Hailey Baker, Tamara McMahon, Carol Fabian, Bruce Kimler, Russ Waitman Management of therapy-Induced Cardiotoxicity in Female Breast Cancer Patients Hailey Baker, Tamara McMahon, Carol Fabian, Bruce Kimler, Russ Waitman

Background Increasingly more women are surviving from breast cancer due to effectiveness of biologics, chemotherapies, and new radiation technology Focus can no longer be solely on survival, but now much concern chronic quality-of- life issues Cardiovascular health is of particular concern in the United States American Society of Clinical Oncology (ASCO) guidelines (August 2016) Unknown if clinicians follow and how that affects patient outcomes

Specific Aims Aim 1: Characterize KUMC breast cancer population Aim 2: Did patients receive appropriate screening for their risk category (based on ASCO guidelines)? Aim 3: Explore potential risk factors for heart failure after cardioabrasive chemo or radiotherapies Aim 4: Investigate whether appropriate cardioprotective agents prevent heart failure

Inclusion & Exclusion Criteria: Females Breast cancer diagnosis SEER Site Summary ICD9 Code 174 ICD10 Code C50 Diagnosed after 01/01/2008 Class of Case 14 Initial diagnosis at KUMC and all of first course treatment or a decision not to treat was done at KUMC. TOTAL = 1632 patients

HERON Cohort: Extent of disease (e.g. stage, ER/PR/HER2 status) Underlying risk factors for cardiovascular (CV) disease Smoking, hypertension, diabetes, dyslipidemia, and obesity Cancer Treatment Cardiotoxic chemotherapy (e.g. anthracyclines, Trastuzumab, kinase inhibitors) Radiation therapy where the heart is in the treatment field Cardiovascular screening (e.g. Echocardiogram) CV Outcomes: Heart failure, low LVEF Prevention Therapy BB, ACEI, or ARBs

High Risk High dose anthracycline (e.g. ≥250 mg/m2 doxorubicin, ≥600 mg/m2 epirubicin) High dose (≥30 Gy) radiotherapy where the heart is in the treatment field Lower dose anthracycline (e.g. <250 mg/m2 doxorubicin, <600 mg/m2 epirubicin) in combination with lower dose radiotherapy (<30 Gy) where the heart is in the treatment field Treatment with lower dose anthracycline (e.g. <250 mg/m2 doxorubicin, <600 mg/m2 epirubicin) or trastuzumab alone, and presence of any of the following risk factors: Multiple (≥2) cardiovascular risk factors, including: smoking, hypertension, diabetes, dyslipidemia, obesity during or after completion of therapy Older (≥60 years) age at cancer treatment Compromised cardiac function (e.g. borderline low LVEF [50-55%], history of myocardial infarction, ≥moderate valvular heart disease) at any time prior to or during treatment Treatment with lower dose anthracycline (e.g. <250 mg/m2 doxorubicin, <600 mg/m2 epirubicin) followed by trastuzumab (sequential therapy) Else = LOW RISK

Aim 1: Characterize Population

Patient Demographics: Language English P = 0.1899 Use ROW percents here

Patient Demographics: Race White

Patient Demographics: Marital Status W D Single Married P = 0.3448

Patient Characteristics: Vital Status Alive Dead Dead Alive P = 0.0003

Patient Characteristics: Stage

Patient Characteristics: BC Type

Patient Characteristics: Chemotherapy Total = 384 patients

Patient Characteristics: Radiotherapy < 3,000 cGY = Low Dose Say “not reported” rather than “0” > 3,000 cGY = High Dose Total = 566 P < 0.0001

Patient Characteristics: Co-Morbidities Risk Age at Dx Smoke Diabetes HTN Dyslipid. Prior MI Total 61 (± 12) 88 (9.2%) 78 (8.1%) 210 (21.9%) 153 (16.0%) 2 (0.21%) 959 1 59 (± 11) 48 (7.2%) 44 (6.6%) 154 (23.0%) 140 (20.9%) (0.15%) 670 ------ 136 122 364 293 3 1,629 P-value 0.0034 0.15 0.24 0.60 0.024 0.46 Age_at_dx = T-test All other variables = chi-squared

