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Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A Retrospective Cohort Study

Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A... DOI:10.1093/jnci/djs317 © The Author 2012. Published by Oxford University Press. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Article risk of Heart Failure in Breast cancer Patients After Anthracycline and t rastuzumab t reatment: A retrospective cohort Study Erin J. Aiello Bowles, Robert Wellman, Heather Spencer Feigelson, Adedayo A. Onitilo, Andrew N. Freedman, Thomas Delate, Larry A. Allen, Larissa Nekhlyudov, Katrina A. B. Goddard, Robert L. Davis, Laurel A. Habel, Marianne Ulcickas Yood, Catherine McCarty, David J. Magid, Edward H. Wagner; for the Pharmacovigilance Study Team Manuscript received January 05, 2012; revised June 13, 2012; accepted June 18, 2012. Correspondence to: Erin J. Aiello Bowles, MPH, Group Health Research Institute, 1730 Minor Ave, Ste 1600, Seattle, WA 98101 (e-mail: bowles.e@ghc.org). Background Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with inci- dent HF/CM. Methods We conducted a population-based, retrospective cohort study of 12 500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regres- sion models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities. Results Among 12 500 women (mean age = 60 years, range = 22–99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemother- apy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/ CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35). Conclusions Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety. J Natl Cancer Inst 2012;104:1293–1305 Breast cancer is one of the most common cancers in the United Data from clinical trials indicate that anthracycline use is asso- States with an estimated 232  620 new diagnoses in 2011 (1). ciated with an approximate 2% increase (10–14) in heart failure Chemotherapeutic regimens for invasive breast cancer in women and/or cardiomyopathy (HF/CM) incidence, and anthracycline include neoadjuvant or adjuvant anthracycline in combination with followed by trastuzumab is associated with an approximate 4% cyclophosphamide (2). A major advance in breast cancer treatment increase (15–19). Clinical trial findings were critical in leading to has been the incorporation of trastuzumab, a monoclonal anti- prescribing warnings and protocols for regular cardiac function body against HER2/neu. Approximately 20%–25% of women with monitoring before and during treatment (20–22). However, trials breast cancer overexpress HER2 and are recommended for trastu- typically exclude older women (eg, aged ≥ 70  years) and women zumab therapy following the completion of anthracycline therapy with major comorbidities; therefore, the association between (3–5). Randomized clinical trials have demonstrated that these reg- anthracycline and/or trastuzumab use and HF/CM in this popula- imens are highly effective in improving disease-free survival (6–9); tion is not well understood. The effectiveness of these treatments however, side effects are not minimal. and risk of cardiotoxicity may differ in community practice. Three jnci.oxfordjournals.org JNCI | Articles 1293 observational studies using Surveillance, Epidemiology, and End received anthracycline and/or trastuzumab. Our final analytic sam- Results (SEER) Medicare data have evaluated HF/CM incidence ple included 12 500 women. Women were followed-up until inci- following treatment with anthracycline, but they were limited to dent HF/CM diagnosis, health plan disenrollment, death, or the older women (aged ≥ 65  years) and did not evaluate trastuzumab end of follow-up on December 31, 2009, whichever came first. (23–25). Therefore, broader population-based estimates of HF/CM This study was approved by the Institutional Review Board risk associated with anthracycline and trastuzumab are unknown. (IRB) for Group Health Cooperative and five other sites that Using data from the health maintenance organization (HMO) ceded review to Group Health Cooperative and separately by the Cancer Research Network (CRN) (26), we evaluated real-world Institutional Review Boards at Marshfield Clinic and Henry Ford. adjuvant anthracycline and trastuzumab use and subsequent inci- We obtained information on women from all sites via a waiver of dent HF/CM risk among a population-based cohort of women consent. aged 18 years or older and diagnosed with invasive breast cancer. We took advantage of observational administrative health plan Data Collection data to conduct this comparative safety study of anthracycline We obtained data from each site’s Virtual Data Warehouse therapy, which was previously examined only in clinical trials or (VDW), which has been described in detail elsewhere (28). The SEER-Medicare populations, and trastuzumab therapy, which, VDW includes standardized variables derived from administra- to our knowledge, has not been evaluated outside of randomized tive databases at each CRN site. A programmer at Group Health clinical trials. Cooperative wrote standardized code for programmers at other sites to execute; programmers then transferred limited datasets to Group Health Cooperative for analysis. Methods Study Population Chemotherapy Exposure The CRN is a consortium of 14 nonprofit research centers based We collected data on chemotherapy administration using vali- in integrated healthcare delivery organizations within the HMO dated VDW procedure codes and pharmacy data, which have been Research Network (26). We included 12 902 women aged 18 years reported previously (29). Chemotherapy procedure data included or older and diagnosed with incident invasive [SEER summary Healthcare Common Procedure Coding System (HCPCS) stages—local, which is confined to the breast, or regional, which and Current Procedural Terminology (CPT)-4 codes; phar- has spread to the lymph nodes (27)] breast cancer from January 1, macy data included National Drug Codes (NDCs). We extracted 1999 through December 31, 2007. All women were enrolled at least HCPCS and NDCs specific to anthracycline and trastuzumab and 12 months before diagnosis in these six CRN sites: Group Health HCPCS, NDCs, and CPT-4 codes related to other chemother- Cooperative, Henry Ford Hospital and Health System, Marshfield apy and administration dates. Because CPT-4 codes do not spe- Clinic, and Kaiser Permanente regions in Colorado, Georgia, cify chemotherapy agents, we coded CPT-4 codes with no other and Northwest. Two additional CRN sites (Kaiser Permanente information as “other” chemotherapy. We extracted treatment Northern California and Harvard Pilgrim Health Care) used data up to 24  months after breast cancer diagnosis. We catego- slightly different inclusion criteria for year of breast cancer diagno- rized women into five mutually exclusive treatment categories: sis. Because of the large population at Kaiser Permanente Northern anthracycline-based only (without trastuzumab; however, women California, we included a 10% random sample of women diagnosed could have received additional chemotherapy such as cyclophos- between January 1, 2001 and December 31, 2007 (chemotherapy phamide), trastuzumab-based only (without anthracycline; though data from 1999 and 2000 were incomplete and not included). all but one woman received additional chemotherapy), anthracy- Harvard Pilgrim data included women receiving care at Harvard cline plus trastuzumab (trastuzumab therapy following anthracy- Vanguard Medical Associates (a multispecialty medical practice) cline therapy), other chemotherapy, or no chemotherapy. and diagnosed from January 1, 1999 through December 31, 2006. To validate chemotherapy data, we compared chemotherapy We excluded women diagnosed with HF/CM before breast regimens from VDW data with medical record review of 400 cancer diagnosis (n = 253 women) or before chemotherapy initia- women (50 from each CRN site). Sensitivities and specificities tion (n = 96 women) because these diagnoses could not be attrib- exceeded 90% for all treatment categories, and positive predictive uted to chemotherapy use. We also excluded women who did not values (PPVs) exceeded 90% for anthracycline alone, trastuzumab receive chemotherapy but were diagnosed with HF/CM within alone, and anthracycline plus trastuzumab treatment, as reported 70  days of breast cancer diagnosis (70  days was the median time previously (29). to “other chemotherapy” initiation; n = 53 women). These women may have been eligible for chemotherapy but likely did not receive Heart Failure Outcome it because of their new HF/CM diagnosis (potentially found dur- Our primary outcome was HF/CM following breast cancer diag- ing cardiac screening before the anticipated chemotherapy initia- nosis, defined using a previously validated algorithm, though not tion). In general, excluded HF/CM patients were older (55% were in breast cancer patients (30). The algorithm uses International >75  years) and had more comorbidities (70.8% had a Charlson Classification of Diseases, Ninth Revision (ICD-9) codes with five comorbidity score ≥ 2 [moderate comorbidity]), compared with different criteria that indicate HF/CM (see Table  1 for criteria, our included cohort (18% were >75 years and 15% had a Charlson ICD-9 codes, and proportion of women classified by each criteria) comorbidity score ≥ 2). Over 50% of excluded HF/CM patients (31). We categorized women as having no HF/CM or incident did not receive any chemotherapy, although 10% of these women HF/CM (occurring after breast cancer treatment). Because 1294 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Table 1. ICD-9 code-based algorithm used to determine HF/CM from administrative data by treatment group* Treatment group No Anthracycline Trastuzumab Anthracycline + Other chemotherapy only only trastuzumab chemotherapy (n=5807 women) (n=3697 women) (n=112 women) (n=442 women) (n=2442 women) Algorithm criteria % % % % % ≥1 primary discharge diagnosis 4.2 2.1 3.6 4.1 5.3 ≥3 secondary discharge diagnoses 0.5 0.2 0 0.5 0.4 ≥2 outpatient diagnoses 2.8 1.7 7.1 7.0 2.5 ≥3 emergency department diagnoses 0 0 0 0 0 ≥2 secondary discharge + ≥1 outpatient diagnosis 0.1 0.1 0 0 0.2 None of the above (no HF/CM) 92.5 95.9 89.3 88.5 91.7 * The study population includes 12 500 women diagnosed with incident invasive breast cancer from January 1, 1999 through December 31, 2007. All women were members of one of eight Cancer Research Network (CRN) integrated health plans for 12 or more months before breast cancer diagnosis. Administrative data included ICD-9 codes for HF/CM as noted by a provider in the medical record and available in the CRN Virtual Data Warehouse (VDW; ICD-9 codes: 398.91, 402. x1, 402.x3, 404.x1, 404.x3, 422.90, 425.4, 425.9, 428.xx). Primary and secondary discharge diagnoses were indicated at the time of the patient’s release from a hospital. Other diagnoses occurred after emergency department release or an outpatient appointment. The algorithm for this study was based on previous HF claims-based algorithms (30,41), with the addition of the 425 “cardiomyopathy” codes because of the nature of cardiotoxicity. The algorithm was validated on a subset of 400 women as previously reported (31). ICD-9 = International Classification of Diseases, Ninth Revision; HF/CM = Heart failure and/or cardiomyopathy. Statistical Analysis administrative data do