Inflammatory Markers, Metabolic Profile, and Psychoneurological Symptoms in Women with Breast Cancer: A Literature Review

Breast cancer is one of the most prevalent cancers in women. The improvement in breast cancer treatment has significantly increased the proportion of survival rate for women with breast cancer. Despite the advancement in breast cancer treatment, a great proportion of survivors suffer from co-occurring psychoneurological symptoms which impact their quality of life. The most frequently reported psychoneurological symptoms among women with breast cancer are depressive symptoms, anxiety, fatigue, sleep disturbances, and pain. These symptoms usually appear as a cluster. Inflammatory activation and serum metabolic alterations have been associated with the etiology of cancer and with various chronic neurocognitive disorders. However, to date, no studies considered the combined effects of inflammatory markers and metabolites in the development of psychoneurological symptoms in women with breast cancer especially those who were treated with chemotherapy. Further clarification of the relationships between the inflammatory markers, serum metabolic alterations, and psychoneurological symptoms in women with breast cancer should be pursued.


Introduction And Background
Breast cancer is one of the most prevalent cancers in women. According to the American Cancer Society (2020), it is expected that more than 276,480 women in the United States of America will be diagnosed with invasive breast cancer [1]. Most of these diagnosed women were projected to be in early stages (I and II) and to survive for more than five years due to the advancement in chemotherapy treatments [2].
The improvement in breast cancer treatment has significantly increased the proportion of survival rate for women, however, despite the advancement in treatment, a great proportion of breast cancer survivors suffer from co-occurring psychoneurological symptoms which may have an adverse impact on their quality of life [3][4][5]. The primary goal of the study is to determine the relationships among inflammatory markers, metabolites changes, and the development, persistence, and severity of the psychoneurological symptoms across time in breast cancer women treated with chemotherapy.

Review Methods
For this paper, PubMed and Web of Science were used to locate related literature. The database was searched without any prior inclusion or exclusion criteria for all peered reviewed articles published till May 31, 2021. In general, there are few studies in this field that were matched with our four descriptors (e.g. psychoneurological symptoms, breast cancer, inflammatory markers, and metabolic profile). Searching processes resulted in nine pertinent studies in the best scenario given that all the Medical Subject Headings (MeSH) terminologies related to the descriptors were used during the searching process. Due to the limited number of articles in searching of the database, we targeted references that were indexed in the two best recent articles related to this phenomenon which finally led to thirteen studies. Most of these studies were about psychoneurological symptoms in women with breast cancer with a majority of studies that enrolled women who were treated with chemotherapy. The first two authors extracted data from all peer-review articles in a standard form includes citation (authors, year), purpose, study design, sample size and characteristics, summary for selected variables (therapies, psychoneurological symptoms, inflammatory markers, and other factors), findings and/or limitations. Narrative analyses considered study design and data quality and validity.

Results and discussion
Eighteen articles were grouped into five categories. The first category includes two studies that proposed a new theoretical model that might explain this phenomenon. The second category includes four studies that investigated the psychoneurological symptoms as an isolated symptom. The third group has six studies that examined psychoneurological symptoms as a cluster of symptoms. The fourth category consists of four studies that examined the relationship between inflammatory markers and psychoneurological symptoms. Finally, the fifth category includes only two articles that described the metabolic profile in a patient with breast cancer. The findings under the five categories were described in the following sections and further information was provided in Table 1 To report the

Conceptual/Theoretical Model: Psychoneurological Symptoms in Breast Cancer
Historically most of the studies in this field were designed to study this phenomenon based on the concept of dysfunction in the pathway of the hypothalamic-pituitary-adrenocortical axis (HPA). Starkweather et al.
(2013a) and Lyon et al. (2014) proposed a new conceptual model to explain the variation of psychoneurological symptoms in women with breast cancer, and this model includes HPA and another three concepts: inflammation, epigenetic, and genomic factors [6,7]. In women with breast cancer, the telomerase shortening and the epigenetics changes may lead to chromosomal instability and development of the psychoneurological symptoms [6].
Nowadays this model is the cornerstone for most of the recent studies funded by the National Institute of Health (NIH) since it's incorporating constructs from the parent model "Symptom Science Model" that was developed by NIH [21]. The two primary constructs adopted in this model from the Symptom Science Model were the biomarkers identification and symptom cluster. This model includes concepts of genetic and inflammatory markers under the construct of biomarkers identification; however, it didn't consider metabolites or metabolic profiles as one of the biomarkers in its design.

Psychoneurological Distress as an Isolated Symptom in Breast Cancer
Articles under the second category had investigated the co-occurrence of psychoneurological distress as an isolated symptom in women with breast cancer. This group includes four longitudinal studies that were conducted over one year. Aboalela et al. (2015) reported that perceived stress was detected in overall patient visits, and it was associated with an impact on chromosomal stability during the treatment period with the highest level of stress being reported at the baseline of the study [8]. Wu et al. (2014) found depressive symptoms were negatively associated with cortisol level but not covaried with adrenocorticotropic hormone (ACTH), epinephrine, and norepinephrine [9]. This category is characterized by longitudinal studies with adequate samples. Studies in this category examined psychoneurological symptoms in women with breast cancer as an isolated symptom, and such concept was reflected in its statistical analyses which were based on the techniques of univariate rather than the multivariate analysis.

