Ming-Xu Hu, Chao-Xin Zhu, Qiao-Qiao Xu, Ke-Feng Sun

1.Heilongjiang Academy of Chinese Medicine, Harbin 150001, China

2.Hailun Hospital of Chinese Medicine, Hailun 152300, China

3.The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China

4.The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, China

Keywords:

ABSTRACT

1. Introduction

Breast cancer is one of the common malignant tumors in women, accounting for 15% of new female malignancies worldwide [1]. In China [2], its mortality rate ranks first among female malignant tumors, and its incidence has been increasing year by year, becoming a major factor that seriously harms women's health. St.Gallen International Breast Cancer Conference [3] divided breast cancer into four subtypes: LuminalA type, LuminalB type, Her2 overexpression type, and basal cell-like type (ie triple negative). In recent years, epidemiology [4] reported that Luminal breast cancer accounts for more than 45% of all breast cancer patients, and endocrine therapy is the first gold standard for Luminal breast cancer treatment. Related studies have shown that [5] the application of selective estrogen receptor modulators (such as tamoxifen) can significantly reduce the 10-year relapse rate and mortality of patients with Luminal breast cancer. However, while benefiting from continuous endocrine therapy, related adverse reactions persist for a long time [6], such as taking tamoxifen (TAM) often causes breast cancer patients to experience hot flashes, irritability, insomnia, depression, etc. Perimenopausal syndromes and irregular menstruation, vulvar pruritus, abnormal vaginal bleeding and other gynecological symptoms, while endometrial inflammation, thickening, polyp and other adverse pathological changes, and the risk of endometrial cancer significantly increased [7].The above adverse reactions seriously affect the mental state of breast cancer patients, leading to emotional depression, decreased quality of life, low immune function, and increased tumor recurrence rates [8-10]. Therefore, how to improve the adverse reactions of patients, regulate the depression status of patients, and make the endocrine therapy continue to be systematically performed, has become a new subject for the treatment of Luminal breast cancer. A large number of clinical and experimental studies [11-12] have shown that traditional Chinese medicine decoctions are effective in preventing and treating endocrine therapy Responses, regulating patients' depression, improving patient compliance, reducing the risk of recurrence and metastasis have significant effects. Although the traditional Chinese medicine decoction is better than Chinese patent medicine on the overall effect of patients' physical and mental regulation, patients often have poor adherence to long-term continuous traditional Chinese medicine decoction, and combined use of traditional Chinese medicine can improve the continuity of traditional Chinese medicine treatment. As related reports [13] suggest that Pingxiao Capsule can inhibit breast cancer cell proliferation, improve the patient's immunity, and effectively improve the patient's quality of life.

In this study, serotonin and dopamine [21] indicators were used to explore the improvement of patients 'depression. Serum T lymphocyte subsets and insulin-like growth factor-1 levels were selected to detect patients' immune function and endometrial changes. Among them, insulin-like growth Factor-1 [25] not only reflects the endometrial changes in patients, but also has a positive correlation with the occurrence and development of endometrial cancer and breast cancer. After seven years of clinical observation, this study combined the continuous treatment of discontinuous traditional Chinese medicine decoction and oral and peaceful capsules, systematically adjusted the patient's physical and psychological aspects, and explored the feasibility of applying traditional Chinese medicine-assisted endocrine therapy to the continuous treatment of patients with Luminal breast cancer.

2. Materials and methods

2.1 General Materials Information

Sixty patients with breast cancer who were treated in our outpatient clinic from February 2012 to February 2019 were selected. The postoperative detection of ER was positive. Each patient received a treatment cycle of 24 months. There were no deaths or withdrawals during the treatment cycle. The inclusion criteria were: ① taking TAM for treatment; ② expected survival time> 6 months; ③ no fertility requirements; ④ premenopausal women; ⑤ Those with a total score of ≥≥17 on the Hamilton Depression Scale (HAMD); those with symptoms such as difficulty falling asleep, chest tightness and rib swelling, early awakening, dreaminess, depression, hot flashes and sweating; all patients signed the informed consent. Exclusion criteria: ① patients with other malignant tumors and mental illness; ② those who have taken antidepressants, antipsychotics and other drugs within 1 week before admission; ③ have been treated with hormones within 6 months before surgery; ④ combined with severe heart, liver and kidney Diseases and infectious diseases; The patients were divided into two groups according to the random number table method, with 30 cases in the control group, aged 38 to 47 years, with an average age of (43.42 ± 4.52) years; 15 cases of breast cancer stage Ⅰ, 15 cases of stage Ⅱ; Observation group of 30 patients, aged 37 to 48 years, with an average age of (43.33 ± 4.24) years; 14 cases of breast cancer stage Ⅰ, 16 cases of stage Ⅱ; the general data of the two groups were not statistically different (P> 0.05). Comparable.

