Survivorship and Breast Cancer in Older Patients

Transcription

1 Survivorship and Breast Cancer in Older Patients Michelle Melisko MD Clinical Professor of Medicine UCSF Helen Diller Family Comprehensive Cancer Center Disclosures Research support: Nektar, Novartis, Lilly, Astra Zeneca, Puma Honorarium/Advisory Boards: Agendia, Eisai Other: I LOVE TO EXERCISE! 1

2 Learning Objectives Review recent exercise and lifestyle intervention studies and their impact on health outcomes in breast cancer survivors Review the evidence supporting the benefit of physical activity, diet, and weight management on outcomes after breast cancer diagnosis Discuss the unique challenges of selecting treatment for older breast cancer patients and explore the value of utilizing a chemotherapy toxicity risk score in this population Abstracts to discuss PD6-04 Lifestyle Intervention Study (LISA) in Early Breast Cancer (BC): An RCT of the Effects of a Telephone-Based Weight Loss Intervention (with Educational Materials) vs Educational Materials Alone on Disease-Free Survival (DFS) GS5-02 Cardiovascular function and the effect of exercise training during adjuvant breast cancer treatment. Results from The EBBA-II trial (NBCG- 14) (Thune) GS5-03 Lifestyle Intervention and Effect on Disease-free Survival in Early Breast Cancer Patients: Interim Analysis from the Randomized SUCCESS C Study (Janni) GS6-04 Development and Validation of a Chemotherapy Toxicity Risk Score for Older Patients with Breast Cancer Receiving Adjuvant/Neoadjuvant Treatment (Magnuson) 2

3 1/28/19 After a breast cancer diagnosis, there is window of opportunity to improve health through lifestyle Weight management Physical Activity Dietary changes Control of HTN, blood sugar, lipids Alcohol consumption Stress reduction/mindfulness Supplements/herbs?? Risk Reduction Through Lifestyle Confusion exists regarding which lifestyle factors impact risk of DEVELOPING breast cancer as compared to those factors that have an influence on recurrence AFTER diagnosis Data on risk reduction through lifestyle has been primarily based on epidemiologic studies Few prospective randomized clinical trials have successfully demonstrated impact of lifestyle changes on breast cancer recurrence risk 3

4 Studies evaluating diet, breast cancer recurrence, and survival Women s Intervention Nutrition Study: Clinical Outcomes PATIENTS (%) Control Diet Relapse-Free Survival* Absolute difference:1% 3% 3% 3% 4% 7% Follow-Up Time (Years) Diet Control * HR (95% CI 0.76 ( ), p=0.034 **From adjusted Cox proportional hazard model; ** p value = Overall Survival Subgroups Group HR, 95% CI All 0.78 ( ) ER+, PgR+ 0.88, ( ) ER+, PgR ( ) ER-, PgR ( ) ER-, PgR ( )** Chlebowski, et al J Natl Cancer Inst 2006;98:1767 4

5 Effect of obesity on prognosis after early-stage breast cancer Denmark data Cumulative incidence of locoregional recurrences and distant metastases among 53,816 pts with earlystage breast cancer in Denmark, 1977 to 2006 Patients with a BMI of 30 kg/m 2 were older and had more advanced disease at dx compared with patients with a BMI <25 kg/m 2 (P <.001) When adjusted for disease characteristics, risk of developing distant metastases after 10 years was significantly increased by 46% Ewertz M et al. JCO 2011;29:25-31 Breast cancer death after 30 years was significantly increased by 38% for patients with a BMI 30 kg/m2 Weight gain after early-stage breast cancer Breast cancer specific mortality and breast cancer recurrence Breast cancer recurrence Breast cancer-specific mortality, stratified by level of weight gain BCSS only impacted by >10% weight gain Breast cancer recurrence NOT associated with weight gain Playdon et al. JNCI 2015;107 5

6 Effect of weight gain after early-stage breast cancer All cause mortality Fixed effects meta-analysis of the association between weight gain 5.0% and all-cause mortality Moderate-level weight gain (5-10% compared to maintenance) WAS NOT associated with worse overall mortality (HR = 0.97, P =.70) Higher weight gain (>10% from baseline) WAS associated with increased mortality (HR = 1.23, P <.001). Playdon et al. JNCI 2015;107 Weight loss Interventions Systematic review of 15 studies Multiple designs often with multicomponent interventions: Focused on change in weight, BMI, % body fat, or % overweight Incorporate diet, physical activity, and behavior modification Personalized lifestyle telephone counseling with face-to-face group-based education Commercial weight loss programs Weight Watchers and/or Curves Group teleconferencing for rural breast cancer survivors 14/15 resulted in statistically significant weight loss Weight loss of 5 % from baseline was reported in 10 out of 15 studies With longer follow up, weight gain is observed in many studies Playdon et al Curr Breast Cancer Rep

