The Effect of Race and Area Deprivation on Symptom Profiles over the Course of Early-Stage Breast Cancer

Purpose: This study compared common symptoms (fatigue, pain), overall physical functioning and changes over time between Black and White women receiving early-stage breast cancer (ESBC) chemotherapy. Methods: A longitudinal, repeated measures comparative design was employed. Time points of symptom measurement (PROMIS domains) at baseline, mid and end point were adjusted as per patient chemotherapy schedule. Analyses: Linear mixed models were applied. Results: There were 147 patients, 36% Black 64% White (54±12 years) recommended to receive early-stage breast cancer chemotherapy with adequate data for symptom analysis. Pain: Main effect of race was significant (F(1, 390) = 29.43, p<.001) for pain with Black patients experiencing significantly higher pain scores compared to White patients at pretherapy (Mean Difference; MD=3.7, p=.034), midpoint (MD=5.8, p=.002), and endpoint (MD=7.8, p<.001). Fatigue: Fatigue significantly increased (deteriorated) at endpoint (MDT1-T3= 8.7, p<.001) for Black patients. Among White patients, fatigue significantly increased at midpoint (MDT1-T2= 5.7) and at endpoint (MDT1-T3=10.1, p<.001; MDT2-T3=4.3, p= .017). Physical function: Black patients had significantly lower physical function scores compared to White patients at midpoint (MD=4.0, p=.027). Physical function decreased by endpoint in Black (MDT1-T3=7.8, p<.001), and White patients (MDT1-T3=7.7, p<.001). Conclusion: Symptom burden significantly increased over the course of chemotherapy for all patients. Scores for pain and physical function were higher overall for Black patients and deteriorated at a greater rate for Black vs. White women over the course of chemotherapy. This assessment holds implication for proactive assessment and mitigation strategies.


INTRODUCTION
Breast cancer is the second most deadly form of cancer among women in the United States and is the leading cause of cancer death among Black women [1,2].In recent years, the mortality rate from breast cancer has decreased due to increased emphasis on early detection and more effective treatments [3].Despite improvements in early detection [4], disparities in treatment and health outcomes remain, with Black American women having the highest mortality rate related to breast cancer among all racial groups [3].Several factors are associated with breast cancer survival disparity including later disease presentation [4] and earlier age at diagnosis for Black women, a historic distrust of the health care system in uencing screening and treatment decisions, and disproportionately poor communities that may offer few supports along the breast cancer care continuum.
Once cancer is diagnosed and treatment begins, disparities exist in the toxicities experienced during treatment.The 2002 State of the Science Conference for Cancer Symptom Management concluded that "all subjects with cancer should have optimal symptom control from diagnosis throughout the course of illness, regardless of personal and cultural characteristics [5]."Fifteen years later, this goal has not been achieved [6,7].To move forward in improving survival and health equity for Black women with breast cancer, further research is needed to deduce why Black women suffer disproportionately with symptom burden during chemotherapy [8].

Racial Disparities in Symptoms Burden
Symptoms burden de ned as the "subjective, quanti able prevalence, frequency, and severity of symptoms placing a physiologic burden on patients and producing multiple negative, physical, and emotional patient responses [8]."Historically, during ESBC, symptom burden increases from baseline to the midpoint of cancer treatment, at which point it remains stable until ESBC is terminated.Worsening symptom burden has been attributed to increasing gastrointestinal symptoms, fatigue, insomnia, and concerns with appearance [9,10].Black women experience more severe symptoms during and post treatment for ESBC [11].Pain and fatigue are the most common distressing symptoms experienced by patients receiving treatment during early-stage cancer treatment.The impact of these symptoms is poor quality of life, and overall diminution of physical function with implications for social, employment and family roles.It is imperative to examine the racial disparities in these symptoms prior to chemotherapy initiation, during and at the completion of chemotherapy.

