1. Addressing the Needs of Breast Cancer Patients Ages 70 and Older UNC Telehealth Series; February 10, 2016 Hyman B. Muss, MD

2. Objectives  Discuss the complexities of the older patient in regard to defining patient function and life expectancy.  Evaluate and define the goals of therapy as well as assess the risks and benefits of adjuvant systemic therapy.  Compose a plan of action for helping to manage metastatic disease in elderly breast cancer patients.

3. The Tsunami of Cancer and Aging

4. 1918 1935 2009 All 79 years Women: 81 Men: 76 U.S. Estimated Life Expectancy

5. Estimated Life-Expectancy of Women by Age and Comorbidity Low/medium: diabetes or myocardial infarction or others. High comorbidity: COPD or congestive heart failure or others Modified from Cho et al,. Ann Intern Med. 2013;159(10):667-76

6. Why is Geriatric Oncology Important ?

7. SEER 2002-2006: Breast Cancer Incidence and Mortality Rates http://seer.cancer.gov/cgi-bin/csr/1975_2006/search.pl Average Age ~ 61

8. Breast Cancer 2013 CA: A Cancer Journal for Clinicians pages 52-62, 1 OCT 2013 DOI: 10.3322/caac.21203 IncidenceMortality

9. U.S. Breast Cancer Death Rates Over Time Smith B D et al. JCO 2011;29:4647-4653

10. Selecting Cancer Treatment in Older Patients Estimate Life Expectancy eprognosis.ucsf.edu Define Goals of Treatment not always longevity.. Calculate Benefits/Risk of Treatment

11. Schonberg Index All cause 5 and 9 yr mortality Variable Patient 1Patient 2 Age 75 Sex Female smoking neverformer BMI 3023 History of Ca No Diabetes NoYes COPD NoYes Hospitalizations past year NoneOnce Self rated health excellentfair Dependent IADL none1 Difficulty walking 1/4 mile NoYes 5 and 9 year Mortality Risk6% and 16%43% and 75% http://eprognosis.ucsf.edu/

12. What’s the goal of treatment?  Early stage breast cancer –Adjuvant therapy to increase cure –Treatment should not be as bad as disease  Metastatic disease –“You can’t improve on being asymptomatic.” –Maintain QOL and function first –Improve symptoms when present –Provide “structured” palliative care

13. Preferences of Seriously Ill I would rather die than have a treatment that causes: Fried et al, NEJM 2002 N=226 with cancer, COPD, ASCVD

14. The Value of Geriatric Assessment  Uncovers problems not found routinely  Many problems have beneficial interventions –Improve function –Quality of life –Survival  Allows for accurate life-expectancy estimate  Can predict cancer related toxicity

15. Brief Geriatric Assessment: 0916 DOMAINASSESSMENT MEASURE Health ProfessionalSelf Reported Functional Status Timed Up and Go KPS- Physician Rated Activities of Daily Living (ADL) Instrumental Activities of Daily Living Karnofsky Self Reported No. of Falls in the last 6 months Co-morbidity Number /Type of Comorbid Conditions No. of Medications Vision and Hearing Assessment Cognition Blessed Orientation Memory-Concentration Psychologic Mental Health Index-17 Social Social Activity Limitation Measure (MOS) Social Support Survey (MOS) NutritionBMI Unintentional Weight Loss 6 mths 10 minutes 20-30 minutes

16. Is cancer the patient’s major illness?

17. Karnofsky performance status ≥80 GA identified deficits (n=984, mean age 73, Age 65-99) Trevor A. Jolly et al. The Oncologist 2015;20:379-385

18. Falls in UNC Cancer Patients  24% of the the patients in the registry reported 1 or more fall in the past 6 months  54% had one fall and 47% had two or more falls  No more than 10% of patients who experience falls have appropriate medical record documentation or referrals.  Older adults who fall were not adequately evaluated by medical oncologists. Outcomes N=70 (100%)95% CI Falls Documented2 (3%)0-10% Gait Assessment19 (13%)10-30% Referrals2 (3%)0-10% Vitamin D Level19 (13%)10-30% Guerard et al, ASCO 2014; JOP 2015