2.2 Method

Initial patients were given TAM (Hainan Hailing Chemical Pharmaceutical Co., Ltd., National Medicine Standard H46020268) orally, 10 mg / time, 2 times / d, and continued to be taken for 24 months. The observation group was treated with the traditional Chinese medicine Chaishao Jieyu Decoction on the basis of the addition, the bupleurum chinensis 15g, White peony 25g, fruit of citron orange (fried) 15g, turmeric, Hedyotis diffusa, August jade, stone Calamus, Lily, Polygala, Angelica, Radix Ginseng, Prunella vulgaris, Tribulus Terrestris, 20g each , Raw Os Draconis，Raw oyster, Psoralea, Cuscuta, Licorice 25g each, Raw Malt 30g, Decoction with water, 1 dose daily, Take it after breakfast and dinner, take 2 months as a course of treatment, and take one course of treatment respectively at the first and second months, the seventh and eighth month, the thirteenth and fourteenth months，the Nineteenth and twentieth months. The observation group also took Pingxiao capsule (Xi'an Zhengda Pharmaceutical Co., Ltd. Z61021330) at the same time, 6 capsules / time, 3 times / d, and continued to take it for 24 months.

2.3 Observation indicators

Patients started with treatment for 24 months as a treatment cycle. Patients collected fasting venous blood in a static state before treatment and at 6, 12, and 24 months of treatment, respectively. After centrifugation, 5 mL of serum was stored at low temperature. Centrifuge at 1000 rpm for 20 minutes, store the supernatant and store at -80°℃ for testing. Enzyme-linked immunosorbent assay was used to detect serotonin (5-HT) and dopamine (DA) levels. Immunoradiometry was used to detect changes in serum T-lymphocyte subsets (CD3 +, CD4 +, CD8 +) in patients with serum diabetes before and after the end of the treatment cycle by flow cytometry.

Adolescent patients underwent vaginal uterine ultrasonography before treatment and at 6, 12, and 24 months of treatment to record endometrial thickness.

2.4 Statistical methods

SPSS 20.0 software is used. The measurement data is expressed as mean±standard deviation（x±s） , and t-test is performed. If the test result is P <0.05, it means that the difference between the groups is statistically significant.

3. Results

3.1 Compare 5-HT and DA levels before and after treatment in two groups of patients

Compared with the control group, the levels of 5-HT and DA in the observation group were significantly increased at the 6th, 12th, and 24th months of treatment, and the differences were statistically significant (△P <0.05), and were significantly higher than the levels before treatment. Statistical significance (▲▲P <0.05). See Table 1 and Table 2.

3.2 Changes in T lymphocyte subsets before and after treatment in the two groups of patients

The results showed that compared with the control group, the percentage of CD3 + and CD4 + increased significantly after treatment in the observation group (t = 2.695, 3.448.△P <0.05), while the percentage of CD8 + decreased significantly (t = 2.223.△P <0.05), The percentage of CD3 + and CD4 + in the observation group after treatment was significantly higher than before treatment, and the percentage of CD8 + was significantly lower than before treatment (▲▲P <0.05); see Table 3.

3.3 Changes in endometrial thickness

Compared with the control group, the endometrial thickness of the observation group was significantly reduced at the 6th, 12th, and 24th months of treatment. Level, the difference was statistically significant (▲▲P <0.05). See Table 4.

3.4 Changes in serum IGF-1 concentrations at different times before and after treatment in the two groups

Compared with the control group, the serum IGF-1 concentration in the observation group was significantly reduced at 6th, 12th and 24th months (t = 3.324, 3.861, 7.185.△P <0.05), and were significantly lower than before treatment (▲P <0.05). ), The difference is statistically significant, showing a downward trend year by year. See and Table 5.

Tab.1 Comparison of levels of 5-HT between two groups（x±s）

Tab.2 Comparison of levels of DA between two groups（x±s）

Tab.3 Comparison of levels of T lymphocyte subsets before and after 24 months treatment between two groups（x±s）

Tab.4 Comparison of endometrial thickness between two groups（x±s）

Tab.5 Comparison of serum IGF-1 levels between two groups（x±s）

Figure 1 Trends in serum IGF-1 levels in the two groups with treatment time Note: The observation group at each time point after treatment was compared with that before treatment P <0.05

4. Discussion

As the most common subtype of breast cancer, Luminal breast cancer [14] is mainly characterized by its insensitivity to chemotherapy and sensitivity to endocrine therapy. Endocrine therapy can effectively improve the internal environment that induces breast cancer growth and reduce the recurrence rate and mortality rate of this type of breast cancer. Therefore, endocrine therapy is one of the main methods for the treatment of Luminal breast cancer. However, the adverse effects of endocrine therapy on the endometrium have also attracted the attention of scholars at home and abroad. Some studies have pointed out that [15] the incidence of endometrial cancer in breast cancer patients treated with TAM is 38.8%, and 19.8% of patients without treatment , Suggesting that continuous TAM treatment can increase the risk of endometrial cancer. At the same time, endocrine therapy will bring many types of menopausal adverse reactions to the patient, such as hot flashes, night sweats, insomnia, palpitations and other symptoms, coupled with the fear of the malignant tumor itself, directly leading to the depression of breast cancer patients. Studies have shown [16] that the incidence of depression and anxiety in breast cancer patients is much higher than that in other cancer patients, which seriously affects the quality of life of patients. Due to the long duration of most endocrine treatments, many of the above adverse reactions and pathological changes cause patients to reduce compliance with endocrine therapies, fail to continue systematic treatment, and cause tumor recurrence.

