Evaluation of overall survival and barriers to surgery for patients with breast cancer treated without surgery: a National Cancer Database analysis

Surgery remains the foundation of curative therapy for non-metastatic breast cancer, but many patients do not undergo surgery. Evidence is limited regarding this population. We sought to assess factors associated with lack of surgery and overall survival (OS) in patients not receiving breast cancer surgery. Retrospective cohort study of patients in the US National Cancer Database treated in 2004–2016. The dataset comprised 2,696,734 patients; excluding patients with unknown surgical status or stage IV, cT0, cTx, or pIS, metastatic or recurrent disease resulted in 1,192,294 patients for analysis. Chi-square and Wilcoxon rank-sum tests were used to assess differences between groups. OS was analyzed using the Kaplan–Meier method with a Cox proportional hazards model performed to assess associated factors. In total 50,626 (4.3%) did not undergo surgery. Black race, age >50 years, lower income, uninsured or public insurance, and lower education were more prevalent in the non-surgical cohort; this group was also more likely to have more comorbidities, higher disease stage, and more aggressive disease biology. Only 3,689 non-surgical patients (7.3%) received radiation therapy (RT). Median OS time for the non-surgical patients was 58 months (3-year and 5-year OS rates 63% and 49%). Median OS times were longer for patients who received chemotherapy (80 vs 50 (no-chemo) months) and RT (85 vs 56 (no-RT) months). On multivariate analysis, age, race, income, insurance status, comorbidity score, disease stage, tumor subtype, treatment facility type and location, and receipt of RT were associated with OS. On subgroup analysis, receipt of chemotherapy improved OS for patients with triple negative (HR 0.66, 95% CI 0.59–0.75, P < 0.001) and HER2+ (HR 0.74, 95% CI 0.65–0.84, P < 0.001) subgroups while RT improved OS for ER+ (HR 0.72, 95% CI 0.64–0.82, P < 0.001) and favorable-disease (ER+, early-stage, age >60) (HR 0.61, 95% CI 0.45–0.83, P = 0.002) subgroups. Approximately 4% of women with breast cancer do not undergo surgery, particularly those with more aggressive disease and lower socioeconomic status. Despite its benefits, RT was underutilized. This study provides a benchmark of survival outcomes for patients who do not undergo surgery and highlights a potential role for use of RT.


INTRODUCTION
Current therapy for breast cancer (BC) most often involves a multimodality approach, with neoadjuvant systemic therapy, surgical resection, and adjuvant radiation therapy (RT) or chemotherapy/hormonal therapy considered on the basis of tumorand patient-related risk factors 1 . Surgery remains the foundation of curative therapy for patients with local-regional disease; 5-year overall survival (OS) rates after surgery for localized disease are 99% and, for regional disease, 85% 2 .
No recommendations or standard of care have been established for patients with BC who do not undergo surgery 1 . Several studies have evaluated the role of definitive RT with or without systemic therapy for patients who do not undergo surgery; local-regional control rates after this therapy have ranged from 50% to 96% [3][4][5][6][7][8][9][10][11] . This approach has been used mostly for elderly women, the group that's most likely to be offered a non-surgical approach for BC 12,13 . The use of stereotactic body radiation therapy (SBRT), which allows delivery of highly conformal and ablative radiation doses, has also been explored as definitive treatment or as an additional boost to conventional RT, with promising early results 6 . Nevertheless, surgery still remains the pillar of successful BC treatment. To date, factors linked with lack of surgery include advanced disease, older age, comorbidities, access to care, and patient preference [12][13][14][15][16][17] .
The limited evidence regarding factors associated with not receiving surgery and oncologic outcomes after such therapy, and the lack of prospective trials, consensus guidelines, or recommended treatment strategies for such patients led us to investigate these gaps on a population level by analyzing the US National Cancer Data Base (NCDB).