7 Lifestyle intervention study (LISA) in early breast cancer (BC): A RCT of the effects of a telephone based weight loss intervention vs educational materials alone Population: N=338 ( of 2150 planned) T1-T3 N0-N3 M0 breast cancer dx in previous year BMI kg/m 2 Health Materials (control) Health Materials + Telephone Lifestyle Intervention 19 calls/2 years Goal: kcal/day deficit minutes/week mod intensity PA Overall Physical Activity (Intervention vs. Control) (p=0.004) Weight loss greater with intervention 4.3 kg vs 0.6 kg at 6 months 3.1 kg vs 0.3 kg at 24 months Goodwin PJ et al J Clin Oncol 2014 LISA DFS Data Goodwin et al, SABCS PD Education Only Lifestyle Intervention DFS: Lifestyle Intervention vs Education Only HR 0.71 (95% CI ), p=0.23 Early termination of accrual reduced power to identify effects of the intervention on DFS and OS. Fewer DFS events were seen in those randomized to the lifestyle intervention (22 vs 30, HR 0.71, 95% CI , p=0.23). Lifestyle Intervention Education Only Baseline (kg) Change at 6 month -5.5% -0.6% 1 yr -5.3% -0.6% 2 yr -3.0% -0.4% 3 yr -2.0% -1.6% 4 yr -1.7% -1.6% 5 yr -1.9% -2.2% 6 yr -2.6% -1.9% 7 yr -2.2% -2.4% 8 yr -0.3% -2.8% A 2 year telephone-based weight loss intervention targeting diet and physical activity led to weight loss in the short-term Weight loss was not maintained at 8 years. Landmark analysis of change in weight from baseline to 24 months showed that weight loss had no impact on later DFS. HR (per kg) 0.98 ( ) p=0.58 OS HR 0.85 (95% CI ), p=0.72 7

8 Cardiovascular function and the effect of exercise training during adjuvant breast cancer treatment. Results from The EBBA-II trial (NBCG-14) Thune et al. On behalf of the Energy Balance and Breast Cancer Aspect study group Risk of death from cardiovascular disease following breast cancer: a systematic review 14 articles assessed risk of CVD mortality in 1,217,910 women with breast cancer % of all women with breast cancer died of CVD Women with breast cancer had a higher risk of CVD mortality than women from the general population Risk of CVD mortality was higher among women with: Older age at breast cancer diagnosis years vs years: HR = 17.9, 95% CI (Colzani 2014) Left-sided tumor Diagnosis in an earlier calendar period Black ethnic origin Gernaat et al. Breast Cancer Res Treat (2017) 164: Colzani et al J Clin Oncol 29:

9 Cardiorespiratory fitness (CRF) and physical activity linked to cancer risk and outcomes CRF and cancer-related mortality Individual and pooled risk estimates from prospective cohort studies that related post-dx physical activity to cancer-specific mortality Low CRF High CRF Pooled effect estimate for Breast Cancer 0.62 Groarke et al. AJCC 2018; Friedenreich et al. Clin Can Res 2016 EBBA-II Objectives - To determine whether a 12-month exercise program comprised of endurance and strength training during adjuvant therapy influence cardiopulmonary function. - Change in VO2max, baseline - 12 months - Evaluate the efficacy and safety profile of the exercise program during adjuvant breast cancer treatment - To determine the recommended type, dose, intensity and duration of exercise Patient population years Breast cancer Stage I/II DCIS/LCIS (3) No known severe illness (heart failure, uncontrolled diabetes etc) Capable of participating in exercise No previous cancer 9

10 Study Procedures 12 Month Intervention 3 weeks post-surgery Group based (10-12 women) Detailed training program Outdoor: moderate-high intensity, stretching, weight bearing 60 min x 2/week min at home (240 min/weekly) Lead by physiotherapists Cardiopulmonary Exercise Testing Non-invasive evaluation of the CV system during exercise on a treadmill until exhaustion Assessments of gas exchange, HR, BP, blood lactate, SPO2 Evaluation of cardiovascular system: heart failure, myocardial ischemia, cardiac valve function, chronotropic incompetence Before surgery, 6 and 12 month Baseline Characteristics 10

