Atherosclerotic Cardiovascular Disease Risk and Longitudinal Risk Factor Management Among Patients With Breast Cancer

Abstract

This retrospective cohort study of patients with nonmetastatic breast cancer details individual estimated atherosclerotic cardiovascular disease (ASCVD) risk at the time of cancer diagnosis and longitudinal preventive medication exposure during post-treatment follow up. Primary or secondary preventive interventions were indicated for a majority of patients at baseline. Modifiable ASCVD risk factors were frequently untreated or uncontrolled during longitudinal follow up.

Background:

Cardiovascular disease is the leading cause of noncancer mortality for breast cancer survivors. Data are limited regarding patient-level atherosclerotic cardiovascular disease (ASCVD) risk estimation and preventive medication use. This study aimed to characterize ASCVD risk and longitudinal preventive medication use for a cohort of patients with nonmetastatic breast cancer.

Patients and Methods:

This retrospective cohort study included 326 patients at an academic medical center in Boston, Massachusetts diagnosed with nonmetastatic breast cancer or ductal carcinoma in situ from January 2009 through December 2015. Patient demographics, clinical characteristics, laboratory studies, medication exposure, and incident cardiovascular outcomes were collected. Estimated 10-year ASCVD risk was calculated for all patients from nonlaboratory clinical parameters.

Results:

Median follow up time was 6.5 years (IQR 5.0, 8.1). At cancer diagnosis, 23 patients (7.1%) had established ASCVD. Among those without ASCVD, 10-year estimated ASCVD risk was ≥20% for 77 patients (25.4%) and 7.5% to <20% for 114 patients (37.6%). Two-hundred and sixteen patients (66.3%) had an indication for lipid-lowering therapy at cancer diagnosis, 123 of whom (57.0%) received a statin during the study. Among 100 patients with ASCVD or estimated 10-year ASCVD risk ≥20%, 92 (92.0%) received an antihypertensive medication during the study. Clinic blood pressure > 140/90 mmHg was observed in 33.0% to 55.6% of these patients at each follow up assessment.

Conclusion:

A majority of patients in this breast cancer cohort had an elevated risk of ASCVD at the time of cancer diagnosis. Modifiable ASCVD risk factors were frequently untreated or uncontrolled in the years following cancer treatment.

Introduction

Cardiovascular disease (CVD) is the leading cause of noncancer mortality for breast cancer survivors. Long-term survivors of breast cancer have nearly twice the risk of CVD-related death as those without breast cancer.¹ Among breast cancer survivors, the competing risk of death from CVD is greater for older individuals with underlying CVD.²

Risk factors for CVD, including hypertension, diabetes, and hyperlipidemia, are frequently identified among breast cancer survivors.³ Clinical practice guidelines support the assessment and management of CVD risk factors and incident CVD among all breast cancer survivors.^4,5 Primary prevention strategies for atherosclerotic CVD (ASCVD) in cancer survivors mirror those recommended for the general population and include regular moderate-intensity exercise, a heart healthy diet, smoking cessation, risk-based lipid lowering therapy, diabetes management, and optimal blood pressure control to prevent ASCVD events.^6,7

Despite these recommendations, it is unclear how incident CVD and major modifiable risk factors for CVD, including hypertension, hyperlipidemia, and diabetes, are managed for breast cancer survivors in clinical practice. Modifiable CVD risk factors are often untreated or uncontrolled in the general population.⁸ Available data suggest ASCVD risk-based statin prescription for primary prevention is used in only a minority of breast cancer patients in routine clinical practice.⁹ While hypertension associated with several classes of anticancer therapy has been well-characterized, data regarding management of hypertension for cancer survivors following completion of cancer therapy are limited.¹⁰

In this single-institution retrospective study, we used robust data abstraction methodology to longitudinally characterize CVD, ASCVD risk factors, and pharmacologic preventive measures amongst a cohort of consecutive patients with newly diagnosed nonmetastatic breast cancer.

Patients and Methods

Study Population

This retrospective study was approved by the Institutional Review Board of Tufts Medical Center. Patients diagnosed with breast cancer at Tufts Medical Center from January 01, 2009 to December 31, 2015 were identified retrospectively from the institutional cancer registry. Patients with nonmetastatic invasive cancer or ductal carcinoma in situ with a minimum of 2 years of clinical follow up were included in the study population and followed through December 31, 2019.

Data Collection

Breast cancer diagnosis and clinical details were previously collected at the time of initial database construction using study-specific abstraction forms and dual data abstraction by study staff, as previously described in a separate analysis.¹¹ Tumor hormone receptor and HER2 status were abstracted from clinical notes. Anatomic cancer stage was determined by review of clinical notes and recorded using the seventh edition of the American Joint Committee on Cancer staging manual, in use at the time of diagnosis.¹²

For this analysis, additional clinical variables were collected from the electronic health record at multiple time points: pretreatment baseline, 6 months after diagnosis, 12 months after diagnosis, and every 12 months thereafter as available until the study end date. Patient demographics were retrieved from the electronic health record. Oncology clinic visit notes were reviewed for data abstraction. Nononcology clinic visit notes were reviewed for data abstraction if an oncology clinic visit note was not available for a specific follow up time point. Collection of breast cancer treatment details, cancer-specific outcomes, and cardiovascular covariates was performed by the study team (S.B., C.B., A.C., H.D., M.F., A.J., M.L., P.P., R.S.) using study-specific standardized data abstraction forms. All abstracted data were confirmed by a physician second reviewer (J.M., S.M.).

Details of frontline systemic cancer treatment, including exposure to chemotherapy, HER2-directed therapy, and endocrine therapy, were abstracted. Laterality, radiation field, and total radiation dose were determined for all patients treated with radiation therapy. Detailed dosimetry data was available for patients treated after 2011 and mean heart dose was determined via dedicated review of the radiation treatment plan under the guidance of a senior radiation oncologist. Cancer-specific events assessed during the follow up period included cancer recurrence and death due to breast cancer. Exposure to cardiotoxic systemic therapy or radiation therapy was also recorded for preceding, recurrent, or subsequent cancer diagnoses referenced in clinical notes.

Diagnoses of coronary artery disease (CAD), heart failure (HF), peripheral vascular disease (PVD), and transient ischemic attack (TIA) or stroke prior to breast cancer diagnosis were recorded as documented by the treating physician and confirmed by a physician reviewer. CVD risk factors, including hypertension, diabetes, hyperlipidemia, obesity, and tobacco use, were recorded as documented by the treating physician at baseline and at each available time point during follow-up. Patients’ documented vital signs and cardiac medication prescriptions were collected at each available time point. High intensity statin therapy was identified according to standard guideline definitions: atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily.¹³ Antihypertensive and diabetes medications were grouped into standard classes.¹⁴ Laboratory studies performed as part of routine care were collected, including lipid panels and hemoglobin A1c.

Cardiovascular events of interest collected during the follow up period after breast cancer diagnosis included CAD diagnoses, acute coronary events, PVD diagnoses, TIA or stroke, atrial fibrillation or atrial flutter diagnoses, HF diagnoses, HF hospitalization, hospitalization due to CVD, and death due to CVD. All events were confirmed by a physician reviewer.

ASCVD Risk Estimation

For each patient, individual 10-year ASCVD risk was estimated at baseline using a sex-specific multivariable risk factor algorithm based on non–laboratory-based predictors of CVD.¹⁵ Factors included in the model are age, body mass index (BMI), systolic blood pressure, treatment for high blood pressure, current smoking status, and diabetes. Data for BMI were missing for 3 patients and baseline blood pressure readings were missing for 10 patients. Missing data were imputed using multiple imputation techniques and combined to calculate a risk estimate for each patient. Patients were categorized by 10-year estimated risk according to guideline definitions of high (≥20%), intermediate (7.5% to <20%), borderline (5% to <7.5%), and low (<5%) risk groups.¹³ For patients with a baseline lipid panel, 10-year ASCVD risk was also estimated using the pooled cohort equations.¹⁶

CV Risk Factor Management

For analysis of indication-consistent statin exposure, accepted indications for lipid-lowering therapy were in accordance with recommendations from the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and included secondary prevention of ASCVD, primary prevention of ASCVD in patients with diabetes, and primary prevention of ASCVD in patients with an estimated 10-year risk of ASCVD ≥7.5%.¹³ For longitudinal assessment of blood pressure control, elevated blood pressure was defined as clinic-documented stage 2 hypertension: systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg.¹⁴

Analysis

Baseline characteristics were summarized using mean and standard deviation for normally distributed continuous variables, median and interquartile ranges for skewed continuous variables, and percentages for categorical variables. Pairwise comparisons and chi-square tests were performed to assess the relationship between race/ethnicity and indication-consistent statin exposure. Point prevalence of cardiovascular risk factors and elevated clinic blood pressure were determined among assessable patients at each study time point. The statistical analysis was performed using SAS version 9.4 statistical software (SAS Institute, Cary, NC).

Results

Patient Characteristics and CVD Risk Factors

Of 627 patients identified from the cancer center registry, 326 patients were included in the study (Figure A.1). Patient characteristics are summarized in Table 1. Median follow up time was 6.5 years (IQR 5.0, 8.1). Median age at diagnosis was 60.7 years (IQR 51.9, 68.5). Patients were predominantly non-Hispanic White (219; 67.2%), Asian (63; 19.3%), or Black (34; 10.4%).

Table 1.

Patient Characteristics by Breast Cancer Subtype

Breast Cancer Subtype – No. (%)a	Full Cohort N = 326 (100)	HR+/HER2− N = 247 (75.8)	HER2+ N = 43 (13.2)	HR−/HER2− N = 31 (9.5)
Median age at diagnosis – years (IQR)	60.7 (51.9, 68.5)	61.9 (52.1, 69.0)	56 (49.6, 61.2)	60.4 (53.2, 73.0)
Age category – no. (%)
<50	66 (20.3)	50 (20.2)	11 (25.6)	5 (16.1)
50-59	91 (27.9)	61 (24.7)	19 (44.2)	10 (32.3)
60-69	97 (29.8)	80 (32.4)	9 (20.9)	5 (16.1)
≥70	72 (22.1)	56 (22.7)	4 (9.3)	11 (35.5)
Median follow up – years (IQR)	6.5 (5.0,8.1)	6.3 (5,8)	6.5 (4.6,8)	6.6 (4.7,8.4)
Race/ethnicity – no. (%)
White	219 (67.2)	170 (68.8)	27 (62.8)	18 (58.1)
Asian	63 (19.3)	47 (19.0)	12 (27.9)	3 (9.7)
Black or African-American	34 (10.4)	24 (9.7)	2 (4.7)	8 (25.8)
Hispanic or Latino	8 (2.5)	5 (2.0)	2 (4.7)	1 (3.2)
Other	2 (0.6)	1 (0.4)	0 (0.0)	1 (3.2)
CVD and risk factors – no. (%)
CAD	16 (4.9)	10 (4.1)	1 (2.3)	4 (12.9)
PVD	3 (0.9)	2 (0.8)	0 (0.0)	1 (3.2)
TIA or Stroke	6 (1.8)	5 (2.0)	1 (2.3)	0 (0.0)
Heart Failure	6 (1.8)	4 (1.6)	2 (4.7)	0 (0.0)
BMI ≥30.0	104 (31.9)	82 (33.2)	10 (23.3)	9 (29.0)
Hypertension	172 (52.8)	127 (51.4)	19 (44.2)	22 (71.0)
Hyperlipidemia	130 (39.9)	100 (40.5)	10 (23.3)	17 (54.8)
Diabetes	49 (15.0)	36 (14.6)	6 (14.0)	5 (16.1)
Current smoker	23 (7.1)	17 (6.9)	2 (4.7)	4 (12.9)
Former smoker	98 (30.1)	77 (31.2)	11 (25.6)	9 (29.0)
Family history of premature CADb	15 (4.6)	12 (4.9)	2 (4.7)	1 (3.2)
Clinical stage − no. (%)
DCIS	46 (14.1)	31 (12.6)	9 (20.9)	1 (3.2)
Stage I	177 (54.3)	139 (56.3)	22 (51.2)	16 (51.6)
Stage II	78 (23.9)	59 (23.9)	10 (23.3)	9 (29.0)
Stage III	25 (7.7)	18 (7.3)	2 (4.7)	5 (16.1)
Estimated 10-year ASCVD Risk – no. (%)
Established ASCVD	23 (7.1)	16 (6.5)	2 (4.7)	4 (12.9)
<4.6% (score ≤8)	72 (22.1)	55 (22.3)	12 (27.9)	4 (12.9)
5.4-7.4% (score 9-10)	40 (12.3)	32 (13.0)	6 (14.0)	2 (6.5)
8.6-18.1% (score 11-17)	114 (35.0)	84 (34.0)	17 (39.5)	12 (38.7)
≥20.9% (score ≥18)	77 (23.6)	60 (24.3)	6 (14.0)	9 (29.0)
Cancer treatment – no. (%)
Surgery	321 (98.5)	244 (98.8)	43 (100)	29 (93.6)
Hormone Therapy	249 (76.4)	218 (88.3)	27 (62.8)	2 (6.5)
Anthracycline	50 (15.3)	30 (12.2)	7 (16.3)	13 (41.9)
Anthracycline Cumulative Dose ≥250 mg/m2	6 (1.8)	4 (1.6)	2 (4.7)	0 (0.0)
Trastuzumab	43 (13.2)	10 (4.1)	33 (76.7)	0 (0.0)
Anthracycline and Trastuzumab	8 (2.5)	1 (0.4)	7 (16.3)	0 (0.0)
Anthracycline for Prior Cancer	12 (3.7)	10 (4.1)	2 (4.7)	0 (0.0)
Radiation Therapy	165 (50.6)	121 (49)	27 (62.8)	17 (54.8)
Left-Sided Radiation Therapy	82 (25.2)	56 (22.7)	18 (41.9)	8 (25.8)
Right-Sided Radiation Therapy	84 (25.8)	55 (22.3)	9 (20.9)	9 (29.0)
Cardiac Dosimetry Available	114 (35.0)	81 (32.8)	18 (41.9)	15 (48.4)
Mean Heart Dose (MHD)	1 (0.5, 1.8)	1 (0.5, 1.6)	1.5 (1, 2.4)	0.6 (0.4, 2.2)
Median Mean Heart Dose – Gy (Left)	1.6 (1.1, 2.2)	1.5 (1.1, 1.9)	1.9 (1.3, 2.5)	1.8 (1.1, 2.8)
Median Mean Heart Dose – Gy (Right)	0.5 (0.4, 0.6)	0.5 (0.4, 0.6)	0.5 (0.5, 0.7)	0.4 (0.4, 0.6)
Median Mean Heart Dose Bilateral	3.3 (3.3, 3.3)	3.3 (3.3, 3.3)	-	-

Abbreviations: ASCVD = atherosclerotic cardiovascular disease; BMI = body mass index; CAD = coronary artery disease; DCIS = ductal carcinoma in situ; Gy = gray; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; IQR = interquartile range; PVD = peripheral vascular disease; TIA = transient ischemic attack.

^aBreast cancer subtype missing for 5 patients.

^bFamily history available for 230 patients.

At the time of breast cancer diagnosis, 23 patients (7.1%) had established ASCVD. Sixteen patients (4.9%) had CAD, 6 patients (1.8%) had a history of TIA or stroke, and 3 patients (0.9%) had PVD. Risk factors for ASCVD were common at the time of breast cancer diagnosis. One hundred seventy-two patients (52.8%) had hypertension, 130 patients (39.9%) had hyperlipidemia, 104 patients (31.9%) had a BMI ≥30, 49 patients (15.0%) had diabetes, 98 patients (30.1%) were former smokers, and 23 patients (7.1%) were current smokers.

ASCVD Risk Estimation

Ten-year estimated ASCVD risk was calculated for the 303 patients (92.9%) without established ASCVD at the time of breast cancer diagnosis using a nonlaboratory risk equation (Figure 1). Ten-year estimated ASCVD risk was ≥20% for 77 patients (25.4%; high risk), 7.5% to <20% for 114 patients (37.6%; intermediate risk), 5% to <7.5% for 40 patients (13.2%; borderline risk), and <5% for 72 patients (23.8%; low risk). Patient characteristics for each risk group are summarized in Table A.1.

Figure 1.

Estimated 10-year ASCVD risk. Histogram of nonlaboratory estimated 10-year ASCVD risk score at the time of breast cancer diagnosis for all patients in the study cohort without a preexisting diagnosis of ASCVD. Colors indicate ASCVD risk category. Abbreviation: ASCVD = atherosclerotic cardiovascular disease.

Ten-year estimated ASCVD risk was calculated using the pooled cohort equations for 134 patients with a baseline lipid profile. Estimated risk was lower with the pooled cohort equations than the nonlaboratory risk equation (median difference −4.52%). Among 91 patients with a baseline lipid profile and 10-year estimated ASCVD risk ≥7.5% by the nonlaboratory risk equation, 28 (30.7%) had a 10-year estimated ASCVD risk <7.5% by the pooled cohort equations (Table A.2).

Breast Cancer Treatment

Most patients had stage I (177; 54.3%) or stage II (78; 23.9%) breast cancer. Forty-three patients (13.2%) had HER2-positive disease and 31 patients (9.5%) had triple-negative disease. For treatment of the index breast cancer, 249 patients (76.4%) received endocrine therapy, 50 patients (15.3%) received an anthracycline, and 43 patients (13.2%) received trastuzumab. One-hundred and sixty-nine patients (51.8%) received radiation therapy of which 114 patients (67.5%) had detailed dosimetry available for review. Median mean heart dose was 1.6 Gy (IQR 1.1, 2.2) for left breast radiation therapy and 0.5 Gy (IQR 0.4, 0.6) for right breast radiation therapy. Twenty-two patients (6.8%) had breast cancer recurrence. Eight patients (2.5%) died during the study period, with 3 deaths attributed to recurrent breast cancer and 2 deaths attributed to a second cancer.

Incident ASCVD Risk Factors

Forty-nine patients (15%) were diagnosed with incident hyperlipidemia, 34 patients (10.4%) were diagnosed with incident hypertension, and 17 patients (5.2%) were diagnosed with incident diabetes during the study period (Table 2). Sixteen patients (4.9%) were diagnosed with 2 or more of the 3. At all follow up time points during the study period, at least 66.9% of assessable patients had 1 or more modifiable risk factors for cardiovascular disease (Figure 2). For time points 5 or more years after breast cancer diagnosis, at least 77.6% of assessable patients had 1 or more modifiable risk factors for cardiovascular disease.

Table 2.

Incident and Cumulative ASCVD Risk Factors and Cardiovascular Disease Diagnoses

	Baseline	Incident	Cumulative
ASCVD risk factors – no. (%)
Hypertension	172 (52.8)	49 (15.0)	221 (67.8)
Hyperlipidemia	130 (39.9)	34 (10.4)	164 (50.3)
Diabetes	49 (15.0)	17 (5.2)	66 (20.2)
Any risk factor (1 or more)	211 (64.7)	83 (25.5)	294 (90.2)
Any risk factor (2 or more)	112 (34.4)	16 (4.9)	128 (39.3)
Cardiovascular disease – no. (%)
Coronary artery disease	16 (4.9)	6 (1.8)	22 (6.7)
Peripheral vascular disease	3 (0.9)	3 (0.9)	6 (1.8)
Transient ischemic attack or stroke	6 (1.8)	9 (2.8)	15 (4.6)
Heart failure	6 (1.8)	11 (3.4)	17 (5.2)
Atrial fibrillation or flutter	5 (1.5)	10 (3.1)	15 (4.6)
Any diagnosis (1 or more)	30 (9.2)	34 (10.4)	64 (19.6)

Abbreviation: ASCVD = atherosclerotic cardiovascular disease.

Figure 2.

Point prevalence of modifiable ASCVD risk factors. Point prevalence of hypertension (red), hyperlipidemia (blue), and diabetes (brown) among all assessable patients at each follow up time point. “1+ risk factor” (black) refers to individuals with 1 or more diagnoses of hypertension, hyperlipidemia, or diabetes.

Incident Cardiovascular Diagnoses and Events

Thirty-four patients (10.4%) had at least 1 new cardiovascular diagnosis after breast cancer diagnosis. Eleven patients (3.4%) were diagnosed with heart failure, 10 patients (3.1%) were diagnosed with atrial fibrillation or atrial flutter, 9 patients (2.8%) were diagnosed with TIA or stroke, 6 patients (1.8%) were diagnosed with CAD, and 3 patients (0.9%) were diagnosed with peripheral vascular disease (Table 2). Four patients (1.3%) had an acute coronary event and 13 patients (4.0%) had a hospitalization for cardiovascular disease. No patients died of a documented cardiovascular cause.

Preventive Medication Exposure

Exposure to lipid-lowering, antihypertensive, and diabetes medications was assessed both at baseline and throughout the study period (Table A.3). Over the entire study period, 174 patients (53.4%) received any lipid-lowering therapy, 192 patients (58.9%) received any antihypertensive medication, and 57 patients (17.5%) received any diabetes medication.

Indication-Consistent Statin Exposure

Statin exposure by patient subgroup is summarized in Table 3. At the time of breast cancer diagnosis, 216 patients (66.3%) had an established indication for lipid-lowering therapy: secondary prevention of ASCVD, primary prevention in the setting of diabetes, or primary prevention for an estimated 10-year ASCVD risk ≥7.5%. Among this group, 77 patients (35.6%) were prescribed a statin at baseline and 123 patients (57.0%) were prescribed a statin at any time during the study period. Among the 35 patients with ASCVD at any time during the study period, 29 (83%) were prescribed a statin with 14 (40%) ever receiving a high-intensity statin. The proportion of Asian and Black patients with estimated ASCVD ≥7.5% receiving a statin at baseline was numerically lower than that for White patients but the difference was not statistically significant (27.8% vs. 31.3%, P = .685; 20.0% vs. 31.3%, P = .304; Table A.4).

Table 3.

Statin Exposure by Patient Subgroup

	N	Any Statin		High-Intensity Statin
		Baseline N = 86	Entire Study Period N = 140	Baseline N = 9	Entire Study Period N = 41
Age – no. (%)
<50	66	4 (6.1)	9 (13.6)	1 (1.5)	1 (1.5)
50-59	91	17 (18.7)	34 (37.4)	0 (0.0)	10 (11.0)
60-69	97	35 (36.1)	56 (57.7)	4 (4.1)	19 (19.6)
≥70	72	30 (41.7)	41 (56.9)	4 (5.6)	11 (15.3)
Race/ethnicity – no. (%)
White	219	59 (26.9)	94 (42.9)	6 (2.7)	26 (11.8)
Asian	63	15 (23.8)	25 (39.7)	1 (1.6)	6 (9.5)
Black or African-American	34	9 (26.5)	17 (50.0)	2 (5.9)	8 (23.5)
Hispanic or Latino	8	3 (37.5)	3 (37.5)	0 (0.0)	0 (0.0)
Other	2	0 (0.0)	1 (50.0)	0 (0.0)	1 (50.0)
ASCVD Diagnosis – no. (%)
Baseline CAD, PVD, or TIA/stroke	23	18 (78.3)	19 (82.6)	3 (13.0)	7 (30.4)
Incident CAD, PVD, or TIA/stroke	12	5 (41.7)	10 (83.3)	1 (8.3)	7 (58.3)
Risk factors – no. (%)
Current smoker (baseline)	23	7 (30.4)	14 (60.9)	0 (0.0)	4 (17.4)
Hyperlipidemia (baseline)	130	76 (58.5)	97 (74.6)	7 (5.4)	28 (21.5)
Hyperlipidemia (incident)	49	3 (6.1)	26 (53.1)	1 (2.04)	6 (12.2)
Hypertension (baseline)	172	71 (41.3)	105 (61.1)	8 (4.6)	33 (19.2)
Hypertension (incident)	34	5 (14.7)	13 (38.2)	1 (2.94)	4 (11.8)
Diabetes (baseline)	49	28 (57.1)	34 (69.4)	4 (8.2)	13 (26.5)
Diabetes (incident)	17	8 (47.1)	11 (64.7)	2 (11.8)	4 (23.5)
Estimated 10-year ASCVD risk – no. (%)
High risk (≥20%)	77	25 (32.5)	42 (54.6)	2 (2.6)	12 (15.6)
Intermediate risk (7.5 to <20%)	114	33 (29.0)	61 (53.5)	3 (2.6)	16 (14.0)
Borderline risk (5 to <7.5%)	40	5 (12.5)	10 (25.0)	1 (2.5)	4 (10.0)
Low risk (<5%)	72	5 (6.9)	8 (11.1)	0 (0.0)	2 (2.8)
Treatment Exposure – no. (%)
Anthracycline	50	6 (12.0)	18 (36.0)	0 (0.0)	6 (12.0)
Trastuzumab	43	7 (16.3)	16 (37.2)	0 (0.0)	4 (9.3)
RT to left	82	16 (19.5)	34 (41.5)	0 (0.0)	7 (8.5)
RT to right	84	31 (36.9)	40 (47.6)	3 (3.6)	13 (15.5)
Mean heart dose <1 Gy	55	12 (21.8)	17 (30.9)	1 (1.8)	4 (7.3)
Mean heart dose ≥1 Gy	59	17 (28.8)	26 (44.1)	0 (0.0)	5 (8.5)

Abbreviations: ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; Gy = gray; PVD = peripheral vascular disease; RT = radiation therapy; TIA = transient ischemic attack.

Longitudinal Blood Pressure Control

Antihypertensive exposure by patient subgroup is summarized in Table A.5. Among 172 patients with a diagnosis of hypertension at baseline, 142 (82.6%) were prescribed an antihypertensive medication at baseline and 161 (93.6%) were prescribed an antihypertensive medication at any point during the study period. Among 34 patients with an incident diagnosis of hypertension during follow up, 23 (67.7%) were prescribed an antihypertensive medication. Among patients with either baseline or incident ASCVD, 32 (91.5%) were prescribed an antihypertensive medication. Among the intermediate and high estimated 10-year ASCVD risk groups, 77 patients (67.5%) and 71 patients (92.2%), respectively, were prescribed an antihypertensive medication at any time point.

The percentage of assessable patients with a clinic-assessed systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg was determined at each follow up time point. An elevated blood pressure was recorded for 20.4% to 29.5% of all patients each time point, with an elevated blood pressure observed in 33.0% to 55.6% of patients with diagnosed ASCVD or 10-year estimated ASCVD risk ≥20% at each time point (Figure 3). One hundred and seventy-three patients (53.1%) had 2 or more elevated blood pressure readings over the course of the study period.

Figure 3.

Point prevalence of elevated clinic blood pressure. Point prevalence of elevated clinic blood pressure, defined as clinic-assessed systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, at each study time point among all assessable patients stratified by baseline ASCVD risk category. Abbreviation: ASCVD = atherosclerotic cardiovascular disease.

Discussion

Patients with breast cancer are at increased risk of developing CVD and modifiable CVD risk factors following cancer treatment.^3,17 As more patients with nonmetastatic breast cancer achieve long-term cancer-specific survival with contemporary treatment approaches, the appropriate management of comorbid CVD and ASCVD risk factors is increasingly important. Data regarding patient-level risk assessment and management are lacking. In this cohort, 66% of patients had an indication for medical intervention for the primary or secondary prevention of ASCVD at the time of breast cancer diagnosis. In the years following breast cancer diagnosis and treatment, a large majority of patients at each follow up time point had at least 1 major modifiable ASCVD risk factor. Optimization of preventive measure utilization for these patients represents a significant opportunity to improve cardiovascular health-associated outcomes.

The pooled cohort equations are the current standard for ASCVD risk estimation but require a complete lipid profile. A lipid profile was available at the baseline time point for only 41% of patients in this cohort. The nonlaboratory risk equation used for the full cohort overestimated ASCVD risk relative to the pooled cohort equations for these patients, though 69.3% of patients with a nonlaboratory estimated 10-year ASCVD risk ≥7.5% also had a pooled cohort equation estimated risk ≥7.5%. Notably, the pooled cohort equations may underestimate ASCVD risk for some patients with breast cancer.¹⁸

Statin therapy decreases the risk of CVD and death among adults estimated to be at increased risk of ASCVD.¹⁹ High-intensity statin therapy is associated with improved clinical outcomes for patients with established ASCVD.²⁰ In this study, statin therapy was underutilized with only 57% of patients with an indication for lipid-lowering therapy at the time of cancer diagnosis ever receiving a statin. Statin utilization was higher among patients with established ASCVD, though the majority of these patients did not receive a guideline-recommended high-intensity statin. ASCVD registry data have demonstrated that women are less likely than men to be prescribed a statin for primary or secondary prevention (adjusted odds ratio 0.7) with 67% of women with an indication for lipid-lowering therapy receiving a statin.²¹ Statin underutilization in our breast cancer cohort may reflect this disparity in the management of dyslipidemia in women in the general population and raises the possibility that statin underutilization is more common among breast cancer patients.

