Abstract
Purpose:
Breast cancer and cardiovascular diseases often share the same risk factors. It is increasingly important to identify risk factors for cardiovascular (CV) events in high-risk breast cancer patients and explore optimal treatment regimens.
Patients and Methods:
Early HER2-positive breast cancer patients at our institution between January 1998 and October 2009 were reviewed. Primary outcome was late-severe-CV-event–free survival, and late severe CV events were defined as cardiovascular death, cardiomyopathy, symptomatic heart failure and myocardial infarction developing 2+ years after breast cancer diagnosis. Kaplan-Meier plots, Cox proportional hazard regressions, and restricted mean survival time were used to evaluate outcomes.
Results:
We identified 2,448 consecutive eligible patients with a median follow-up time of 111.0 months (interquartile range, 52.0–151.8 months). 136 patients had late severe CV events and 752 died of any cause (533 (70.9%) died of primary breast cancer; 12 (1.6%) died of cardiovascular disease). Hypertension (hazard ratio [HR], 1.546; 95% confidence interval [95%CI], 1.030–2.320; P=0.036) and history of coronary artery disease (CAD) (HR, 3.333; 95%CI, 1.669–6.656; P<0.001) were associated with worse late-severe-CV-event–free survival. Anthracycline-containing regimens (HR, 1.536; 95%CI, 0.979–2.411; P=0.062) was not a significant risk factor for CV events in multivariate analysis. Regimens containing both anthracycline and anti-HER2 therapy were prognostic for better OS (HR, 0.515; 95%CI, 0.412–0.643; P<0.001).
Conclusions:
Hypertension and CAD history were independent prognostic factors for late severe CV events. Adding anti-HER2 agents to anthracycline-containing regimens did not substantially increase the risk for late severe cardiotoxicity and conferred better overall survival.
Keywords: HER2-positive breast cancer, cardiovascular events, survival, cardiovascular disease risk factors, anthracycline
INTRODUCTION
Owing to improved therapies and early cancer detection programs, the number of breast cancer survivors is steadily increasing [1]. The most common cause of non-relapse-related mortality in this population is cardiovascular disease (CVD), and as breast cancer survivors age, their likelihood of developing CVD risk factors (CVRFs), including hypertension, hyperlipidemia, diabetes, and obesity, increases [2]. This mortality possibility is amplified by cardiovascular complications related to cancer therapy, some of the most effective of which also confer CVRFs that can lead to premature morbidity and death [3].
Human epidermal growth factor receptor 2 (HER2), also known as HER2/neu and ErbB2, is a member of the epidermal growth factor family and is essential for cardiac development [4]. The overexpression of HER2 is evident in 15% of breast cancers [5]. Trastuzumab and pertuzumab are monoclonal antibodies that can inhibit the oncogenic signaling of HER2 and can induce antibody-dependent cell-mediated cytotoxicity (ADCC) [6], significantly improving the survival in HER2-positive breast cancer; however, it can also cause reversible cardiac dysfunction and heart failure [7]. Anthracycline-containing chemotherapy regimens has long been used for breast cancer, and there is a limit for life-time cumulative dose of anthracyclines due to irreversible cardiomyopathy and heart failure (HF) even years after exposure [8]. A recent study reported that even low cumulative doses of anthracycline (<250 mg/m2) could cause cardiotoxicity [9]. Anthracycline-induced cardiotoxicity was especially seen among patients who already have CVRFs [10].
The actual incidence of late cardiotoxicity among breast cancer patients, especially those who survive for >10 years, is low and difficult to examine due to lack of large dataset with long follow-up, while studies of cardiovascular outcomes and treatments have been an important issue in childhood cancer survivors [11]. A recent study evaluated the associations among early cardiotoxicity caused by anthracyclines and CV-event-free survival and OS [12]. Thus, identifying patients at increased risk for (both early and late) cardiotoxicity is an unmet clinical need for optimizing treatment regimens without compromising anti-cancer efficacy [13].
The prevalence of cardiotoxicity is difficult to determine because of variability in definition, potentially delayed presentation, different chemotherapy regimens employed, and shared cardiovascular risk factors. Additionally, few studies included data on shared risk factors for cancer and cardiovascular disease to help delineate the drivers of cardiovascular disease risk in survivors.
HER2-positive breast cancer patients treated with anti-HER2 agents and/or anthracyclines are vulnerable to developing CV events. To explore the CVRFs significantly associated with CV events and OS, we focused on the enrichment population— HER2-positive breast cancer survivors.
We sought to identify CVRFs that are significantly associated with CV events and OS after treatment of HER2-positive breast cancer, and the results may advise CVRF control and regimen choice in HER2-positive breast cancer patients at high risk of CV events, optimizing life expectancy and quality of life for long-term survivors.