Patient Characteristics: BMI Use 2 decimals for P-values P-value = 0.2876

Aim 1: Conclusions Demographics: Treatment Characteristics: English-speaking white married women who are primarily still living with mostly stage 1-2 ER+PR+HER-breast cancer Higher mortality in low-risk population Unequal proportions of breast cancer stages between risk groups Treatment Characteristics: The majority of patients who received chemotherapy were treated with anthracyclines or Trastuzumab The majority of patients who received radiation were high-risk patients given high-dose radiotherapy to the breast More high-risk women received anthracyclines than low-risk women Co-Morbidities: Low-Risk = slightly older & higher rates of dyslipidemia Otherwise, very similar demographics and characteristics Higher mortality in low risk: (1) risk categories aren’t properly identifying who is at risk of all-cause mortality or (2) high risk women are being more closely monitored than low risk women or (3) low-risk women had more severe disease (6.5% had stage 4 vs. 1.5% of high-risk women with stage 4)

AIM 2: Did patients receive appropriate screening for risk category?

ASCO Guidelines: Pre-Treatment Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline “Clinicians should perform a comprehensive assessment in cancer patients that includes a history and physical examination, screening for cardiovascular disease risk factors (hypertension, diabetes, dyslipidemia, obesity, smoking), and an echocardiogram prior to initiation of potentially cardiotoxic therapies.” Recommendations as of 15 August 2016

Pre-Treatment Screening Frequency Table: Interpretation: Chi-Square p-value < 0.001 If you’re at higher risk of CV disease, you have 5.66X higher odds of receiving pre- treatment screening with an echo

Pre-Treatment LVEF by Risk Category

ASCO Guidelines: During Treatment Recommendation 4.3 Routine surveillance imaging may be offered during treatment in asymptomatic patients considered to be at increased risk (Recommendation 1.1) of developing cardiac dysfunction. In these individuals, echocardiography is the surveillance imaging modality of choice that should be offered. Frequency of surveillance should be determined by healthcare providers based upon clinical judgment and patient circumstances. (Evidence-based; Benefits outweigh harms; Evidence quality: Intermediate; Strength of Recommendation: Moderate) Recommendation 4.4 No recommendations can be made regarding continuation/discontinuation of cancer therapy in individuals with evidence of cardiac dysfunction. This decision, made by the oncologist, should be informed by close collaboration with a cardiologist, fully evaluating the clinical circumstances, and considering the risks/benefits of continuation of therapy responsible for the cardiac dysfunction. (Informal consensus; Benefits outweigh harms; Evidence quality: Insufficient) Recommendation 4.5 Clinicians may use routine echocardiographic surveillance in patients with metastatic breast cancer continuing to receiving trastuzumab indefinitely. The frequency of cardiac imaging for each patient should be determined by healthcare providers, based upon clinical judgment and patient circumstances. (Evidence-based and Informal Consensus; Benefits outweigh harms; Evidence quality: Low; Strength of Recommendation: Moderate) During treatment was defined as 1 year

Screening Intervals P < 0.0001 0.0009 0.0197 0.0484 0.1673 Include percent rows here too - Only look at cardioresults here; the high numbers might be from orders

Change in LVEF by Screening Intervals Why are there greater than 100% here? methods: assumptions – we’re taking this from HERON as given, we can’t validate Repress the decimals here

Aim 2: Conclusions Pre-Treatment Echo: During Treatment Echo: Most patients are receiving appropriate pre-treatment screening echocardiograms for their respective risk category. Women at higher risk were more likely to receive pre-treatment echocardiograms. However, there is still room for improvement because there were 23% of high risk women that did not receive pre-treatment echocardiograms During Treatment Echo: High-risk patients receive significantly more echocardiograms before and after treatment through 9 months Biggest drop in LVEF occurs between months 3 and 6 for low-risk women Biggest drop in LVEF occurs between months 0 and 3 and months 9 and 12 for high-risk women Low-risk women – need to follow them closely for the first 3 months High-risk women – need to follow them closely for at least a full year

AIM 3: explore potential risk factors for Heart Failure in BC patients Do the presence of these risk factors predict who will get CHF in the future?