11 Adherence and Adverse Events (AE) Cardiovascular capacity (VO 2max ) Adherence to the intervention Overall cardiovascular function based on age Attending exercise sessions, % 70% overall AE s: Fatigue during CPET/exercise, one injured shoulder VO 2max 8-10 % reduction/10yrs Final results - The EBBA-II (NBCG-14) All participants (n= 545) No chemotherapy (n=242) 0.3 % increase 8.9 % decrease 1.6 % increase 2.7 % decrease Receiving chemotherapy (n=295) 14.3 % decrease 0.8 % decrease 6.4 % decrease The EBBA-II trial met its primary endpoint in the exercise group All subgroups of patients benefited from physical activity during breast cancer treatment Future direction: Breast cancer patient receiving chemotherapy should be offered tailored exercise program based on assessed pre-treatment level of physical function 11

12 PD5-03 Lifestyle Intervention and Effect on Diseasefree Survival in Early Breast Cancer Patients: Interim Analysis from the Randomized SUCCESS C Study Janni et al SUCCESS C study design (open-label, multicenter, 2x2 factorial design, randomized controlled Phase III study) LI arm non-li arm Endocrine treatment: First randomization: 3 cycles FEC100 followed by 3 cycles docetaxel vs. 6 cycles docetaxel / cyclophosphamide Second randomization for lifestyle intervention: LI arm: Standardized and structured telephone and mail-based lifestyle intervention program with the aim of individual weight loss by diet and physical activity Non-LI arm: General recommendations for healthy lifestyle 12

13 Methods: Lifestyle intervention Intensified lifestyle intervention program (LI arm): ü 2-year standardized and structured telephone and mail-based intervention program (goals: individual weight loss, diet and physical activity) ü Intervention addressing behavioral and motivational issues related to weight management (maintaining motivation, emotional distress, time management) - 19 telephone contacts with trained lifestyle coaches - detailed patient workbook supplemented with mailings with focus on weight management - regular mailings of newsletters (weight loss intervention materials) at month 7 and 14 - up to three additional telephone calls and mailings to address key issues or problems General recommendations for healthy lifestyle (non-li arm): ü standardized mail-based educational support focussing on healthy living (including mailings after completion of chemotherapy and at month 12) ü 2-years of lifestyle information at regular intervals by either a newsletter or a lifestyle magazine Patient characteristics (n = 2292) Patients in the two randomization arms well balanced with regard to clinicopathological characteristics (all p > 0.10) Patient and tumor characteristics* LI arm (n = 1146) non-li arm (n = 1146) Age (years) Body mass index (kg/m 2 ) Tumor size (n, %) Nodal stage (n, %) Histological grading (n, %) Histological type (n, %) Hormone receptor status (n, %) Menopausal status (n, %) Adjuvant chemotherapy (n, %) pt pt pt3/pt pn pn G G G ductal lobular other negative positive premenopausal postmenopausal FEC-Doc DocC

14 Weight change by lifestyle intervention arm ITT analysis Intensified lifestyle intervention program was successful in reducing patients weight (from start of LI intervention to 2-year follow up): LI arm (n = 828): weight loss 1.0 kg (95% CI to -1.39) non-li arm (n = 816): weight gain 0.95 kg (95% CI 0.61 to 1.30) Disease-free survival (DFS) and overall survival (OS) by lifestyle intervention arm ITT analysis 14

15 Explorative subgroup analysis: Completion of lifestyle intervention (yes/no) In the LI arm a much lower proportion of patients completed the 2-year lifestyle intervention program compared to the non-li arm completer non-completer LI arm 552 (48.2%) 594 (51.8%) non-li arm 925 (80.7%) 221 (19.3%) Total 1477 (64.4%) 815 (35.6%) Completers in the two randomization arms well balanced with regard to clinicopathological characteristics (all p > 0.10) In the LI arm, there were moderate, but significant differences between completers and non-completer for: Age: p = 0.013; older fewer Grade: p = 0.043; higher grade fewer Hormone receptor status: p = 0.004; ER neg fewer Weight loss (from start of LI intervention to 2- year follow up) only observed in patients of the LI arm that completed the intensified lifestyle intervention program Explorative subgroup analysis: Completion of lifestyle intervention (yes/no) DFS median observation time: completer: 64.4 months, non-completer: 58.9 months (p < 0.001) OS median observation time: completer: 64.7 months, non-completer: 63.3 months (p < 0.001) 15