METHODS
Patients and data collection
Our study was approved by the MD Anderson’s Institutional Review Board (protocol ID: PA18–0481). Consecutive women aged ≥18 years who received a primary pathological diagnosis of non-stage IV HER2-positive breast cancer without other cancer at The University of Texas MD Anderson Cancer Center between January 6, 1998 and October 27, 2009 were identified. Two trained physicians reviewed the medical records and pathological reports to extract the related data on patient and tumor related characteristics, treatment records, and survival information. Then a senior physician checked for consistency and performed a final data check. All patients had complete disease information, including subtype and American Joint Committee on Cancer stage; known diabetes mellitus (DM), hypertension, coronary artery disease (CAD) history, hyperlipidemia status at diagnosis; and complete therapy information. HER2-positivity was defined as an immunohistochemical staining score of 3+ and/or HER-2/neu gene amplification defined as HER2/CEP 17 ratio >2.2. Nuclear staining ≥10% of estrogen receptor (ER) was considered strongly positive. The left ventricular ejection fraction (LVEF) was evaluated by a multiple-gated acquisition (MUGA) scan or echocardiography and was obtained from the medical records at baseline, every 3 months during trastuzumab-based therapy, and after completion of adjuvant trastuzumab if available. Additionally, patients who developed CHF usually received angiotensin-converting enzyme inhibitors and β-blockers at MD Anderson Cancer Center.
The study was conducted in accordance with the Declaration of Helsinki and was approved by the University of Texas MD Anderson Cancer Center Institutional Review Board.
Ascertainment of cardiovascular events, definition of late severe cardiovascular events and study outcomes
Cardiovascular events were captured by searching the EPIC electronic medical record system among both inpatient and outpatient claims for ICD-9 clinical modification diagnostic codes identifying MI (410.1, 410.4, 410.7, 410.8, 410.9, 411.1, 411.81, 411.89), HF (428.0−428.4, 428.21, 428.22, 428.23, 428.32, 428.9), cardiomyopathy (425.4, 429.9), angina (413, 413.9), CAD (414, 414.01), stroke (434.91), atrial fibrillation (427.31), and other CVDs (423, 423.2, 423.3, 423.8, 423.9, 424, 424.1, 424.2, 424.3, 424.9, 433.1, 433.11, 433.9). The ICD-9 codes and definitions of early CV events and late severe CV events were summarized in Supplementary table S1.
Late severe CV events were defined as cardiovascular events developing 2+ years after HER2-positive breast cancer diagnosis, and were classified as CV death, cardiomyopathy, symptomatic heart failure and myocardial infarction. According to the results of severe CV events captured by ICD-9 codes, two authors (X. H. and A. Q.) independently checked the four types of severe CV events and graded events of cardiomyopathy, symptomatic heart failure and myocardial infarction. The National Death Index, which contains ICD-9 codes for underlying cause of death, medical records and follow-up documents review were used to ascertain cardiovascular deaths. In our study, HF was defined as signs or symptoms of congestive HF and a decrease in the LVEF below the normal level (50%); or signs or symptoms of HF, and left ventricular hypertrophy or left atrial enlargement, or diastolic dysfunction (classified according to both the 2009 ASE and 2016 ASE/EACVI guidelines) [14]. Severe cardiomyopathy and myocardial infarction were set as grade 3 to 4 according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE, version 4.03). If the information needed to distinguish between grades or CV versus non-CV death was insufficient, these data fields were coded as the lower grade and non-CV death. In case of disagreement, a third author (S. J. Y.) was consulted to break ties.
Early CV Events, occurring within 2 years of breast cancer diagnosis, included cardiomyopathy, angina, CAD, MI, stroke, atrial fibrillation, HF, other CVDs, and cardiovascular death. Overall CV Events included any early and late CV Events occurring after a breast cancer diagnosis.
The primary outcome was set as late-severe-CV-event-free survival to explore the factors associated with the late severe CV events after therapy. The secondary outcomes included early CV event incidence, OS, and overall CV-event-free survival. The late-severe-CV-event-free survival was defined as the time from the date of breast cancer diagnosis to the date of first late severe CV event, death, or last follow-up, as described in a previous study [15]. Overall CV-event-free survival was defined as the time from the date of diagnosis to the date of first overall CV event, death, or last follow-up. OS duration was the time from the date of breast cancer diagnosis to the date of death or last follow-up.
Statistical analysis
Differences in baseline characteristics between groups were assessed using Student’s independent t-test and chi-squared test. We used a multivariate logistic regression model to assess factors associated with early-CV-event incidence since the events were observed within 2 years after diagnosis; Kaplan-Meier analysis with a log-rank test to compare CV-event-free survival and OS distributions by CVRFs, chemotherapy regimens, and other factors; and Cox proportional hazard regression to assess the effects of potential predictors on late severe CV events and OS. Propensity-score-matching was used to identify a cohort of patients with similar baseline CVRFs in groups treated with anthracycline-containing regimens without anti-HER2 therapy group and anthracycline combined with anti-HER2 therapy: those results are shown in the supplementary material. The restricted mean survival time (RMST) at 10 years was calculated to compare overall CV-event-free survival between patients treated with no chemotherapy or with anthracycline-free regimens and those with anthracycline-containing regimens for crossed plot. The RMST ratio was calculated to adjust for related prognostic factors.
All statistical analyses were performed with SPSS 22.0 (IBM Corporation, Armonk, NY, USA) and R statistical software (version 3.4.4, R Foundation for Statistical Computing, Vienna, Austria). P<0.05 was considered statistically significant.