CHF Risk: Diabetes Mellitus If you have DM at your breast cancer diagnosis, you have 4.47X higher odds of experiencing heart failure than someone without DM

CHF Risk: Hypertension If you have HTN at your breast cancer diagnosis, you have 3.32X higher odds of experiencing heart failure than someone without HTN

CHF Risk: Dyslipidemia A relative risk greater than 1 indicates that the probability of positive response is greater in row 1 than in row 2. Similarly, a relative risk less than 1 indicates that the probability of positive response is less in row 1 than in row 2. The strength of association increases with the deviation from 1. If you have dyslipidemia at your breast cancer diagnosis, you have 2.58X higher odds of experiencing heart failure than someone without dyslipidemia

CHF Risk: Smoke Status If you smoke at your breast cancer diagnosis, you have 3.03X higher odds of experiencing heart failure than someone who doesn’t smoke

CHF Risk: Family History of Heart Disease If you have a family history of CV disease at your breast cancer diagnosis, you have 1.59X higher odds of experiencing heart failure than someone who doesn’t have a family history of heart disease

CHF Risk: Risk Category Risk categories are improperly identifying at risk individuals High risk people are followed more closely RISK CATEGORY AT DIAGNOSIS – this is their treatment risk If you have a higher risk of CV disease at your breast cancer diagnosis, you have 0.62X lower odds of experiencing heart failure than someone who is lower risk

Aim 3: Conclusions Risk Factor Rank of Risk Factor Risk Odds Ratio Diabetes Mellitus 1 4.47 Hypertension 2 3.32 Smoking Status 3 3.03 Dyslipidemia 4 2.58 Family History 5 1.59 Risk Category 6 0.62 RISK ODDS RATIO DOES’NT CONFER STATISTICAL SIGNIFICANCE Put in a p-value here Do logistic binary regression in SAS or multivariate regression Diabetes Mellitus is the most significant risk factor for experiencing CHF Women at higher risk may be monitored more closely, which prevents experiencing heart failure in the future

Aim 4: Investigate whether appropriate Cardioprotective agents prevent chf

Were patients treated appropriately? Low_EF = < 50 Low_EF_Treated = BB/ACEI/ARB within 30 days of first LVEF < 50 Discrepency (67 vs. 294) may show we’re not properly identifying people who are having cardiac dysfunction NOTE: only 67 patients in the entire cohort received a heart failure ICD9 or ICD10 code

Was risk associated with likelihood of appropriate cardioprotective treatment? NO! High risk women are not treated more effectively, so this would argue that our risk categories are not properly identifying at-risk individuals Define treatment as home medications that they’re already taking, so they may not have been started on a new medication Time interval of low LVEF and start to protective therapy

Did appropriate treatment affect odds of developing heart failure? Relative-risk includes 1, so we can’t be confident in this result

Aim 4: Conclusions The majority (86%) of patients who had a LVEF < 50% were not prescribed cardioprotective medications (BB, ACEI, or ARB) within 30 days of their abnormal echo result Risk at diagnosis did not affect a woman’s odds of receiving appropriate treatment at CHF diagnosis Unable to conclude with certainty whether treatment with cardioprotective medications affects your odds of developing heart failure May be underdiagnosing heart failure in breast cancer survivors, which could skew results

Overall Conclusions Aim 1: Characterize breast cancer population Similar characteristics between high and low-risk cohorts Aim 2: Did patients receive appropriate screening for their risk category? Most patients are receiving appropriate pre-treatment screening echocardiograms for their respective risk category. High-risk patients receive significantly more echocardiograms before and after treatment through 9 months Aim 3: Explore potential risk factors for heart failure after cardioabrasive chemo or radiotherapies Diabetes mellitus was the most significant risk factor for higher odds of developing CHF High risk appeared to be protective for CHF, possibly due to closer clinical follow-up Aim 4: Investigate whether appropriate cardioprotective agents prevent heart failure Most patients did not receive cardioprotective chemotherapies when their LVEF < 50%

Future Directions No recommendation can be made on the risk of cardiac dysfunction in cancer patients with any of the following treatment exposures: Lower dose anthracycline (e.g. <250 mg/m2 doxorubicin, <600 mg/m2 epirubicin) or trastuzumab alone, and no additional risk factors (as defined in 1.1) Lower dose radiotherapy (<30 Gy) where the heart is in the treatment field, and no additional cardiotoxic therapeutic exposures or risk factors (as defined in 1.1) Kinase inhibitors No recommendations can be made regarding the use of cardioprotective strategies (dexrazoxane, continuous infusion, liposomal formulation) in patients receiving lower (e.g. <250 mg/m2 doxorubicin, <600 mg/m2 epirubicin) cumulative dose of anthracyclines. - Cox regression survival analysis

Questions?? Thanks! Kansas medicine – journal Weaknesses Look at death status & cause of death Move risk to before demographics People may already be taking BB/ACE/ARB, so see if the low numbers are because of that Bruce: echo up 1 year before treatment for pre_tx_echo surgery may increase echo use NOTE: ASCO guidelines say to have two co-morbidities to put in high risk, but don’t know how to code that…