Pain
Black women report more severe pain during ESBC than White women [12,13].Ongoing disparities in the treatment of Black patients' pain is a contributing factor, as Black patients are less likely to receive guideline concordant care and are more likely to have their pain underestimated by healthcare providers [14].Additionally, higher pain intensity is associated with higher pain interference (i.e., the effect of pain on activities: cognitive, social, physical, and recreation), fatigue, sleep disturbances, depression, and anxiety [12,15].

Fatigue
Compared to white women with breast cancer, Black women have higher levels of fatigue across domains (physical, emotional, etc.) shortly after diagnosis as well as during the early post-treatment survivorship phase (i.e., 6 to 18 months posttreatment) [16].Emotional fatigue declined, and vigor increased from diagnosis to approximately 6 months post-treatment in White patients; whereas these symptoms remain stable among Black women with ESBC [16].

Physical Function.
Disparity in physical function has been reported between Black & White women during treatment and during cancer survivorship [17,18].Black women were more than twice as likely to have a greater degree of physical functioning limitation compared to white breast cancer survivors, but this nding was signi cantly attenuated after adjusting for BMI, smoking status, and the presence of other co-morbid conditions associated with physical activity limitations [18].Another study supported the mediating role of socioeconomic factors where racial differences in physical and functional wellbeing have been 50% attenuated by socioeconomic differences that impact Black women's ability to manage cancer and treatment-related symptoms such as differences in physical activity and co-morbid conditions [17].

The Importance of Considering Social Context
Social contextual determinants of health contribute to both the risk and outcomes of breast cancer and may also contribute to disparities in symptom burden.Social contextual factors include race and gender, but also include socially patterned access to social, education, and economic resources, as well as exposure to other environmental hazards within communities.Lifetime cumulative stress caused by the stressors of poverty and discrimination may accelerate aging, and thus the symptom experience [19].
In addition, psychosocial stress in early life has also been associated with elevated in ammation markers among women with breast cancer [20].Black women are more likely than white women to have lower SES and are more likely to be exposed to psychosocial stressors in early childhood such as abuse and neglect [21].The cumulative impact of disparities in social contextual factors may increase the risk and adversely impact breast cancer outcomes through allostatic load or more rapid biological aging.The area deprivation index (ADI),a composite of neighborhood characteristics including poverty, housing, employment, and education, is associated with symptom burden, symptoms of depression and anxiety [22], including psychological well-being and quality-of-life [23] in patients with cancer.Little research has looked to area deprivation within longitudinal data.
Previous work exploring racial differences in symptom burden during ESBC has focused primarily on pain [24], and retrospective assessments were often cross-sectional or time points were not individualized for each patient treatment course of therapy [12,24], which may not re ect a granular, over time assessment of symptoms during the treatment trajectory.This study aims to advance our understanding of racial disparity in symptom burden during ESBC while considering the individual chemotherapy schedule and overcoming these methodological shortcomings.

PURPOSE
Limited studies have assessed racial disparities in pain, fatigue, and physical function prior to chemotherapy initiation and changes over the course of treatment, while adjusting for individual timing of chemotherapy for BC patients.The aims of this study are to describe and compare the symptom burden (fatigue, pain, and physical functioning) and change over time between Black and White women receiving ESBC chemotherapy while considering social determinants of health.

