Race is Associated with Completion of Neoadjuvant Chemotherapy for Breast Cancer

Abstract

Introduction:

Completion of prescribed neoadjuvant chemotherapy (NACT) for breast cancer is paramount to patients obtaining full benefit from the treatment; however, factors affecting NACT completion are not known. We hypothesized that race is a predictor of completion of NACT in patients with breast cancer.

Methods:

All patients with breast cancer treated with NACT from 2009-2016 at a single institution were stratified by completion of NACT and by race. Univariate analysis and multivariable logistic regression were used to identify patient and tumor characteristics which affected the rate of NACT completion.

Results:

Ninety-two (74%) of 124 patients completed their prescribed NACT. On univariate analysis, white patients were more likely to complete NACT than non-white patients (76% vs 50%, p=0.006). Non-white patients were more likely to have government insurance and larger pre-chemotherapy tumors (both, p<0.05), but these factors were not associated with rates of NACT completion. After controlling for age, insurance status, tumor size, and estrogen receptor (ER) status, whites remained associated with completion of NACT (OR 3.65, p=0.014).

Conclusion:

At our institution, white patients with breast cancer were more likely than non-white patients to complete NACT. Further investigation into the underlying factors impacting this disparity is needed.

Introduction

Breast cancer is the most common cancer in women, representing 30% of all female cancers and leading to over 40,000 deaths per year in the United States.¹ In select breast cancer patients, the survival benefit of chemotherapy is well established. Multiple studies have shown equivalent survival among patients who receive neoadjuvant or adjuvant chemotherapy.² Many patients with large primary tumors or locally advanced breast cancer are treated with neoadjuvant chemotherapy (NACT), which has the potential benefit of downstaging the tumor, allowing for a less extensive operation. The use of NACT also allows for early assessment of the efficacy of systemic therapy and in some cases can lead to a pathologic complete response (pCR) in which no residual tumor is found in the resection specimen. Pathologic complete response acts as a surrogate for risk of recurrence risk overall survival, particularly in estrogen receptor (ER)-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancers.^{3, 4}

Racial disparities in outcomes for multiple malignancies including breast cancer have been described extensively, with worse survival for non-white patients compared to white patients.^5–9 The racial differences observed in outcomes of breast cancer have been attributed to many factors, including different tumor biology, less frequent screening, less aggressive treatment, and failure to seek medical care and follow up.^9–11 While NACT leads to improved outcomes for patients with locally advanced breast cancer, the factors that affect whether patients complete their prescribed NACT regimens are not known. The objective of this study was to assess the impact of race on completion of NACT at our institution. Given the benefits of NACT and the known racial disparities in outcomes, we hypothesized that race would be a predictor of completion of NACT in patients with breast cancer.

Methods

Patient Population

All patients with breast cancer who were treated with NACT at the University of Virginia Health System from January 1, 2009 through December 31, 2016 were identified using an institutional Clinical Data Repository (CDR). The CDR contains patient demographics, including age, body mass index, sex, race, insurance, medical comorbidities, tobacco use, and genetic mutations. Using CDR data, patient race was categorized as white or non-white (which included black, Hispanic, Asian, and other). Insurance status was defined as private, government (Medicaid, Medicare), or no insurance. Tumor characteristics (stage, size, pathology, hormone receptor status, HER2 status, and multifocality), type of operation, and details concerning the chemotherapy were abstracted by review of the electronic medical record . The Institutional Review Board at the University of Virginia approved waiver of consent for this study (Protocol #18801).

Data Analysis

Univariate analyses were used to compare preoperative factors and postoperative outcomes by both NACT completion status and race. Data were compared using Chi-square (χ²) test for categorical variables and appropriate parametric and non-parametric tests for continuous variables. Patients were then divided based on completion of prescribed NACT regimen, and a multivariable logistic regression model was created to identify independent predictors of NACT completion. Dependent variables were chosen a priori based on clinical factors shown previously to affect NACT completion and included at a rate of 1:10 for events in the population. A p-value < 0.05 was used for statistical significance. SAS version 9.4 (SAS Company, Cary NC) was used for all analyses.

