Association between depression and anxiety status of breast cancer patients before adjuvant chemotherapy and chemotherapy‐induced adverse events

Abstract Purpose Patients with breast cancer are more likely to experience psychological distress than the general population. This study aimed to explore the relationship between depression and anxiety status measured before chemotherapy and adverse events during adjuvant chemotherapy in Chinese breast cancer patients. Methods This prospective study was conducted on 290 postoperative early‐stage breast cancer patients (response rate 96.7%) in China. Depression and anxiety status before adjuvant chemotherapy were assessed by the Hospital Anxiety and Depression Scale (HADS). Adverse events that occurred throughout the course of chemotherapy were graded and recorded according to Common Terminology Criteria for Adverse Events (CTCAE) 4.02. Results The rates of depression and anxiety were 20.0% and 31.4%, respectively, at baseline. The incidence of grade two or higher myelosuppression induced by chemotherapy was correlated with depression before chemotherapy (p = 0.037). Multivariate analysis showed that the incidence of myelosuppression was significantly related to depression before chemotherapy (p = 0.032). There was no association between depression and anxiety status and other adverse events (p > 0.05). Conclusions We observed an association between depression status in breast cancer patients receiving adjuvant chemotherapy and chemotherapy‐induced myelosuppression. Monitoring the depression status of breast cancer patients before chemotherapy may help to optimize the management of adverse events.


| INTRODUCTION
Breast cancer is the most common malignancy among women worldwide. In 2020, more than 400,000 women were diagnosed with breast cancer in China, ranking first among new cancer cases. 1 The treatment modalities for primary breast cancer include surgery, chemotherapy, radiotherapy and hormonal therapy, among which adjuvant chemotherapy is an important strategy to improve the survival of breast cancer patients. Although chemotherapy improves the survival rate of these patients, the aggressiveness of the chemotherapy regimen may elicit adverse side effects. In fact, cancer and treatment-related adverse effects are major stressors among breast cancer patients undergoing treatment for the disease. 2 Adverse events mainly included gastrointestinal events, anemia, myelosuppression, alopecia and liver-enzymeabnormalities.
During the long treatment period, breast cancer patients often suffer from a variety of psychological distress, such as depression and anxiety. 3 Breast cancer survivors have been found to be more likely to develop depression than the general population. Previous metaanalyses have reported that the prevalence of anxiety and depression among breast cancer patients reached 41.9% and 32.2%, respectively. 4,5 Similarly, breast cancer survivors in China were found to experience a high level of depression and anxiety symptoms. 6 Independent risk factors for the development of depression include age, social status, and underlying diseases. 7,8 It has long been recognized that depression and anxiety can affect the physiological function, treatment compliance, 9 and quality of life of patients with breast cancer and may even be an important factor for survival in these patients. 10 Depression may also cause immune dysfunction through an overactive hypothalamic-pituitary-adrenal (HPA) axis. 11 Patients with immune dysfunction may be more likely to experience chemotherapy-related adverse events during chemotherapy. Indeed, the relationship between depression and anxiety status and adverse events induced by chemotherapy in Chinese patients with breast cancer remains unclear. Further prospective trials exploring this relationship are essential to closing this knowledge gap.
In our study, we investigated the relationship between depression and anxiety status and adverse events during adjuvant chemotherapy in Chinese breast cancer patients with the purpose of identifying high-risk patients through psychological state monitoring to better manage adverse events in this population.

| Patient selection
We identified 300 patients from a prospective, observational cohort with a primary diagnosis of breast cancer between March 1, 2019 and 30 April, 2021 in the Medical Oncology Department at the National Cancer Center in China. Ethical approval was obtained from the Institutional Review Board of the National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital. This study has been registered on Clini calTr ials.gov database.
Inclusion criteria included the following: (a) age 18-75 years, (b) had undergone surgery for breast cancer, (c) were diagnosed with stage I-III breast cancer, (d) planned to receive postoperative adjuvant chemotherapy, and (e) voluntarily provided written informed consent. Those who (1) had difficulty in understanding the questionnaire or communicating in Chinese, (2) had a history of psychiatric disorders, (3) had a history of neoadjuvant chemotherapy before surgery, or (4) had metastatic disease were excluded from the study.

| Demographic and clinical characteristics
The demographic data consisted of age, educational level, menopausal status, and family history of cancer. The clinical characteristics included tumor stage, chemotherapy regimens, and number of chemotherapy cycles.