RESULTS
Patients
Of the 2,993 consecutive patients with HER2-positive breast cancer initially identified, 545 were excluded because they were male (12), had unknown stage information (11), had stage IV cancer (497), lacked information about DM status (2), or lacked complete chemotherapy regimen information (23). The remaining 2,448 patients were included.
Baseline characteristics are given in Table 1. The mean patient age was 50.0±11.6 years. Over a median follow-up duration of 111.0 months (interquartile range, 52.0–151.8 months), 136 patients had late severe CV events, and 740 developed local relapse or distant metastases. Baseline characteristics by chemotherapy regimens are given in Table S2 (online only). Compared with patients treated with anthracycline-containing regimens, those treated with no chemotherapy or with anthracycline-free regimens had higher rates of DM (30.2%), hyperlipidemia (13.4%), and CAD (4.2%) at diagnosis.
Table 1:
Baseline characteristics of patients diagnosed with HER2-positive breast cancer between 1998 and 2009 (N=2448)
| Characteristic | n (%) |
|---|---|
| Age, years | |
| <50 | 1183 (48.3) |
| ≥50 | 1265 (51.7) |
| Chemotherapy regimen | |
| A+H | 739 (30.2) |
| A | 978 (40.0) |
| None/other* | 731 (29.9) |
| None | 443 (18.1) |
| Other | 288 (11.8) |
| with H | 219 (8.9) |
| without H | 69 (2.8) |
| Chemotherapy type | |
| Neoadjuvant | 975 (39.9) |
| Adjuvant | 1473 (60.2) |
| Year of diagnosis | |
| 1998–2004 | 1424 (58.2) |
| 2005–2009 | 1024 (41.8) |
| Race/ethnicity | |
| White | 1631 (66.6) |
| Hispanic | 372 (15.2) |
| Other | 445 (18.2) |
| Nuclear grade | |
| I/II | 487 (19.9) |
| III | 1893 (77.3) |
| Unknown | 63 (2.6) |
| ER status | |
| Negative | 1175 (48.0) |
| Positive | 1260 (51.5) |
| Unknown | 13 (0.5) |
| Disease stage | |
| 0/I | 745 (30.4) |
| II | 1026 (41.9) |
| III | 677 (27.7) |
| Menopausal status | |
| Pre-/peri-menopausal | 1092 (44.6) |
| Post-menopausal | 1365 (55.8) |
| DM | |
| No | 1985 (81.1) |
| Yes | 463 (18.9) |
| Hypertension | |
| No | 2073 (84.7) |
| Yes | 375 (15.3) |
| Hyperlipidemia | |
| No | 2221 (90.7) |
| Yes | 227 (9.3) |
| CAD history | |
| No | 2392 (97.7) |
| Yes | 56 (2.3) |
| BMI | |
| <30 | 1402 (57.3) |
| ≥30 | 675 (27.6) |
| Unknown | 371 (15.2) |
| Endocrine therapy | |
| No | 1372 (56.05) |
| Yes | 1076 (43.95) |
| Left-side radiation | |
| None | 1630 (66.6) |
| Done | 818 (33.4) |
| Radiation therapy | |
| None | 896 (36.6) |
| Done | 1552 (63.4) |
Regimens without anthracycline or anthracycline combined with anti-HER2 agents.
Abbreviations: A, anthracycline-containing; BMI, body mass index; CAD, coronary artery disease; DM, diabetes mellitus; ER=estrogen receptor; H, anti-HER2-agent−containing; HER2, human epidermal growth factor receptor 2.
CV Event analyses
Late severe CV Events
The late severe CV events details in our cohort was shown in Table S3 (online only). Among patients who developed late severe CV events, 66 (48.5%) had HF, 40 (29.4%) cardiomyopathy, 19 (14.0%) MI and 11 (8.1%) cardiovascular death (Table S4, online only). Table S5 shows distributions of late severe CV events by patient age, chemotherapy regimens, and previous CVRFs. Kaplan-Meier analysis revealed that race, disease stage, hypertension, and CAD history were significant prognostic factors (Table 2). The 10-year late-severe-CV-event-free survival rate was significantly worse for patients treated with anthracycline-containing regimens, hypertension, or a history of CAD. Multivariate analysis revealed that Hispanic race and breast carcinoma in situ /early-stage disease were associated with a higher probability of late-severe-CV-event-free survival. Regimens containing anthracyclines (HR, 1.536; 95CI, 0.979–2.411; P=0.062) were not significantly different with no or anthracycline-free regimens. Kaplan-Meier analysis also revealed that the late-severe-CV-event-free survival rate of patients treated with regimens containing anthracyclines but not anti-HER2 agents and patients treated with regimens containing both anthracycline and anti-HER2 agents did not differ significantly (P=0.590; Figure S1, online only). In a propensity-score-matching cohort, regimens containing anthracyclines and anti-HER2 agents were associated with similar late-severe-CV-event-free survival compared with regimens containing anthracyclines without anti-HER2 agents after matching for hypertension, hyperlipidemia, DM, BMI, and CAD history (HR, 0.856; 95CI, 0.573–1.280; P=0.449) (Table S6).