Results

One hundred twenty-four patients with breast cancer were treated with NACT over the eight-year study period at our institution. Eighty-six patients (69%) in the cohort were white and 38 (31%) were non-white; of the non-white patients, 31 (82%) were black. The differences in patient and tumor characteristics of those who completed NACT versus those who did not complete NACT are listed in Table 1. The differences in patient and patient tumor characteristics of white versus non-white patients are listed in Table 2. Of note, white patients were more likely to have ER-positive tumors than non-white patients (69% vs 45%; p=0.01). Non-white patients were more likely to have government insurance and larger pre-chemotherapy tumors (both p<0.05), but these factors did not affect rates of NACT completion. Overall, 92 patients (74%) completed NACT as prescribed. On univariate analysis, white patients were more likely to complete NACT than non-white patients (76% vs 50%, p=0.006).

Table 1.

Patient and Tumor Characteristics by Completion of Neoadjuvant Chemotherapy (NACT)

	NACT Completed (n=92)	NACT Not Completed (n=32)	p-value
Patient Age at Diagnosis (years)	49.4 (41.0-57.0)	52.4 (43.0-61.0)	0.21
Pre-NACT BMI (kg/m2)	29.8 (24.9-33.8)	31.5 (27.3-33.9)	0.09
Post-NACT BMI (kg/m2)	29.3 (25.1-32.7)	30.9 (27.3-33.1)	0.11
Female	90 (98)	32 (100)	0.40
White	70 (76)	16 (50)	0.006
Insurance			0.07
Government	34 (38)	19 (61)
Private	48 (53)	10 (32)
None	8 (8.9)	2 (6.5)
Type 2 Diabetes	9 (9.8)	5 (16)	0.37
On Metformin	6 (6.5)	4 (13)	0.28
On Insulin	5 (5.4)	2 (6)	0.86
Tobacco Use
Current	21 (23)	9 (28)	0.55
Ever	35 (38)	18 (56)	0.07
Genetic Mutation			0.53
BRCA1	4 (4.4)	3 (9.4)
BRCA2	3 (3.3)	0 (0.0)
Other	2 (2.2)	1 (3.1)
Clinical T Stage			0.30
T0	0 (0.0)	1 (3.1)
T1	12 (13)	3 (9.4)
T2	37 (40)	17 (53)
T3	32 (35)	8 (25)
T4	11(12)	3 (9.4)
Clinical N Stage			0.60
N0	26 (28)	11 (34)
N1	55 (60)	15 (47)
N2	8 (8.7)	4 (13)
N3	3 (3.3)	2 (6.3)
Clinical M Stage			0.55
M0	91 (99)	32 (100)
M1	1 (1.1)	0 (0.0)
Tumor size (cm)	3.5 (2.3-4.2)	3.1 (1.8-4.4)	0.32
Multifocal disease	21 (23)	8 (25)	0.80
Breast Surgery
Lumpectomy	39 (42)	12 (38)	0.63
Mastectomy	53 (58)	20 (63)	0.63
Lymph Node Surgery
ALND	57 (62)	16 (50)	0.24
SLNB	46 (50)	16 (50)	1.00
Pre-NACT SLNB	6 (6.5)	1 (3.1)	0.47
Pathology
Ductal	80 (87)	28 (88)	0.94
Lobular/Other	12 (l3)	4 (13)
Receptor Status
ER Positive	56 (61)	20 (63)	0.87
PR Positive	46 (50)	18 (56)	0.54
HER2 Positive	11 (12)	7 (22)	0.17
Previous Breast RT	2 (2.2)	1 (3.1)	0.76

Categorical variables are reported as N(%) and continuous variables as median (IQR).

NACT=Neoadjuvant chemotherapy; BMI=Body mass index; BRCA=BReast CAncer gene; ALND=Axillary lymph node dissection; SLND=Sentinel lymph node biopsy; ER=Estrogen receptor; PR=Progesterone receptor; HER2=Human epidermal growth factor 2; RT=Radiotherapy

Table 2.

