1 approaches to metastatic disease in breast cancer anne f. schott, md university of michigan
TRANSCRIPT
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1
Approaches to Metastatic Disease in Breast Cancer
Anne F. Schott, MD
University of Michigan
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The Goals
• Maximizing the quality of life (QoL),• Prevention and palliation of symptoms• Prolongation of survival
• Not cure in the vast majority of patients • How to optimally use the tools we have to
maximize patient quality of life and lengthen survival?
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Prognostic Factors in Patients With Metastatic Breast CancerPrognostic factor Favorable Unfavorable
Performance status Good Poor
Sites of disease Bone, soft tissue Viscera, CNS
No. of sites of disease Few Multiple
Hormone receptor status Positive Negative
Her-2/neu status NegativePositive (significance less clear in Her-2/neu inhibitors era)
Disease-free interval >2 years <2 years
Prior adjuvant therapy No Yes
Prior therapy for MBC No Yes
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Kaplan–Meier curves illustrating overall survival for patients with de novo stage IV versus relapsed disease.
Dawood S et al. Ann Oncol 2010;21:2169-2174
© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Survival differences among women with de novo stageIV and relapsed breast cancer
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Survival differences among women with de novo stage IV and relapsed breast cancer
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Survival differences among women with de novo stage IV and relapsed breast cancer
VariableHazard ratio
Lower 95%
Upper 95%
P value
Relapsed versus de novo 1.75 1.47 2.08 <0.0001
Race (black versus white) 1.38 1.18 1.61 <0.0001
Race (Hispanic and other versus white)
0.88 0.75 1.03 0.112
Age at metastasis 1.01 1.00 1.01 0.0004
Year of metastatic diagnosis 1.01 0.98 1.03 0.606
LVI (positive versus negative) 1.19 1.08 1.32 0.001
HR (positive versus negative) 0.59 0.53 0.66 <0.0001
Grade (III versus I/II) 1.51 1.34 1.71 <0.0001
Visceral or other metastases versus bone only
1.39 1.24 1.56 <0.0001
Multiple or brain metastases versus bone only
2.10 1.80 2.43 <0.0001
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Influences on Treatment Choices
• Hormone receptor status of the primary tumor or its metastases
• HER-2/neu status• The duration of the relapse-free interval since primary
diagnosis• The location and extent of metastases (visceral versus
nonvisceral)• Previous treatment (including its effects and tolerance)• Patient symptoms• Patient preferences• Anticipated side-effects of treatment • Availability and access to treatment
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Patient Case #1
• 46 year old woman, breast cancer 6 years ago, postmenopausal due to TAH, presents with a supraclavicular lymph node
• Biopsy – ER positive, PR negative, Her-2 negative
• Prior therapy AC x 4 and tamoxifen x 5 years, completed two years ago
• Staging evaluation with CT scan shows pleural metastases, several small lung metastases, and slightly enlarged mediastinal lymph nodes
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Options in this case
• Chemotherapy• Chemotherapy combined with hormonal
therapy• Hormonal therapy• Clinical trial
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Chemotherapy vs Tamoxifen vs Concurrent Therapy
Tam AC Tam + AC
Response 22.1% 45.1% 51.3%
Clinical Benefit 80% 88% 91%
Median Survival 22.8 mo 22.5 mo 19.04 mo
• Although median survival not improved for chemo over tamoxifen, RR increased: patients did not all cross over
• Led to recommendation of hormonal therapy first – retest in modern day?
ANZ BCTG 7802
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Concurrent chemotherapy and hormonal therapy
• No survival benefit seen in metastatic setting with combined tamoxifen with cytotoxic chemotherapy
• Adjuvant setting suggests worse outcome of chemotherapy concurrent with tamoxifen (SWOG 8814)
• Would this hold true for aromatase inhibitors?
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Characteristics of Hormone Sensitive MBC• A long disease-free interval (>2 years)• No (or limited) visceral involvement• Limited metastatic sites and disease-
related symptoms and• Slow disease progression
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Why Use Hormonal Therapy Alone Metastatic Disease?• ER rich tumors less responsive to chemotherapy
– less likely to have pCR in neoadjuvant setting– less likely to benefit in adjuvant setting
• Hormonal therapy can be used longer than chemotherapy with fewer side effects
• Minimal disease, asymptomatic disease, non-life-threatening disease if ER or PR positive should get hormonal therapy– bone-only metastases, bone/pleura, lymph node
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Selection of Hormonal Agents-Postmenopausal
• Aromatase inhibitors superior to tamoxifen first line
• Fulvestrant equal to anastrozole, following tamoxifen failure
Hormonal Therapy for Metastatic DiseasePost-Menopausal
ONLY
Aromatase Inhibitor
Aromatase inhibitor Fulvestrant
Aromatase inhibitor Fulvestrant Megestrol acetate
Androgens2nd aromatase
inhibitorMegestrol acetate
Tamoxifen
Tamoxifen
Fulvestrant
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Newer Strategies for Endocrine Responsive Breast Cancer?