METHODS
This study employed a longitudinal, repeated measures (baseline, midpoint, and completion of chemotherapy assessment timepoints were included in this analysis based on patient chemotherapy treatment plan; total timepoints range for all patients = 3-15), comparative, mixed-methods design.Women with early-stage BC in Western Pennsylvania and Northeast Ohio were followed over the course of chemotherapy.A convenience sample of patients who are: female, Black or White race, 18 years of age or older, and prescribed chemotherapy for a diagnosis of invasive breast cancer (stages 1-3) were included.Prior chemotherapy, metastatic breast cancer, impaired cognition, inability to understand English, and receiving treatment outside the clinic of consent were exclusion criteria.Further details regarding recruitment, enrollment, and data collection are reported by Nugent et al [25].
Prior to Covid -19 research restrictions, eligible participants were approached by a research assistant in the clinic prior to receiving their rst chemotherapy treatment.Following Covid-19 restrictions, the recruitment and consent were obtained by telephone and online.Informed consent was obtained and baseline measures were completed by phone, online, or via paper forms.To capture the full range of changes in symptoms distress over the trajectory of ESBC chemotherapy, we included three time points: prior to chemotherapy (i.e., baseline), midpoint of treatment, and completion of chemotherapy (endpoint) for each patient.The data collection schedule was tailored to the individual patient's chemotherapy schedule.For example, if a patient needed to have a 7-day treatment delay due to neutropenia, the data collection schedule was adjusted by 1 week.

Ethical approval
was received from the Institutional Review Boards of (1) University of Pittsburgh (IRB number 19050299) and (2) University Hospitals Cleveland Medical Center (IRB number 02-18-60C).

Measures
Area Deprivation.The Area Deprivation Index (ADI) is a multidimensional evaluation of a neighborhood's socioeconomic status [26].The Area Deprivation Index (ADI), developed by the Health Resources and Services Administration [26], allows for neighborhood rankings by socioeconomic status deprivation, a composite of several factors (income, education, employment, and housing quality).Scores range from 0 to 100, with higher scores indicating higher deprivation.National ADI was derived by entering participants' home addresses at the time of study enrollment into a publicly available interactive website [27].Post o ce boxes are neither considered geographically representative nor included within American Community Survey metrics; thus, ADI was not calculated for participants who entered P.O.Boxes.The ADI median (61) was used to categorize participant into high ADI (n = 74; 50.7%), meaning living in areas of greater deprivation, and low ADI (n = 72; 49.3%), indicating living in areas of less deprivation.
Race.Patient race was identi ed as either White or Black based on both self-reported demographic questionnaire and medical chart review.
The PROMIS-29 Pro le (v2.0) was used to measure symptom burden [28].The PROMIS-29 is 5-point Likert scale and it includes seven domains (anxiety, depression, fatigue, sleep disturbance, physical function, ability to participate in social roles and activities, and pain).For this paper, symptom burden was de ned through measurements of fatigue, pain, and physical function.Raw scores for all domains were converted into T-scores using the Health Measures System (mean of general US adult reference population = 50, SD = 10).Higher PROMIS T-scores represent more of the concept being measured (i.e., worse fatigue and pain and better physical function).The clinical threshold to evaluate within-group change or to make a between-group comparison generally ranges between 2 and 6 T-score points [29].

Analytic Approach
Data were analyzed using IBM® SPSS®, version 27 [30].Descriptive data (mean, standard deviation, frequency, and percentages) for raw data were provided.Pearson's correlations (Spearman coe cients) were used to examine the bivariate associations of study variables.Linear mixed models were applied to determine whether signi cant differences existed among PROMIS domains over the three time points between Black and White patients.In the linear mixed model, we adjusted for area deprivation and then examined whether symptoms burden (pain, physical function, and fatigue) varied by race over the three time points.

Participants
There were 147 patients, 36% Black, 64% White with a mean age of 54 ± 12 years.Time average between prechemotherapy and midpoint (42 ± 16 days = 5.6 ± 2.3 weeks) and between midpoint and endpoint (71 ± 22days = 9.8 ± 3.2 weeks).Demographic and clinical characteristics of the sample are presented in Table 1.Pain.Black patients, compared to White patients, experienced signi cantly higher scores for pain across all time points, with a mean difference (MD) of 3.7 (p = .034)prior (baseline) to chemotherapy initiation, 5.8 at midpoint (p = .002),and 7.8 by completion of chemotherapy (p < .001).After adjusting for area deprivation, the main effect of race was still signi cant (F(1, 390) = 29.43,p < .001)for pain with Black patients experiencing signi cantly higher pain scores compared to White patients at midpoint (Mean Difference; 4.7, p = .02).This disparity was more pronounced by the completion of chemotherapy (MD = 7.8, p < .001).Pain scores deteriorated signi cantly over time for Black patients (within group change) who reported signi cant increase in pain scores by the completion of chemotherapy (MD T1−T3 =6.2, p = .010;MD T2−T3 =5.8, p = .024).There were no signi cant changes in pain scores over time among White patients.Refer to Table 3 for marginal means contrasts for mixed models depicting within group changes and Table 4 for marginal means contrasts between Black and White at the three time points.