not capture results of echocardiograms We described the distribution of chemotherapy use by patient or other methods for measuring left ventricular ejection fraction characteristics, including the median and interquartile range (LVEF), we could not use LVEF findings in our HF/CM defin- (25th–75th percentile) for follow-up time (time for follow-up ition. The PPV of the algorithm for any HF/CM diagnosis during treatment until incident HF/CM diagnosis, health plan the period from 12 months before to 12 months after breast can- disenrollment, death, or December 31, 2009, whichever came first). cer diagnosis was 68.6% (95% confidence interval [CI] = 44.9% to We then used Cox proportional hazards regression to calculate 85.4%), which we have shown earlier (31). The PPV for incident hazard ratios (HRs) with 95% (CIs) for HF/CM associated with HF/CM during the 12 months after breast cancer diagnosis was time-varying chemotherapy exposures. Each participant began 33.3% (95% CI = 12.8% to 63.1%) (31); this estimate was based accruing person-time on the date of chemotherapy initiation (ie, on only four true-positive HF/CM patients, but it suggests that index date) and stopped accruing person-time at the time of incident the performance may be worse for the period after breast cancer HF/CM diagnosis, health plan disenrollment, death, or December diagnosis. PPV also varied by the definition of the gold standard, 31, 2009, whichever came first. We used day 70 after diagnosis as a and the estimates above included 24  “indeterminate” diagnoses proxy for the index date for unexposed women. Using time-varying (those that could not be definitively classified as HF/CM) as nega- exposures allowed us to account for changes in chemotherapy use. tives in the gold standard. When we included patients with “inde- For example, women were considered anthracycline-based-only terminate” HF/CM diagnoses as positives in the gold standard, users until they started trastuzumab therapy; thereafter, they were the PPV of the algorithm increased to 81.9% (95% CI = 58.0% considered anthracycline plus trastuzumab users. We adjusted to 93.7%), as reported previously (31). We did not have gold all models for covariates that were either jointly associated with standard data to evaluate the PPV for incident heart failure after chemotherapy and HF/CM risk (confounders) or associated solely chemotherapy initiation or beyond 12 months after breast cancer with HF/CM risk in a bivariate manner at P values less than .05. diagnosis. These included CRN site (eight sites mentioned earlier), age at diagnosis (grouped as <55, 55–64, 65–74, ≥75  years), Charlson Covariates comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis Each CRN site maintains its own tumor registry in compliance (localized vs regional), year of diagnosis (categorical for each year), with North American Association of Central Cancer Registries and radiation treatment (yes vs no). (NAACCR) standards, or contracts with their local state or SEER Survivor curves and the corresponding cumulative incidence tumor registries. From tumor registry data, we collected data on curves were estimated from the adjusted Cox model using the breast cancer diagnosis date, age at diagnosis (<55, 55–64, 65–74, method described by Breslow (34,35). All covariates were set to ≥75 years), race (American Indian or Alaskan Native, Asian, black, their respective mean values as estimated from the overall sample. white), ethnicity (non-Hispanic white vs Hispanic), summary stage The annual cumulative incidence up to year 5 for each chemother- (localized vs regional), lymph node status (positive vs negative), and apy group, both overall and by age group, was estimated at the most radiation therapy (yes vs no) as defined by NAACCR classifica- proximal event time observed in the data. Numbers of patients at tions. Using VDW data, we calculated the Charlson comorbid- risk are presented as the number under observation at the begin- ity index (0, 1, 2, ≥3) that weights up to 19 comorbid conditions ning of each time interval. depending on their seriousness, using the Deyo index based on the In order to assess any violations to the proportional hazards presence of relevant ICD-9 codes in the year before breast cancer assumption in our primary analysis (average hazards ratios for diagnosis (32,33). jnci.oxfordjournals.org JNCI | Articles 1295 chemotherapy exposure during the entire study period), we per- <65 years, 55.3%; regional summary stage, 11.5%; Charlson score formed exploratory analyses to characterize changes of the hazard ≥2, 16.2%; and radiation therapy received, 58.6%). Recipients of ratio over time for each chemotherapy exposure. Toward this end, trastuzumab-based therapy without anthracycline, though small we allowed the hazard ratio for each chemotherapy exposure to in number, were older (age ≥65  years, 32.2%) and had more vary with time by including an interaction with time in our models. comorbidities (Charlson score ≥2, 21.4%) than women in other The degree to which the proportional hazards assumption was vio- treatment groups. lated for covariates was assessed through the use of the likelihood ratio test for interactions between covariates and time, as well as Risk of HF/CM by Chemotherapy Exposure inspection of residual plots. Interactions with time were statistically Women were followed-up until incident HF/CM diagnosis, health significant at P values less than .05 for age, stage, site, Charlson plan disenrollment, death, or December 31, 2009, whichever came score, and year of diagnosis. Review of residual plots yielded very first. The adjusted cumulative HF/CM incidence for the first little in the way of substantial proportional hazards violations, and 5 years of follow-up (the median follow-up time was 4.4 years) is most were focused in areas of sparse data. We conducted sensi- shown in Figure  1. The HF/CM incidence among anthracycline tivity analyses with stratified models when there was evidence of recipients increased with increasing follow-up time (year 1 vs year a potential deviation from the proportional hazards assumption. 5, cumulative incidence = 1.2% [95% CI = 1.0% to 1.5%] vs 4.3% Sensitivity analyses yielded minimal changes in primary estimates; [95% CI = 3.5% to 5.0%]) and was similar to the incidence among thus, we present results based on the primary, unstratified analysis. recipients of other chemotherapy (year 1 vs year 5, cumulative inci- We conducted several sensitivity analyses in order to address dence = 1.3% [95% CI = 1.0% to 1.6%] vs 4.5% [95% CI = 3.7% potential limitations and biases in observational administrative to 5.3%]). The cumulative HF/CM incidence among recipients data. We conducted Cox regression analyses after changing the of anthracycline plus trastuzumab was 6.2% (95% CI  =  4.1% to proxy index date to 234 days after breast cancer diagnosis (the 75th 8.2%) after 1 year of follow-up and continued to increase to 20.1% percentile of time to “other chemotherapy” initiation) in unex- (95% CI = 14.0% to 25.6%) by 5 years. The risk of incident HF/ posed women; excluding women with comorbidities (Charlson CM among all women was statistically significantly increased for score >1; n = 1854 women); excluding women who initiated ther- anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), apy more than 12  months after breast cancer diagnosis (n  =  519 trastuzumab without anthracycline (HR = 4.12, 95% CI = 2.30 to women); and excluding women diagnosed before 2004 (when there 7.42), anthracycline plus trastuzumab (HR = 7.19, 95% CI = 5.00 was limited use of trastuzumab in the adjuvant setting; n  =  6779 to 10.35), and other chemotherapy (HR = 1.49, 95% CI = 1.25 to women). Further, we conducted stratified analyses by CRN site and 1.77), compared with no chemotherapy (Table 3). age group. The majority of analyses were conducted in Stata 11 (StataCorp, Risk of HF/CM by Age at Breast Cancer Diagnosis College Station, TX); cumulative incidence estimates were The 5-year cumulative incidence for HF/CM associated with estimated with SAS version 9.2 for Windows (SAS Institute Inc, anthracycline use increased with increasing age (among age Cary, NC). All hypothesis tests were two-sided, and we considered <55  years, cumulative incidence  =  1.2% [95% CI  =  0.0% to P values less than .05 statistically significant. 26.1%]; among age 55–64  years, cumulative incidence =2.9% [95% CI = 1.8% to 4.0%]; among age 65–74 years, cumulative inci- dence = 6.2% [95% CI = 3.9% to 8.5%]; and among age ≥75 years, results cumulative incidence  =  10.6% [95% CI  =  3.9% to 16.9%]; Characteristics of Patients by Chemotherapy Use Figure 2, A–D). The 5-year cumulative incidence for HF/CM asso- Among 12  500 women who were diagnosed with invasive breast ciated with anthracycline plus trastuzumab use also increased with cancer from January 1, 1999 through December 31, 2007, chemo- increasing age (among age <55 years, cumulative incidence = 7.5% therapy use was as follows: 5807 (46.5%) received no chemother- [95% CI  =  0.0% to 85.9%]; among age 55–64  years, cumula- apy, 3697 (29.6%) received anthracycline-based chemotherapy tive incidence  =  11.4% [95% CI  =  4.2% to 18.1%]; among age alone, 112 (0.9%) received trastuzumab-based therapy without 65–74  years, cumulative incidence  =  35.6% [95% CI  =  12.5% to anthracycline, 442 (3.5%) received anthracycline plus trastuzumab, 52.5%]; and among age ≥75 years, cumulative incidence = 40.7% and 2442 (19.5%) received other chemotherapy (Table  2). The [95% CI = 0.0% to 71.6%]; Figure 2, A–D). The 5-year cumula- mean age of the population was 60  years (range  =  22–99  years), tive incidences for HF/CM associated with other chemotherapy 85.8% were of white race, and the median follow-up time was use were greatest among the two oldest age groups (among age 4.4 years (interquartile range [IQR] = 2.6–6.9 years). Women who 65–74  years, cumulative incidence  =  8.7% [95% CI  =  6.3% to received anthracycline alone or anthracycline plus trastuzumab 11.0%] and among age ≥75  years, cumulative incidence  =  18.7% were younger (age <65  years, 86.4% and 89.6%, respectively), [95% CI = 14.5% to 22.6%]; Figure 2, C and D). diagnosed at later stages (regional SEER summary stage, 54.2% The hazard ratios for HF/CM associated with chemotherapy use and 61.0%, respectively), had fewer comorbidities (Charlson score decreased with increasing age (Table  3). For example, the hazard ≥2, 10.0% and 7.7%, respectively), and were slightly more likely to ratio for HF/CM associated with anthracycline use alone was statis- receive radiation therapy (yes, 61.0% and 59.4%, respectively) than tically significant among women younger than 55 years (HR = 2.52, women who received other chemotherapy (age <65 years, 54.2%; 95% CI  =  1.20 to 5.29) but not among women 55–64  years SEER regional summary stage, 25.4%; Charlson score ≥2, 19.8%; (HR = 1.61, 95% CI = 0.94 to 2.78) or older. The hazard ratios for and radiation therapy received, 55.2%) or no chemotherapy (age incident HF/CM associated with anthracycline plus trastuzumab 1296 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Table 2. Characteristics of invasive breast cancer patients by adjuvant treatment* Treatment group No chemo- Anthracycline Trastuzumab Anthracycline Other chemo- therapy (n=5807 only (n=3697 only (n=112 + trastuzumab therapy (n=2442 All (n=12500 women) women) women) (n=442 women) women) women) Characteristic No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) Age at diagnosis, y <55 1112 (19.1) 2131 (57.6) 40 (35.7) 272 (61.5) 706 (28.9) 4261 (34.1) 55–64 1489 (25.6) 1063 (28.8) 36 (32.1) 124 (28.1) 617 (25.3) 3329 (26.6) 65–74 1606 (27.7) 423 (11.4) 19 (17.0) 38 (8.6) 622 (25.5) 2708 (21.7) ≥75 1600 (27.6) 80 (2.2) 17 (15.2) 8 (1.8) 497 (20.4) 2202 (17.6) Race American Indian or Alaskan Native 9 (0.2) 11 (0.3) 0 (0.0 0 4 (0.9) 11 (0.5) 35 (0.3) Asian 203 (3.6) 149 (4.1) 4 (3.6) 27 (6.2) 94 (3.9) 477 (3.9) Black 443 (7.8) 527 (14.5) 16 (14.5) 51 (11.8) 193 (8.0) 1230 (10.0) White 5016 (88.5) 2952 (81.1) 90 (81.8) 352 (81.1) 2103 (87.6) 10 513 (85.8) Ethnicity Non-Hispanic 5165 (97.5) 3310 (95.9) 95 (96.0) 386 (95.1) 2237 (96.8) 11 193 (96.8) Hispanic 133 (2.5) 141 (4.1) 4 (4.0) 20 (4.9) 75 (3.2) 373 (3.2) Summary stage† Localized 5066 (88.5) 1683 (45.8) 67 (60.9) 171 (39.0) 1797 (74.6) 8784 (71.1) Regional 660 (11.5) 1991 (54.2) 43 (39.1) 268 (61.0) 612 (25.4) 3574 (28.9) Lymph nodes Negative 5181 (89.2) 1654 (44.7) 72 (64.3) 164 (37.1) 1843 (75.5) 8914 (71.3) Positive 626 (10.8) 2043 (55.3) 40 (35.7) 278 (62.9) 599 (24.5) 3586 (28.7) Charlson score‡ 0 3983 (68.6) 2897 (78.4) 67 (59.8) 350 (79.2) 1567 (64.2) 8864 (70.9) 1 881 (15.2) 430 (11.6) 21 (18.8) 58 (13.1) 392 (16.1) 1782 (14.3) 2 635 (10.9) 284 (7.7) 13 (11.6) 26 (5.9) 303 (12.4) 1261 (10.1) ≥3 308 (5.3) 86 (2.3) 11 (9.8) 8 (1.8) 180 (7.4) 593 (4.7) Radiation therapy No 2355 (41.4) 1397 (39.0) 58 (54.2) 174 (40.6) 1067 (44.8) 5051 (41.5) Yes 3331 (58.6) 2182 (61.0) 49 (45.8) 255 (59.4) 1317 (55.2) 7134 (58.5) Diagnosis year 1999–2003 3229 (55.6) 2054 (55.6) 26 (23.2) 94 (21.3) 1376 (56.3) 6779 (54.2) 2004–2007 2578 (44.4) 1643 (44.4) 86 (76.8) 348 (78.7) 1066 (43.7) 5721 (45.8) * Women were diagnosed with breast cancer between January 1, 1999 and December 31, 2007. Chemotherapy use was extracted from the Cancer Research Network (CRN) Virtual Data Warehouse (VDW) procedure and pharmacy data up to 24 months after breast cancer diagnosis. Chemotherapy procedure data included Healthcare Common Procedure Coding System (HCPCS) and Current Procedural Terminology (CPT)-4 codes; pharmacy data included National Drug Codes (NDCs). “Anthracycline only” indicates treatment without trastuzumab, although women could have received additional chemotherapy such as cyclophosphamide. “Trastuzumab only” indicates treatment without anthracycline, although all but one woman received additional chemotherapy. “Anthracycline + trastuzumab” indicates trastuzumab therapy following anthracycline therapy. “Other chemotherapy” indicates CPT-4 codes without any information about specific chemotherapy agents, or HCPCS and NDCs that specified chemotherapy drugs other than anthracycline or trastuzumab. Diagnosis year was categorized as 1999–2003 and 2004–2007 because there was little trastuzumab use in the adjuvant setting before 2004. † Surveillance, Epidemiology, and End Results (SEER) summary stages: local, which is confined to the breast, or regional, which has spread to the lymph nodes (27). ‡ Charlson comorbidity index, which weights up to 19 comorbid conditions depending on their seriousness, using the Deyo index based on the presence of relevant International Classification of Diseases, Ninth Revision (ICD-9) codes in the year before breast cancer diagnosis (32,33). We categorized the score as 0, 1, 2, and ≥3, which represent an increasing scale of comorbid conditions but do not equate to a specific number of comorbid conditions. use were statistically significant among the three younger age (Table  3). In general, stronger associations between chemother- groups (among age <55 years, HR = 16.36 [95% CI = 6.59 to 40.65]; apy exposure and incident HF/CM were observed on changing among age 55–64 years, HR = 6.69 [95% CI = 3.09 to 14.48]; and the index date of unexposed women (n  =  12  500), and excluding among age 65–74 years, HR = 8.34 [95% CI = 3.97 to 17.50]). The women with higher comorbidity scores (n  =  10  646), or women hazard ratios for HF/CM associated with other chemotherapy who initiated chemotherapy more than 12 months after diagnosis use were statistically significant among the three older age groups (n = 11 981). Excluding women diagnosed before 2004 or stratify- (among age 55–64 years, HR = 1.82 [95% CI = 1.03 to 3.20]; among ing by CRN site did not greatly alter results, though confidence age 65–74 years, HR = 1.73 [95% CI = 1.28 to 2.34]; and among age intervals were much wider because of the smaller sample size (data ≥75 years, HR = 1.40 [95% CI = 1.11 to 1.78]). not shown). Sensitivity Analyses Discussion We also conducted several sensitivity analyses to address poten- tial limitations and biases in observational administrative data. This study had two goals: 1) to describe real-world adjuvant anthra- No appreciable differences with primary analysis were obtained cycline and trastuzumab use and 2)  to evaluate incident HF/CM jnci.oxfordjournals.org JNCI | Articles 1297 Figure  1. Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy group. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no). risk associated with adjuvant anthracycline and/or trastuzumab among women who received trastuzumab alone and a sevenfold use in a population-based cohort of women with breast cancer. In increase in the risk of HF/CM for those who received anthracy- our study, women who received anthracycline alone or anthracy- cline plus trastuzumab. To our knowledge, this study is the first cline plus trastuzumab were younger and had fewer comorbidities to examine associations between anthracycline and/or trastuzumab than women who received other chemotherapy or no chemother- reception and HF/CM in a cohort of breast cancer patients broader apy. These results suggest substantial individualization of adjuvant than Medicare-eligible women or clinical trial participants. chemotherapy administration by age and comorbidity in commu- Consistent with previous studies, the majority of women nity practice. The overall risk of incident HF/CM was statistic- 65  years or older in our population received no chemotherapy ally significantly increased among women who used anthracycline (36). Among older women who did receive chemotherapy, most alone compared with no chemotherapy, but the overall risk of inci- received agents other than anthracycline or trastuzumab. Women dent HF/CM was even greater among women who used trastu- who received anthracycline alone or with trastuzumab tended to zumab. Compared with women who received no chemotherapy, have lower comorbidity prevalence, based on Charlson score. On our hazard ratios suggest a fourfold increase in the risk of HF/CM the other hand, the small group of women (0.9%) who received 1298 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Table  3. Associations between adjuvant chemotherapy exposure and incident HF/CM among women diagnosed with invasive breast cancer* Primary analysis Sensitivity analyses All women Changing index date in Excluding women with Excluding late chemother- (n=12 500) unexposed† (n=12 500) comorbidities‡ (n=10 646) apy initiators§ (n=11 981) Chemotherapy use Adjusted HR (95% CI) Adjusted HR (95% CI) Adjusted HR (95% CI) Adjusted HR (95% CI) All ages No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 1.40 (1.11 to 1.76) 1.43 (1.13 to 1.81) 1.52 (1.18 to 1.97) 1.40 (1.11 to 1.77) Trastuzumab only 4.12 (2.30 to 7.42) 4.33 (2.41 to 7.80) 4.36 (2.21 to 8.58) 5.26 (2.91 to 9.50) Anthracycline + trastuzumab 7.19 (5.00 to 10.35) 7.35 (5.09 to 10.62) 7.94 (5.36 to 11.76) 7.19 (4.84 to 10.68) Other chemotherapy 1.49 (1.25 to 1.77) 1.53 (1.29 to 1.83) 1.33 (1.16 to 1.76) 1.44 (1.19 to 1.73) Age <55 y No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 2.52 (1.20 to 5.29) 2.65 (1.22 to 5.76) 3.42 (1.42 to 8.24) 2.49 (1.18 to 5.23) Trastuzumab only 15.46 (4.51 to 52.96) 16.20 (4.62 to 56.77) 15.90 (3.79 to 66.66) 17.60 (5.09 to 60.86) Anthracycline + trastuzumab 16.36 (6.59 to 40.65) 16.96 (6.62 to 43.46) 18.26 (6.39 to 52.18) 17.31 (6.70 to 44.74) Other chemotherapy 1.85 (0.77 to 4.45) 1.95 (0.78 to 4.83) 2.69 (0.98 to 7.37) 1.81 (0.74 to 4.44) Age 55–64 y No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 1.61 (0.94 to 2.78) 1.56 (0.90 to 2.71) 1.75 (0.94 to 3.28) 1.61 (0.93 to 2.81) Trastuzumab only 10.76 (3.92 to 29.52) 10.19 (3.69 to 28.10) 14.88 (4.66 to 47.53) 11.81 (4.28 to 32.59) Anthracycline + trastuzumab 6.69 (3.09 to 14.48) 6.40 (2.94 to 13.94) 10.79 (4.70 to 24.77) 6.05 (2.66 to 13.77) Other chemotherapy 1.82 (1.03 to 3.20) 1.75 (0.99 to 3.10) 1.77 (0.91 to 3.44) 1.77 (0.98 to 3.19) Age 65–74 y No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 1.22 (0.79 to 1.86) 1.30 (0.84 to 2.00) 1.49 (0.94 to 2.35) 1.18 (0.77 to 1.82) Trastuzumab only — — — — Anthracycline + trastuzumab 8.34 (3.97 to 17.50) 9.21 (4.35 to 19.54) 9.37 (4.22 to 20.80) 6.23 (2.74 to 14.18) Other chemotherapy 1.73 (1.28 to 2.34) 1.81 (1.33 to 2.46) 1.86 (1.31 to 2.64) 1.70 (1.22 to 2.36) Age ≥75 y No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 0.76 (0.39 to 1.48) 0.78 (0.40 to 1.53) 0.58 (0.25 to 1.36) 0.79 (0.41 to 1.54) Trastuzumab only 2.57 (0.81 to 8.18) 2.76 (0.86 to 8.79) 2.26 (0.55 to 9.31) 3.64 (1.13 to 11.74) Anthracycline + trastuzumab 3.54 (0.86 to 14.65) 3.36 (0.81 to 13.94) 3.18 (0.76 to 13.41) 11.30 (2.36 to 54.13) Other chemotherapy 1.40 (1.11 to 1.78) 1.44 (1.13 to 1.83) 1.16 (0.85 to 1.57) 1.32 (1.02 to 1.72) * Analyses were conducted using multivariable Cox proportional hazards regression to estimate the risk of HF/CM associated with time-varying chemotherapy exposures to account for changes in chemotherapy use. Each participant began accruing person-time on the date of chemotherapy initiation (ie, index date) and stopped accruing person-time at the time of incident HF/CM diagnosis, health plan disenrollment, death, or December 31, 2009, whichever came first.. All models were adjusted for CRN site (eight sites mentioned earlier), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), diagnosis year (categorical for each year), and radiation treatment (yes vs no). The primary analysis (first column and first row) included all women; subsequent analyses (following rows) were stratified by age groups (<55, 55–64, 65–74, ≥75 years). Sensitivity analyses were conducted in order to address potential limitations and biases in observational administrative data. HF/CM = heart failure and/or cardiomyopathy; HR = hazard ratio; CI = confidence interval; — = no HF/CM events occurred among these women. † Increased the index date to 234 days after breast cancer diagnosis in unexposed women to exclude any additional possibility of prevalent HF/CM. ‡ Excluded women with comorbidities (ie, women with a Charlson score >1; n = 1854 women). § Excluded late chemotherapy initiators, that is, women who initiated chemotherapy more than 12 months after breast cancer diagnosis (n = 519 women). trastuzumab alone had the highest prevalence of comorbidities. treatments are much more likely to be monitored for cardiac fail- These findings show that typical clinical trial exclusions based on ure than young women receiving no chemotherapy. These results patients’ age and comorbidities do occur in real-world settings suggest that clinical trials may underestimate the magnitude of but to a lesser extent than in clinical trials (37–39). This treatment HF/CM risk following anthracycline plus trastuzumab use in com- selection bias, especially by age, may alter cardiac risk estimates and munity practice. safety profiles of these drugs in community settings. Our results for older women showed little to no increase in Our results for HF/CM risk among women less than 65 years HF/CM risk among anthracycline-alone users compared with who received anthracycline alone were similar to clinical trial women who received no chemotherapy. This finding conflicts results (10–14). However, the risk of HF/CM among women who with SEER-Medicare studies, which have estimated statistically received trastuzumab with or without anthracycline in our study— significant hazard ratios ranging from 1.2 to 2.5 (23–25). This especially among younger women—was unexpectedly higher discrepancy is likely a result of avoidance of anthracycline-based than clinical trial estimates (15–19). Excluding women with more therapy in older women; only 11.2% of women 65 years or older in comorbidities did not substantially change our results. The high our study were prescribed anthracycline. Earlier SEER-Medicare hazard ratios associated with anthracycline plus trastuzumab may studies included only data from the 1990s; our study of more partially stem from detection bias, as young women receiving these recent years likely reflects more careful treatment dosing, the jnci.oxfordjournals.org JNCI | Articles 1299 Figure  2. Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy and age groups. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up, by age at diagnosis. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no). A) Age <55 years. B) Age 55–64 years. C) Age 65–74 years. D) Age ≥75 years. practice of additional heart monitoring, and availability of non– but many people are not and still receive these treatments in com- anthracycline-based treatment alternatives. munity practice. Thus, clinical trials may have better internal val- Observational comparative safety and effectiveness studies idity than observational studies because they can reduce bias from using administrative data are important to conduct for several rea- confounding factors through randomization; however, their exter- sons. First, the ability to collect automated administrative data on nal validity is often worse because of selection bias and eligibility a large number of diverse people, as was the case in our study, is criteria. The opposite is often true for observational studies, with often a more cost-effective alternative to extensive medical record better external validity than clinical trials but at the expense of review on a small number of patients. But second, and perhaps even internal validity. more important, observational studies allow for estimation of risks Therefore, limitations of observational studies, particularly those and benefits in community practice, which includes patients who using administrative data such as ours, cannot be ignored. A primary may not be eligible for clinical trials. Clinical trials may provide example in our analyses is that our administrative coding algorithm more relevant estimates for patients who are eligible candidates, for incident HF/CM is prone to misclassification. Our PPV for HF/ 1300 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Figure 2. (Continued) CM suggests that administrative codes include a substantial percent- to occur immediately after cancer diagnosis and before initiation of age of false-positive diagnoses, which would result in overestimated chemotherapy, and documentation of cardiac disease in such patients cumulative HF/CM incidence. For example, our 5-year cumula- will justify the avoidance of potentially cardiotoxic agents. Because tive incidence of HF/CM among women exposed to anthracycline of these potential detection biases, these population-based incidence plus trastuzumab may be 13.9%, based on a PPV of 69%, rather estimates of cardiotoxicity associated with chemotherapy should be than 20.1%; it could range from 6.6% to 16.5% if the PPV was interpreted with caution. Even in the presence of false-positive diag- 33% or 82%, respectively. More precise incidence rates would not noses and misclassification, our results suggest a greater risk of HF/ only require validation of outcomes through chart review but also CM than that previously estimated from clinical trials. Our study has improved documentation and surveillance for cardiotoxicity in rou- a few additional limitations. Relying entirely on administrative data tine practice. If diagnostic coding is more common among patients limited the details of our data collection and, subsequently, the extent after treatment with potentially cardiotoxic agents presumably owing of our analyses. For example, we had no information on drug dose, to increased surveillance, this may result in overattribution from these the types of chemotherapy in the “other chemotherapy” group, LVEF observational associations. For example, detection bias or misclassifi- measures, and breast cancer recurrence—elements typically meas- cation may explain the increased HF/CM incidence among women ured and evaluated in clinical trials. For example, LVEF is typically receiving trastuzumab alone, although these estimates are based on a ascertained before anthracycline or trastuzumab administration, and small sample size. Increased screening for cardiac disease is also likely if reduced, the patient would not be considered eligible for clinical jnci.oxfordjournals.org JNCI | Articles 1301 Figure 2. (Continued) trial enrollment. In real-world practice, the frequency of LVEF test- different cardiovascular risk profiles, residual confounding likely ing varied widely across CRN sites, and a sizeable proportion never still exists, especially among older women. Adjusting for specific received one of these tests based on a detailed review of the medical cardiovascular-related comorbidities, such as hypertension and dia- record (31). If LVEF testing had been routinely used in clinical prac- betes rather than Charlson comorbidity score, may have reduced tice and available from administrative data, it may have allowed for residual confounding but we did not collect these data at all CRN more appropriate comparisons across exposure groups. Further, we sites. Therefore, our incidence rates may not represent the “truth” may have been able to evaluate permanent vs transient HF/CM. HF/ of community practice; however, they show strong signals for asso- CM following trastuzumab may be reversible with drug discontinu- ciations between anthracycline, trastuzumab, and HF/CM. ation, whereas HF/CM following anthracycline may be permanent In conclusion, we noted increased risks of incident HF/CM (18,40). Accurate administrative data on LVEF testing and results associated with anthracycline plus trastuzumab administration. would have been necessary to conduct this analysis. While risk of anthracycline-associated HF/CM among women More broadly, selection bias in community-based studies of less than 65 years was similar to results from randomized clinical cancer treatment is likely to be prominent and uncontrollable. trials, trastuzumab-associated HF/CM risk (whether administered We noted profound differences in age, comorbidities, stage of alone or following anthracycline) was greater than that previously disease, and other factors among women receiving various treat- reported. Our results highlight the importance of generalizability ment options. Although our primary analyses attempted to adjust in applying clinical trial findings to community settings; although for these differences to account for treatment selection biases and similar to clinical trial results, these population-based results cannot 1302 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Figure 2. 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Notes 21. Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom The authors would like to acknowledge the contributions of the CRN National Cancer Research Institute recommendations for monitoring. Br Pharmacovigilance Study team members. The members are Diana Buist, PhD, J Cancer. 2009;100(5):684–692. Elizabeth Trice Loggers, MD, PhD, Andy Bogart, MS, Nick Vanneman, MA, Roy 22. Martin M, Esteva FJ, Alba E, et al. Minimizing cardiotoxicity while opti- Pardee, MS, JD, Lisa Temposky, Beth Lapham, and Sarah McDonald (Group mizing treatment efficacy with trastuzumab: review and expert recommen- Health Research Institute); Beth Syat, MPH, and Priscilla Velentgas, PhD dations. Oncologist. 2009;14(1):1–11. (Harvard Pilgrim Health Care Institute); Karen Wells (Henry Ford Hospital 23. Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. and Health System); Christina Clarke (Kaiser Permanente Colorado); Lauren Congestive heart failure in older women treated with adjuvant anthracy- Perkins, MS (Kaiser Permanente Georgia); Larry Kushi, ScD, Alan Go, MD, and cline chemotherapy for breast cancer. J Clin Oncol. 2007;25(25):3808–3815. Angela Capra (Kaiser Permanente Northern California); Mark Hornbrook, PhD, 24. Doyle JJ, Neugut AI, Jacobson JS, Grann VR, Hershman DL. Joanna Bulkley, PhD, Tia Kauffman, MPH, Eresha Bluth, Chuhe Chen, PhD, Chemotherapy and cardiotoxicity in older breast cancer patients: a Padmavati Dandamudi, MBBS, MPH, and Carmel Wax (Kaiser Permanente population-based study. J Clin Oncol. 2005;23(34):8597–8605. Northwest); Jessica Engel, RN, FNP, AOCN, Paul Hitz, and Terrie Kitchner 1304 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 (Marshfield Clinic), and Arnold Potosky, PhD (Georgetown University). CM); Marshfield Clinic Research Foundation, Marshfield, WI (AAO); National Dr Allen has received consulting fees from Amgen, Janssen Scientific Affairs, and Cancer Institute, Bethesda, MD (ANF); Division of Cardiology, University of the Robert Wood Johnson Foundation. Colorado, Aurora, CO (LAA); Department of Population Medicine, Harvard The authors are solely responsible for the design of the study; the collection, Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, and analysis, and interpretation of the data; the writing of the manuscript; and the Department of Medicine, Harvard Vanguard Medical Associates, Boston, MA decision to submit the manuscript for publication. (LN); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (KABG); Center for Health Research-Southeast, Kaiser Permanente Affiliations of authors: Group Health Research Institute, Group Health Georgia, Atlanta, GA (RLD); Division of Research, Kaiser Permanente Northern Cooperative, Seattle, WA (EJAB, RW, EHW); Institute for Health Research, California, Oakland, CA (LAH); Department of Research, Henry Ford Hospital Kaiser Permanente Colorado, Denver, CO (HSF, TD, DJM); Department of and Health System, Detroit, MI (MUY); Essentia Institute of Rural Health, Hematology/Oncology, Marshfield Clinic Weston Center, Weston, WI (AAO, Duluth, MN (CM). jnci.oxfordjournals.org JNCI | Articles 1305 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Journal of the National Cancer Institute Pubmed Central

Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A Retrospective Cohort Study

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© The Author 2012. Published by Oxford University Press. All rights reserved.
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0027-8874
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1460-2105
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10.1093/jnci/djs317
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Abstract

DOI:10.1093/jnci/djs317 © The Author 2012. Published by Oxford University Press. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Article risk of Heart Failure in Breast cancer Patients After Anthracycline and t rastuzumab t reatment: A retrospective cohort Study Erin J. Aiello Bowles, Robert Wellman, Heather Spencer Feigelson, Adedayo A. Onitilo, Andrew N. Freedman, Thomas Delate, Larry A. Allen, Larissa Nekhlyudov, Katrina A. B. Goddard, Robert L. Davis, Laurel A. Habel, Marianne Ulcickas Yood, Catherine McCarty, David J. Magid, Edward H. Wagner; for the Pharmacovigilance Study Team Manuscript received January 05, 2012; revised June 13, 2012; accepted June 18, 2012. Correspondence to: Erin J. Aiello Bowles, MPH, Group Health Research Institute, 1730 Minor Ave, Ste 1600, Seattle, WA 98101 (e-mail: bowles.e@ghc.org). Background Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with inci- dent HF/CM. Methods We conducted a population-based, retrospective cohort study of 12 500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regres- sion models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities. Results Among 12 500 women (mean age = 60 years, range = 22–99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemother- apy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/ CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35). Conclusions Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety. J Natl Cancer Inst 2012;104:1293–1305 Breast cancer is one of the most common cancers in the United Data from clinical trials indicate that anthracycline use is asso- States with an estimated 232  620 new diagnoses in 2011 (1). ciated with an approximate 2% increase (10–14) in heart failure Chemotherapeutic regimens for invasive breast cancer in women and/or cardiomyopathy (HF/CM) incidence, and anthracycline include neoadjuvant or adjuvant anthracycline in combination with followed by trastuzumab is associated with an approximate 4% cyclophosphamide (2). A major advance in breast cancer treatment increase (15–19). Clinical trial findings were critical in leading to has been the incorporation of trastuzumab, a monoclonal anti- prescribing warnings and protocols for regular cardiac function body against HER2/neu. Approximately 20%–25% of women with monitoring before and during treatment (20–22). However, trials breast cancer overexpress HER2 and are recommended for trastu- typically exclude older women (eg, aged ≥ 70  years) and women zumab therapy following the completion of anthracycline therapy with major comorbidities; therefore, the association between (3–5). Randomized clinical trials have demonstrated that these reg- anthracycline and/or trastuzumab use and HF/CM in this popula- imens are highly effective in improving disease-free survival (6–9); tion is not well understood. The effectiveness of these treatments however, side effects are not minimal. and risk of cardiotoxicity may differ in community practice. Three jnci.oxfordjournals.org JNCI | Articles 1293 observational studies using Surveillance, Epidemiology, and End received anthracycline and/or trastuzumab. Our final analytic sam- Results (SEER) Medicare data have evaluated HF/CM incidence ple included 12 500 women. Women were followed-up until inci- following treatment with anthracycline, but they were limited to dent HF/CM diagnosis, health plan disenrollment, death, or the older women (aged ≥ 65  years) and did not evaluate trastuzumab end of follow-up on December 31, 2009, whichever came first. (23–25). Therefore, broader population-based estimates of HF/CM This study was approved by the Institutional Review Board risk associated with anthracycline and trastuzumab are unknown. (IRB) for Group Health Cooperative and five other sites that Using data from the health maintenance organization (HMO) ceded review to Group Health Cooperative and separately by the Cancer Research Network (CRN) (26), we evaluated real-world Institutional Review Boards at Marshfield Clinic and Henry Ford. adjuvant anthracycline and trastuzumab use and subsequent inci- We obtained information on women from all sites via a waiver of dent HF/CM risk among a population-based cohort of women consent. aged 18 years or older and diagnosed with invasive breast cancer. We took advantage of observational administrative health plan Data Collection data to conduct this comparative safety study of anthracycline We obtained data from each site’s Virtual Data Warehouse therapy, which was previously examined only in clinical trials or (VDW), which has been described in detail elsewhere (28). The SEER-Medicare populations, and trastuzumab therapy, which, VDW includes standardized variables derived from administra- to our knowledge, has not been evaluated outside of randomized tive databases at each CRN site. A programmer at Group Health clinical trials. Cooperative wrote standardized code for programmers at other sites to execute; programmers then transferred limited datasets to Group Health Cooperative for analysis. Methods Study Population Chemotherapy Exposure The CRN is a consortium of 14 nonprofit research centers based We collected data on chemotherapy administration using vali- in integrated healthcare delivery organizations within the HMO dated VDW procedure codes and pharmacy data, which have been Research Network (26). We included 12 902 women aged 18 years reported previously (29). Chemotherapy procedure data included or older and diagnosed with incident invasive [SEER summary Healthcare Common Procedure Coding System (HCPCS) stages—local, which is confined to the breast, or regional, which and Current Procedural Terminology (CPT)-4 codes; phar- has spread to the lymph nodes (27)] breast cancer from January 1, macy data included National Drug Codes (NDCs). We extracted 1999 through December 31, 2007. All women were enrolled at least HCPCS and NDCs specific to anthracycline and trastuzumab and 12 months before diagnosis in these six CRN sites: Group Health HCPCS, NDCs, and CPT-4 codes related to other chemother- Cooperative, Henry Ford Hospital and Health System, Marshfield apy and administration dates. Because CPT-4 codes do not spe- Clinic, and Kaiser Permanente regions in Colorado, Georgia, cify chemotherapy agents, we coded CPT-4 codes with no other and Northwest. Two additional CRN sites (Kaiser Permanente information as “other” chemotherapy. We extracted treatment Northern California and Harvard Pilgrim Health Care) used data up to 24  months after breast cancer diagnosis. We catego- slightly different inclusion criteria for year of breast cancer diagno- rized women into five mutually exclusive treatment categories: sis. Because of the large population at Kaiser Permanente Northern anthracycline-based only (without trastuzumab; however, women California, we included a 10% random sample of women diagnosed could have received additional chemotherapy such as cyclophos- between January 1, 2001 and December 31, 2007 (chemotherapy phamide), trastuzumab-based only (without anthracycline; though data from 1999 and 2000 were incomplete and not included). all but one woman received additional chemotherapy), anthracy- Harvard Pilgrim data included women receiving care at Harvard cline plus trastuzumab (trastuzumab therapy following anthracy- Vanguard Medical Associates (a multispecialty medical practice) cline therapy), other chemotherapy, or no chemotherapy. and diagnosed from January 1, 1999 through December 31, 2006. To validate chemotherapy data, we compared chemotherapy We excluded women diagnosed with HF/CM before breast regimens from VDW data with medical record review of 400 cancer diagnosis (n = 253 women) or before chemotherapy initia- women (50 from each CRN site). Sensitivities and specificities tion (n = 96 women) because these diagnoses could not be attrib- exceeded 90% for all treatment categories, and positive predictive uted to chemotherapy use. We also excluded women who did not values (PPVs) exceeded 90% for anthracycline alone, trastuzumab receive chemotherapy but were diagnosed with HF/CM within alone, and anthracycline plus trastuzumab treatment, as reported 70  days of breast cancer diagnosis (70  days was the median time previously (29). to “other chemotherapy” initiation; n = 53 women). These women may have been eligible for chemotherapy but likely did not receive Heart Failure Outcome it because of their new HF/CM diagnosis (potentially found dur- Our primary outcome was HF/CM following breast cancer diag- ing cardiac screening before the anticipated chemotherapy initia- nosis, defined using a previously validated algorithm, though not tion). In general, excluded HF/CM patients were older (55% were in breast cancer patients (30). The algorithm uses International >75  years) and had more comorbidities (70.8% had a Charlson Classification of Diseases, Ninth Revision (ICD-9) codes with five comorbidity score ≥ 2 [moderate comorbidity]), compared with different criteria that indicate HF/CM (see Table  1 for criteria, our included cohort (18% were >75 years and 15% had a Charlson ICD-9 codes, and proportion of women classified by each criteria) comorbidity score ≥ 2). Over 50% of excluded HF/CM patients (31). We categorized women as having no HF/CM or incident did not receive any chemotherapy, although 10% of these women HF/CM (occurring after breast cancer treatment). Because 1294 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Table 1. ICD-9 code-based algorithm used to determine HF/CM from administrative data by treatment group* Treatment group No Anthracycline Trastuzumab Anthracycline + Other chemotherapy only only trastuzumab chemotherapy (n=5807 women) (n=3697 women) (n=112 women) (n=442 women) (n=2442 women) Algorithm criteria % % % % % ≥1 primary discharge diagnosis 4.2 2.1 3.6 4.1 5.3 ≥3 secondary discharge diagnoses 0.5 0.2 0 0.5 0.4 ≥2 outpatient diagnoses 2.8 1.7 7.1 7.0 2.5 ≥3 emergency department diagnoses 0 0 0 0 0 ≥2 secondary discharge + ≥1 outpatient diagnosis 0.1 0.1 0 0 0.2 None of the above (no HF/CM) 92.5 95.9 89.3 88.5 91.7 * The study population includes 12 500 women diagnosed with incident invasive breast cancer from January 1, 1999 through December 31, 2007. All women were members of one of eight Cancer Research Network (CRN) integrated health plans for 12 or more months before breast cancer diagnosis. Administrative data included ICD-9 codes for HF/CM as noted by a provider in the medical record and available in the CRN Virtual Data Warehouse (VDW; ICD-9 codes: 398.91, 402. x1, 402.x3, 404.x1, 404.x3, 422.90, 425.4, 425.9, 428.xx). Primary and secondary discharge diagnoses were indicated at the time of the patient’s release from a hospital. Other diagnoses occurred after emergency department release or an outpatient appointment. The algorithm for this study was based on previous HF claims-based algorithms (30,41), with the addition of the 425 “cardiomyopathy” codes because of the nature of cardiotoxicity. The algorithm was validated on a subset of 400 women as previously reported (31). ICD-9 = International Classification of Diseases, Ninth Revision; HF/CM = Heart failure and/or cardiomyopathy. Statistical Analysis administrative data do not capture results of echocardiograms We described the distribution of chemotherapy use by patient or other methods for measuring left ventricular ejection fraction characteristics, including the median and interquartile range (LVEF), we could not use LVEF findings in our HF/CM defin- (25th–75th percentile) for follow-up time (time for follow-up ition. The PPV of the algorithm for any HF/CM diagnosis during treatment until incident HF/CM diagnosis, health plan the period from 12 months before to 12 months after breast can- disenrollment, death, or December 31, 2009, whichever came first). cer diagnosis was 68.6% (95% confidence interval [CI] = 44.9% to We then used Cox proportional hazards regression to calculate 85.4%), which we have shown earlier (31). The PPV for incident hazard ratios (HRs) with 95% (CIs) for HF/CM associated with HF/CM during the 12 months after breast cancer diagnosis was time-varying chemotherapy exposures. Each participant began 33.3% (95% CI = 12.8% to 63.1%) (31); this estimate was based accruing person-time on the date of chemotherapy initiation (ie, on only four true-positive HF/CM patients, but it suggests that index date) and stopped accruing person-time at the time of incident the performance may be worse for the period after breast cancer HF/CM diagnosis, health plan disenrollment, death, or December diagnosis. PPV also varied by the definition of the gold standard, 31, 2009, whichever came first. We used day 70 after diagnosis as a and the estimates above included 24  “indeterminate” diagnoses proxy for the index date for unexposed women. Using time-varying (those that could not be definitively classified as HF/CM) as nega- exposures allowed us to account for changes in chemotherapy use. tives in the gold standard. When we included patients with “inde- For example, women were considered anthracycline-based-only terminate” HF/CM diagnoses as positives in the gold standard, users until they started trastuzumab therapy; thereafter, they were the PPV of the algorithm increased to 81.9% (95% CI = 58.0% considered anthracycline plus trastuzumab users. We adjusted to 93.7%), as reported previously (31). We did not have gold all models for covariates that were either jointly associated with standard data to evaluate the PPV for incident heart failure after chemotherapy and HF/CM risk (confounders) or associated solely chemotherapy initiation or beyond 12 months after breast cancer with HF/CM risk in a bivariate manner at P values less than .05. diagnosis. These included CRN site (eight sites mentioned earlier), age at diagnosis (grouped as <55, 55–64, 65–74, ≥75  years), Charlson Covariates comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis Each CRN site maintains its own tumor registry in compliance (localized vs regional), year of diagnosis (categorical for each year), with North American Association of Central Cancer Registries and radiation treatment (yes vs no). (NAACCR) standards, or contracts with their local state or SEER Survivor curves and the corresponding cumulative incidence tumor registries. From tumor registry data, we collected data on curves were estimated from the adjusted Cox model using the breast cancer diagnosis date, age at diagnosis (<55, 55–64, 65–74, method described by Breslow (34,35). All covariates were set to ≥75 years), race (American Indian or Alaskan Native, Asian, black, their respective mean values as estimated from the overall sample. white), ethnicity (non-Hispanic white vs Hispanic), summary stage The annual cumulative incidence up to year 5 for each chemother- (localized vs regional), lymph node status (positive vs negative), and apy group, both overall and by age group, was estimated at the most radiation therapy (yes vs no) as defined by NAACCR classifica- proximal event time observed in the data. Numbers of patients at tions. Using VDW data, we calculated the Charlson comorbid- risk are presented as the number under observation at the begin- ity index (0, 1, 2, ≥3) that weights up to 19 comorbid conditions ning of each time interval. depending on their seriousness, using the Deyo index based on the In order to assess any violations to the proportional hazards presence of relevant ICD-9 codes in the year before breast cancer assumption in our primary analysis (average hazards ratios for diagnosis (32,33). jnci.oxfordjournals.org JNCI | Articles 1295 chemotherapy exposure during the entire study period), we per- <65 years, 55.3%; regional summary stage, 11.5%; Charlson score formed exploratory analyses to characterize changes of the hazard ≥2, 16.2%; and radiation therapy received, 58.6%). Recipients of ratio over time for each chemotherapy exposure. Toward this end, trastuzumab-based therapy without anthracycline, though small we allowed the hazard ratio for each chemotherapy exposure to in number, were older (age ≥65  years, 32.2%) and had more vary with time by including an interaction with time in our models. comorbidities (Charlson score ≥2, 21.4%) than women in other The degree to which the proportional hazards assumption was vio- treatment groups. lated for covariates was assessed through the use of the likelihood ratio test for interactions between covariates and time, as well as Risk of HF/CM by Chemotherapy Exposure inspection of residual plots. Interactions with time were statistically Women were followed-up until incident HF/CM diagnosis, health significant at P values less than .05 for age, stage, site, Charlson plan disenrollment, death, or December 31, 2009, whichever came score, and year of diagnosis. Review of residual plots yielded very first. The adjusted cumulative HF/CM incidence for the first little in the way of substantial proportional hazards violations, and 5 years of follow-up (the median follow-up time was 4.4 years) is most were focused in areas of sparse data. We conducted sensi- shown in Figure  1. The HF/CM incidence among anthracycline tivity analyses with stratified models when there was evidence of recipients increased with increasing follow-up time (year 1 vs year a potential deviation from the proportional hazards assumption. 5, cumulative incidence = 1.2% [95% CI = 1.0% to 1.5%] vs 4.3% Sensitivity analyses yielded minimal changes in primary estimates; [95% CI = 3.5% to 5.0%]) and was similar to the incidence among thus, we present results based on the primary, unstratified analysis. recipients of other chemotherapy (year 1 vs year 5, cumulative inci- We conducted several sensitivity analyses in order to address dence = 1.3% [95% CI = 1.0% to 1.6%] vs 4.5% [95% CI = 3.7% potential limitations and biases in observational administrative to 5.3%]). The cumulative HF/CM incidence among recipients data. We conducted Cox regression analyses after changing the of anthracycline plus trastuzumab was 6.2% (95% CI  =  4.1% to proxy index date to 234 days after breast cancer diagnosis (the 75th 8.2%) after 1 year of follow-up and continued to increase to 20.1% percentile of time to “other chemotherapy” initiation) in unex- (95% CI = 14.0% to 25.6%) by 5 years. The risk of incident HF/ posed women; excluding women with comorbidities (Charlson CM among all women was statistically significantly increased for score >1; n = 1854 women); excluding women who initiated ther- anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), apy more than 12  months after breast cancer diagnosis (n  =  519 trastuzumab without anthracycline (HR = 4.12, 95% CI = 2.30 to women); and excluding women diagnosed before 2004 (when there 7.42), anthracycline plus trastuzumab (HR = 7.19, 95% CI = 5.00 was limited use of trastuzumab in the adjuvant setting; n  =  6779 to 10.35), and other chemotherapy (HR = 1.49, 95% CI = 1.25 to women). Further, we conducted stratified analyses by CRN site and 1.77), compared with no chemotherapy (Table 3). age group. The majority of analyses were conducted in Stata 11 (StataCorp, Risk of HF/CM by Age at Breast Cancer Diagnosis College Station, TX); cumulative incidence estimates were The 5-year cumulative incidence for HF/CM associated with estimated with SAS version 9.2 for Windows (SAS Institute Inc, anthracycline use increased with increasing age (among age Cary, NC). All hypothesis tests were two-sided, and we considered <55  years, cumulative incidence  =  1.2% [95% CI  =  0.0% to P values less than .05 statistically significant. 26.1%]; among age 55–64  years, cumulative incidence =2.9% [95% CI = 1.8% to 4.0%]; among age 65–74 years, cumulative inci- dence = 6.2% [95% CI = 3.9% to 8.5%]; and among age ≥75 years, results cumulative incidence  =  10.6% [95% CI  =  3.9% to 16.9%]; Characteristics of Patients by Chemotherapy Use Figure 2, A–D). The 5-year cumulative incidence for HF/CM asso- Among 12  500 women who were diagnosed with invasive breast ciated with anthracycline plus trastuzumab use also increased with cancer from January 1, 1999 through December 31, 2007, chemo- increasing age (among age <55 years, cumulative incidence = 7.5% therapy use was as follows: 5807 (46.5%) received no chemother- [95% CI  =  0.0% to 85.9%]; among age 55–64  years, cumula- apy, 3697 (29.6%) received anthracycline-based chemotherapy tive incidence  =  11.4% [95% CI  =  4.2% to 18.1%]; among age alone, 112 (0.9%) received trastuzumab-based therapy without 65–74  years, cumulative incidence  =  35.6% [95% CI  =  12.5% to anthracycline, 442 (3.5%) received anthracycline plus trastuzumab, 52.5%]; and among age ≥75 years, cumulative incidence = 40.7% and 2442 (19.5%) received other chemotherapy (Table  2). The [95% CI = 0.0% to 71.6%]; Figure 2, A–D). The 5-year cumula- mean age of the population was 60  years (range  =  22–99  years), tive incidences for HF/CM associated with other chemotherapy 85.8% were of white race, and the median follow-up time was use were greatest among the two oldest age groups (among age 4.4 years (interquartile range [IQR] = 2.6–6.9 years). Women who 65–74  years, cumulative incidence  =  8.7% [95% CI  =  6.3% to received anthracycline alone or anthracycline plus trastuzumab 11.0%] and among age ≥75  years, cumulative incidence  =  18.7% were younger (age <65  years, 86.4% and 89.6%, respectively), [95% CI = 14.5% to 22.6%]; Figure 2, C and D). diagnosed at later stages (regional SEER summary stage, 54.2% The hazard ratios for HF/CM associated with chemotherapy use and 61.0%, respectively), had fewer comorbidities (Charlson score decreased with increasing age (Table  3). For example, the hazard ≥2, 10.0% and 7.7%, respectively), and were slightly more likely to ratio for HF/CM associated with anthracycline use alone was statis- receive radiation therapy (yes, 61.0% and 59.4%, respectively) than tically significant among women younger than 55 years (HR = 2.52, women who received other chemotherapy (age <65 years, 54.2%; 95% CI  =  1.20 to 5.29) but not among women 55–64  years SEER regional summary stage, 25.4%; Charlson score ≥2, 19.8%; (HR = 1.61, 95% CI = 0.94 to 2.78) or older. The hazard ratios for and radiation therapy received, 55.2%) or no chemotherapy (age incident HF/CM associated with anthracycline plus trastuzumab 1296 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Table 2. Characteristics of invasive breast cancer patients by adjuvant treatment* Treatment group No chemo- Anthracycline Trastuzumab Anthracycline Other chemo- therapy (n=5807 only (n=3697 only (n=112 + trastuzumab therapy (n=2442 All (n=12500 women) women) women) (n=442 women) women) women) Characteristic No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) Age at diagnosis, y <55 1112 (19.1) 2131 (57.6) 40 (35.7) 272 (61.5) 706 (28.9) 4261 (34.1) 55–64 1489 (25.6) 1063 (28.8) 36 (32.1) 124 (28.1) 617 (25.3) 3329 (26.6) 65–74 1606 (27.7) 423 (11.4) 19 (17.0) 38 (8.6) 622 (25.5) 2708 (21.7) ≥75 1600 (27.6) 80 (2.2) 17 (15.2) 8 (1.8) 497 (20.4) 2202 (17.6) Race American Indian or Alaskan Native 9 (0.2) 11 (0.3) 0 (0.0 0 4 (0.9) 11 (0.5) 35 (0.3) Asian 203 (3.6) 149 (4.1) 4 (3.6) 27 (6.2) 94 (3.9) 477 (3.9) Black 443 (7.8) 527 (14.5) 16 (14.5) 51 (11.8) 193 (8.0) 1230 (10.0) White 5016 (88.5) 2952 (81.1) 90 (81.8) 352 (81.1) 2103 (87.6) 10 513 (85.8) Ethnicity Non-Hispanic 5165 (97.5) 3310 (95.9) 95 (96.0) 386 (95.1) 2237 (96.8) 11 193 (96.8) Hispanic 133 (2.5) 141 (4.1) 4 (4.0) 20 (4.9) 75 (3.2) 373 (3.2) Summary stage† Localized 5066 (88.5) 1683 (45.8) 67 (60.9) 171 (39.0) 1797 (74.6) 8784 (71.1) Regional 660 (11.5) 1991 (54.2) 43 (39.1) 268 (61.0) 612 (25.4) 3574 (28.9) Lymph nodes Negative 5181 (89.2) 1654 (44.7) 72 (64.3) 164 (37.1) 1843 (75.5) 8914 (71.3) Positive 626 (10.8) 2043 (55.3) 40 (35.7) 278 (62.9) 599 (24.5) 3586 (28.7) Charlson score‡ 0 3983 (68.6) 2897 (78.4) 67 (59.8) 350 (79.2) 1567 (64.2) 8864 (70.9) 1 881 (15.2) 430 (11.6) 21 (18.8) 58 (13.1) 392 (16.1) 1782 (14.3) 2 635 (10.9) 284 (7.7) 13 (11.6) 26 (5.9) 303 (12.4) 1261 (10.1) ≥3 308 (5.3) 86 (2.3) 11 (9.8) 8 (1.8) 180 (7.4) 593 (4.7) Radiation therapy No 2355 (41.4) 1397 (39.0) 58 (54.2) 174 (40.6) 1067 (44.8) 5051 (41.5) Yes 3331 (58.6) 2182 (61.0) 49 (45.8) 255 (59.4) 1317 (55.2) 7134 (58.5) Diagnosis year 1999–2003 3229 (55.6) 2054 (55.6) 26 (23.2) 94 (21.3) 1376 (56.3) 6779 (54.2) 2004–2007 2578 (44.4) 1643 (44.4) 86 (76.8) 348 (78.7) 1066 (43.7) 5721 (45.8) * Women were diagnosed with breast cancer between January 1, 1999 and December 31, 2007. Chemotherapy use was extracted from the Cancer Research Network (CRN) Virtual Data Warehouse (VDW) procedure and pharmacy data up to 24 months after breast cancer diagnosis. Chemotherapy procedure data included Healthcare Common Procedure Coding System (HCPCS) and Current Procedural Terminology (CPT)-4 codes; pharmacy data included National Drug Codes (NDCs). “Anthracycline only” indicates treatment without trastuzumab, although women could have received additional chemotherapy such as cyclophosphamide. “Trastuzumab only” indicates treatment without anthracycline, although all but one woman received additional chemotherapy. “Anthracycline + trastuzumab” indicates trastuzumab therapy following anthracycline therapy. “Other chemotherapy” indicates CPT-4 codes without any information about specific chemotherapy agents, or HCPCS and NDCs that specified chemotherapy drugs other than anthracycline or trastuzumab. Diagnosis year was categorized as 1999–2003 and 2004–2007 because there was little trastuzumab use in the adjuvant setting before 2004. † Surveillance, Epidemiology, and End Results (SEER) summary stages: local, which is confined to the breast, or regional, which has spread to the lymph nodes (27). ‡ Charlson comorbidity index, which weights up to 19 comorbid conditions depending on their seriousness, using the Deyo index based on the presence of relevant International Classification of Diseases, Ninth Revision (ICD-9) codes in the year before breast cancer diagnosis (32,33). We categorized the score as 0, 1, 2, and ≥3, which represent an increasing scale of comorbid conditions but do not equate to a specific number of comorbid conditions. use were statistically significant among the three younger age (Table  3). In general, stronger associations between chemother- groups (among age <55 years, HR = 16.36 [95% CI = 6.59 to 40.65]; apy exposure and incident HF/CM were observed on changing among age 55–64 years, HR = 6.69 [95% CI = 3.09 to 14.48]; and the index date of unexposed women (n  =  12  500), and excluding among age 65–74 years, HR = 8.34 [95% CI = 3.97 to 17.50]). The women with higher comorbidity scores (n  =  10  646), or women hazard ratios for HF/CM associated with other chemotherapy who initiated chemotherapy more than 12 months after diagnosis use were statistically significant among the three older age groups (n = 11 981). Excluding women diagnosed before 2004 or stratify- (among age 55–64 years, HR = 1.82 [95% CI = 1.03 to 3.20]; among ing by CRN site did not greatly alter results, though confidence age 65–74 years, HR = 1.73 [95% CI = 1.28 to 2.34]; and among age intervals were much wider because of the smaller sample size (data ≥75 years, HR = 1.40 [95% CI = 1.11 to 1.78]). not shown). Sensitivity Analyses Discussion We also conducted several sensitivity analyses to address poten- tial limitations and biases in observational administrative data. This study had two goals: 1) to describe real-world adjuvant anthra- No appreciable differences with primary analysis were obtained cycline and trastuzumab use and 2)  to evaluate incident HF/CM jnci.oxfordjournals.org JNCI | Articles 1297 Figure  1. Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy group. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no). risk associated with adjuvant anthracycline and/or trastuzumab among women who received trastuzumab alone and a sevenfold use in a population-based cohort of women with breast cancer. In increase in the risk of HF/CM for those who received anthracy- our study, women who received anthracycline alone or anthracy- cline plus trastuzumab. To our knowledge, this study is the first cline plus trastuzumab were younger and had fewer comorbidities to examine associations between anthracycline and/or trastuzumab than women who received other chemotherapy or no chemother- reception and HF/CM in a cohort of breast cancer patients broader apy. These results suggest substantial individualization of adjuvant than Medicare-eligible women or clinical trial participants. chemotherapy administration by age and comorbidity in commu- Consistent with previous studies, the majority of women nity practice. The overall risk of incident HF/CM was statistic- 65  years or older in our population received no chemotherapy ally significantly increased among women who used anthracycline (36). Among older women who did receive chemotherapy, most alone compared with no chemotherapy, but the overall risk of inci- received agents other than anthracycline or trastuzumab. Women dent HF/CM was even greater among women who used trastu- who received anthracycline alone or with trastuzumab tended to zumab. Compared with women who received no chemotherapy, have lower comorbidity prevalence, based on Charlson score. On our hazard ratios suggest a fourfold increase in the risk of HF/CM the other hand, the small group of women (0.9%) who received 1298 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Table  3. Associations between adjuvant chemotherapy exposure and incident HF/CM among women diagnosed with invasive breast cancer* Primary analysis Sensitivity analyses All women Changing index date in Excluding women with Excluding late chemother- (n=12 500) unexposed† (n=12 500) comorbidities‡ (n=10 646) apy initiators§ (n=11 981) Chemotherapy use Adjusted HR (95% CI) Adjusted HR (95% CI) Adjusted HR (95% CI) Adjusted HR (95% CI) All ages No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 1.40 (1.11 to 1.76) 1.43 (1.13 to 1.81) 1.52 (1.18 to 1.97) 1.40 (1.11 to 1.77) Trastuzumab only 4.12 (2.30 to 7.42) 4.33 (2.41 to 7.80) 4.36 (2.21 to 8.58) 5.26 (2.91 to 9.50) Anthracycline + trastuzumab 7.19 (5.00 to 10.35) 7.35 (5.09 to 10.62) 7.94 (5.36 to 11.76) 7.19 (4.84 to 10.68) Other chemotherapy 1.49 (1.25 to 1.77) 1.53 (1.29 to 1.83) 1.33 (1.16 to 1.76) 1.44 (1.19 to 1.73) Age <55 y No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 2.52 (1.20 to 5.29) 2.65 (1.22 to 5.76) 3.42 (1.42 to 8.24) 2.49 (1.18 to 5.23) Trastuzumab only 15.46 (4.51 to 52.96) 16.20 (4.62 to 56.77) 15.90 (3.79 to 66.66) 17.60 (5.09 to 60.86) Anthracycline + trastuzumab 16.36 (6.59 to 40.65) 16.96 (6.62 to 43.46) 18.26 (6.39 to 52.18) 17.31 (6.70 to 44.74) Other chemotherapy 1.85 (0.77 to 4.45) 1.95 (0.78 to 4.83) 2.69 (0.98 to 7.37) 1.81 (0.74 to 4.44) Age 55–64 y No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 1.61 (0.94 to 2.78) 1.56 (0.90 to 2.71) 1.75 (0.94 to 3.28) 1.61 (0.93 to 2.81) Trastuzumab only 10.76 (3.92 to 29.52) 10.19 (3.69 to 28.10) 14.88 (4.66 to 47.53) 11.81 (4.28 to 32.59) Anthracycline + trastuzumab 6.69 (3.09 to 14.48) 6.40 (2.94 to 13.94) 10.79 (4.70 to 24.77) 6.05 (2.66 to 13.77) Other chemotherapy 1.82 (1.03 to 3.20) 1.75 (0.99 to 3.10) 1.77 (0.91 to 3.44) 1.77 (0.98 to 3.19) Age 65–74 y No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 1.22 (0.79 to 1.86) 1.30 (0.84 to 2.00) 1.49 (0.94 to 2.35) 1.18 (0.77 to 1.82) Trastuzumab only — — — — Anthracycline + trastuzumab 8.34 (3.97 to 17.50) 9.21 (4.35 to 19.54) 9.37 (4.22 to 20.80) 6.23 (2.74 to 14.18) Other chemotherapy 1.73 (1.28 to 2.34) 1.81 (1.33 to 2.46) 1.86 (1.31 to 2.64) 1.70 (1.22 to 2.36) Age ≥75 y No chemotherapy 1.00 (referent) 1.00 (referent) 1.00 (referent) 1.00 (referent) Anthracycline only 0.76 (0.39 to 1.48) 0.78 (0.40 to 1.53) 0.58 (0.25 to 1.36) 0.79 (0.41 to 1.54) Trastuzumab only 2.57 (0.81 to 8.18) 2.76 (0.86 to 8.79) 2.26 (0.55 to 9.31) 3.64 (1.13 to 11.74) Anthracycline + trastuzumab 3.54 (0.86 to 14.65) 3.36 (0.81 to 13.94) 3.18 (0.76 to 13.41) 11.30 (2.36 to 54.13) Other chemotherapy 1.40 (1.11 to 1.78) 1.44 (1.13 to 1.83) 1.16 (0.85 to 1.57) 1.32 (1.02 to 1.72) * Analyses were conducted using multivariable Cox proportional hazards regression to estimate the risk of HF/CM associated with time-varying chemotherapy exposures to account for changes in chemotherapy use. Each participant began accruing person-time on the date of chemotherapy initiation (ie, index date) and stopped accruing person-time at the time of incident HF/CM diagnosis, health plan disenrollment, death, or December 31, 2009, whichever came first.. All models were adjusted for CRN site (eight sites mentioned earlier), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), diagnosis year (categorical for each year), and radiation treatment (yes vs no). The primary analysis (first column and first row) included all women; subsequent analyses (following rows) were stratified by age groups (<55, 55–64, 65–74, ≥75 years). Sensitivity analyses were conducted in order to address potential limitations and biases in observational administrative data. HF/CM = heart failure and/or cardiomyopathy; HR = hazard ratio; CI = confidence interval; — = no HF/CM events occurred among these women. † Increased the index date to 234 days after breast cancer diagnosis in unexposed women to exclude any additional possibility of prevalent HF/CM. ‡ Excluded women with comorbidities (ie, women with a Charlson score >1; n = 1854 women). § Excluded late chemotherapy initiators, that is, women who initiated chemotherapy more than 12 months after breast cancer diagnosis (n = 519 women). trastuzumab alone had the highest prevalence of comorbidities. treatments are much more likely to be monitored for cardiac fail- These findings show that typical clinical trial exclusions based on ure than young women receiving no chemotherapy. These results patients’ age and comorbidities do occur in real-world settings suggest that clinical trials may underestimate the magnitude of but to a lesser extent than in clinical trials (37–39). This treatment HF/CM risk following anthracycline plus trastuzumab use in com- selection bias, especially by age, may alter cardiac risk estimates and munity practice. safety profiles of these drugs in community settings. Our results for older women showed little to no increase in Our results for HF/CM risk among women less than 65 years HF/CM risk among anthracycline-alone users compared with who received anthracycline alone were similar to clinical trial women who received no chemotherapy. This finding conflicts results (10–14). However, the risk of HF/CM among women who with SEER-Medicare studies, which have estimated statistically received trastuzumab with or without anthracycline in our study— significant hazard ratios ranging from 1.2 to 2.5 (23–25). This especially among younger women—was unexpectedly higher discrepancy is likely a result of avoidance of anthracycline-based than clinical trial estimates (15–19). Excluding women with more therapy in older women; only 11.2% of women 65 years or older in comorbidities did not substantially change our results. The high our study were prescribed anthracycline. Earlier SEER-Medicare hazard ratios associated with anthracycline plus trastuzumab may studies included only data from the 1990s; our study of more partially stem from detection bias, as young women receiving these recent years likely reflects more careful treatment dosing, the jnci.oxfordjournals.org JNCI | Articles 1299 Figure  2. Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy and age groups. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up, by age at diagnosis. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no). A) Age <55 years. B) Age 55–64 years. C) Age 65–74 years. D) Age ≥75 years. practice of additional heart monitoring, and availability of non– but many people are not and still receive these treatments in com- anthracycline-based treatment alternatives. munity practice. Thus, clinical trials may have better internal val- Observational comparative safety and effectiveness studies idity than observational studies because they can reduce bias from using administrative data are important to conduct for several rea- confounding factors through randomization; however, their exter- sons. First, the ability to collect automated administrative data on nal validity is often worse because of selection bias and eligibility a large number of diverse people, as was the case in our study, is criteria. The opposite is often true for observational studies, with often a more cost-effective alternative to extensive medical record better external validity than clinical trials but at the expense of review on a small number of patients. But second, and perhaps even internal validity. more important, observational studies allow for estimation of risks Therefore, limitations of observational studies, particularly those and benefits in community practice, which includes patients who using administrative data such as ours, cannot be ignored. A primary may not be eligible for clinical trials. Clinical trials may provide example in our analyses is that our administrative coding algorithm more relevant estimates for patients who are eligible candidates, for incident HF/CM is prone to misclassification. Our PPV for HF/ 1300 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Figure 2. (Continued) CM suggests that administrative codes include a substantial percent- to occur immediately after cancer diagnosis and before initiation of age of false-positive diagnoses, which would result in overestimated chemotherapy, and documentation of cardiac disease in such patients cumulative HF/CM incidence. For example, our 5-year cumula- will justify the avoidance of potentially cardiotoxic agents. Because tive incidence of HF/CM among women exposed to anthracycline of these potential detection biases, these population-based incidence plus trastuzumab may be 13.9%, based on a PPV of 69%, rather estimates of cardiotoxicity associated with chemotherapy should be than 20.1%; it could range from 6.6% to 16.5% if the PPV was interpreted with caution. Even in the presence of false-positive diag- 33% or 82%, respectively. More precise incidence rates would not noses and misclassification, our results suggest a greater risk of HF/ only require validation of outcomes through chart review but also CM than that previously estimated from clinical trials. Our study has improved documentation and surveillance for cardiotoxicity in rou- a few additional limitations. Relying entirely on administrative data tine practice. If diagnostic coding is more common among patients limited the details of our data collection and, subsequently, the extent after treatment with potentially cardiotoxic agents presumably owing of our analyses. For example, we had no information on drug dose, to increased surveillance, this may result in overattribution from these the types of chemotherapy in the “other chemotherapy” group, LVEF observational associations. For example, detection bias or misclassifi- measures, and breast cancer recurrence—elements typically meas- cation may explain the increased HF/CM incidence among women ured and evaluated in clinical trials. For example, LVEF is typically receiving trastuzumab alone, although these estimates are based on a ascertained before anthracycline or trastuzumab administration, and small sample size. Increased screening for cardiac disease is also likely if reduced, the patient would not be considered eligible for clinical jnci.oxfordjournals.org JNCI | Articles 1301 Figure 2. (Continued) trial enrollment. In real-world practice, the frequency of LVEF test- different cardiovascular risk profiles, residual confounding likely ing varied widely across CRN sites, and a sizeable proportion never still exists, especially among older women. Adjusting for specific received one of these tests based on a detailed review of the medical cardiovascular-related comorbidities, such as hypertension and dia- record (31). If LVEF testing had been routinely used in clinical prac- betes rather than Charlson comorbidity score, may have reduced tice and available from administrative data, it may have allowed for residual confounding but we did not collect these data at all CRN more appropriate comparisons across exposure groups. Further, we sites. Therefore, our incidence rates may not represent the “truth” may have been able to evaluate permanent vs transient HF/CM. HF/ of community practice; however, they show strong signals for asso- CM following trastuzumab may be reversible with drug discontinu- ciations between anthracycline, trastuzumab, and HF/CM. ation, whereas HF/CM following anthracycline may be permanent In conclusion, we noted increased risks of incident HF/CM (18,40). Accurate administrative data on LVEF testing and results associated with anthracycline plus trastuzumab administration. would have been necessary to conduct this analysis. While risk of anthracycline-associated HF/CM among women More broadly, selection bias in community-based studies of less than 65 years was similar to results from randomized clinical cancer treatment is likely to be prominent and uncontrollable. trials, trastuzumab-associated HF/CM risk (whether administered We noted profound differences in age, comorbidities, stage of alone or following anthracycline) was greater than that previously disease, and other factors among women receiving various treat- reported. Our results highlight the importance of generalizability ment options. Although our primary analyses attempted to adjust in applying clinical trial findings to community settings; although for these differences to account for treatment selection biases and similar to clinical trial results, these population-based results cannot 1302 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 Figure 2. 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J Clin Oncol. ease, and the risks of death and hospitalization in adults with chronic heart 2007;25(25):3859–3865. failure: the Anemia in Chronic Heart Failure: Outcomes and Resource 19. Untch M, Muscholl M, Tjulandin S, et al. First-line trastuzumab plus epi- Utilization (ANCHOR) Study. Circulation. 2006;113(23):2713–2723. rubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety Funding and efficacy data from the Herceptin, Cyclophosphamide, and Epirubicin This work was supported by the National Cancer Institute at the National (HERCULES) trial. J Clin Oncol. 2010;28(9):1473–1480. Institutes of Health through an administrative supplement to the Cancer 20. Mackey JR, Clemons M, Cote MA, et al. Cardiac management during adju- Research Network (grant number U19 CA 79689 to EHW). vant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol. 2008;15(1):24–35. Notes 21. Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom The authors would like to acknowledge the contributions of the CRN National Cancer Research Institute recommendations for monitoring. Br Pharmacovigilance Study team members. The members are Diana Buist, PhD, J Cancer. 2009;100(5):684–692. Elizabeth Trice Loggers, MD, PhD, Andy Bogart, MS, Nick Vanneman, MA, Roy 22. Martin M, Esteva FJ, Alba E, et al. Minimizing cardiotoxicity while opti- Pardee, MS, JD, Lisa Temposky, Beth Lapham, and Sarah McDonald (Group mizing treatment efficacy with trastuzumab: review and expert recommen- Health Research Institute); Beth Syat, MPH, and Priscilla Velentgas, PhD dations. Oncologist. 2009;14(1):1–11. (Harvard Pilgrim Health Care Institute); Karen Wells (Henry Ford Hospital 23. Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. and Health System); Christina Clarke (Kaiser Permanente Colorado); Lauren Congestive heart failure in older women treated with adjuvant anthracy- Perkins, MS (Kaiser Permanente Georgia); Larry Kushi, ScD, Alan Go, MD, and cline chemotherapy for breast cancer. J Clin Oncol. 2007;25(25):3808–3815. Angela Capra (Kaiser Permanente Northern California); Mark Hornbrook, PhD, 24. Doyle JJ, Neugut AI, Jacobson JS, Grann VR, Hershman DL. Joanna Bulkley, PhD, Tia Kauffman, MPH, Eresha Bluth, Chuhe Chen, PhD, Chemotherapy and cardiotoxicity in older breast cancer patients: a Padmavati Dandamudi, MBBS, MPH, and Carmel Wax (Kaiser Permanente population-based study. J Clin Oncol. 2005;23(34):8597–8605. Northwest); Jessica Engel, RN, FNP, AOCN, Paul Hitz, and Terrie Kitchner 1304 Articles | JNCI Vol. 104, Issue 17 | September 5, 2012 (Marshfield Clinic), and Arnold Potosky, PhD (Georgetown University). CM); Marshfield Clinic Research Foundation, Marshfield, WI (AAO); National Dr Allen has received consulting fees from Amgen, Janssen Scientific Affairs, and Cancer Institute, Bethesda, MD (ANF); Division of Cardiology, University of the Robert Wood Johnson Foundation. Colorado, Aurora, CO (LAA); Department of Population Medicine, Harvard The authors are solely responsible for the design of the study; the collection, Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, and analysis, and interpretation of the data; the writing of the manuscript; and the Department of Medicine, Harvard Vanguard Medical Associates, Boston, MA decision to submit the manuscript for publication. (LN); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (KABG); Center for Health Research-Southeast, Kaiser Permanente Affiliations of authors: Group Health Research Institute, Group Health Georgia, Atlanta, GA (RLD); Division of Research, Kaiser Permanente Northern Cooperative, Seattle, WA (EJAB, RW, EHW); Institute for Health Research, California, Oakland, CA (LAH); Department of Research, Henry Ford Hospital Kaiser Permanente Colorado, Denver, CO (HSF, TD, DJM); Department of and Health System, Detroit, MI (MUY); Essentia Institute of Rural Health, Hematology/Oncology, Marshfield Clinic Weston Center, Weston, WI (AAO, Duluth, MN (CM). jnci.oxfordjournals.org JNCI | Articles 1305

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