• What is the role of combination endocrine therapy in metastatic disease?– S0226: anastrozole +/- fulvestrant– TAMRAD/Bolero2 adding everolimus
• What new agents can be used in hormonal combinations to overcome endocrine resistance?
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HR = 0.80 (95% CI 0.68 - 0.94)
Median PFS
Combination 15.0 mos (95% CI 13.2-18.4)
Anastrozole 13.5 mos (95% CI 12.1-15.1)
0.00
0.25
0.50
0.75
1.00
Pro
gres
sion
-free
sur
viva
l
345 193 92 39 11 3 0AN + FV349 199 114 53 21 8 2AN
N at risk
0 12 24 36 48 60 72Months since registration
Anastrozole + Fulvestrant (268 events)
Anastrozole (297 events)Stratified log-rank p = 0.0070
All eligible patients (n=694)Progression-Free Survival in S0226
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Overal l
Prior tamNo prior tam
MeasurableNon-measurable
Age 65+Age < 65
De novo0-5 years5-10 years10 years+
Bone onlyVisceralNon-v isceral
HER2-negativeHER2-pos itive
No prior chemoPrior chemo
Combination better Combination worse
.4 .6 .8 1 1.2 1.4 1.6Hazard ratio
Hazard ratio with 95% confidence intervalsUnplanned subset analys is
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RTreatment A:
exemestane (EXE) + everolimus (EVE) (n=485)
Treatment B:
exemestane + placebo (n=239)Randomized
2:1
N= 724 ER+, previously non-steroidal aromatase inhibitor treated MBC patients
Primary Outcome: Progression Free Survival
Baseline characteristics were well balanced; median age was 62 years; 56% had visceral involvement and 84% were sensitive to prior hormone therapy. Prior therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%) and chemotherapy for metastatic disease (25%).
BOLERO-2
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EVE + EXE PBO + EXE HR p-value
PFS (interim analysis)
(median, months)7.4 3.2 0.44
(95% CI: 0.36-0.53)<1 x 10-16
PFS (central assessment)
(median, months)11.0 4.1 0.36
(95% CI: 0.28-0.45)<1 x 10-16
Overall survivalinterim analysis planned after 182 deaths (December 2011)
23.1% in everolimus arm29.3% in placebo arm
RESULTSMedian follow up of 12.5 months
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Patient case #2
• 53 year old diagnosed 2 years ago, Stage II ER-, PR-, Her-2 neu –
• Received AC-Taxol, lumpectomy and RT• CXR incidentally showed lung nodule• Recurrence also detected in liver and
lymph nodes • Biopsy confirmed same receptor profile• Asymptomatic, PS 0
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Question
• What would you recommend for this patient?– Single agent chemotherapy– Combination chemotherapy– Observation
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The Goals
• Maximizing the quality of life (QoL),• Prevention and palliation of symptoms• Prolongation of survival
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Active single agents in breast cancer
• Taxanes– Docetaxel, paclitaxel
• Anthracyclines– Doxorubicin, epirubicin,
liposomal doxorubicin• Alkylating agents• Fluoropyrimidines
– 5-FU, capecitabine• Vinorelbine• Ixabepilone • Eribulin
• Gemcitabine• Platinums• Topo I inhibitors
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Additive
Synergistic
Antagonistic
Concept of Additive, Synergistic, and Additive Combination Regimens
+
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Commonly Used Combination Therapies: Preclinical Predictions• Doxorubicin + cyclophosphamide• Doxorubicin + Docetaxel• Docetaxel + capecitabine• Platinums + taxanes• Gemcitabine + taxanes• Gemcitabine + cisplatinum• Vinorelbine + docetaxel• Vinorelbine + capecitabine• Cyclophosphamide + capecitabine
• Additive• Antagonistic• Synergistic• Synergistic• Synergistic• Additive• Synergistic• Additive• Synergistic
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Table 2 – Main characteristics of randomized controlled trials testing chemotherapy regimens reported 2000-2007
Total number of trials (n < 150 excluded) 63
Median trial size 305
Main research questions
Combination versus combination 20
Combination versus single agent 13
Single agent versus single agent 3
Combination versus sequential single agent 3
Dose questions
High-dose therapy 3
Dose 4
Dose intensity 2
Dose schedule 3
Drug formulation 9
Duration 3
Statistically significant benefit
In response rate 19 (30%)
In PFS 22 (35%)
In OS 8 (13%)
QOL Measured in 19 (30%)
Cochrane Review:
Wilcken, Dear
European Journal Of Cancer 4 4 ( 2 0 0 8 ) 2 2 1 8 –2 2 2 5