Patient and Tumor Characteristics by Race

	White (n=86)	Non-White (n=38)	p-value
Patient Age at Diagnosis (years)	50.7 (42.0-60.0)	48.9 (39.0-56.0)	0.37
Pre-NACT BMI (kg/m2)	29.6 (24.5-33.8)	31.8 (27.4-33.9)	0.051
Post-NACT BMI (kg/m2)	29.3 (24.8-32.9)	30.7 (27.0-32.7)	0.22
Female	85 (99)	37 (97)	0.55
Insurance			0.0092
Government	30 (36)	23 (62)
Private	48 (57)	10 (27)
None	6 (7.1)	4 (11)
Type 2 Diabetes	11 (13)	3 (7.9)	0.43
On Metformin	9 (11)	1 (2.6)	0.14
On Insulin	5 (5.8)	2 (5.3)	0.90
Tobacco Use
Current	19 (22)	11 (29)	0.41
Ever	36 (42)	17 (45)	0.77
Genetic Mutation			0.072
BRCA1	2 (2.3)	5 (13)
BRCA2	3 (3.5)	0 (0.0)
Other	2 (2.3)	1 (2.6)
Clinical T Stage			0.83
T0	1 (1.2)	0 (0.0)
T1	12 (14)	3 (7.9)
T2	37 (43)	17 (45)
T3	27 (31)	13 (34)
T4	9 (10)	5 (13)
Clinical N Stage			0.95
N0	25 (29)	12 (32)
N1	49 (57)	21 (55)
N2	8 (9.3)	4 (11)
N3	4 (4.7)	1 (2.6)
Clinical M Stage			0.50
M0	85 (99)	38 (100)
M1	1 (1.2)	0 (0.0)
Tumor size (cm)	3.1 (2.0-4.0)	4.1 (2.5-5.1)	0.026
Multifocal disease	22 (26)	7 (18)	0.39
Breast Surgery
Lumpectomy	36 (42)	15 (39)	0.80
Mastectomy	50 (58)	23 (61)	0.80
Lymph Node Surgery
ALND	52 (61)	21 (55)	0.59
SLNB	43 (50)	19 (50)	1.00
Pre-NACT SLNB	5 (5.8)	2 (5.3)	0.90
Pathology
Ductal	79 (92)	29 (76)	0.017
Lobular/Other	7 (8.1)	9 (24)
Receptor Status
ER Positive	59 (69)	17 (45)	0.012
PR Positive	49 (57)	15 (39)	0.072
HER2 Positive	13 (l5)	5 (13)	0.78
Previous Breast RT	3 (3.5)	0 (0.0)	0.24

Categorical variables are reported as N(%) and continuous variables as median (IQR).

NACT=Neoadjuvant chemotherapy; BMI=Body mass index; BRCA=BReast CAncer gene; ALND=Axillary lymph node dissection; SLND=Sentinel lymph node biopsy; ER=Estrogen receptor; PR=Progesterone receptor; HER2=Human epidermal growth factor 2; RT=Radiotherapy

There were no differences in pCR between patients who did and did not complete NACT (32% vs 34%; p=0.77). There was also no difference in local, regional, or distant recurrence based on completion of NACT (p=0.26, 0.76, and 0.34, respectively). There was no difference in pCR rates between white and non-white patients (37% vs 21%; p=0.08). Non-white patients were more likely to experience local, regional, and distant recurrences (all, p<0.01). Outcomes stratified by NACT completion and by race are shown in Tables 3 and 4, respectively.

Table 3.

Unadjusted Patient Outcomes by Completion of Neoadjuvant Chemotherapy

Outcome	NACT Completed (n=92)	NACT Not Completed (n=32)	p-value
Breast pCR	29 (32)	11 (34)	0.77
Pathologic Evidence of Treatment (Breast)	76 (83)	22 (69)	0.10
Pathologic Evidence of Treatment (Node)	44 (52)	15 (48)	0.75
Positive Margins	3 (3)	2 )	0.46
Adjuvant Chemotherapy	19 (21)	6 (19)	0.82
Adjuvant RT	87 (95)	27 (84)	0.07
Recurrence
Local	2	2 (6)	0.26
Regional	2	1	0.76
Distant	11 (12)	6 (19)	0.34

Categorical variables are reported as N(%).

pCR=pathologic complete response; RT=Radiotherapy

Table 4.