Patient characteristics and patterns of care
To examine variables associated with not undergoing surgery, we analyzed 1,192,294 patients with BC, of whom 50,626 (4.3%) did not undergo surgery (Fig. 1). Evaluating the trend of no-surgery overtime there is a significant correlation as patients who did not undergo surgery decreased from 4.7% in 2004 to 3.5% in 2009, and then increased from 3.5% in 2009 to 5.3% in 2016 (P < 0.001). Reasons for not receiving surgery included not being planned as part of initial treatment (55.6%), refusal by the patient and/or family member (13.6%), recommended but unknown if performed (10.9%), unknown if surgery was recommended or performed (7.7%), contraindicated due to patient risk factors (7.7%), recommended but not performed without an identifiable reason (2.9%), and surgery was recommended but patient was deceased prior to having surgery (1.5%).
Finally, of the entire cohort 19,107 (1.6%) patients received no therapy at all compared to 1,111,800 (93.2%) patients who received some form of treatment (surgery, chemotherapy, radiation therapy, or hormone therapy). Surprisingly, Charlson/ Deyo comorbidity score was inversely associated with receipt of any treatment (P < 0.001) as patients without any comorbidities were more likely to not receive any therapy (44.4%) than those with one or more comorbidities ( Table 2).
Finally, we performed an exploratory analysis comparing survival outcomes for non-surgical patients who received hormone therapy compared to those who received any other treatment (chemotherapy and or radiation therapy) or no treatment at all. Surprisingly the cohort receiving endocrine therapy alone had inferior OS than those who received any other treatments (chemotherapy and/or radiation therapy) or those who didn't receive any treatment (p-Value < 0.001) with median OS of 38.1, 75.9, and 75.0 months respectively.