16 Explorative subgroup analysis: Survival by lifestyle intervention arm (completers only) Limitations of the study Low adherence to intensified life style intervention Explorative and non-planned interim analysis Patients in the non-li arm may be less well documented Relatively low number of events Potential bias (health status, motivation) unaccounted for: Healthy participant effect? Conclusions Based on a potential bias between completers and noncompleters, the results of the exploratory interim analysis should be interpreted with appropriate caution Multivariable adjusted Cox regression Hazard ratio (LI arm vs. non-li arm) 0.51 (95% CI ); p = Further analyses (long-term f/u, additional outcomes, predictive factors) are planned Results of further trials, such as BWEL, awaited The Breast Cancer Weight Loss Trial NCT Primary Outcome: Invasive Disease Free Survival Interim weight change analysis Study status: 55% enrolled Results expected

17 Alcohol Consumption: After Breast Cancer Pooling Project 9,329 breast cancer patients dx from 1990 to 2006 with Stage I-III breast ca from three prospective US cohorts Life after Cancer Epidemiology (LACE) Study, the Women s Healthy Eating and Living (WHEL) Study, and breast cancer patients from the Nurses Health Study Cohort entry was a mean of 2.1 years post-diagnosis Alcohol intake was assessed at using a food frequency questionnaire 5,422 women (58%) were considered drinkers with a median of 5.3 g/day Regular alcohol intake (6.0 g/day) WAS NOT associated with risk of recurrence HR for 6 to less than 12 g/day, 1.03; 95% CI, HR for 12 to less than 24 g/day, 1.12; 95% CI, HR for 24 g/day, 1.04; 95% CI, Kwan et al, Cancer Epidem Bio Prev 2012 After Breast Cancer Pooling Project However risk varied by menopausal status Postmenopausal women who regularly consumed alcohol (6.0 g/day) had increased risk of recurrence (HR, 1.19; 95% CI, ) Alcohol intake was not associated with mortality Association of alcohol consumption and recurrence stratified by estrogen related factors Kwan et al, Cancer Epidem Bio Prev

18 Alcohol and Outcomes after Breast Cancer Diagnosis Meta-analysis of nearly 30K Cases Pre-diagnostic alcohol intake and overall mortality Post-diagnostic alcohol intake and overall mortality Ali AM et al. Alcohol Consumption and Survival after a Breast Cancer Diagnosis. A literature-based Meta-analysis and Collaborative Analysis of Data for 29,239 Cases. Cancer Epidemiol Biomarkers Prev, 2014 Alcohol use and breast cancer survival among participants in the Women's Health Initiative Included women from the WHI (observation study/clinical trials) who were diagnosed with breast cancer (n=7,835; post-dx alcohol use only available for 25% of the population =1,928 women) Median follow up 7.9 years Outcomes: Overall and breast-cancer-specific mortality Assessed if changes in drinking habits after diagnosis are related to mortality Compared to never and past alcohol consumers, women who drank alcohol prediagnosis: Had somewhat higher household incomes Were somewhat more likely to be past or current smokers; current users of HRT (E+P); non-hispanic whites; college graduates Lowry et al, Cancer Epidem Bio Prev

19 WHI Alcohol Consumption Results Women who drank alcohol prior to their breast cancer diagnosis had a nonstatistically significant 24% (95% CI: ) reduced risk of breast-cancer-specific (BCS) mortality and a 26% (95% CI: ) reduced risk of all-cause mortality Alcohol consumption was associated with a 49% (95% CI: ) reduced risk of BCS mortality among ER- patients with no change in risk observed among ER+ patients (HR=0.97; 95% CI: ) Post-diagnosis alcohol consumption, and change in consumption after diagnosis, did not appear to be associated with all-cause or BCS mortality Conclusion: From a public health perspective, the evidence does not suggest that modification of alcohol intake after a breast cancer diagnosis is warranted, nor does it warrant concerns about pre-diagnosis intake in relation to breast cancer survival. Lowry et al, Cancer Epidemiol Biomarkers Prev Lifestyle Changes CAN Have An Impact Increasing physical activity has shown positive results in both prospective cohort studies and randomized trials Maintaining compliance with lifestyle interventions even on trial is challenging Many weight loss strategies are effective but weight regain is common Still unknown whether weight loss or some other factor associated with exercise results in improved outcomes Alcohol intake AFTER breast cancer may not be as important as its impact on increasing risk of developing breast cancer 19