Table 2:
Late-severe-CV-event–free survival among patients diagnosed with HER2-positive breast cancer between 1998 and 2009 (N=2448)
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Covariate | 10-year CV-event-free survival rate (95%CI) | P * | HR (95%CI) | P * |
| Chemotherapy regimen | 0.003 | |||
| None/anthracycline-free | 96.0 (94.4–97.7) | 1 [Reference] | ||
| Anthracycline-containing | 92.0 (90.5–93.5) | 1.536 (0.979–2.411) | 0.062 | |
| Age, years | 0.415 | |||
| <50 | 93.6 (92.0–95.3) | |||
| ≥50 | 92.8 (91.1–94.5) | |||
| Race/ethnicity | 0.007 | |||
| White | 93.3 (91.8–94.7) | 1 [Reference] | ||
| Hispanic | 96.5 (94.3–98.7) | 0.449 (0.234–0.862) | 0.016 | |
| Other | 90.0 (86.7–93.5) | 1.358 (0.909–2.029) | 0.135 | |
| ER status | 0.733 | |||
| Negative | 92.8 (91.0–94.6) | |||
| Positive | 93.5 (91.9–95.0) | |||
| Unknown | – | |||
| Disease stage | <0.001 | |||
| In situ | 98.9 (96.7–100.0) | 0.136 (0.018–1.024) | 0.050 | |
| Early stage | 94.2 (92.9–95.5) | 0.558 (0.392–0.796) | 0.001 | |
| Locally advanced | 89.3 (86.4–92.2) | 1 [Reference] | ||
| Menopausal status | 0.514 | |||
| Pre-/peri-menopausal | 93.7 (92.0–95.4) | |||
| Post-menopausal | 92.8 (91.2–94.4) | |||
| Nuclear grade | 0.291 | |||
| I/II | 92.0 (89.2–94.8) | |||
| III | 93.7 (92.4–95.0) | |||
| Unknown | 87.6 (77.9–98.7) | |||
| DM | 0.914 | |||
| No | 93.1 (91.8–94.4) | |||
| Yes | 93.7 (91.2–96.3) | |||
| Hypertension | <0.001 | |||
| No | 93.8 (92.6–95.0) | 1 [Reference] | ||
| Yes | 89.7 (86.1–93.5) | 1.546 (1.030–2.320) | 0.036 | |
| Hyperlipidemia | 0.433 | |||
| No | 93.0 (91.7–94.2) | |||
| Yes | 95.4 (92.5–98.4) | |||
| CAD history | <0.001 | |||
| No | 93.4 (92.2–94.6) | 1 [Reference] | ||
| Yes | 83.9 (73.3–96.1) | 3.333 (1.669–6.656) | <0.001 | |
| BMI | 0.260 | |||
| <30 | 93.6 (92.1–95.1) | |||
| ≥30 | 92.4 (90.1–94.7) | |||
| Unknown | 93.1 (89.8–96.6) | |||
| Left-side radiation | 0.745 | |||
| None | 93.2 (91.7–94.6) | |||
| Done | 93.2 (91.2–95.3) | |||
| Radiation therapy | 0.353 | |||
| None | 93.9 (92.1–95.8) | |||
| Done | 92.8 (91.3–94.3) | |||
P values <0.05 are statistically significant.
Abbreviations: BMI, body mass index; CAD, coronary artery disease; CV event, cardiovascular event; CI, confidence interval; DM, diabetes mellitus; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio.
Early CV Events
In our study, 312 (12.8%) patients had at least one early CV event. Early CV events included HF (3.8%), CAD (2.3%), and other CVDs (8.5%). 51.7% of patients who had early CV events were ≥50 years old. Patients treated with anthracyclines and anti-HER2 agents had the highest incidence of early CV events (13.7%), while those treated with anthracyclines without anti-HER2 had 12.3%. The incidence of early CV events in patients treated with regimens without anthracyclines or anti-HER2 agents was 11.8%. Among patients who had early CV events, 18.5% had at least one risk factor; 55.4% had CAD history, 21.9% had hypertension, and 20.1% had DM at breast cancer diagnosis (Table S7).
In the multivariate logistic regression model, age ≥50 years, hypertension, DM, CAD, stage II or III disease, and regimens containing both an anthracycline and anti-HER2 agents independently predicted early CV events (Table 3).
Table 3:
Predictors of early CV events, multivariate logistic regression model (N=2448)
| Variable | OR (95%CI) | P * |
|---|---|---|
| Age, ≥50 years vs. <50 years | 1.475 (1.121–1.944) | 0.006 |
| Hypertension, yes vs. no | 1.451 (1.050–1.990) | 0.022 |
| DM, yes vs. no | 1.641 (1.196–2.236) | 0.002 |
| CAD history, yes vs. no | 7.591 (4.256–13.662) | <0.001 |
| Hyperlipidemia, yes vs. no | 1.045 (0.695–1.540) | 0.827 |
| AJCC stage, II vs. 0/I | 1.960 (1.388–2.793) | <0.001 |
| AJCC stage, III vs. 0/I | 1.655 (1.133–2.432) | 0.010 |
| Chemotherapy regimen, anthracycline vs. no anthracycline/none | 0.728 (0.508–1.045) | 0.085 |
| Chemotherapy regimen, anthracycline and anti-HER2 vs. no anthracycline/none | 1.841 (1.316–2.592) | <0.001 |
| BMI, ≥30 vs. <30 | 1.079 (0.811–1.429) | 0.600 |
P values <0.05 are statistically significant.