"Authentic Surgery": "Melancholia hurts the liver, worrying about hurting the spleen, thinking about the heart, those who do not want to, will cause meridians to be astringent, coalesce and nucleate, named Ruyan", clearly stated [17] depression and breast cancer Happening relationship. Liver loss, blood stagnation and stasis of the collaterals are the pathogenesis of the disease. Chai Shao JieYu decoction is based on a large number of clinical practices and has conducted in-depth research in molecular biology and serum metabolomics [18]. The antidepressant effect has been fully confirmed by basic research.In this decoction, Bupleurum and Baihuo adjust the liver qi, converge yin and relieve depression. fruit of citron orange (fried),turmeric, Tribulus terrestris, Polygala, Raw Os Draconis，Raw oyster, raw malt raw malt Relieve stagnation and calm the mind. Angelica sinensis, figwortroot, Psoralen, Cuscuta seeds,peonies, Licorice nourish qi and nourish blood, clear away heat and trouble. Hedyotis diffusa, August Zha, Prunella vulgaris and Jiangan Clear Liver and silting detoxify. Various medicines are combined to achieve the effect of relieving liver and stagnation, replenishing qi and clearing heat. Intermittent oral administration of traditional Chinese medicine decoction can timely and effectively adjust the physical and mental state of patients, and has a more effective effect on breast cancer patients for endocrine therapy. And Pingxiao Capsule [19-20] is composed of traditional Chinese medicines such as turmeric, alum, saltpeter, coriander shell, Faeces Trogopterori, dried lacquer, nux-vomica and so on. Effects such as righteousness and dispelling evil can perform overall adjustment on patients with breast cancer, and have exact curative effect on corresponding endometrial proliferative diseases. It is easy to take, the effect is exact, and the patient is easy to accept.

Related reports pointed out [21]: 5-HT and DA in the brain are important excitatory neurotransmitters in the central nervous system, and their concentration changes are closely related to the occurrence of depression. The results of this study show that: in the observation group, the serum 5-HT and DA levels of the observation group were increased year by year, which was significantly higher than that before treatment (▲P <0.05) and the control group (△P <0.05). This method can effectively improve the depression of Luminal breast cancer during endocrine therapy. At the same time, the percentage of CD3 + and CD4 + in the observation group of patients in this study after 24 months of treatment was significantly higher than before treatment (▲P <0.05) and the control group (△P <0.05), while the percentage of CD8 + decreased significantly and was significantly lower than before treatment (▲P <0.05) and control group (△P <0.05). This shows that this method can significantly improve the immune function of breast cancer patients and inhibit tumor recurrence. Related studies have shown that [22], the incidence of endometrial inflammation, thickening, and canceration of polyps in breast cancer patients receiving TAM has been increasing year by year. Insulin-like growth factor-1 (IGF-1) plays an important role in regulating reproductive endocrine. Endometrial cancer, breast cancer, and colorectal cancer and other malignant tumor tissues have abnormally increased expression of IGF-1 and its receptors, and the increased expression of IGF-1 and its receptors is related to the degree of differentiation of malignant tumors, The prognosis is related [24, 25]. Therefore, how to inhibit endometrial thickening and related IGF-1 expression has become the key to the success or failure of endocrine therapy for Luminal breast cancer. This study confirmed that the endometrial thickness and serum IGF-1 concentration of the observation group treated with the Chinese medicine Chaichao Jieyu decoction and Pingxiao capsules were significantly lower than those before treatment (▲P <0.05) and the control group (△P <0.05). And it shows a downward trend year by year, indicating that this method can continuously inhibit endometrial thickening and serum IGF-1 factor expression, and effectively prevent the possibility of endometrial canceration.

In summary, this study combines the continuous treatment of the traditional Chinese medicine Chaishao Jieyu decoction and intermittent oral Hepingxiao capsules, which are complementary to each other, and can continue to regulate the psychological state and immune function of patients undergoing endocrine therapy for Luminal breast cancer. Inhibit endometrial thickening and serum IGF-1 factor expression, systematically adjust the patient's physical and psychological aspects, improve many adverse reactions caused by endocrine therapy, prevent tumor recurrence, the effect is accurate, it is worth promoting.