19. “If your time hasn’t come yet, not even a doctor can kill you.” Leigh Stoecker

20. Predictive Model Risk factors for Grade 3-5 ToxicityOR (95% CI)Score Age ≥73 yrs1.8 (1.2-2.7)2 GI/GU cancer vs. other cancer2.2 (1.4-3.3)3 Standard dose vs. reduced2.1 (1.3-3.5)3 Polychemotherapy vs. single agent1.8 (1.1-2.7)2 Hemoglobin (male: <11, female: <10)2.2 (1.1-4.3)3 Creatinine Clearance (Jelliffe –ideal wt) <342.5 (1.2-5.6)3 1 or more falls in last 6 months2.3 (1.3-3.9)3 Hearing impairment (fair or worse)1.6 (1.0-2.6)2 Limited in walking 1 block (MOS)1.8 (1.1-3.1)2 Assistance required in medication intake1.4 (0.6-3.1)1 Decreased social activity (MOS)1.3 (0.9-2.0)1 Possible score range: 0-25; ROC 0.72 Hurria JCO 29:3457, 2011

21. Ability of (A) risk score versus (B) physician-rated Karnofsky performance status (KPS) to predict grade 3-5 chemotherapy toxicity. Hurria A et al. JCO 2011;29:3457-3465 ©2011 by American Society of Clinical Oncology

22. Optimizing Adjuvant Treatment ?

23. Selecting Adjuvant Therapy: “3” Types of Breast Cancer Type/FrequencyTreatmentComment Hormone Receptor Positive ER and/or PR) AND HER-2 negative (about 70% of pts) Endocrine therapy for most Chemotherapy for some New Genetic based assays can help select who needs chemotherapy Most relapse > 5 years HER-2 positive ANY ER or PR (About 15% of pts) Chemotherapy AND anti- HER-2 therapy for most Endocrine Rx if hormone receptor positive Major improvements in outcome with anti-HER-2 Rx Most relapse < 5 years ER AND PR AND HER-2 negative “triple negative: (About 15% of pts) Chemotherapy for most More common in younger pts and A-A pts More chemo is better Most relapse < 5 yrs

24. Hazard Rate of Relapse According to Subtype Cossetti, Gelmon et al. JCO 2015;33:65-73 1986-92 2004-8 86-92 (3589)04-08 (3589) Adj chemo 26%50% Adj Endo 46%86% Anti HER2 072% >= 70 years 25%23%

25. Chemotherapy Use in US: Regimen use v year of diagnosis (A) younger than age 65 years and (B) older than age 65 years. Barcenas et al. JCO 2014;32:2010-2017 Age < 65Age > 65

26. Adjuvant Endocrine Therapy Older Pts  Risk reductions –30% for mortality –50% for recurrence  AI or Tam>AI (or Tam?)  Not all patients need it –Low risk for recurrence –Short life-expectancy  Adherence and Compliance key

27. Letrozole vs Placebo 70+ Letrozole = 681; Placebo = 642 Muss et al NCIC MA17 JCO 2008 (QOL slight inc bodily pain, vasomotor at 2 years)

28. Just imagine what the data would look like if patients actually took their medications.

29. Rules of Thumb Adjuvant Chemo Older Patients Percent Improvement 10- year Overall Survival Action <3%No Chemotherapy 3-5%Chemotherapy for some >5% Consider based on life expectancy and goals

30. What Chemotherapy? Adjuvant online and Predict + 1 st Generation AC = CMF = FEC6 (B-36) Q2w paclitaxel x 4 (40101) 2 nd Generation TC x 4 FAC or FECx6; not so sure 3 rd Generation Anthracycline + taxane Caveats Proportional reductions key but not verified in older women AML/MDS, cardiac toxicity higher in elders.

