incidence rate among cases of female malignant tumors in China, accounting for approximately 69,500 deaths annually [
1]. Presently, the management system for breast cancer has not been well-established in Chinese society. The problems related to the poor management of breast cancer mainly include poor control of the accompanying diseases (such as hypertension, hyperglycemia, and dyslipidemia). Elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor for cardiovascular diseases. Cardiovascular deaths in breast cancer patients account for 16.3% of all deaths [
2]. Therefore, early identification and control of lipid-related risk factors during the treatment of breast cancer may help improve the prognosis of patients.
Previous studies have shown that the incidence of dyslipidemia in breast cancer patients is higher than that in healthy people [
3,
4]. Abnormal lipid metabolism is considered to be related to the occurrence and progression of breast cancer, and the potential mechanism is known to mainly affect the proliferation and apoptosis of cancer cells [
5]. Some studies have shown that dyslipidemia is a high risk factor for the poor prognosis of breast cancer [
6,
7]. A past study reported that dyslipidemia before neoadjuvant chemotherapy affected the pathological complete response (pCR) rate of breast cancer [
8]. However, other studies have suggested that baseline dyslipidemia is a good prognostic factor for breast cancer [
9,
10]. The effect of dyslipidemia on the prognosis of breast cancer remains controversial. Most of these previous studies focus on the serum lipid level at a certain cut-off time, while ignoring the impact of the full-course lipid level on the prognosis of breast cancer.
Previous studies suggest that dyslipidemia deteriorated after postoperative chemotherapy in breast cancer patients [
11,
12]. Moreover, the effect of chemotherapy on the deterioration of dyslipidemia is long-lasting [
13]. In addition, dyslipidemia worsens after neoadjuvant chemotherapy [
14]. Neoadjuvant chemotherapy is an important treatment method and a screening platform for breast cancer patients with poor prognosis; patients with non-pCR usually have a poor prognosis, and deteriorated dyslipidemia may further worsen the prognosis of non-pCR patients. However, the reported effects of different chemotherapy regimens on dyslipidemia are not consistent [
11,
15]. Therefore, during chemotherapy-related decision-making, it is necessary to consider the effects of different chemotherapy schemes on lipid metabolism, which warrants accurate reference information.
Therefore, this retrospective study collected the serum lipid data of patients with breast cancer during the entire neoadjuvant therapy and analyzed the effect of the chemotherapy regimen on the serum lipid level, the correlation between the serum lipid level and clinicopathological features, and the effect of the serum lipid level on pCR and disease-free survival (DFS).
Methods
Patient selection
We retrospectively analyzed the clinical outcomes of 312 patients with primary breast cancer who were treated at the Henan Cancer Hospital from July 1, 2017 to May 31, 2018.
The study inclusion criteria included the following: (1) female gender; (2) invasive breast cancer with clear estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 status; (3) patients who had not received any drugs (including statins, phenoxyaromatic acids, niacin drugs, and cholesterol-absorption inhibitors) or treatments (including portal vena cava shunt and terminal ileectomy) that could affect the serum lipid levels within a month before baseline serum sample collection; (4) patient at stages II–III of breast cancer (AJCC 7th edition); (5) all patients had reiceived neoadjuvant therapy followed by surgery, whose postoperative pathological information was available; (6) patients whose complete follow-up data was available.
The subject exclusion criteria were as follows: (1) patients with bilateral breast cancer; (2) those with advanced breast cancer; (3) those with the presence of other primary tumors in combination; (4) those with inflammatory breast cancer; (5) those with other systemic diseases that could not tolerate chemotherapy; (6) and/or those with incomplete chemotherapy cycle.
All patients underwent surgery after the completion of neoadjuvant therapy. Radiotherapy or endocrine therapy was conducted in accordance with the clinicopathological characteristics of the patients.
The data on the clinicopathological features were collected, which included the age, height, weight, menstrual status, T stage, N stage, breast cancer molecular type, chemotherapy regimen, date of surgery, postoperative pathology, whether radiotherapy was applied, recurrence time, recurrence site, the baseline serum lipid level, the preoperative serum lipid levels, and the serum lipid levels from the time of treatment until the end of follow-up. The cut-off time for follow-up was June 30, 2022.