| Assessment instruments
The Hospital Anxiety and Depression Scale (HADS) was used to assess the psychological status of our patients, which was developed in English by Zigmond and Snaith in 1983 12 and then translated and validated in Cantonese/ Chinese in 1995 by Lam et al. 13 Questionnaires were provided to the patients to complete before the first cycle of chemotherapy to evaluate their anxiety and depression before chemotherapy. The scale includes two parts: anxiety (anxiety, A) and depression (depression, D), with a total of 14 items-7 items with single numbers for anxiety and 7 items with double numbers for depression. Each item is scored 0-3 points. Total scores for each subscale are calculated individually, with a higher score indicating more anxiety or distress. In each of the two subscales, a score of below 8 indicates no anxiety/depression, [8][9][10] indicates possible anxiety/depression case, and 11-21 indicates definite anxiety/depression. 14 Thus, based on previous research, we adopted a threshold subscale score of 8 for anxiety and depression in this study.
All patients received 4 or 6-8 cycles of conventional chemotherapy regimens include anthracycline-, taxane-, or combined anthracycline-and taxane-based chemotherapy specified by the National Comprehensive Cancer Network (NCCN) guidelines (Version 3.2018 to Version 1.2021), based on their disease states, and for Her2-positive patients, anti-Her2 has been added. Dexamethasone and 5-hydroxytryptamine receptor (5HT3) prophylactic antiemetic therapy were administered before each cycle of chemotherapy for moderate and low emetogenic chemotherapy. Dexamethasone, 5HT3, and neurokinin-1 (NK-1) receptor antagonist prophylactic antiemetic therapy were administered to patients receiving hyperemetic chemotherapy. Adverse events (gastrointestinal events, anemia, myelosuppression, alopecia, elevation of transaminase) in each chemotherapy cycle were continuously monitored and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.2. We recorded and analyzed the most serious grades of each adverse event in patients. Finally, the most serious adverse event during chemotherapy was recorded for follow-up analysis.

| Statistical analysis
Statistical analysis was performed using SPSS 22.0 software. Cronbach's α values were calculated to assess the internal consistency of each questionnaire. Chi-squared analysis was used to examine whether there was a significant relationship between adverse events induced by chemotherapy and psychological symptoms and demographic and clinical characteristics. We used a logistic regression model to investigate potential risk factors for adverse events. A probability value of p < 0.05 was considered statistically significant.

| Patient characteristics
A total of 300 breast cancer patients fulfilled the inclusion criteria, and all patients provided informed consent. Eight patients dropped out due to discontinuation of treatment at our hospital, and two patients were excluded due to incomplete questionnaires. Thus, a total of 290 valid cases were analyzed, and information on the demographic and clinical characteristics of these patients were presented in Table 1. The Eastern Cooperative Oncology Group (ECOG) performance scores of all patients were 0-1. Internal consistency measurements of the HADS subscale questionnaires before chemotherapy yielded Cronbach's alpha coefficients of 0.883, respectively. Overall, the mean age of the patients was 47.09 ± 9.45 years, and 40.7% were older than 50 years. And 5.9% of patients received anthracycline-based chemotherapy, 40.3% of patients received taxane-based chemotherapy and 53.8% of patients received combined anthracycline-and taxane-based chemotherapy. Among them, more than half of the patients were diagnosed with stage II cancer (50.7%), and 85.5% of patients received 6-8 cycles of chemotherapy decided by their physicians.

| Correlation between anxiety or depression and adverse events
First, the most common adverse events observed in our study were grade 2 or higher myelosuppression (84.1%). A total of 26.9% of the patients experienced grade 2 or higher gastrointestinal events, while more than half of the patients (54.5%) experienced grade 1 or higher elevated transaminase. The incidences of grade 2 or higher T A B L E 1 Demographics and clinical characteristics of the patients (N = 290) anemia and alopecia were 22.1% and 16.2%, respectively. Afterward, we analyzed the differences of common adverse events induced by chemotherapy (including gastrointestinal events, anemia, alopecia, and elevation of transaminase) in different psychological status before chemotherapy, and we found that the occurrence of grade two or higher myelosuppression during chemotherapy in patients with depression was higher than that in patients without depression before chemotherapy (93.1% vs. 81.9%, p = 0.037). No statistically significant result was found between anxiety and myelosuppression during chemotherapy (p = 0.234). There was no statistical significance between depression and anxiety status and other adverse events, including gastrointestinal events, anemia, alopecia, and elevation of transaminase (p > 0.05) ( Table 2).

