Background
In the United States, racial disparities in breast cancer outcomes are well-documented, with non-Hispanic Black (NHB) women more likely to die of their disease than their non-Hispanic White (NHW) counterparts.1–3 The disparity is in part attributed to stage and subtype—NHB women are more likely to be diagnosed with a metastatic cancer and/or a triple-negative subtype, both of which have a poor prognosis due to limited treatment options.4,5 However, our group recently reported that the most pronounced racial disparities in breast cancer mortality were observed among women with nonmetastatic, estrogen receptor–positive (ER+) tumors.6,7 Such tumors are known to have a favorable prognosis, given multiple highly effective biomarker-driven treatment regimens.8 One explanation for such paradoxical findings is that disparities in survival outcomes among women with early-stage or ER+ disease may result from factors downstream of their cancer diagnosis, such as the failure to receive guideline-concordant care (GCC).9
Clinical guidelines for women diagnosed with stage I–III breast cancer have been developed based on results from multiple clinical trials, and failure to receive GCC has adverse effects on breast cancer outcomes.10–13 Nonadherence to guidelines could arise from multiple factors, including structural racism, barriers to access, tumor and patient characteristics, or clinician and patient preferences.11 Therefore, nonadherence to clinical guidelines may be a contributing factor to the observed race disparity in breast cancer mortality.9,14 Observational studies assessing adherence to clinical guidelines are important in understanding patient outcomes; however, few studies have examined the receipt of GCC as a possible driver of disparate outcomes in a population-based setting.
To address this knowledge gap, we evaluated how failure to receive GCC contributes to breast cancer mortality overall and to disparities in breast cancer mortality among NHB and NHW women diagnosed with a first primary stage I–III breast cancer in metropolitan Atlanta, Georgia.
Patients and Methods
Study Population
Using the Georgia Cancer Registry (GCR), we identified women diagnosed with breast cancer between 2010 and 2014 while residing in metropolitan Atlanta (ie, Fulton, DeKalb, Gwinnett, Cobb, or Clayton counties). Patients with breast cancer were included if they were diagnosed with an invasive stage I–III first primary breast tumor and were classified as being NHW or NHB. Race was based on US Census Bureau definitions, and Hispanic ethnicity was determined by the North American Association of Central Cancer Registries Hispanic Identification Algorithm.15,16 Additional criteria required that women had information available for assigning tumor subtype (ER, the progesterone receptor used to define women as hormone receptor–positive [HR+] or hormone receptor–negative [HR–], and HER2 expression) and had received surgery as part of their local therapy. Hormone receptor and HER2 status were used to assign women as HR+/HER2−, HR+/HER2+, HR−/HER2+, or HR−/HER2−. Detailed information on the differences between women who received surgery (94.6%) and those who did not (5.4%) are reported in supplemental eTables 1–3 (available with this article at JNCCN.org). Follow-up information was available on patients through December 31, 2016. The outcome of interest was breast cancer mortality (ICD-10-CM code C50), which was determined from death certificate data.
Exposure Assessment
Guideline Care
Receipt of guideline care was determined based on the 2011 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer (Table 1).17 The NCCN Guidelines were used to inform the indication for each type of breast cancer therapy for every patient in our dataset. Information regarding the type of surgery received (mastectomy vs breast-conserving surgery), tumor receptor status (ER, progesterone receptor, and HER2 expression), tumor size, lymph node involvement, and 21-gene recurrence score data (obtained via direct linkage with Genomic Health Inc.) were ascertained from the GCR (supplemental eTables 4–7).
We first grouped women based on their breast cancer subtype as HR+/HER2−, HR+/HER2+, HR−/HER2+, or HR−/HER2−, as described in the previous section. These derived tumor subtypes informed the type of biomarker-driven therapies (endocrine therapy and anti-HER2 therapy) that a patient should receive. We then examined the possible combinations of surgery type, tumor size, lymph node status, and 21-gene recurrence score to determine treatment indications. Based on these patient-level data in the GCR, each woman was classified as indicated, discretionary, not indicated, or indeterminate (missing) for each type of therapy. The latter occurred among 6.6% of NHB women and 5.2% of NHW women.