DISCUSSION
This paper compared symptom burden (fatigue, pain, and physical function) and the changes experienced throughout chemotherapy between Black and White women with early-stage breast cancer.
The importance of this study lies in its novelty of examining these commonly reported symptoms at a time point often overlooked in the literature-prior to chemotherapy initiation.Furthermore, tracking changes at time points that re ect the full symptom trajectory including mid and endpoint of chemotherapy for each patient while considering the in uence of area deprivation.
Notable disparities in pain present at pretherapy and escalate over the course of chemotherapy.
Prior to chemotherapy initiation, Black patients reported scores 4 points greater than White patients indicating a clinically signi cant difference.This could linked to the distress occurring while anticipating treatment [31], psychological and physical symptoms, area deprivation, and worsened economic hardships [32].This disparity continued to escalate over the course of chemotherapy, with Black patients reporting 6 points greater at midpoints and 8 points greater toward the completion of chemotherapy.This aligns with a cross-sectional study of 40 women with BC stages I-III, status post-initial radiation or chemotherapy for breast cancer, where Black patients (58%) had signi cantly higher pain scores [12] and another study where Black patients reported more pain-related interference with function than White patients [33].Our study contributes to the existed knowledge of racial disparities in a period that is overlooked in the literature; prior to chemotherapy initiation; and showed that the exacerbation of pain was greater among Black women over the course of chemotherapy.
Furthermore, within group changes emphasized disparity as a clinically notable deterioration in pain scores over the course of chemotherapy was evident for Black patients only.The continuous deterioration in pain scores for Black patients across the chemotherapy aligns with a recent study by Hu et al.where Black women with ESBC, followed from the initiation of chemotherapy to one year later, were more likely to experience signi cant increases in physical and psychological symptom burden during chemotherapy.
This greater symptoms burden was associated with less adherence to adjuvant endocrine therapy suggesting that better symptom management for Black women can reduce racial disparities in adherence and cancer outcomes [34].Our ndings, along with previous research on racial disparities, provide evidence that Black patients endorse higher rates for pain [35].However, evidence has shown that Black patients receive inadequate and biased pain assessments and treatment by clinicians and other healthcare providers [36].Measures ensuring that clinicians and other healthcare providers deliver appropriate assessment and pain assessment to all patients should be taken.
Adjusting for Area lessened racial disparity in pain prior to chemotherapy initiation.
Area deprivation broadly refers to the lack of economic social resources in a neighborhood [37].
we adjusted for area deprivation in the models, the racial differences in pain at baseline were not statistically signi cant.In addition, patients residing in areas of greater deprivation from this sample, reported higher pain and worse physical function by the completion of chemotherapy.This is consistent with previous studies where patients with advanced cancer who lived in areas of greater deprivation reported worse symptom burden and worse symptoms of depression and anxiety [22].Clinicians need to consider neighborhood deprivation when examining racial disparity.The ADI can be utilized in healthcare systems as it is an objective and publicly available measure of social context.High ADI scores can prompt healthcare providers to conduct further assessment of the patients socioeconomic needs and provide the appropriate referral and support within the community.This could mitigate the in uence of neighborhood deprivation on racial disparities in symptoms burden.
Racial disparities were noted for physical function at midpoint.

