Racial and Ethnic Disparities in the Refusal of Surgical Treatment in Women 40 Years and Older With Breast Cancer in the United States Between 2010 and 2017

Purpose Although surgical resection is the main modality of treatment for breast cancer, some patients elect to refuse the recommended surgery. We assessed racial and ethnic differences in women 40 years and older who received or refused to receive surgical treatment for breast cancer in the United States and whether racial disparities in mortality were affected by their differences in the prevalence of refusal for surgical treatment Methods We studied 277,127 women with breast cancer using the Surveillance, Epidemiology, and End Results (SEER) data and performed multivariable logistic regressions to investigate the association between surgery status of breast cancer and race/ethnicity. Additionally, we performed Cox logistic regression analyses to determine the predictors of mortality outcomes. Results Of 277,127 patients with breast cancer, 1,468 (0.53%) refused to receive the recommended surgical treatment in our cohort. Non-Hispanic Black women were 112% more likely to refuse recommended surgical treatment for breast cancer compared to their non-Hispanic White counterparts [adjusted odds ratio: 2.12, 95% confidence interval (CI)=1.82-2.47]. Women who underwent breast conserving surgery [hazards ratio (HR): 0.15, 95% CI: 0.13-0.16] and mastectomy (HR:0.21, 95% CI: 0.18-0.23) had lower hazard ratios of mortality as compared to women who refused the recommended treatment after adjusting for covariates. Race/ethnicity was associated with refusal for recommended surgery, especially among non-Hispanic Black women. Also, surgery refusal was associated with a higher risk of all-cause and breast cancer-related mortality. These disparities stress the need to tailor interventions aimed at raising awareness of the importance of following physician recommendations among minorities. quadrant of the breast, upper-outer quadrant of the breast, lower-outer quadrant of the breast, and axillary tail of the breast); tumor stage ( localized only, regional with direct extension, regional with lymph nodes only, and regional with both direct extension and lymph nodes); and adjuvant treatment: radiotherapy (yes/no) and chemotherapy (yes/no).


INTRODUCTION
Breast cancer is the most prevalent cancer and the second leading cause of cancer-related deaths after lung cancer among U.S. women [1][2][3][4]. In 2021, it is estimated that approximately 281,550 new cases of invasive breast cancer will be diagnosed, and 43,600 women will die from breast cancer in the U.S. Approximately 3.8 million U.S. women currently live with a history of breast cancer [2,3]. Additionally, nearly 1 in 8 (13%) women in the U.S. will be diagnosed with invasive breast cancer, and 1 in 39 (2.6%) will die of it [1,2,4,5]. Breast cancer incidence rates are highest among non-Hispanic (NH) Whites (130.8 per 100,000 women) and NH Blacks (126.7 per 100,000 women). NH Black women have the highest recorded breast cancer death rate (28.4 deaths per 100,000) and are more likely at any age to die from breast cancer as compared to other ethnic groups [2,6] .
It is well documented that the main modality of treatment for breast cancer is surgical resection either in the form of lumpectomy (breast-conserving surgery -BCS) or modified mastectomy (removal of the entire breast) based on pathological characteristics, which is often followed by adjuvant treatment such as radiation therapy and/or chemotherapy [2,7,8] . However, corroboration from controlled clinical trials showed that there has been increasing concern that cancer patients in the U.S. do not receive the full benefit of effective and appropriate cancer treatment [9,10].
Although surgical treatment has been proven effective, research showed that some patients develop various setbacks. Post-surgery patients may develop declining psychosocial functioning with respect to their quality of life, cancer-related distress, sexual dysfunction, body image dysmorphism, anxiety, and depression, hence affecting surgery refusal rates [7,[11][12][13]. Previous analyses have also found age, race, marital status, and income level to be associated with surgery refusal, with NH Black patients being less likely to receive breast cancer surgical treatment [7,[14][15][16]. However, these studies focused on data prior to 2014. Information and data on patients diagnosed in more recent years is needed. Also, the extent to which these disparities result from differences in cancer molecular subtype characteristics among a large and ethnically diverse cohort of older women remains unexplored.
The acknowledgement of treatment refusal has led to various quality improvement measures to better direct strategies to improve surgical utilization, patient satisfaction, and cancer care outcome [17][18][19]. Understanding which patients are potentially likely not to abide by the recommended treatment and when the treatment is most likely to be curative, would be of great clinical benefit. This information should also help address, identify, and reduce cancer care outcome disparities. Therefore, this study aimed to determine if there were racial and ethnic disparities in the prevalence of refusals for definitive surgeries in women with early-stage breast cancer who were recommended for surgeries, whether the refusal of receiving the recommended surgeries was associated with an increased risk of mortality, and whether racial disparities in mortality were affected by their differences in the prevalence of refusal for surgical treatment.