Abbreviations: AJCC, American Joint Committee on Cancer; BMI=body mass index; CAD, coronary artery disease; CV, cardiovascular; CI, confidence interval; DM, diabetes mellitus; HER2, human epidermal growth factor receptor 2; OR, odds ratio.
Overall CV Events
The anthracycline-containing regimens, age ≥50 years, post-menopausal status, DM, hypertension, and CAD history were significantly associated with worse overall CV-event-free survival in univariate analysis. Hispanic race, carcinoma in situ, and early-stage disease were protective factors for overall CV-event-free survival.
RMST analysis revealed that anthracycline-containing regimens were not significantly associated with worse overall CV-event-free survival. Age ≥50 years, hypertension, and CAD history remained significantly associated with worse overall CV-event-free survival (Table 4).
Table 4:
Overall CV-event-free survival among patients diagnosed with HER2-positive breast cancer between 1998 and 2009 (N=2448)
| Kaplan-Meier univariate analysis | RMST analysis | |||
|---|---|---|---|---|
| Covariate | 10-year CV-event-free survival rate (95%CI) | P * | RMST ratio (95%CI) | P * |
| Chemotherapy regimen | 0.001 | |||
| None/anthracycline-free | 80.7 (77.6–83.9) | 1 [Reference] | ||
| Anthracycline-containing | 73.3 (71.1–75.7) | 0.965 (0.928–1.004) | 0.075 | |
| Age, years | <0.001 | |||
| <50 | 78.6 (76.1–81.3) | 1 [Reference] | ||
| ≥50 | 72.7 (70.0–75.4) | 0.950 (0.906–0.996) | 0.034 | |
| Race/ethnicity | 0.027 | |||
| White | 75.1 (72.8–77.5) | 1 [Reference] | ||
| Hispanic | 81.8 (77.7–86.2) | 1.044 (0.996–1.093) | 0.073 | |
| Other | 71.9 (67.4–76.8) | 0.955 (0.905–1.007) | 0.086 | |
| ER status | 0.649 | |||
| Negative | 74.6 (71.8–77.4) | |||
| Positive | 76.3 (73.8–78.9) | |||
| Unknown | 81.8 (61.9–100.0) | |||
| Disease stage | <0.001 | |||
| In situ | 91.9 (86.6–97.5) | 1.251 (1.160–1.349) | <0.001 | |
| Early stage | 77.3 (75.1–79.5) | 1.141 (1.090–1.195) | <0.001 | |
| Locally advanced | 68.1 (64.1–72.3) | 1 [Reference] | ||
| Menopausal status | 0.020 | |||
| Pre-/peri-menopausal | 77.1 (74.4–80.0) | 1 [Reference] | ||
| Post-menopausal | 74.3 (71.8–76.9) | 1.025 (0.978–1.074) | 0.306 | |
| Nuclear grade | 0.982 | |||
| I/II | 74.6 (70.4–79.1) | |||
| III | 75.8 (73.7–77.9) | |||
| Unknown | 76.7 (65.5–89.8) | |||
| DM | <0.001 | |||
| No | 76.6 (74.6–78.7) | 1 [Reference] | ||
| Yes | 71 (66.7–75.5) | 0.951 (0.898–1.006) | 0.082 | |
| Hypertension | <0.001 | |||
| No | 77.3 (75.3–79.3) | 1 [Reference] | ||
| Yes | 66.2 (61.1–71.6) | 0.912 (0.852–0.975) | 0.007 | |
| Hyperlipidemia | 0.065 | |||
| No | 75.8 (73.8–77.8) | |||
| Yes | 73.1 (67.4–79.3) | |||
| CAD history | <0.001 | |||
| No | 76.6 (74.8–78.5) | 1 [Reference] | ||
| Yes | 29.9 (19.2–46.5) | 0.507 (0.345–0.745) | 0.001 | |
| BMI | 0.116 | |||
| <30 | 76.5 (74.1–79.0) | |||
| ≥30 | 73.0 (69.4–76.7) | |||
| Unknown | 77.1 (72.2–82.3) | |||
| Left-side radiation | 0.571 | |||
| None | 75.3 (73.0–77.7) | |||
| Done | 76.0 (72.8–79.3) | |||
| Radiation therapy | 0.915 | |||
| None | 75.8 (72.7–79.0) | |||
| Done | 75.4 (73.1–77.9) | |||
P values <0.05 are statistically significant.
Abbreviations: BMI, body mass index; CAD, coronary artery disease; CV, cardiovascular; CI, confidence interval; DM, diabetes mellitus; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; RMST, restricted mean survival time.