Strengths and Limitations
To our knowledge, our study is the rst to look the racial differences in the most common reported symptoms of pain and fatigue and physical function while accounting for the in uence of area deprivation and considering patient-individualized timing of chemotherapy initiation, midpoint, and completion.This study addressed the methodological limitations identi ed in previous research including the utilization of longitudinal data with a focus on time points that re ect the full picture of changes in symptoms while receiving chemotherapy, including a substantially larger sample size, and accounting for area deprivation which is considered a valid measure re ecting patient social status and associated with health-related outcomes.However, these ndings should be interpreted with caution, considering any distress or anxiety that triggered by the COVID-19 pandemic [41], which might have in uenced the symptoms burden.
Clinical Implications and Future Research The baseline symptoms that patients bring to BC prior to chemotherapy initiation and the rate at which symptoms deteriorate must inform medical oncology practice.Practitioners and clinicians should consider symptom burden prior to chemotherapy initiation to accurately identify patients with prior symptoms that could be related to other comorbidities or the stage of diagnosis and avoid mistakenly attributing these symptoms as chemotherapy-related toxic effects.
Symptom management strategies need to be patient-centered, incorporating the differences that race may bring to the symptom experience during breast cancer chemotherapy.Frequent reports of physicians not recognizing the severity of symptoms underline the need for a change systemically, as providers are only able to initiate treatment if they are aware of the symptom burden [42].
Black patients have the greatest unmet needs regarding symptom burden but are also less likely to be assertive and communicate concern e ciently with their physicians [43,44].While this may primarily be a problem of cultural barriers in a non-concordant patient-physician relationship [45], a standardized measurement of symptom assessment and management is essential to attenuate the likelihood of chemotherapy dose reduction or cessation for Black patients.
Understanding symptoms burden within the context of race prior to and during chemotherapy could provide better understanding of the in uence of racial disparities on the breast cancer chemotherapy experience.Establishing these symptom differences can help to provide the impetus to proactive, targeted symptom management.

Consent to participate
Informed consent was obtained from all individual participants included in the study.

Consent to publish
Not applicable

Table 1
Comparative statistics for primary outcomes and other study variables are presented in Table2.

Table 3
The Marginal Means Contrasts for the Mixed Models: Within Group Changes The Means for each Combination of Within-Subject Variable: Pain

Table 4 :
The Marginal Means Contrasts for the Mixed Models between Black and White The Marginal Means Contrasts between-Subject Variables for the Mixed Model: Pain Physical function.Adjusting for area deprivation, main effect of race was signi cant (F(1, 391) = 11.00,p < .001)for physical function.Black patients had signi cantly lower physical function scores compared to White patients at midpoint (MD = 4.0, p = .027).Physical function decreased among Black patients by *.The mean difference is signi cant at the .05level.Fatigue.Adjusting for area deprivation, the main fatigue scores signi cantly increased (deteriorated) by endpoint (MD T1−T3 = 8.7, p < .001)for Black patients.Among White patients, fatigue signi cantly [40]39]atients experienced in physical function by the end of chemotherapy, Black patients experienced this deterioration earlier in the chemotherapy course with signi cantly lower physical function compared to White patients at midpoint.This could be attributed to the worsening in pain levels that Black patients reported compared to their White counterparts.While there are many interventions to target poor physical function such as support groups, exercise, nutrition, and mindfulness programs, the success of these for Black patients during treatment is not identi ed[38,39].Culturally tailored interventions have shown improvement in other areas of breast cancer such as improving screening rates among African American and other minorities[40].Culturally tailored symptom assessment and management needs to be a top priority to ensure personalized cancer care for not just treatment, but in symptom assessment and management as well.
Ethics approval and consent to participateThis study was approved by the Institutional Review Boards of the University of Pittsburgh (IRB number 19050299), the University Hospitals Medical Center/Case Western Reserve University (IRB number 02-18-60C), and Allegheny Health Network (IRB number 2018-115), prior to commencement of human subject research.The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki.