1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. Aim 1: Characterize Population

8. Patient Demographics: Language
English
P =
Use ROW percents here

9. Patient Demographics: Race
White

10. Patient Demographics: Marital StatusW D
Single
Married
P =

11. Patient Characteristics: Vital Status
Alive
Dead
Dead
Alive
P =

12. Patient Characteristics: Stage

13. Patient Characteristics: BC Type

14. Patient Characteristics: Chemotherapy
Total = 384 patients

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

16. 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

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

18. Aim 1: Conclusions Demographics: Treatment Characteristics:
English-speaking white married women who are primarily still living with mostly stage 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)

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

20. 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

21. 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

22. Pre-Treatment LVEF by Risk Category

23. 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

24. 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

25. 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

26. 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

27. 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?

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. Aim 4: Investigate whether appropriate Cardioprotective agents prevent chf

36. 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

37. 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

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

39. 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

40. 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%

41. 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

42. 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…