Survival analysis
The results of the univariate and multivariate analyses of OS are given in Table 5. In our study, 136 patients had late severe CV events and 752 died of any cause (533 (70.9%) died of primary breast cancer, 12 (1.6%) died of cardiovascular disease). Patients treated with regimens containing both an anthracycline and anti-HER2 agents had a higher 10-year OS rate than those with regimens containing an anthracycline without anti-HER2 agents or regimens containing no anthracycline or anti-HER2 agents. Patients with no hypertension or CAD history at breast cancer diagnosis had significantly higher OS rates than did patients with the risk factors. Patients with carcinoma in situ /early-stage disease or pre-/peri-menopausal status had substantially higher OS rates.
Table 5:
10-year OS among patients diagnosed with HER2-positive breast cancer between 1998 and 2009 (N=2448)
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Covariate | 10-year OS rate (95%CI) | P * | HR (95%CI) | P * |
| Chemotherapy regimen | <0.001 | |||
| A+H | 79.6 (76.6–82.8) | 0.515 (0.412–0.643) | <0.001 | |
| A | 61.2 (58.0–64.5) | 1.149 (0.964–1.369) | 0.121 | |
| None/other† | 72.5 (69.0–76.2) | 1 [Reference] | ||
| Age, years | <0.001 | |||
| <50 | 71.5 (68.8–74.4) | 1 [Reference] | ||
| ≥50 | 68.6 (65.9–71.4) | 1.255 (1.026–1.535) | 0.027 | |
| ER status | 0.006 | |||
| Negative | 66.3 (63.4–69.3) | 1 [Reference] | ||
| Positive | 73.5 (70.9–76.2) | 0.813 (0.703–0.941) | 0.006 | |
| Unknown | 72.7 (50.6–100.0) | 0.408 (0.129–1.289) | 0.127 | |
| Race/ethnicity | 0.070 | |||
| White | 69.7 (67.4–72.1) | |||
| Hispanic | 75.0 (70.4–80.0) | |||
| Other | 67.0 (62.3–72.0) | |||
| Disease stage | <0.001 | |||
| In situ | 91.8 (86.0–97.9) | 0.142 (0.074–0.271) | <0.001 | |
| Early stage | 73.9 (71.6–76.2) | 0.475 (0.406–0.555) | <0.001 | |
| Locally advanced | 57.6 (53.8–61.7) | 1 [Reference] | ||
| Menopausal status | 0.005 | |||
| Pre-/peri-menopausal | 71.5 (68.6–74.5) | 1 [Reference] | ||
| Post-menopausal | 68.8 (68.6–74.5) | 1.027 (0.837–1.260) | 0.802 | |
| Nuclear grade | 0.351 | |||
| I/II | 70.7 (66.4–75.3) | |||
| III | 70 (67.8–72.3) | |||
| Unknown | 65.4 (53.9–79.4) | |||
| DM | 0.050 | |||
| No | 70.6 (68.5–72.8) | |||
| Yes | 67.5 (63.0–72.3) | |||
| Hypertension | <0.001 | |||
| No | 71.4 (69.3–73.5) | 1 [Reference] | ||
| Yes | 62.5 (57.4–68.0) | 1.194 (0.984–1.448) | 0.073 | |
| Hyperlipidemia | 0.554 | |||
| No | 69.8 (67.8–71.9) | |||
| Yes | 71.7 (65.7–78.4) | |||
| CAD history | <0.001 | |||
| No | 70.4 (68.5–72.4) | 1 [Reference] | ||
| Yes | 51.8 (39.0–68.8) | 1.783 (1.225–2.595) | 0.003 | |
| BMI | <0.001 | |||
| <30 | 70.1 (67.5–72.7) | 1 [Reference] | ||
| ≥30 | 75.1 (71.6–78.7) | 0.716 (0.598–0.857) | <0.001 | |
| Unknown | 59.9 (54.5–65.9) | 1.329 (1.090–1.622) | 0.005 | |
| Left-side radiation | 0.410 | |||
| None | 70.0 (67.6–72.5) | |||
| Done | 70.0 (66.7–73.5) | |||
| Radiation therapy | 0.961 | |||
| None | 69.9 (66.6–73.3) | |||
| Done | 70.1 (67.7–72.6) | |||
P values <0.05 are statistically significant.
No chemotherapy or regimens without anthracycline or anti-HER2 agents.
Abbreviations: A, anthracycline-containing; BMI, body mass index; CAD, coronary artery disease; CI, confidence interval; DM, diabetes mellitus; ER, estrogen receptor; H, anti-HER2-agent−containing; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; OS, overall survival.
Multivariate analysis revealed a significantly lower risk for all-cause mortality for patients treated with regimens containing both anthracyclines and anti-HER2 agents and those with ER-positive status, carcinoma in situ or early-stage disease, or BMI ≥30. Age ≥50 years and CAD history were significantly associated with worse OS. However, after adjustment for related prognostic factors, menopausal status and hypertension had no significant effect on OS.
DISCUSSION
In this cohort study of HER2-positive breast cancer patients, we found that the presence of certain CVD risk factors—hypertension and CAD history—were significantly associated with worse late-severe-CV-event-free survival, higher early-CE incidence, and worse overall CV-event-free survival. Moreover, the regimens of limited cycles of an anthracycline combined with anti-HER2 therapy were tolerable, associated with better survival, and did not increase the risk of late severe CV events relative to anthracycline-containing regimens alone.