Data source, study design and patient selection
This analysis utilized the Surveillance, Epidemiology, and End Results (SEER) database. SEER is a cancer registry program supported by the National Cancer Institute (NCI) that aims to provide reliable incidence and survival data [20]. We selected the SEER research plus data, 18 registries, Nov 2020 database, which covers nearly 28% of the U.S. population [21] . A detailed description of the database and data collection can be found elsewhere [20]. The study subjects were de-identified and there was no patient contact; thus, the study is exempt from an Institutional Review Board's review.
We conducted a retrospective cohort study using secondary data of women aged 40 years and older with a primary diagnosis of breast cancer between 2010 and 2017 in the SEER areas of the U.S. We focused on women 40 years and older to capture women at risk of being diagnosed with breast cancer based on the American Cancer Society breast cancer screening recommendation [22]. We investigated the racial and ethnic disparities between women who received surgery to treat their breast cancer and those who refused the surgical recommendation. Additionally, we assessed the differences in breast cancer survival outcomes by surgery type (recommended but refused surgery versus BCS versus Mastectomy).
We used the SEER Stat software 8.3.8 to identify all women over 40 years old with breast cancer as the first primary diagnosis from 2010 to 2017 (n=404,240). We included patients for whom surgery was performed or recommended or for whom surgery was not performed due to patients' refusal. We excluded patients with grade IV tumor, distant tumor stage, or unknown race, income, marital status, area of residence, tumor sites, breast cancer subtypes, and ineligible for surgery (figure 1). The new sample size was 277, 127 and then 267,999 following logistic and cox regression analyses when observations with missing values were dropped.

Main exposure
Race/ethnicity was classified into non-Hispanic White, non-Hispanic Black, Hispanic, and other. For the secondary analysis, surgery type was categorized into breast conserving surgery (BCS), mastectomy, and no surgery (i.e., patient refused) was assessed as a predictor of death. Only those ineligible cases for surgery were excluded ( figure   1).

Outcomes
Surgery treatment was the main outcome of interest and dichotomized as "surgery performed" and "surgery recommended but not performed, patient refused". We also looked at death from any causes, death from breast cancer, and 5-year survival as secondary outcomes. All-cause mortality was a dichotomous variable (yes/no).
Patients who died of any causes at end of the study were categorized as "yes", and those who did not were categorized as "no". Breast cancer related death was a dichotomous variable. Patients who died of breast cancer at the end of the study were categorized as "yes", and those who died of other causes were "censored".

Survival months
For overall mortality, survival time was calculated from the date of diagnosis to the date of death, or the date of last follow-up (December 31, 2017) as indicated in the SEER registry. For the breast cancer-related mortality, survival time was calculated from the date of diagnosis to the date of breast cancer related death, or the date of last follow-up as indicated in the SEER registry.

Tumor characteristics and adjuvant treatment
The following tumor characteristics and treatment variables were obtained from SEER and assessed based on findings from previous studies [7,8,11,14]: year of diagnosis ( 2010, 2011, 2012, 2013, 2014, 2015, 2016, and 2017); tumor subtype ( luminal A, luminal B, HER2 enriched, and triple negative); tumor grade (Grade I, grade II, and grade III); tumor site (nipple, centra portion of the breast, upper-inner quadrant of the breast, lower-inner quadrant of the breast, upper-outer quadrant of the breast, lower-outer quadrant of the breast, and axillary tail of the breast); tumor stage ( localized only, regional with direct extension, regional with lymph nodes only, and regional with both direct extension and lymph nodes); and adjuvant treatment: radiotherapy (yes/no) and chemotherapy (yes/no).

Statistical Analysis
We performed descriptive statistics to review the characteristics of the cohort stratified by race/ethnicity and by surgery status. We used Pearson's Chi-square test to determine if the differences were statistically significant. We performed crude and multivariable logistic regression to assess the association between the surgical treatment of breast cancer and its predictors, mainly race/ethnicity. We performed crude and adjusted Cox proportional hazards regressions to determine the association between surgery types and race/ethnicity and the mortality outcomes (death and survival). SAS version 9.4 and STATA 16.1 were used to perform the analyses.