DISCUSSION
This study represents the largest analysis of women who did not undergo surgical resection as part of therapy for breast cancer, and is the first to look at outcomes for these patients according to subtype. Overall, 4.3% women in the United States did not receive surgery for non-metastatic breast cancer. When comparing patients who did vs did not have surgery, our findings suggest that several oncologic and socioeconomic factors influence the likelihood of having surgery; having lower socioeconomic status and more advanced or complicated disease translated into being less likely to receive surgery. Further, the survival outcomes among patients treated without surgery highlight the potential value of RT when surgery cannot be used. Indeed, RT among such patients seems to be grossly underused, with only 7.3% of patients receiving it, despite being associated with improved OS.
Socioeconomic factors have been previously reported to be major barriers to accessing care for BC. The influence of financial toxicity on patients' decisions regarding breast surgery has been evaluated. Women who make ≤$45,000/year have been shown to prioritize the cost of treatment over breast preservation or appearance 18 . Moreover, about one-quarter to one-third of women with BC experience significant financial hardship from treatment costs 18,19 . While evidence suggests that surgical costs are on the order of approximately 5-10% less than that of RT for breast cancer, adjuvant RT has been shown to be highly costeffective thus suggesting a possible value-driven approach for patients who cannot receive or decline surgery 20,21 . Insurance status has been shown to be associated with advanced disease stage at diagnosis and poorer OS among patients with BC 22,23 , with one report of increased risks of mortality of 49% for uninsured patients and 40% for patients with Medicaid 23 . Notably, insurance status and out-of-pocket costs have also been shown to correlate with not receiving surgery for lung cancer 24 . Cost clearly affects a patient's decision to proceed with treatment, and based on this evidence the costs associated with surgery may be a deterrent for low-middle class women. Minority women may be particularly vulnerable because of superimposed access-to-care issues. This sentiment is reiterated by Jagsi and colleagues in a report showing minority women with BC to be at disproportionately high risk of financial toxicity 19 . Further, evidence has shown that Black women are more prone to experiencing treatment delays, not following treatment recommendations, or declining treatment, all of which significantly affect mortality 22,23 . Education level can also affect a patient's ability to comply with treatment and participate in early screening. Women with less education have been shown to present with more advanced disease, which in turn may affect candidacy for surgery. A large population study from China reported that women who attended university (vs women with no formal education) were much less likely to present with locally advanced disease (17.7% vs 31.5%) 25 . This finding probably stems from participation in screening programs, as a large meta-analysis revealed that women of the highest education level were much more likely to undergo annual mammography, and women of low educational status were significantly less likely to follow screening recommendations 26 . Additionally, it is important to highlight the role of the healthcare provider and the presence of implicit bias and systemic racism that may negatively impact access and or treatment recommendations for minority patients 27 . Overall there is an abundance of evidence in both oncologic and surgical series that show significant healthcare disparities affecting black and minority patients while controlling for other socioeconomic factors [28][29][30][31][32][33] . In summary, these findings highlight the importance of identifying patients with limited financial resources, those with lower education status, and those who are of racial minorities early in the care cycle to provide additional social support to minimize potential financial toxicity and to provide early education to help facilitate informed decision-making about BC detection and treatment. This also highlights the importance of acknowledging the reality of implicit bias in healthcare providers and working towards educated a more diverse and culturally competent generation of physicians. Beyond socioeconomic status, several clinical factors also were found to be associated with not receiving surgery. Both advanced age and the presence of comorbidities can influence adherence to standard treatment protocols among patients with non-metastatic BC, including the choice of definitive and adjuvant therapy 12,34 . In contrast, the presence of higher disease stage and more aggressive disease biology in patients who do not have surgery probably corresponds with subsequent delays in care related to the aforementioned socioeconomic barriers that may precipitate progression of disease, thereby precluding surgery 35 . This concept is unfortunately enhanced for Black women, who are 4-5 times more likely to incur delays in excess of 60 days in BC management, resulting in significantly less surgical-directed therapy (7.5% vs 1.5%) relative to White women 36 . Discontinuation of therapy can also influence surgical status, particularly for minority women receiving neoadjuvant therapy before surgery. A secondary analysis of the SWOG S8814/S8897 trials found that Black women, despite having more aggressive disease features, were more likely to have early discontinuation of cancer-directed therapy (11% vs 7%), resulting in inferior oncologic outcomes 37 . Again, these findings emphasize the importance of providers being aware and identifying patients with such vulnerabilities to minimize possible delays in care and maximize adherence to optimal cancer-directed therapy.
While the survival outcomes reported in this series are inferior to historical survival rates for patients with BC, it is important to acknowledge that these patients had more advanced disease, with more aggressive features, greater comorbidities, and lower socioeconomic status. Interestingly, prior studies evaluating the use of definitive RT alone or in combination with systemic therapy have shown highly variable outcomes, with 3-to 5-year OS rates ranging from 38% to 95% [3][4][5][6][8][9][10][11] . A Belgian study was one of the first to evaluate definitive RT for operable BC and reported 5-year and 10-year OS rates of 67% and 29% 10 . Interestingly, that study found that radiation dose was the strongest predictor of local disease control, with higher doses required to reach local control outcomes comparable to those after surgical resection 10 . The benefit of combined chemoradiation for the definitive management of BC was reported in a series of 250 patients managed with neoadjuvant chemotherapy with 5-year OS rates of 95% for those with stage I disease, 94% for stage IIA, 80% for stage IIB, 60% for stage IIIA, and 58% for stage IIIB disease 11 . These findings highlight the importance of using multimodality therapy when surgery is not used. Interestingly, our subgroup analysis showed that patients with more aggressive disease biology (TNBC and HER2 + ) derived a benefit from chemotherapy whereas those with ER + or favorable disease derived an exclusive benefit from RT.
These findings are intuitive given the higher rates of metastatic disease for HER2 + and TNBC subtypes, which make chemotherapy the ideal treatment approach 38 . The poorer outcomes observed on univariate analysis of hormonal therapy in our analysis seem to be related to patient heterogeneity, as the use of hormones was not an independent predictor of worse outcome on multivariable analysis. While patients receiving hormone therapy alone were noted to have inferior OS compared to those receiving any other treatment or no treatment at all we suspect this finding is most likely due to the influence of confounding factors and/or selection bias Similar findings were observed in a series evaluating definitive hormone therapy for women aged >75 years, which reported that 35% of patients developed progressive disease suggesting that hormone therapy may not be the optimal therapeutic option for patients who do not undergo surgery 39 . Another possible explanation of the inferior OS in such patients is that considering hormone therapy may offer little benefit in non- surgical patients with the gross disease, the use of hormone therapy may only be introducing potential cardiovascular toxicity which may be driving worse OS in this cohort. A recent systemic review addressed this topic and reported elevated cardiovascular disease including venous thromboembolism, myocardial infarction, stroke and other disorders in non-metastatic breast cancer patients treated with tamoxifen 40 . Despite the reported benefit of RT for all patients, and specifically for those with luminal A/B (ER + ) receptor-based surrogate subtypes and favorable disease, RT was significantly underused in this cohort. This seems to be a missed opportunity considering the available evidence supporting the use of definitive RT in such cases. To date most studies of definitive RT have involved elderly female patients. Interestingly, two such series with similar patient cohorts but different RT regimens reported drastically different OS rates. A study by Maher et al included 70 elderly female patients treated with definitive hypofractionated RT with tamoxifen and reported an excellent 3-year OS rate of 87% 5 . In contrast, Courdi et al evaluated the use of definitive SBRT with hormone therapy and found a 5-year OS rate of only 38% 4 . This difference may reflect the lower rate of treatment compliance and lack of regional nodal irradiation in the SBRT study. A more recent study comparing local control rates between breast-conserving therapy and definitive SBRT for elderly women with favorable disease features reported equivalent 7-year rates of cause-specific survival of 96.4% 3 . Thus although surgical resection is still preferred for BC treatment, some patients with favorable disease features, especially those who are >60 years old with ER + , cT1-2N0 disease, may be candidates for definitive RT with acceptable long-term survival outcomes.
Several inherent limitations of this NCDB study must be acknowledged. Aside from OS, the NCDB lacks other clinically relevant endpoints such as local-regional recurrence, diseasespecific survival, patient-reported outcomes, and toxicity. Additional limitations include coding accuracy and the presence of confounding factors which may impact the reliability and generalizability of this analysis. Finally, even though the NCDB contains data on roughly 70% of cancer patients treated in the United States, the data are at the hospital level rather than the population level, and thus the findings are not necessarily generalizable to the entire US population 41 . Despite these limitations, this study represents the largest series reported to date of patients who did not receive surgery for BC and provides important insights into key socioeconomic factors that may affect access to surgery.
In conclusion, more than 4% of women with non-metastatic breast cancer in the United States do not receive surgery. Overall this study highlights the importance of several socioeconomic factors, including being Black, having low income, being uninsured or having public insurance, and having a low education level, that may act as barriers to optimal oncologic management with surgery. This information should function to bring such vulnerable patients to the attention of providers so that they can offer early intervention and additional social support to improve adherence to recommended treatments and enhance patients' abilities to make informed decisions. This study further establishes a benchmark for survival expectations for patients who cannot or choose not to undergo surgery for breast cancer. We also suggest tailored treatment options for such patients that emphasize the use of chemotherapy for those with TNBC or HER2 + disease while favoring definitive RT for those with ER + cancers. Overall our findings call for prospective evaluation of definitive RT for elderly patients with early-stage ER + breast cancer who are not candidates for surgery.