Once the indication for each therapy was determined, we assessed whether the patient received therapy consistent with the NCCN Guidelines17 using GCR treatment data. The GCR regularly collects information on surgery type and initiation of chemotherapy, radiation, and endocrine therapies. Anti-HER2 therapies were captured as chemotherapy in the GCR analytic database until 2013 and were coded as immunotherapy in subsequent years. Using natural language processing (NLP), we searched the treatment-related text fields of the GCR database for specific character strings related to an indication of trastuzumab receipt before 2013.18 In addition, there were 271 women (3.6%) who did not have information available on the initiation of endocrine therapy. For these women, we used NLP to identify the receipt of endocrine therapy in treatment-related text fields.
Patients who were indicated for a treatment regimen and did not receive it, or those who received therapy without an indication, were classified as having received non-GCC for that treatment modality. Conversely, if a patient’s indication was consistent with the receipt or nonreceipt of a specific therapy, then the patient was classified as guideline-concordant. Among women for whom a therapy was discretionary (based on the NCCN Guidelines17), any value (eg, receipt, nonreceipt, and missing/unknown value) resulted in a classification of guideline-concordant for that therapy.
Our primary exposure of interest was receipt of GCC across all treatment modalities and for each individual treatment modality. In a sensitivity analysis, we allowed for each patient to have any one therapy not meeting guideline care.
Covariates
We collected information on age at diagnosis (continuous), stage of disease (I–III), derived breast cancer subtype (HR+/HER2−, HR+/HER2+, HR−/HER2+, or HR−/HER2−), a US Census–derived area-based measure of socioeconomic status (SES; 0% to <5%, 5% to <10%, 10% to <20%, and 20%–100% below poverty level), marital status (single, married, divorced/separated/other), and insurance type (private, Medicare, Medicaid, military/other, and uninsured). SES status is based on census tract–level poverty data that are published annually from the American Community Survey19 and have been used widely in population-based studies.20,21
Statistical Methods
Descriptive statistics were calculated as median values with interquartile ranges or as n (%) for covariates of interest across the NHB and NHW population subgroups. We also report the frequency (%) of women who failed to receive GCC by treatment modality.
Follow-up was defined as time in months, from the date of surgery until whichever was first: (1) a mortality event, (2) the last date of contact in registry, or (3) December 31, 2016. We used multivariable-adjusted Cox proportional hazard models to calculate the hazard ratios (HRs) and 95% confidence intervals for the association between the receipt of GCC for joint concordance of all treatment modalities and each treatment modality independently with breast cancer mortality.
To address our second aim, we estimated the association between race and breast cancer mortality and whether this association was modified by the receipt of GCC (yes/no). Interaction describes the differences in the effect of one exposure across the strata of another exposure, which depends on the scale.22,23 In this analysis, we assessed additive and multiplicative interaction for the effect of race on breast cancer mortality by receipt of GCC.24 The presence of interaction between race and GCC was estimated with the common referent approach to calculate the relative excess risk due to interaction (RERI), evaluating the departure of the effect on the additive scale.24,25 We calculated the 95% confidence interval for the RERI using the delta method.23,26,27 The presence of multiplicative interactions, indicating whether the combined effect of race and GCC was greater than the product of the individual effects, was assessed by comparing stratum-specific effect estimates.25
We verified the proportional hazards assumption for all variables by checking the ln-ln survival curves for any gross violation.28 Potential confounders included in the models were based on a priori knowledge and graphical-based methods (using a directed acyclic graph).29 For the association between receipt of GCC and breast cancer mortality, confounders included race, disease stage, age at diagnosis, SES, derived breast cancer subtype, and insurance type (supplemental eFigure 1). For the interaction model including race and GCC, age at diagnosis was the only confounder identified, based on our graphical assessment (supplemental eFigure 2). The other covariates (eg, disease stage, SES, derived breast cancer subtype, and insurance type) are on the causal path between race and breast cancer mortality, and including them in the model could have potentially induced bias.30 However, to be consistent with prior studies of race disparities in breast cancer outcomes, we present additional results from analyses adjusting for disease stage, SES, derived breast cancer subtype, and insurance type.
The association between GCC and breast cancer mortality may be susceptible to immortal person-time bias31,32 because of exposure assignment after the initiation of follow-up, which could lead to a mortality event occurring before the start of an indicated treatment. To evaluate the potential bias, we performed landmark analyses. We extended the initiation of follow-up in 3-month intervals, up until 12 months after the recorded date of surgery for each treatment modality and combination. All analyses were conducted using R version 3.5 (R Foundation for Statistical Computing) and SAS 9.4 (SAS Institute Inc).