Sociodemographic Characteristics
A description of the sample baseline characteristics stratified by race/ethnicity is provided in Table 1. The proportion of patients with triple negative breast cancer was 20.38% among non-Hispanic Black patients while the proportion was 9.15% and 10.88% among non-Hispanic and Hispanic patients respectively. The proportion of patients with Grade 3 tumors was 43.78% among non-Hispanic Black patients, 26.78% among non-Hispanic White, and 33.56% among Hispanic patients. The descriptive analysis also showed differences in marital status within racial groups. Non-Hispanic Black had the lowest percentage of being married or with a domestic partner (37.80%) while it was 61.99% and 58.39% among non-Hispanic Whites and Hispanics respectively.
A description of the sample baseline characteristics stratified by surgery treatment status is provided in Table 2.
Overall, 0.53% of women with breast cancer refused the recommended breast cancer treatment The surgery refusal rate was higher in non-Hispanic Black women (0.91%) than in non-Hispanic Whites (0.49%), Hispanics (0.45%), and others (0.57%). Chi-square test comparing women who underwent surgery as recommended versus those who did not reveal statistically significant differences (p<0.0001) by patient and tumor characteristics. Although non-Hispanic Black patients represented 10.19% of all women with breast cancer, they accounted for 17.29 % of breast cancer women who refused to get the treatment as recommended as compared to 10.19% of those who did in our cohort. On the other hand, non-Hispanic White patients accounted for 63.12% of the patients who refused to undergo surgery as prescribed. The proportion of women who refused the recommended surgery were higher for ≥80 years and for those who had a localized, luminal A, grade II moderately differentiated tumor located in the upper-outer quadrant of the breast.

Primary outcome on surgery refusal
The surgery refusal rate was higher in non-Hispanic Black women (0.91%) than in non-Hispanic Whites (0.49%), Hispanics (0.45%), and others (0.57%). The multivariable logistic regression analysis showed that non-Hispanic Black women had 112% higher odds (AOR: 2.12, 95% CI=1.82-2.47) of refusing the recommended surgery performed compared to non-Hispanic Whites after adjusting for sociodemographic and tumor characteristics as shown in table 3. Additionally, women aged ≥80 years compared to those aged 40-49 years old and those with luminal B, HER2, triple negative compared to those with luminal A were less likely to undergo the recommended surgery as recommended (Table 3). There was an increasing trend in the proportion of women receiving the recommenced surgery by year of diagnosis from 2013 to 2017. Women residing in metropolitan counties of 250 thousand to 1 million residents had the highest odds (AOR=1.17, 95% CI= 1.02-1.34) of receiving the recommended surgery compared to women residing in counties in metropolitan areas with populations greater than 1 million.

Secondary outcome on mortality
All-cause mortality: Table 4  after adjusting for covariates. Women who underwent mastectomy were also significantly less likely to die of breast cancer than women who refused the recommended surgery (HR: 0.21,95% CI= 0.18-0.23). Similar to that of allcause mortality, non-Hispanic Black women had the highest crude hazard of breast cancer mortality (HR=1.88, 95% CI=1.80-1.98). After adjusting for surgery type and other covariates, the hazard of breast cancer-specific mortality remained significantly higher among non-Hispanic Blacks (HR=1.13, 95% CI=1.01-1.37). Women with HER2 enriched and triple negative tumors were significantly more likely to die of breast cancer as compared to luminal A with hazard ratios of 3.06 (95% CI= 2.11-4.44) and 7.30 (95% CI= 5.88-9.06) respectively. A significantly higher hazards of breast cancer-specific mortality were observed in those with grade III cancer, regional tumors with both direct and lymph node involvement, tumors located in the lower-inner quadrant of the breast, and 80 years or more.