The combination of an anthracycline and anti-HER2 agents represents the drug set we have used most extensively in HER2-positive breast cancer and for which we have the most data. We sought to help individuals complete their cancer treatment without serious complications, even though they had a number of underlying cardiovascular risk factors. We found that the addition of anti-HER2 therapy to anthracyclines did not increase the risk of late severe CV events, compared with anthracyclines alone. According to a recent study [16], the combination of anti-HER2 therapy and anthracycline-containing chemotherapy was well tolerated. In the 5-year follow-up, there were 18.1% patients underwent any cardiovascular events. The cardiovascular events rate was similar in those anti-HER2 agents combined with anthracycline-containing or anthracycline-free group. Moreover, the combination therapy translated into better survival than anthracyclines alone, which suggests that the addition of anti-HER2 agents to anthracycline-based regimens can improve survival outcomes without increasing risk for late severe CV events. It was in accordance with an earlier report that the benefit of combining trastuzumab with anthracyclines outweighs the risk of CV events [17].
Buzdar et al.[18] reported that the combination of limited cycles of anthracycline and trastuzumab is tolerable. In their small study, 3 patients had >10% decrease in ejection fraction in total 23 patients treated with anthracycline and trastuzumab and none of them developed clinical congestive heart failure. Moreover, the NOAH trial compared the addition of trastuzumab to chemotherapy alone in neoadjuvant chemotherapy population, and found that only 2 (<2%) patients underwent CHF [19]. It means that the cardiotoxicity of trastuzumab combined with anthracycline was overestimated. Our study concluded that the combination therapy of anthracycline and anti-HER2 agents did not increase the risk of late severe CV events, and patients treated with the combination therapy should be monitored carefully for signs of early CV events which might be potentially reversible. In a study by Hershman et al. [20], hypertension was the only preexisting CVRF associated with cardiotoxicity in patients treated with anthracyclines. Our study revealed that hypertension, in addition to CAD history, is significantly associated with a high risk for cardiotoxicity, in accordance with the finding by Pinder et al. and Suter et al. [21, 22]. In a population-based cohort study conducted by Thavendiranathan et al. [23], hypertension and CAD were associated with higher risk for HF. Studies using risk score calculators to identify the patients at high risk for cardiotoxicity conducted by Rushton et al. [24] and Ezaz et al. [25] both identified hypertension as a risk factor. Together, these findings suggest that an aggressive effort to reduce hypertension in breast cancer patients may be warranted. However, the exact mechanism by which CAD contributes to cardiotoxicity remains unclear, and further studies are necessary [26]. Given the results observed in our study, an aggressive effort to reduce hypertension in HER2-positive breast cancer patients treated with anthracycline may be worth considering.
We found that age was not an independent prognostic factor for late severe CV events but was a significant prognostic factor for early CV event incidence and worse overall CV- event-free survival and OS, possibly because older patients with a history of breast cancer have a higher risk of CVD-related death than do patients without a history of breast cancer [27]. Older patients are more likely to have a subclinical myocardial injury and more cardiac morbidity, whereas the cardiotoxicity caused by anti-HER2 agents is reversible [28]. It was reported that patients older than 80 years had more than twice the risk of HF as patients aged 65–80 years old [20]. The small percentage of patients ≥50 years in our study may explain why age was not an independent prognostic factor for late severe CV events.
Obesity is associated with better survival in various cancers [29]. Higher BMI was a protective factor for long-term survival in the present study, and obesity was not a risk factor for cardiotoxicity. But obesity was not a significant factor for survival in ER-negative and HER2-positive subgroup [30]. Our findings also contrast with those of Guenancia et al. [31], who reported that overweight and obesity are risk factors for cardiotoxicity in patients treated with anthracycline with or without anti-HER2 agents. Several factors may contribute to these studies’ disparate findings. For example, Guenancia et al. did not separately assess obesity-related CVD risk factors such as hypertension and diabetes. In addition, they considered the proportion of patients with cardiotoxicity but not the time from breast cancer diagnosis to CV events. In accordance with our finding that DM is not an independent prognostic factor for CV events, Peairs et al. [32] concluded that diabetes is associated with poor prognosis not because of the disease itself, but because of its comorbidities.
Race was a significant prognostic factor for CV events. Hispanic patients have low CVD rates [33], but they had higher rates of CVD risk factors, including obesity, diabetes, and hyperlipidemia, compared with patients of other races. This phenomenon may be due to acculturation, a lack of data consistency in conjunction with other nutritional and social factors, and/or salmon bias that foreign-born persons who have lived in the United States for some time return to their countries of origin in significant numbers when their health deteriorates [34, 35]; however, the exact mechanism is unclear.