Unadjusted_Patient Outcomes by Race

Outcome	White (n=86)	Non-White (n=38)	p-value
Breast pCR	32 (37)	8 (21)	0.076
Pathologic Evidence of Treatment (Breast)	70 (81)	28 (74)	0.33
Pathologic Evidence of Treatment (Node)	42 (53)	17 (47)	0.60
Positive Margins	2	3 (8)	0.15
Adjuvant Chemotherapy	14 (16)	11 (29)	0.11
Adjuvant RT	80 (93)	34 (89)	0.50
Recurrence
Local	0 (0.0)	4 (11)	0.0022
Regional	0	3 (8)	0.0083
Distant	7 (8)	10 (26)	0.0067

Categorical variables are reported as N(%).

pCR=pathologic complete response; RT=Radiotherapy

The most common reason for failure to complete NACT was chemotherapy toxicity, noted in 9 (60%) white patients and 11 (65%) non-white patients. Neurologic side effects were the most common toxicity in non-white patients and occurred in none of the white patients (24% vs 0%; p=0.038). In white patients, the toxicity was most commonly gastrointestinal. Other factors included cancer progression, patient choice, and psychosocial issues. Reasons for lack of completion of NACT are shown in Table 5. There were no differences in chemotherapy regimens prescribed to white compared to non-white patients, and the majority of both white and non-white patients (64% and 71%, respectively) received TAC (Taxotere, Adriamycin, cyclophosphamide). Table 6 shows details of chemotherapy regimens by race.

Table 5.

Reasons for Lack of Neoadjuvant Chemotherapy Completion

Reason	White (n=15)	Non-White (n=17)	p-value
Cancer Progression on NACT	2	1	0.59
Chemotherapy Toxicity	9 (60)	11 (65)	>0.99
Cytopenia	2 (13)	1	0.59
Gastrointestinal	3 (20)	1	0.32
Infection	2	3 (18)	>0.99
Neurologic/Pain	0	4 (24)	0.038
Other	2	2	1
Patient Choice	1 (	2	>0.99
Psychosocial Issues	3 (20)	0	0.92
Reason Not Documented	0	3 (18)	0.23

Categorical variables are reported as N(%).

NACT = Neoadjuvant Chemotherapy

Table 6.

Neoadjuvant Chemotherapy Regimens by Race

Regimen	White (n=86)	Non-White (n=38)	p-value
TC	6 (7)	1 )	0.33
TAC	55 (64)	27 (71)	0.44
AC-TC	10 (12)	2	0.27
CT	1	3 (8)	0.051
CAF	0	1	0.31
TCHP	8 (9)	4 (11)	0.83
TCH	4 (4.7\\)	0	0.31
CMF	2	0	>0.99

Categorical variables are reported as N(%).

TC= taxotere, cyclophosphamide; TAC= taxotere, adriamycin, and cyclophosphamide; AC-TC= adriamycin, cyclophosphamide, taxol, carboplatin; CT= carboplatin, taxol; CAF= cyclophosphamide, adriamycin, 5-FU; TCHP= taxol, carboplatin, herceptin, pertuzumab; TCH= taxol, carboplatin, Herceptin; CMF= cyclophosphamide, methotrexate, 5-FU

A multivariable logistic regression analysis was performed to determine the independent contribution of race on completion of NACT (Table 7). After controlling for age, insurance status, tumor size, and ER status, white race remained associated with completion of NACT (OR 3.65, p=0.014).

Table 7.

Factors Independently Associated with_Completion of Chemotherapy

Parameter	Odds Ratio (95% Confidence Interval)	p-value
Age at Diagnosis	0.97 (0.93-1.01)	0.10
Race (ref=White)	3.65 (1.30-10.30)	0.014
Tumor Size	1.35 (1.01-1.81)	0.047
Insurance (ref=Private)	1.95 (0.76-5.01)	0.16
ER status (ref=Positive)	0.74 (0.28-1.95)	0.54

ER=Estrogen receptor

Discussion

The present study aimed to investigate the effect of race on the completion of the prescribed course of NACT for breast cancer patients at a single academic institution. Through the use of a retrospective chart review, we found that white patients were more likely to complete prescribed NACT as compared to non-white patients; this difference remained after adjusting for insurance status. Although racial disparities in treatment of breast cancer and outcomes have been well documented, the majority of studies examining rates of completion of chemotherapy in breast cancer have been focused on the completion of adjuvant chemotherapy. The racial disparity identified in the present study is consistent with previous findings that non-white patients are less likely to complete adjuvant breast cancer chemotherapy and are more likely to have dose reductions and treatment delays compared to white patients.^12–14

