Breast Cancer in the United States: A Cross-Sectional Overview

Introduction Breast cancer remains the most commonly diagnosed malignancy in women. It encompasses considerable heterogeneity in pathology, patient clinical characteristics, and outcome. This study describes factors associated with overall survival (OS) of breast cancer in an updated national database. Methods We conducted a retrospective analysis of patients with breast cancer diagnosed between 2004 and 2016 based on the National Cancer Database. Categorical variables were summarized using frequencies/percentages, whereas continuous variables were summarized using the median/interquartile range (IQR). OS was explored using the Kaplan-Meier method. Results Data from n = 2,671,549 patients were analyzed. The median age at diagnosis was 61 years (range 18-90). 75% were non-Hispanic (NH) White; 11% were NH-Black; 4.7% were Hispanic-White; 0.1% were Hispanic-Black; and 3.4% were Asian. Most cases (73%) presented with ductal carcinoma histology; while 15% with lobular carcinoma. Rarer subtypes included epithelial-myoepithelial, fibroepithelial, metaplastic, and mesenchymal tumors. OS was associated with molecular subtype, histologic subtype, and AJCC clinical staging. Survival also correlated with race: a cohort including Asians and Pacific Islanders had the best survival, while Black patients had the worst. Finally, facility type also impacted outcome: patients at academic centers had the best survival, while those at community cancer programs had the worst. Conclusion This large database provides a recent and comprehensive overview of breast cancer over 12 years. Molecular subtype, histologic subtype, stage, race, and facility type were correlated with OS. In addition to the educational perspective of this overview, significant factors impacting the outcome identified here should be considered in future cancer research on disparities.


Introduction
Breast cancer (BC) is the most common cancer in women worldwide and is second to lung cancer as the biggest cancer-related killer in developed countries [1]. While the incidence of female BC continues to rise annually, most commonly driven by hormone receptor-positive, nonmetastatic disease, the mortality rate has dropped around 40% from 1989 to 2017 [1].
The American Cancer Society estimates that in early 2019, there were around 4 million women with a history of BC living in the United States [1]. In this large population of individuals with BC, there is considerable heterogeneity in demographic, clinical, and pathological disease character-istics. This study aims at providing an overview of BC characteristics and prognostic factors in over 2.6 million patients with breast cancers diagnosed between 2004 and 2016 from the National Cancer Database (NCDB).

Patient Data.
We conducted a retrospective analysis of breast cancer data extrapolated from the National Cancer Database (NCDB) registry. The NCDB is a United Statesbased, nationwide repository for cancer cases, contributed to by over 1400 Commission on Cancer-(CoC-) and American College of Surgeon-(ACS-) sanctioned facilities. It is estimated to include 70% of all cancer cases in the United States [2]. Hospitals participating in the NCDB contributed the de-identified data used in this study, which was accessed based on a grant award. All contributing institutions collect patient data prospectively and are required to observe the quality practices for accurate documentation of prognostic data, treatment, and patient outcomes [3]. The data were accessed on a Participant User File (PUF) based award, and this study was approved by the Cleveland Clinic Institutional Review Board. Records from patients with American Joint Committee on Cancer (AJCC) clinical stages I-IV breast cancer, diagnosed between 2004 and 2016, were identified within the NCDB data set.

Statistical Analysis.
Categorical variables were summarized using frequencies and percentages, whereas continuous variables were summarized using the median and interquartile range (IQR). Overall survival time was calculated from the date of diagnosis to the date of death, and patients still alive were censored at their date of last contact. The Kaplan-Meier method estimated the overall survival probability. The log-rank test was used to compare groups in analyses stratified according to disease stage. Survival was also evaluated by receptor subtype, histologic subtype, race, and facility type. All statistical analyses were conducted using R software version 3.6.1 (R Core Development Team, Vienna, Austria).