20 GS6-04 Development and Validation of a Chemotherapy Toxicity Risk Score for Older Patients with Breast Cancer Receiving Adjuvant/NeoadjuvantTreatment Allison Magnuson and Arti Hurria On Behalf of the Cancer and Aging Research Group 42.8% of breast cancers occur in patients 65 and older NCI - SEER. Cancer Statistics

21 Older women receive less aggressive treatment and have higher mortality from early-stage breast cancer Initial treatment for stage II breast cancer by age at diagnosis. Receipt of chemotherapy among women with estrogen receptor negative, lymph node positive, stage I/II breast cancer. Schonberg et al. J Clin Oncol CARG Toxicity Tool - Developed and validated in older adults with all solid tumor malignancies ØAge 72 years ØGI/GU Cancer ØStandard Dose ØPolychemotherapy ØHemoglobin (male: <11, female: <10) ØCreatinine Clearance (Jelliffe-ideal wt <34) ØFall(s) in last 6 months ØHearing impairment (fair or worse) ØLimited in walking 1 block (MOS) ØAssistance required in medication intake (IADL) ØDecreased social activity (MOS) Age Tumor/ Treatment Variables Labs Geriatric Assessment Variables Hurria et al. J Clin Oncol

22 Objective ØTo build upon the CARG score by developing and validating a breast cancer specific adjuvant chemotherapy toxicity score for older patients (CARG-BC) ØTo evaluate the CARG-BC s association with: dose modifications reduced relative dose intensity hospitalizations Eligibility Criteria Age 65 Stage I-III BC To receive adjuvant or neoadjuvant chemotherapy Timepoint 1: Timepoint 2: Across 16 Institutions Pre-chemo Post-chemo Geriatric Assessment Study Schema Treatment (Drugs, Dose, Schedule, Duration) Toxicity Grading (NCI CTCAE v. 4.0) Dose Modifications Geriatric Assessment 22

23 Disease and Treatment Characteristics Median Age (Range): 70 (65-85) Adjuvant Treatment 82.3% Poly Chemotherapy 90.1% Anthracycline-Based Regimen 38.1% Standard Dose 97.5% Treatment Related Outcomes Ø 24% required a dose reduction during therapy Ø 26% had a dose delay Ø 24% discontinued therapy Ø 25% received a relative dose intensity < 85% Ø 23% had a hospitalization during treatment 23

24 CARG-BC Risk Score Risk factors for Gr. 3-5 Toxicity OR (95% CI) Score CARG Score: Medium Risk High Risk 2.47 ( ) 2.26 ( ) Anthracycline 1.37 ( ) 1 Stage II/III 1.79 ( ) 2 Duration of tx > 3 months 2.98 ( ) 4 Abnormal liver function 2.21 ( ) 3 Limited in walking a mile 2.22 ( ) 3 Lack of someone to provide advice 2.34 ( ) 3 3 CARG-BC Model Performance CARG-BC Score 100% Grade 3-5 Toxicities 80% 60% 40% 20% 0% 21% 45% 79% Low (0-5) Medium (6-9) High (10-19) P<0.001 AUC 0.76 (95% CI ) P=0.18 AUC 0.64 (95% CI ) 24

25 100% CARG-BC Model Performance CARG-BC Score 100% MD KPS Grade 3-5 Toxicities 80% 60% 40% 20% 0% 21% 45% 79% Low (0-5) Medium (6-9) High (10-19) 80% 60% 40% 20% 0% 45% 43% 55% % P<0.001 AUC 0.76 (95% CI ) P=0.21 AUC 0.53 (95% CI ) CARG-BC For Other Outcomes Dose Delay Dose Reduction P<0.001 P<0.001 Hospitalization RDI <85% P<0.001 P<

26 ØDeveloped and validated a chemotherapy toxicity risk score (CARG-BC) that predicts toxicity for older patients with stage I-III BC ØThe CARG-BC score is also associated with dose reduction, delay, reduced RDI, and hospitalizations ØThis tool could be considered as part of adjuvant treatment decision-making Conclusions Love your patients as much as you can. Give them as much as you can, with all of your heart. They are in a vulnerable place, and kindness and compassion go such a long way. Arti Hurria, MD, FASCO 26