Patient selection
This retrospective cohort study used data from the NCDB, a national hospital-based cancer registry co-sponsored by the American College of Surgeons and the American Cancer Society that includes clinical and socioeconomic data for roughly 70% of patients with newly diagnosed cancer 41,42 . We queried the NCDB for female patients aged 18 years or more with invasive primary BC diagnosed from 2004 to 2016 (and subsequently for those diagnosed in or after 2010, to account for HER2 status). Exclusion criteria were having stage IV, unknown, cT0, cTx or pTis -stage, unknown surgical status, recurrent disease or metastatic disease, and being male (Fig. 1).

Statistical analysis
Descriptive statistics were used to summarize patient characteristics. Chisquare or Fisher exact tests were used to test for differences between categorical variables, and Wilcoxon rank-sum or Kruskal-Wallis tests were used to detect differences in continuous variables between groups 43 . OS was measured from the time of diagnosis to the time of death or last follow-up among patients treated without surgery from 2010 through 2015 (n = 29,340) to capture receptor-based subtype surrogates. OS time for patients alive at the time of last contact was censored at the time. The OS distribution was estimated by the Kaplan-Meier method 44 , with log-rank tests used to test for differences in survival between groups 45 . Regression analyses of survival data based on the Cox proportional hazards model were conducted for OS outcome 46 . All tests were two-sided, and P values of <0.05 were considered statistically significant. All analyses were conducted using SAS (version 9.4, Cary, NC) and S-plus (version 8.04, TIBCO Software Inc., Palo Alto, CA) statistical software.

Ethics
The University of Texas MD Anderson Cancer Center institutional review board deemed our analysis of this public database to be exempt from review because its constituent data have been anonymized and are compliant with the Health Insurance Portability and Accountability Act and thus was approved for completion.

Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.

DATA AVAILABILITY
The data generated and analyzed during this study are described in the following data record: https://doi.org/10.6084/m9.figshare.14618769 47 . The data underlying the study are clinical and socioeconomic data from the National Cancer Database (https://www.facs.org/quality-programs/cancer/ncdb). Interested parties can query the NCDB for female patients aged 18 years or more with invasive primary breast cancer diagnosed from 2004 to 2016. However, the data were used under license from the NCDB, and so applications to access the data must be made to the NCDB. The analyses of the data are contained in the SAS file 'ncdbjune2019.sas7bdat'. These data are also not openly available as the Data Use Agreement between the authors and the NCDB states that NCDB approval must be sought before the authors can share the data. To request access to these data, contact the corresponding author.