Disparate patterns of ASCVD risk factor prevalence have been reported for specific racial and ethnic subgroups in the United States.²² Among patients in this cohort whose indication for statin therapy was estimated ASCVD risk ≥7.5%, a numerically smaller proportion of Asian and Black patients were receiving a statin at the time of breast cancer diagnosis as compared to White patients. Although not statistically significant, this observation is consistent with other data demonstrating racial disparities in lipid-lowering therapy use for the primary prevention of ASCVD and subsequent CVD-associated mortality.^23,24

Intensive blood pressure management in patients at increased risk of CVD results in lower rates of adverse cardiovascular events and all-cause mortality.²⁵ At all follow up time points, we observed that approximately 30% to 50% of patients with baseline hypertension or at increased risk of ASCVD had an uncontrolled systolic or diastolic blood pressure and 53% of patients had 2 or more elevated blood pressure readings over the course of the study. While a “white coat” effect cannot be excluded as we do not have access to ambulatory blood pressure readings, the consistency of the finding over many years of follow up despite broad antihypertensive exposure suggests the need for improved blood pressure control. Method-ological differences limit direct comparison, but contemporaneous community-based cardiovascular disease cohort data suggest similar rates of uncontrolled blood pressure among women in the general population.⁸

The efficacy of diabetes management was not able to be captured for each diabetic patient due to inconsistent availability of laboratory studies and inadequate data regarding screening for and management of diabetes-related complications. Notably, diabetic patients in this study had minimal exposure to SGLT2 inhibitors and GLP-1 receptor agonists. The study period largely preceded the publication of clinical trial data demonstrating the cardiovascular benefits of these agents.²⁶ Future studies should assess the use of cardioprotective diabetes medications among breast cancer survivors.

This study utilized a rigorous data collection method with granular longitudinal follow up, offering insight into patterns of ASCVD risk factors and preventive measure utilization among this patient population. Several limitations should be noted. This is a retrospective analysis of breast cancer patients treated at a single medical center. Many patients initially identified from the cancer registry were excluded due to follow up duration of less than 2 years, potentially introducing selection bias with regards to baseline characteristics and observed associations. ASCVD risk estimation could not be performed with the pooled cohort equations for all patients due to limited availability of baseline lipid profiles. Several critical interventions for ASCVD prevention, including dietary modification, physical activity, and smoking cessation efforts, were not assessed. Patients may have received care at other medical facilities from which records were not available. Sample size limitations and low cardiovascular and cancer-specific event rates prevented an assessment of the relationship between estimated ASCVD risk, observed preventive measures, and adverse outcomes. Extending follow up beyond the time frame assessed here would provide additional insight into the longitudinal interaction between breast cancer and cardiovascular outcomes in this cohort.

Conclusion

CVD is the leading threat to the long-term health and well-being of breast cancer survivors. This study demonstrated that many breast cancer survivors have an elevated estimated 10-year risk of ASCVD at the time of breast cancer diagnosis and that many have inadequate management of ASCVD risk factors during longitudinal follow up after completion of breast cancer treatment. Increased attention to CVD prevention should be a priority for oncology and nononcology providers to improve long-term CVD-associated outcomes and mortality amongst breast cancer survivors.

Clinical Practice Points.

• Breast cancer patients are at increased risk of cardiovascular disease relative to the general population, likely due to several mechanisms including shared risk factors and exposure to cardiotoxic therapies during breast cancer treatment.

• Atherosclerotic cardiovascular disease (ASCVD) risk estimation is recommended to guide preventive medication use. In this patient cohort, two-thirds of patients had an elevated estimated 10-year ASCVD risk and were eligible for lipid-lowering therapy at the time of cancer diagnosis. Despite this high-risk profile, many patients did not receive lipid-lowering therapy during longitudinal follow up after cancer treatment.

• Intensive blood pressure control has been associated with improved ASCVD-associated outcomes. Many high-risk patients in this cohort had uncontrolled clinic blood pressures during long-term follow up despite broad antihypertensive medication exposure, consistent with undertreatment.

• Optimizing modifiable cardiovascular disease risk factor management represents a significant opportunity to address the leading cause of noncancer mortality for breast cancer survivors.

Data Availability

The dataset generated and analyzed during the current study are available from the corresponding author upon reasonable request.