There is no clear explanation for how race affects completion rates of NACT in patients with breast cancer, because prior studies are sparse and have yielded conflicting results.^{15, 16} Killelea et al. conducted a large retrospective study utilizing the National Cancer Data Base and found that NACT was utilized more frequently for black, Hispanic, and Asian women than for white women, but this observation was largely explained by those groups presenting with more advanced primary tumors as well as greater rates of triple-negative and HER2-positive disease.¹⁵ Though this study did report that non-white patients had a longer time from diagnosis to the start of NACT and from the start of NACT until surgery than did white patients, the authors did not examine NACT completion rates by race. In contrast, Andic et al. found no difference in the likelihood of completing prescribed NACT or in the timing of therapy completion between races; however this was a smaller, retrospective review specifically evaluating women with inflammatory breast cancer, whereas the present study included all types of breast cancer.¹⁶

In our study, it is important to note that the discrepancy in NACT completion among races persisted even after controlling for insurance status, which serves as a proxy for socioeconomic status. We therefore, cannot fully attribute the racial disparity found in this study to affordability of or access to oncologic care. There are a number of possible explanations for this finding, and the roles of social and health system barriers must be considered. Wheeler et al. described a variety of underlying factors affecting cancer care quality, including type and volume of the heath system, distance to care, availability of specialists, and provider preferences.¹⁷ Transportation and inability to work while undergoing treatment are some of the known barriers to cancer care. Our institution provides oncologic care to patients from all over the state of Virginia which can necessitates substantial,distances to travel for many patients, and the associated costs may be especially difficult for some patients.

While a greater proportion of non-white patients failed to complete NACT as compared to white patients, drug toxicity was the most common reason for lack of completion noted in both groups, and NACT regimens did not differ between white and non-white patients. This observation suggests that non-white patients may be affected disproportionately by the side effecgs f chemotherapy side. Interestingly, neurologic side effects or pain were the most frequent form of toxicity leading to lack of completion of NACT in non-white patients but were not noted as a cause in any white patients. Prior studies have found that minorities are often undertreated for cancer-related pain, which could contribute to patients and providers deciding to terminate or dose-reduce NACT.^{18, 19} Cytopenia and infection, both cited as causes for stopping NACT in our study, may also vary by race, and lesser baseline white blood cell counts in black patients have been associated previously with increased treatment delays during breast cancer chemotherapy. ²⁰ Further investigation into racial discrepancies in the profiles of the side effectsof the various drugs may help to explain the differences in completion of both adjuvant and neoadjuvant chemotherapy in this population.

There are also known differences in the perception of health care systems as well as in emotional regulation and coping mechanisms between different racial groups. For example, psychosocial researchers hypothesize that black patients have different culturally defined ways of processing emotions and that downplaying certain emotions tied to a diagnosis of cancer and its treatment could contribute to decreased adherence among this patient population.²¹ Furthermore, rates of depression are substantial among cancer patients; indeed, black patients with depression tend to exhibit more somatic symptoms compared to white patients. These somatic symptoms may intensify chemotherapy-related side effects, contributing to the greater proportion of non-white \patients stopping NACT due to drug toxicity noted in our study.²¹

The rates of pCR in this study were not different between white and non-white patient populations despite the difference in status of completion of NACT. There is no consensus within the literature about the effect of race on pCR. Though most studies have not found a difference, some have found lesser rates of a pCR in racial minorities, especially when stratified by certain tumor subtypes. ^{15, 22–24} Non-white patients in the present study were more likely to have ER-negative tumors, which have been shown to have a grater rate of pCR when compared to ER-positive tumors.²⁵ This finding may explain why rates of pCR were equivalent despite non-white patients receiving less of the prescribed NACT.

Our study has some notable limitations. It is a single-institution, retrospective study. This did, however, allow for more thorough chart review and consistency of prescribed treatments, but it also resulted in a relatively small study size potentially limiting the generalizability of the results. Additionally, the retrospective design precludes the demonstration of causality. Given the contemporary study period, a meaningful assessment of long-term survival could not be conducted. Lastly, determination of the reasons for lack of NACT completion relied on retrospective review of physician notes, which may have not captured all of the clinical and psychosocial factors impacting treatment decisions.

In conclusion, white patients were more likely to complete the prescribed course of NACT than non-white patients even after controlling for socioeconomic and tumor-related factors. These disparities in breast cancer treatment may have important clinical implications including decreased rates of pCR, increased recurrence, and decreased survival for non-white patients. While it is unclear exactly why these disparities exist, decreased completion of chemotherapy regimens provides an intervenable target for decreasing the racial disparity in breast cancer outcomes. Further research is needed to elucidate the underlying factors impacting these disparities so that clinicians can more effectively work to eliminate them in the future.