31. 10 year all cause mortality 75 year old, ER+, 1-2 cm, grade 2 Average healthPoor health (+10) From www.adjuvantonline May 2012www.adjuvantonline

32. Hospitalizations with Adjuvant Chemotherapy A: All B: Adjusted for growth factors CMF 14% >65. Barcenas et al. JCO 2014;32:2010-2017

33. Anti-HER-2 Rx in Elderly  Estimate survival –Treat like younger if > 5yrs  Cardiology consult if CHF risk factors –Consider proactive β-blocker or ACE inhibitor  What about anti-HER 2 therapy alone? –ATEMPT: TDM-1 vs paclitaxel/trastuzumab –Freedman for Alliance/ACCRU –Ado-trastuzumab emtansine (TDM-1) Pts who decline chemo/T or docs afraid to give it ≥65, Stage 1-3, q3 wks x 1 yr, GA, biomarkers

34. Probabilities of Disease-free Survival and Recurrence-free Interval. Stage 1 HER2+ BC: paclitaxel + trastuzumab Tolaney SM et al. N Engl J Med 2015;372:134-141

35. Most Common Adverse Events Occurring during Protocol Therapy. Tolaney SM et al. N Engl J Med 2015;372:134-141

36. Predict plus (UK) for HER-2 + http://www.predict.nhs.uk http://www.predict.nhs.uk ER-ER+ 75, screen detected, 2.0 cm, grade 2 N-, second generation chemotherapy

37. Bone Metastases: Response

39. Therapy for Metastases in Older Patients Type/FrequencyTreatment Strategy Hormone Receptor Positive ER and/or PR) AND HER-2 negative (about 70%) Endocrine therapy for most until certain not working AND symptoms THEN Chemotherapy HER-2 positive ANY ER or PR (About 15%) Hormone Receptor Positive: Endocrine Rx with concurrent or sequential anti-HER-2 therapy OR Anti-HER- 2 Rx usually with chemotherapy ER AND PR AND HER-2 negative “triple negative: (About 15%) Chemotherapy

40. Kindler, Gentler Chemotherapy  Capecitabine  Low-dose cyclophosphamide/methotrexate  Weekly taxanes  Eribulin  Liposomal doxorubicin  Weekly anthracyclines  Vinorelbine  Gemcitabine

41. Yow 1410 (BCRF 1334) Trial Design 6 PRE 12 Assessments p16 INK4a Pre, 6 months, one year Lean Body Mass (Dexa) Pre, 6 months, one year Geriatric Assessment/Questionnaires Activity and Sleep tracker: continuous Age ≥ 65 years Stage 1-3 Breast Cancer Chemotherapy completed Randomiz e Control Physical Activity 3 Time/Months Walking Concurrent RO-1 trial without exercise intervention will serve as control

42. Metrics – What We Measure Metric Measure Description Geriatric Assessment (CARG) Measures function (physical and mental), other diseases, anxiety, depression, nutrition and social support Health Behavior Questionnaire Exercise and Alcohol Use Short Physical Performance Battery Engagement in Physical Activity OEE/Outcome Expectations for Exercise FitBit (data capture throughout chemotherapy) Physical activity log daily during chemotherapy Physical function CBC, renal, hepatic, albumin Basic organ function Biomarkers (p16, IL-6, D-Dimer, CRP Markers of inflammation and aging DEXA scan for Muscle mass Lean body mass and fat mass CTCAE (during chemotherapy) Side effects of treatment – MD reported PRSM (PRO – during chemotherapy Patient reported side effects FACT-Breast Quality of life FACIT-Fatigue Fatigue PSEFSM/Perceived Self-Efficacy for Fatigue Self- Management Program satisfaction

43. Functional Status Comorbidities Key Factors Contributing to Decision Making Finances Age Individual’s Treatment Decision Cancer Stage Psychological Status Cancer Therapeutics Organ Function Cognition Spirituality Polypharmacy Social Support Culture Literacy From Hurria

44. January 2016

45. Thank You