Psychoneurological Distress as Cluster of Symptoms in Breast Cancer
The third category has six studies that investigated psychoneurological distress as a cluster of symptoms. In this category, findings of these studies were ranked in the following order: (1) two descriptive crosssectional studies, (2) one longitudinal study, and (3) finally three secondary data analysis studies that were based on randomized clinical trials.
Cross-sectional studies: So et al. (2009) reported the existence of significant correlations between four symptoms (e.g. fatigue, pain, anxiety, and depression), and they interpreted these findings as evidence supporting the presence of symptoms cluster in women with breast cancer [5]. Thornton, Andersen, and Blakely (2010) reported a similar cluster of symptoms (e.g. pain, depression, and fatigue) that was associated with latent variable indicated HPA (e.g. cortisol, ACTH, epinephrine, and norepinephrine) [12].
Longitudinal study: In 2009, Liu et al. found that breast cancer chemotherapy-treated women reported a triad cluster of a symptom (sleep, fatigue, and depression). Also, they found that women who started with a large cluster index continued to experience worse symptoms compared with women who began with a lower cluster index [13].
Secondary data analysis studies: Bender et al. (2005) identified three types of symptom clusters which were co-occurred with the three phases of breast cancer experience [2]. Each cluster was composed of symptoms related to fatigue, mood problems, and perceived cognitive impairment. Kim et al. (2008) reported two distinct clusters: a psychoneurological cluster (depressed mood, cognitive disturbance, fatigue, insomnia, and pain), and an upper gastrointestinal cluster (nausea, vomiting, and decreased appetite) [14]. Kim et al. (2008) reported that demographic and clinical variables were not significantly associated with symptom clusters [14]. Interestingly, this finding was inconsistent with the third study published by the same authors which found that a higher level of education and chemotherapy treatment were significantly associated with a higher and constant pattern of symptom clusters [11].
The third category provides support for the existence of psychoneurological distress as a cluster of symptoms in women with breast cancer. The most commonly reported symptoms in the cluster of psychoneurological symptoms were depressed mood, cognitive disturbance, fatigue, insomnia, and pain.

Psychoneurological Symptoms and Inflammatory Markers in Breast Cancer
Inflammatory markers are chemical substances released by human body cells which have an effect on the interaction and communication between cells. Lyon et al. (2008) reported that all systemic cytokines were higher in women with a positive biopsy for breast cancer compared with the women with negative biopsy results [18]. This study was followed by Starkweather et al. (2013b) who reported significant differences between high and low symptoms composite score for IL-6 and IL-7 [17].
The findings in both studies were promising and maybe help to understand the biological mechanisms underlying the development of the psychoneurological symptoms. However, there are many limitations in the two studies. First, psychoneurological symptoms were not investigated in Lyon et al. (2008) study. Second, Starkweather et al. (2013b) study was a secondary data analysis based on an original experiment that did not monitor participants over a long time. The limitations of these two studies were considered by two longitudinal published studies [15,16]. Lyon et al. (2016) found there were significant associations between cognitive performance and cytokines from different classes [16]. Moreover, Starkweather et al. 2017 found that across the time of the study there was an inverse association between levels of C-reactive protein (CRP) and cognitive efficiency [15].

Psychoneurological Symptoms and Metabolic Profile in Breast Cancer
Metabolic profile or the metabolic phenotype is a reflection of the end products of cellular processes, and the changes in its concentration either in tissue or the circulation. There are many reported evidence that cancer cell metabolism differs from that of normal cell metabolism [22] The advances in metabolomics as a biomarker were widely used across different diseases, and it was found to be helpful in the prediction and prognosis of the illnesses. 1 H-NMR spectroscopy is one of the noninvasive techniques that can detect more than 100 metabolites. Louis et al. (2016) found that 1 H-NMR spectroscopy technique was able to classify 99% of patients with breast cancer based on their metabolic profile [20]. A recent pilot study correlates between global and targeted metabolic phenotypes and the psychoneurological symptoms in women with breast cancer were encouraging [19]. This study found symptoms of pain and fatigue were strongly associated with global and several targeted metabolites [19]. Concerning the tryptophan pathway, this study found women after chemotherapy had a higher level of pain and fatigue and a significantly higher concentration of acetyl-L-alanine, indoxyl sulfate, kynurenine levels, and kynurenine/tryptophan [19].
This category provides support for the existence of a correlation between psychoneurological and the metabolic phenotype. However, these studies were few and in the infancy stage. Thus more studies with various designs were needed. Further, such studies were needed to consider the combined or the simultaneous alteration in inflammatory markers and metabolite and their influence on the development, persistence, and severity of psychoneurological symptoms in women with breast cancer.
Findings of this review were summarized in a proposed model. The proposed theoretical model/framework was developed to explain the phenomenon of development, persistence, and severity of psychoneurological symptoms in women with breast cancer that was treated by chemotherapy ( Figure 1).

Conclusions
In general, several pieces of evidence support the existence of psychoneurological symptoms as clusters in women with breast cancer. However, to date, no study has considered the combined effects of inflammatory activation and metabolic profile in the development of the psychoneurological symptoms in women with breast cancer. We recommend further studies should shed light on the following phenomenon in that chemotherapy will induce an alteration in the inflammatory markers and serum metabolites among breast cancer women treated with chemotherapy, and such alterations are required for the development, persistence, and severity of the psychoneurological symptoms.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.