Number of patients
In the multivariate analysis, after adjusting for age, prechemotherapy depression status, chemotherapy regimens, 8th edition of AJCC Tumor-Node-Metastasis (TNM) stage, and number of chemotherapy cycles (univariate analysis between myelosuppression and demographic and clinical factors were shown in Table Table S1), we found that prechemotherapy depression status was independently associated with the incidence of grade two or higher myelosuppression induced by chemotherapy, and this was statistically significant (p = 0.032). In other words, these patient populations are more likely to develop myelosuppression (odds ratio [OR] = 3.258 [1.106-9.598]).
The results of the multivariate analysis of the correlation between depression status before chemotherapy and myelosuppression induced by chemotherapy are shown in Table 3.

| DISCUSSION
We conducted this study to explore the relation between psychological distress and adverse events induced by chemotherapy. We used the HADS scale to assess psychological status as it has been used as a criterion for evaluating depression and anxiety in previous studies. [15][16][17][18] In this study, we analyzed 290 patients with breast cancer in China, and the rate of depression and anxiety were 20.0% and 31.4%, which were comparable to previous reports. 3,19,20 The results reported in other studies also indicate the importance of assessing the mental health of such patients throughout the entire cancer treatment process. 21,22 Post hoc analysis showed that depression before chemotherapy was associated with the incidence of myelosuppression during the entire chemotherapy process. This indicates that patients with depression in these populations are more likely to develop myelosuppression during the course of chemotherapy. Thus, it is very important to screen the psychological status of breast cancer patients before chemotherapy. We found no correlation between anxiety and adverse events during chemotherapy and there was no in-depth mechanism exploration at present. Further mechanism research may be carried out in the future. In this study, the patients received conventional chemotherapy regimens, and no granulocyte colony-stimulating factor was used for primary prevention of myelosuppression. A total of 84.1% of patients had grade 2 or higher myelosuppression, which is similar to previous study results. 23 The occurrence of myelosuppression in our study reflected the true condition of the patients after receiving chemotherapy. Therefore, the conclusions drawn by our study have high credibility and may offer guidance regarding clinical decision-making.
The possible reason for these conclusions may be that psychological distress in the form of depression and anxiety can cause immune dysfunction. In previous studies, psychological distress is considered to dysregulate immune function in several ways, including the exacerbation of chronic inflammation, the suppression of protective immunity, and the enhancement of immunosuppressive mechanisms. [24][25][26][27] Activation of the HPA axis, which is well recognized in individuals with depression, inhibits immune system activity by releasing cortisol and disrupts the immune microenvironment. 28,29 Therefore, breast cancer patients experiencing depression are more prone to myelosuppression during chemotherapy. In addition, depression, anxiety, or a combination of both is associated with increased recurrence and mortality in patients with breast cancer. 10 Hence, oncologists should try to identify patients with depression before chemotherapy and take measures when necessary to relieve psychological distress.
Some retrospective studies have been conducted to explore the role of psychological distress in chemotherapyinduced nausea and vomiting, and the results suggest that anxiety plays a role in the perception, frequency, intensity, and severity of nausea and other chemotherapy-induced side effects. 30 In our study, univariate analysis showed that depression and anxiety were not associated with gastrointestinal events. This result is different from the results of previous studies. 31,32 The reason may be because in the present study, the patients received preventive antiemetic treatment before chemotherapy, which reduced the incidence of gastrointestinal adverse events to a nonsignificant level. This also suggests that preventive antiemetic treatment can relieve nausea and vomiting in patients. In addition, there was no statistically significant association between psychological status and elevated transaminases, anemia, and alopecia. This indicates that depression and anxiety in breast cancer patients do not affect the incidence of such adverse events.
In this work, we demonstrated, for the first time, that depression status is an independent factor associated with myelosuppression induced by chemotherapy in Chinese breast cancer patients. This work measured the depression and anxiety status of breast cancer patients before the course of chemotherapy. Patients with depression before chemotherapy were found to be more likely to develop grade two or higher myelosuppression during chemotherapy. These findings indicate that oncologists should make efforts to measure the depression status of breast cancer patients before chemotherapy. Nevertheless, proper psychological care is still necessary after screening. 33 Before starting chemotherapy, it is necessary for oncologists to consider not only the patient's tumor development and disease experience but also their psychological status, including depression and other psychological symptoms. 34,35 Moreover, oncologists and nurses should perform intervention measures when patients with severe psychological symptoms are identified to ensure that they can successfully complete chemotherapy, which is of great significance for preventing tumor recurrence and improving patient prognosis.
As intended, this study assessed the psychological status of breast cancer patients being monitored at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and identified factors associated with chemotherapy-induced myelosuppression, which will help oncologists and nurses offer better support to breast cancer patients. Nevertheless, some limitations should be noted. First, this study was conducted at a single institute. Second, the population size was relatively small. Additional studies with larger populations should be conducted to improve the validity of our conclusions in the future. Third, our study was merely an observational study, without intervention on patients, thus it was impossible to draw any conclusions about causality.
In conclusion, we demonstrated in this exploratory study that the depression status of breast cancer patients was correlated with the incidence of grade two or higher myelosuppression throughout the course of chemotherapy, and populations with prechemotherapy depression were more likely to develop myelosuppression. These findings suggest that oncologists should focus more attention on monitoring the depression status of breast cancer patients before chemotherapy, which might help to improve the management of adverse events, and ensure the safety of patients.