Results
We identified 7,046 (2,784 NHB and 4,262 NHW) study-eligible women treated with surgery in the metropolitan Atlanta area. On average, NHB women were younger (median age, 56 vs 60 years), less likely to have private health insurance (57% vs 64%), and less likely to live in a high-SES neighborhood (6.2% vs 32%) compared with NHW women (Table 2). Receipt of overall GCC was comparable between NHB and NHW women (65% vs 63%, respectively; Table 3. Receipt of overall GCC was similar for NHB and NHW women with HR+/HER2−, HR+/HER2+, or HR−/HER2− breast cancer (68% vs 65%; 60% vs 60%; 82% vs 80%, respectively), whereas NHB women diagnosed with HR−/HER2+ breast cancer were less likely to receive GCC compared with NHW women (66% vs 72%, respectively). Across individual treatment modalities, NHB and NHW women were nearly equally likely to receive guideline-concordant radiation (88% vs 91%), chemotherapy (87% vs 86%), endocrine (83% vs 80%), and HER2-targeted (95% vs 96%) therapies (Table 3).
Patient Demographic, Clinicopathologic, and Treatment Characteristics
Receipt of Overall GCC and Individual Treatment Modalities
Main Effects
We observed an increase in the hazard of breast cancer mortality among women who did not receive GCC (HR, 1.74; 95% CI, 1.37–2.20) compared with those who did. We similarly found an increase in the hazard of breast cancer mortality among women who were discordant for chemotherapy (HR, 1.69; 95% CI, 1.24–2.31), radiation therapy (HR, 1.92; 95% CI, 1.36–2.71), endocrine therapy (HR, 1.70; 95% CI, 1.29–2.24), and anti-HER2 therapy (HR, 1.81; 95% CI, 1.21–2.71) (Table 4). Mutual adjustment of the individual treatment modalities yielded similar results (data not shown).
Multivariable-Adjusted Association Between Receipt of GCC and Breast Cancer Mortality
In our sensitivity analysis, defining a patient with GCC as having received at least 3 treatment modalities consistent with guidelines, we observed a slightly more pronounced estimate of association (HR, 2.43; 95% CI, 1.72–3.42). These results suggest that the potential misclassification of GCC is not an explanation for our observed results. In our landmark analyses, we saw similar HR estimates as we increased the time since surgery for receipt of GCC. Our findings are thus robust to any potential immortal person-time bias (supplemental eTable 8).
Racial Disparities
The overall racial disparity in breast cancer mortality in our cohort was 1.98 (95% CI, 1.59–2.46),7 which persisted even within the strata of the receipt of overall GCC (Table 5). Among women who received GCC across all treatment modalities, we observed a 2-fold increase in the NHB–NHW hazard of breast cancer mortality (HR, 2.17; 95% CI, 1.61–2.91). Among those who did not receive GCC, the NHB–NHW HR was similar, although less pronounced (HR, 1.81; 95% CI, 1.28–2.91; Table 5). In the common referent approach to assess departure on the additive scale, NHW women receiving discordant care had no greater risk of mortality compared with NHW women receiving concordant care. Conversely, NHB women had a 2-fold increased mortality rate regardless of whether they received overall concordant or discordant care.
Association Between Receipt of GCC and Breast Cancer Mortality
Although NHB women were consistently more likely to die of their disease compared with NHW women, most pronounced race disparities were among those who received GCC for most independent therapeutic regimens (Table 5). Among women who were discordant for chemotherapy, radiation, or anti-HER2 therapy, the racial disparity in breast cancer mortality was attenuated and near-null. One exception was for endocrine therapy, with NHB women classified as receiving discordant care having a 2.35-fold increased hazard of breast cancer mortality compared with NHW women classified as received discordant care (95% CI, 1.48–3.73). The disparity among women concordant for endocrine therapy was less pronounced (NHB vs NHW HR, 1.92; 95% CI, 1.50–2.45). There was no evidence of additive or multiplicative interaction between race and receipt of GCC in breast cancer mortality. In models additionally adjusting for stage, insurance type, derived breast cancer subtype, and SES, we observed similar although attenuated associations in the disparities across treatment modalities (Table 5).
Discussion
We observed that as clinical guidelines would suggest, failure to receive GCC was associated with an increased hazard of breast cancer mortality. This was noted for the receipt of GCC overall and across each treatment modality. Despite the importance of GCC for health outcomes, the receipt of GCC did not seem to influence racial disparities in breast cancer mortality. Although NHB and NHW women were equally likely to receive care consistent with guidelines for all treatment modalities combined, NHB women had a nearly 2-fold increase in breast cancer mortality compared with their NHW counterparts within the strata of GCC receipt.