Discussion
This large dataset from the NCDB provides a comprehensive, recent overview of clinicopathologic and sociodemographic factors in patients with BC, spanning over more than a decade. The most prevalent molecular subtype of BC continues to be HR+/HER2-negative, followed, interestingly, by HR +/HER2-positive, HR-/HER2-negative, and HR/HER2+ disease ( Table 2). Molecular biomarkers are primarily determined using immunohistochemical staining methods and serve as the cornerstone of clinical decision-making in BC [5]. With the vast majority of BC cases having HR+ disease, and ER+ or PR+ disease continuing to be the most common type of BC diagnosed [1], it is likely that hormonal-based therapy will remain the mainstay of BC treatment moving forward, including the treatment of HR+/HER-2 positive subtypes in early and advanced stages of BC [6,7].
However, researchers have also been interested in the extent to which BC histological subtype carries with it prognostic and predictive significance. This large, crosssectional study outlines a range of atypical histological subtypes (contributing 27% of all BC cases), in addition to invasive lobular carcinomas, other rare tumors, including papillary, epithelial-myoepithelial, metaplastic, and mesenchymal morphologies ( Table 2). The rarity of these subtypes has been a limiting factor to research investigating the significance of morphology on outcomes. We found that histological subtype may be associated with disparities in overall survival. This may be due to the relationship between tumor histology and differences in metastatic potential. As an example, patients with metastatic lobular carcinoma are more likely to have disease involvement of the bone, but are less likely to have multiple secondary disease sites at diagnosis, compared to those with ductal carcinoma [8]. Also, emerging evidence has suggested that histology should be included as one of the considerations when determining the most appropriate treatment course [5,[8][9][10][11][12]. Thus far, the National Comprehensive Cancer Network has designated the novel categories of "favorable" or "unfavorable" to histological subtypes and recommends triaging optimal management based on this classification [13]. The use of this large registry has helped confirm the prevalence of these tumor types and emphasizes the importance of furthering our knowledge of these less common histological types.
AJCC clinical staging correlated with survival as expected, with the best 5-year OS and 10-year OS noted in patients diagnosed with stage 0 (95% and 83%, respectively). Most patients were diagnosed at early stages (Table 2), which is very encouraging. What is noteworthy is the 5-year OS of 23% for patients with stage IV BC, which was once reported to be as low as 10% for patients diagnosed between 1985 and 1990 [14]. 10-year OS is more scarcely reported [15], but were often not reached in cohort studies before 2000 [16]. This improvement is welcomed news and contributed to by decades of advances in treatment and successful targeted approaches in the field of metastatic breast cancer. The data also suggest that patients with HR+ tumors have the best prognosis, with similar 5year OS noted for HR+/HER2-and HR+/HER2+ compared to HR/HER2+, followed by HR-/HER2-, which had the worst outcome.    Journal of Cancer Epidemiology This study reiterates the significant impact of race on both immediate and long-term survival, with Black patients exhibiting the worst survival (Table 3, Figure 1). This finding is consistent with descriptive reports that Black patients are more likely to be uninsured or underinsured [17], have more comorbidities [18], be diagnosed at later stages [1], and experience more treatment delays [18] compared to their White counterparts. Additionally, Black patients are more likely to have triple-negative breast cancer (TNBC) [17,19], an aggressive subtype of the disease. Interestingly, a cohort including Asians and Pacific Islanders was noted to have the best survival (Table 3, Figure 1). This superior outcome is consistent with data published by the American Cancer Society showing these patients were more likely to be diagnosed at earlier stages of disease [1]. More research is needed to understand the experience of BC in understudied minority groups-including Asians, Pacific Islanders, and Native Americans-and better understand possible lifestyle or biological characteristics correlated with survival. Additionally, more efforts continue to be needed to end racial disparities affecting Black patients with BC, which has continued to exist over several decades.
Finally, this study has also suggested there is a significant relationship between facility type used for treatment and cancer survivorship. OS was best when patients were treated at designated academic centers, followed by integrated network comprehensive community cancer programs, and community cancer programs. This relationship appears to be independent of disease stage, such that academically-designated centers have superior OS across all stages. The disparity was more apparent when considering long-term survival (10-year OS), which is rarely reported in the literature. Previous studies have reported that facility type was significantly associated with time-to-treatment [20,21] as well as choice of treatment [22] in patients with BC, which may, at least in part, explain our observed differences in survival. More research is needed to better understand potential differences in the patient population, or quality and consistency of care provided based on facility type. Survival analyses in this manuscript are based on univariable testing, so there is a potential for confounding that has not been accounted for that should be explored in future research. Additionally, overall survival metrics reflect mortality due to comorbidities not of primary interest in this manuscript, such as cardiac and lung disease. However, the NCDB does not report cancer-related mortality.
In conclusion, this large research document using the NCDB provides a recent and comprehensive overview of BC over the last 12 years. A favorable prognosis was noted for HR+ tumors regardless of HER2 status. HR-/HER2+ tumors had an inferior prognosis compared to HR+ tumors, but the worst outcome was noted for HR-/HER2+ disease. The latter 2 subtypes can, therefore, be considered high-risk for treatment and surveillance purposes. A notable increase in survival was identified in patients with metastatic breast cancer over the past decade, calling for continuing research efforts in this field. Significant clinicopathological and sociodemographic factors impacting outcomes were identified in this study and could be considered for future research focusing on cancer disparities.

Data Availability
The data that support the findings of this study are available from the American College of Surgeons/American Cancer Society but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the American College of Surgeons/American Cancer Society.

Additional Points
Highlights. There is considerable pathological and clinical heterogeneity in breast cancer. By race: a cohort of Asians and Pacific Islanders had the best survival, while Blacks had the worst. Patients treated at academic centers had the best survival, while those at community cancer programs had the worst. Data on 10-year overall survival in metastatic disease is improved from previously-reported.

Ethical Approval
Ethical approval was obtained from the Cleveland Clinic Institutional Review Board (IRB) prior to conducting this study. All patient data was strictly de-identified and provided, with approval, from the American College of Surgeons as part of the National Cancer Database.