Anthracycline agents were previous reported to be associated with late cardiotoxicity in breast cancer patients. The risk of HF for patients with anthracycline was 50% higher than those without chemotherapy in 5 years after diagnosis [36]. In our study, regimens containing both anthracycline and anti-HER2 agents increased the incidence of early CV events compared with regimens containing anthracycline alone. This finding is similar to previous reports [37, 38]. However, late-severe-CV-event−free survival rates did not differ significantly between patients treated with regimens containing both anthracycline and anti-HER2 agents and patients treated with anthracycline alone. These apparently contradictory findings might be explained by the fact that the mechanism by which anti-HER2 agents cause cardiotoxicity is different from that by which anthracycline cause cardiotoxicity [39]. Most cardiac events induced by anthracycline occurred within 1 year. The addition of anti-HER2 agents may not have contributed to the late severe cardiotoxicity because these agents do not cause the ultrastructural changes that anthracycline can and because their toxicity abates after therapy ends. It suggested that the combination of anthracycline and anti-HER2 therapy can be used in patients with hypertension and CAD history with careful monitoring of early cardiotoxicity. We consider the CV-event-free survival rather than CV event rate may be more suitable for evaluating the influence of anthracycline agents and anti-HER2 therapy and quality of life in breast cancer survivors. Our study had the limitations of retrospective studies. Retrospective ṅstudies only show statistical associations and cannot prove causal relationships. In a retrospective study, there is no way to ensure that no outcomes are not missing. Other potential limitations are as follows.
First, our search of ICD-9-Clinical Modification diagnostic codes to identify patients who had CV events may have underestimated the true CV event incidence. Moreover, there may be indication bias when comparing the cardiotoxicity of regimens containing anthracycline without anti-HER2 agents and regimens containing anthracycline and anti-HER2 agents in our study. HER2-positive breast cancer patients who did not receive anti-HER2 agents may have contraindications for anti-HER2 therapy, and another potential confounder in our analysis was that most anti-HER2 therapy was not available until 2002. However, we analyzed a propensity-score matched cohort in the supplementary material, and the hazard ratio results were in accordance with findings from the unmatched cohort. Moreover, most patients with hypertension at diagnosis may take angiotensin-converting enzyme inhibitors and β-blockers while a few may not. These medications may influence the risk for cardiac toxicity. In addition, because the number of patients with CAD history in our study was limited, we did not have adequate statistical power to further evaluate the benefits of different regimens as covariates in survival analyses. About half of HER2-positive breast cancers are also positive for female hormone receptor(s). Aromatase inhibitors may be used in conjunction with anti-HER2 agents. There is an increase in cardiac adverse events associated with aromatase inhibitors relative to tamoxifen, which may be related to cardiotoxicity of aromatase inhibitors or cardioprotection by tamoxifen. A meta-analysis supports the latter explanation[40]. In this study, we did not address endocrine therapy, and is another limitation. Despite the above limitations, this is the first cohort study to report associations between CVRFs for CV events and OS in patients with HER2-positive breast cancer with a median follow-up duration of almost 10 years. And our results were based on complete history of baseline CAD and cardiovascular risk factors, accurate cardiovascular toxicities information, and enrichment population of cardiotoxicity in our study. Moreover, we took into account multiple covariates in the tumor-related and demographic domains.
In conclusion, hypertension and a history of CAD at diagnosis are associated with worse late-severe-CV-event−free survival and overall CV-event-free survival and higher early-CV-event incidence. However, the addition of combined anthracycline an anti-HER2 therapy resulted in significantly higher early CV events, but not long-term CV events and conferred better survival in this study population. For patients at high risk for CV events, comprehensive management of CVD risk factors and appropriate therapy options can improve survival without aggravating cardiotoxicity. For early HER2-positive breast cancer patients with hypertension and CAD history at high risk for CV events, anthracycline-containing regimens combined with anti-HER2 therapy may be an acceptable alternative used with caution. The addition of pertuzumab to trastuzumab and chemotherapy did not increase cardiac toxicity [41, 42]. Our study may also be applicable to patients receiving pertuzumab and trastuzumab nowadays.
Supplementary Material
Translational Relevance.
It is increasingly important to explore the late-onset cardiotoxicity and overall survival in HER2-positive breast cancer survivors who received anti-HER2 therapy and anthracyclines especially those with cardiovascular disease risk factors. However, it is difficult to examine due to lack of large dataset with long follow-up. Our cohort study has found that only hypertension and coronary artery disease history were substantially associated with worse late-severe-cardiovascular-event-free survival, overall cardiovascular-event-free survival and early-cardiovascular-event incidence. Adding anti-HER2 agents to anthracycline did not increase the risk for late severe cardiotoxicity and conferred better survival among the study population. Our study can provide some evidence to guide comprehensive cancer treatment and comorbidity/cardiovascular complications management for HER2-positive breast cancer patients.
ACKNOWLEDGMENTS
The authors acknowledge Joe Munch in the Department of Scientific Publications and Jeanie F. Woodruff, BS ELS in the Department of Emergency Medicine at MD Anderson for editing the manuscript.
Funding:
No specific funding for this research. MD Anderson Cancer Center was supported by the National Cancer Institute [MD Anderson Cancer Center Support Grant number P30 CA016672] of the National Institutes of Health.
Authors’ disclosures of potential conflicts of interest:
Dr. Yeung had research funding by DepoMed, Inc. and Bristol-Myer Squibb, and was on an advisory board for Celgene Corporation.
Footnotes
All other authors declare no competing interests.
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