There are few previous population-based studies on receipt of GCC in relation to racial disparities in breast cancer mortality. Early investigations (circa 1990–2005) have reported that minority women are less likely to receive appropriate adjuvant therapy, although findings appear to be mixed and few studies report survival disparities.33,34 The most recent, a study among women residing in rural Georgia, reported that NHB women were more likely to receive GCC compared with NHW women.33 However, the authors of that study did not evaluate treatment modalities in combination with racial disparities in breast cancer mortality. Similarly, in the CDC's Patterns of Care Study, investigators likewise reported a greater proportion of NHB women received guideline care for chemotherapy.36 Both of these previous studies included women diagnosed with invasive breast cancer prior to the introduction of the 21-gene recurrence score and consideration of tumor subtype for chemotherapy, which may partially explain the differences.37 Chemotherapy indication for women aged >70 years is subject to underlying comorbidities. The study in rural Georgia considered women aged >70 years to have a discretionary indication for chemotherapy, whereas the CDC study included chemotherapy indication for women aged >70 years because they were able to adjust for underlying comorbidities. In our study, we did not use age as an indicator for chemotherapy, but our results were similar in a sensitivity analysis excluding these women (data not shown). Another potential difference between our study and previous studies is that the metropolitan Atlanta area is a diverse population with approximately 50% NHB residents. This may mitigate some of the initial barriers in treatment initiation compared with rural regions in the southeast or other areas in the United States.
Although our study captured guideline care based on the indication and receipt of breast cancer therapies, we did not capture information on other aspects regarding quality of care, such as treatment facility characteristics or healthcare access, that may have influenced the observed results.38 Higher-quality care may lead to additional workup by tumor boards or care coordination, leading to better treatment timelines, which may not be equitable across racial/ethnic groups.39
We acknowledge several limitations of this study. Our intent was to understand the association between receipt of guideline-concordant first-line therapy and breast cancer mortality and potential racial disparities in this mortality; however, we did not account for the timing of treatment initiation, duration, or completion of adjuvant therapies, which have been associated with patient outcomes and may vary by race.40–42 We excluded women who did not receive surgery, which likely represents a population with poor outcomes compared with women who did receive surgery. Further exploration of the decision to forgo surgical treatment is important for future research. We similarly did not have information on adherence to endocrine therapy. In the United States, poor adherence and early discontinuation of endocrine therapy have been previously reported, with some studies suggesting racial differences.43–45 These may be important considerations for future investigations as we work to identify multilevel targets for intervention. We assumed that women who were discretionary for a treatment modality received GCC, but further exploration of the decision to forgo adjuvant therapy (and potential racial disparities within that decision) may be important for future research. Receipt of anti-HER2 therapy was determined using NLP from GCR treatment text fields among women diagnosed before 2013, which could result in misclassification of anti-HER2 therapy. To evaluate the ability of our NLP to correctly classify women as having received/not received anti-HER2 therapy, we compared results with the GCR treatment variable for women diagnosed after 2013. Results were largely consistent; we observed a 99% specificity and 97% sensitivity using the GCR treatment variable as the gold standard. Although treatment-related data in cancer registries are often underreported and may be subject to misclassification,46 our findings are similar to those of Guy et al,35 who used chart abstraction to identify first-line therapy. Finally, we were unable to collect information on comorbid conditions, which may impact both treatment adherence and efficacy.32 Women with coronary artery disease or diabetes at diagnosis often have poor completion of taxane-based chemotherapy and are more likely to experience adverse effects from breast cancer treatments, which may affect prognosis.48 Such comorbidities are more likely to present among NHB women, which could in part contribute to the observed disparity.49
Conclusions
Racial disparities in breast cancer survival outcomes are complex.50 In this study, we observed that although GCC was important for patient prognosis overall, we did not find evidence that differences in receipt of GCC contributed to disparate cancer outcomes between NHB and NHW women with breast cancer. Rather, NHB women consistently had worse breast cancer survival outcomes than NHW women, regardless of GCC status. Future studies may be strengthened from a multilevel approach to incorporate information on healthcare access, neighborhood characteristics, characteristics of the treating facilities, treatment duration and completion, and the presence and management of comorbid conditions.
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