DISCUSSION
Racial disparities in access to healthcare, including breast cancer treatment, have been widely reported in the U.S. [23][24][25]. In this nation-wide large cohort of women aged 40 years and above with a primary diagnosis of breast cancer in the United States from 2010 to 2017, we sought to assess racial and ethnic disparities in undergoing the recommended surgery. The findings from our study suggest that race/ethnicity, increasing age, tumor subtypes, income, area of residence (rural vs. urban), and year of diagnosis are significant predictors of whether the recommended surgery for breast cancer was performed for women aged 40 years and older.
Non-Hispanic Blacks were more likely to refuse getting surgery as recommended for breast cancer compared to Non-Hispanic Whites. This finding can be attributed to low socioeconomic status (SES) and distrust of health care among racial minorities [7,24,26]. Evidence shows that income and employment are major determinants of a person's refusal to undergo recommended surgery [7,27]. This is partly explained in that people with low income may not have health insurance or the financial resources to cover the cost of treatment or any additional out-ofpocket expenses required for a recommended surgery for breast cancer [7,27]. However, contrary to what has been previously documented in other studies, higher median household income (>75,000) at the census tract level was significantly associated with an increased odds of refusing the recommended surgery in our study. The reason for this finding is unclear. Additionally, this study is limited since we did not have access to insurance coverage and employment status data for different racial and ethnic groups. This study also revealed that non-Hispanic Black women were diagnosed at more advanced stages of breast cancer for which surgery may not be curative. This is similar to a study that found that NH Black women were 3 times (OR, 3.00 [95% CI, 2.41 to 3.75]) more likely to not undergo mammography screening and 2.5 times (OR, 2.49 [CI, 1.59 to 3.92]) more likely to present with a more advanced stage of breast cancer at diagnosis as compared to White women [28] . For persons who present with more advanced stages of breast cancer for which surgery may not be curative, a decision to undergo a recommended surgery may not seem favorable especially when it weighed against the economic burden following the procedure.
Increasing age was also significantly associated with an increased odds of refusing recommended surgery being performed, which was disproportionate for women aged 80 years and older compared to those aged 40-49 years.
Advanced age is associated with an increased risk for comorbidities and decreased survival after cancer treatment [29,30] . As such, these patients may not have had the recommended surgery performed because they may be sicker or have a decreased life expectancy from other comorbidities or from advanced age. Additionally, breast cancer screening after the age of 74 years is controversial and not recommended especially for average-risk older women with less than 10 years life expectancy [30][31][32]. Hence, women with breast cancer after 70 years could present with an advanced stage of breast cancer or may refuse surgery as this treatment may not impact life expectancy. We were unable to assess the relationship between advanced age, comorbidities, and likelihood of undergoing recommended surgery because the publicly available SEER data does not include clinical information on comorbid conditions. This study also explored the extent to which disparities in receipt of breast cancer surgery were due to molecular subtype characteristics in an ethnically diverse cohort of older women in the United States. Our study revealed that women with breast cancer subtypes luminal B and HER2 enriched and triple negative as compared to luminal A subtype were more likely to refuse recommended breast cancer surgery. This was particularly true for HER2 enriched tumors and triple negative tumors, which have been more closely associated with aggressive tumor features such as increased tumor size, positive lymph nodes and lymphovascular invasion [33] . Although different negative prognostic factors exist for different breast cancer subtypes, studies have found that cases with HER2 and triple negative tumors, predominantly diagnosed among racial minorities such as African American and American Indian/ Native Alaska women, have the worst 5-year survival and overall survival among the other subtypes [33,34]. As such, cases with more aggressive subtypes such as HER2 enriched may likely present at more advanced stages of breast cancer at diagnosis for which surgery may not be curative and this may impact the decision to pursue recommended surgery for breast cancer.
Similar to other studies, women who received a recommended surgery for breast cancer treatment had a better survival probability as compared to those who refused recommended treatment [4,8]. Significant predictors of death following a breast cancer diagnosis included age 80 years or more, HER2 enriched and triple negative tumors and tumor features suggestive of advanced disease such as tumor grade III and lymph node involvement. As previously discussed, HER2 enriched and triple negative tumors, which were mostly present among African American women, were associated with aggressive disease [33][34][35][36]. This suggests that breast tumor subtypes' impact on breast cancer disease progression may be a significant contributor of whether recommended surgery is refused or performed and could ultimately affect survival benefit from breast cancer surgery particularly among NH Black women.
The study strengths include the use of the SEER database, a large nationally representative cancer registry which allows for generalizability of results to the general population in the US. Additionally, to our knowledge, this is one of the few studies to examine the refusal of surgery for breast cancer specifically by examining and adjusting for tumor stage, grade, and molecular subtype.
One of the limitations of this study is that the information on chemotherapy and radiation therapy were incomplete, thus their interpretations should be done with caution. Additionally, the SEER database lacks the detailed clinical and circumstantial information for each patient. There is therefore the potential for residual confounding as we were limited in our ability to control for other potential confounders such as comorbidities. Furthermore, the lack of detailed clinical information limits our ability to fully understand the reasons why a recommended surgery for breast cancer treatment was not performed. There is also the potential for selection bias since individuals who were excluded from the analysis could be significantly different in examined characteristics from those included in the analysis.

CONCLUSION
In conclusion, this study highlights the racial and ethnic disparity in the receipt of a recommended surgery for breast cancer treatment in the United States. Although NH Black women are disproportionately affected by breast cancer, they are more likely to refuse a recommended surgery for breast cancer treatment even when it is the main modality of treatment. Refusal of surgery for breast cancer treatment can negatively impact survival in this vulnerable group.
Physicians should be cognizant of the predictors of surgery refusal. Also, targeted and culturally relevant interventions should be implemented for this at-risk population.

Statements and Declarations
Funding: This study was supported in part by the NIH grants (numbers R01AG058971 and

R01AG067498)
Competing Interests: The authors have no relevant financial or non-financial interests to disclose Author Contributions: All authors contributed to the study conceptualization and design. Data curation and analysis were performed by Pierre Fwelo and Gabriel Huynh. All authors contributed to the redaction of the manuscript. All authors read and approved the final manuscript.

Ethics Approval:
The study subjects were de-identified and there was no patient contact; thus, the study is exempt from an Institutional Review Board's review.

Data Availability:
The datasets generated during and/or analyzed during the current study are not publicly available due to SEER's Data use agreement and terms. The data access requests should be directly made to SEER https://service.cancer.gov/seer-data-access Tables & Figures   Table 1