In this study, the status of ER, PR, HER2, and Ki-67 were detected by IHC conducted at the Pathology Department of our hospital. The HR positivity criteria were ER ≥ 1% or PR ≥ 1%; HER2-positive standard: IHC detection of HER2 was 3 + or 2 + , fluorescence in situ hybridization (FISH) detection was HER-2 amplification (HER2/chromosome enumeration probe 17 [CEP17] ratio ≥ 2.0, average HER2 copy number ≥ 4.0 signals per cell; or HER2/CEP17 ratio < 2.0, average HER2 copy number ≥ 6.0 signals per cell). While Ki-67 cut-off criteria varied across the centers, we considered a sample to be Ki-67-high if the proliferation index was > 14%. T staging was confirmed via ultrasound or magnetic resonance imaging (MRI); N staging with positive palpation or suspicious imaging was confirmed through fine needle biopsy or core needle biopsy (AJCC 7th edition). PCR was defined as the absence of residual tumor cells in the primary tumor (breast pCR) and axillary lymph nodes (axillary pCR) after neoadjuvant chemotherapy (ypT0ypN0). DFS was defined as the period from surgery to disease relapse or death from any cause. We collected data on the postoperative recurrence, metastasis information, and DFS of all patients.
Data collection and evaluated parameters
The serum lipid levels were measured before the treatment, before surgery, and at each follow-up examination after surgery. The automatic biochemical analyzer in our hospital was used to measure the concentration of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) in the serum of the patients.
The criteria for determining dyslipidemia were referred from those prescribed by the Joint Committee for the Development of Chinese Adult Dyslipidemia Prevention and Control Guidelines [
16], as follows: serum TGs ≥ 2.26 mmol/L; serum TC ≥ 6.22 mmol/L; serum LDL-C ≥ 4.14 mmol/L; serum HDL-C < 1.04 mmol/L. The full-course dyslipidemia was defined as the detection of dyslipidemia thrice or more during the whole study process. As body mass index (BMI) could be related to the serum lipid levels, we assigned the patients into 3 groups based on their body mass index (BMI). BMI was calculated using the following formula: BMI = weight (kg)/height*height (m
2). BMI grading was performed in accordance with the World Health Organization's grading scale.
Chemotherapy regimens
The neoadjuvant chemotherapy regimens in this study were conducted as follows:
(1)
TEC (docetaxel 75 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2,, every 3 weeks for 6 cycles).
(2)
EC-T/EC-TH (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles, followed by docetaxel 100 mg/m2 and/or trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance dose, every 3 weeks for 4 cycles).
(3)
TCH (docetaxel 75 mg/m2, carboplatin AUC 6, and trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance dose, every 3 weeks for 6 cycles).
(4)
TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2, every 3 weeks for 4 cycles).
TEC, EC-T, and EC-TH are taxane-plus-anthracyclines-based regimens; TC and TCH are taxane-based regimens.
Statistical analysis
The SPSS 23.0 was used for statistical analyses. The correlation between the serum lipids level and the clinical data was analyzed by the χ2 test, with p < 0.05 considered as the significance threshold. Univariate analysis of factors associated with recurrence and metastasis was evaluated by the χ2 test. Independent risk factors affecting prognosis were analyzed by multivariate COX regression. Factors with p < 0.05 in the COX regression analysis were considered independent prognostic factors. The Kaplan–Meier survival curve was employed to reflect the effect of serum lipid levels on survival at different time points.
Discussion
Breast cancer is the most commonly diagnosed cancer in women and the leading cause of cancer death [
17]. The incidence of dyslipidemia in breast cancer patients is higher than that in healthy people [
3,
4]. Both the impact of chemotherapy on serum lipids and the impact of serum lipids on prognosis are controversial [
6‐
11,
15]. Neoadjuvant chemotherapy provides a choice of intensive treatment for non-pCR patients. Meanwhile, neoadjuvant chemotherapy is a good experimental platform, which can screen out the prognostic factors of breast cancer. Therefore, we collected clinicopathological data of patients receiving neoadjuvant therapy and conducted a series of analyses on the relationship between dyslipidemia and clinicopathological features, the effect of chemotherapy on serum lipids, and the effect of serum lipids on cancer prognosis.
Currently, chemotherapy remains one of the most important treatment methods for breast cancer. While killing tumor cells, chemotherapeutic drugs can also affect other body indicators of the patients, which includes normal blood cells, liver functions, and serum lipids. Serum lipids are the collective term used to mainly refer to TC, TG, HDL-C, and LDL-C. Previous studies have shown that the levels of TG, TC and LDL-C in breast cancer patients significantly increased after chemotherapy, while the levels of HDL-C decreased [
12,
15,
18,
19]. Paclitaxel-based chemotherapy significantly worsens dyslipidemia [
20], while anthracycline-based chemotherapy has a slight impact on the deterioration of dyslipidemia [
11]. However, a study found that anthracycline drugs significantly lower HDL-C levels than taxanes [
15]. Briefly, the effect of different chemotherapy regimens on serum lipids is controversial. In our study, both the taxane-plus anthracycline-based regimens and the taxane-based regimens led to an increase in the levels of TC, TG, and LDL-C, but a decrease in the level of HDL-C. This finding is consistent with the results of previous studies. Therefore, chemotherapy patients need to closely monitor for any change in their serum lipid levels to achieve good control.
Numerous pieces of evidence indicate that changes in lipid metabolism can affect cancer cell proliferation, differentiation, and other processes [
21]. In animal experiments, dyslipidemia can promote the progress of breast cancer cells [
22,
23]. Previous clinical studies also reported that dyslipidemia is a high risk factor for the poor prognosis of breast cancer [
6,
7]. However, some studies have reported that baseline dyslipidemia is a good prognostic factor for breast cancer [
9,
10]. Interestingly, some studies reported that statins can improve the prognosis of breast cancer [
24‐
26]. It is unknown whether there exists a correlation between the above two findings. However, the mechanism by which statins can improve the prognosis of cancer remains unclear. In a word, the current researches on the role of serum lipids in the prognosis of breast cancer remain controversial. This controversy may be attributed to the fact that the serum lipid level at a certain time point could not be representative of the serum lipid level during the entire treatment duration. We found that preoperative dyslipidemia reduces the axillary pCR rate. In terms of prognosis, our results revealed that the baseline lipid level was not significantly associated with DFS, but the full-course lipid level was significantly associated with DFS in breast cancer patients. Therefore, we should pay close attention to the control of serum lipids during the whole course of breast cancer treatment, which can improve the prognosis of patients.
Endocrine therapy is an important subset of systemic therapy for HR + /HER2- breast cancer. Endocrine therapy drugs mainly involve tamoxifen, anastrozole, letrozole, and exemestane. The effects of different endocrine therapy drugs on serum lipid changes in previous studies are controversial. Some studies have reported that tamoxifen and exemestane reduce the risk of dyslipidemia in breast cancer patients [
27‐
29]. However, in another study, both exemestane and letrozole treatment lead to detrimental changes in the lipid profile of postmenopausal women with breast cancer [
30]. The proportion of dyslipidemia in patients taking trozole/anastrozole was numerically higher than that in patients taking tamoxifen/toremifene and exemestane in our study. The lack of statistical difference here may be attributed to the small sample size. However, the effect of endocrine drugs on specific indicators of serum lipids was not analyzed in the present study owing to the small sample size. We plan to continue exploring this issue in our future research. The choice of endocrine therapy drugs should be carefully selected based on each individual's serum lipid levels.
The strength of this study lies in that we collected and analyzed the full-course serum lipid data. This study, however, has some limitations, such as the retrospective research design. The short follow-up time may have affected the results of the prognosis analysis. In addition, our data were collected from a single center.
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