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Author # patient
s
Arm A Arm B OS A OS B p-Value Toxicity/QOL
Feher, O 410 Epirubicin Gemcitabine 19.1 11.8 0.0004 Toxicity similar
O’Shaughnessy 511 Docetaxel/capecitabine
Docetaxel 14.5 11.5 0.0126 Arm A more toxic but trend to less decrease in QOL. Cost effective
Jassem, J 267 Doxorubicin/paclitaxel
FAC 23.3 18.3 0.013 Arm A neutropaenia. Arm B emesis
Albain, KS 529 Paclitaxel/gemcitabine
Paclitaxel 18.5 15.8 0.018 Arm A more toxic
Bontenbal, M 216 Docetaxel/doxorubicin
FAC 22.6 16.2 0.019 Arm A more FN
Stockler, M 325 Intermittent or continuous capecitabine
CMF 22.0 18.0 0.02 Capecitabine HFS. CMF FN
Jones, S 449 Docetaxel Paclitaxel 15.4 12.7 0.03 Docetaxel more toxic. QOL same
Icli, F 201 Oral etoposide/cisplatin
Paclitaxel 14.0 9.5 0.039 Toxicity similar
8/63 Trials With Survival Benefit
None of these trials included a sequential crossover design
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Combination A-Taxol vs. Single Agent Sequential: E1193
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Combination Capecitabine + Docetaxel
Crossover in only 25% of patients (non-US population)
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Cyclophosphamide (CPA) Effect on Capecitabine Metabolism
CPA
31
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S0430RIBBON-1
( NJ Robert, ASCO 2009)
RIBBON-2(Brufsky,
SABCS 2009)
Thomas et al (J Clin Oncol 25:5210-5217
SOLTI(Baselga,
SABCS 2009)
S0430
CAPE Combinator
Placebo/Bevacizumab
Placebo/Bevacizumab
Control/Ixabeplione
Placebo/Sorafenib CPA
# of pts 206/409 47/97 377/375 114/115 96
Prior chemos0123
100%ExcludedExcludedExcluded
Excluded100%
ExcludedExcluded
9%/7%49%/48%37%/41%
6%/5%
54%/43%45%/57%ExcludedExcluded
54%32%14%
Excluded
ER or PR +ER- PR-Her2-Her 2+Unknown
NR NR49%/47%26%/24%14%/16%11%/13%
68%/77%29%/17%Excluded
3%/6%
56%?37%?6%?1%
Response 23.6%/35.4% NR 14%/35% 30.7%/38.3% 36%
PFS (months) 5.7/8.6 4.1/6.9 4.2/5.8 4.1/6.4 5.9
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Combination vs. Single Agent Chemotherapy• Consistent increases in response rate with
combination vs. single agent therapy• Consistent increase in toxicity as well• Increase in response rate could be seen with
either synergistic, additive, OR ANTAGONISTIC combinations
• The only true test of a survival benefit (for combination vs use at all) in patients who are not gravely ill includes a “crossover” design
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Patient case #2.B
• 53 year old diagnosed 2 years ago, Stage II ER-, PR-, Her-2 neu –
• Received AC-Taxol, lumpectomy and RT• Presented with right upper quadrant pain.
Recurrence detected in bone, liver and lymph nodes
• Biopsy confirmed same receptor profile• Highly symptomatic, PS 2
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Question
• In addition to symptom management, what would you recommend for this patient?– Single agent chemotherapy– Combination chemotherapy– Observation
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Selection of chemotherapy agents in metastatic disease• Patient characteristics
– Prior therapy exposures (anthracycline, taxane)– Residual toxicity (neuropathy)– GI function (capecitabine)
• Patient preferences– Alopecia– Oral versus IV– Weekly versus q 3 weeks
• Tumor characteristics?– Are there any identifiers for chemotherapy response?
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ASCO Clinical Practice Guideline Update on the Use of Chemotherapy Sensitivity and Resistance Assays
Recommendation Category 2004 and 2011 Recommendations
Use of CSRAs
The use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting.
Chemotherapy treatment decisions
Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences.
Future research:evaluating CSRAs in clinical trials
Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.
JCO August 20, 2011 vol. 29 no. 24 3328-3330
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Treatment Duration
• Fixed chemotherapy length?• How long?
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Results of search strategy.
Gennari A et al. JCO 2011;29:2144-2149
©2011 by American Society of Clinical Oncology
Duration of Chemotherapy for Metastatic Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials
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Overall survival.
Gennari A et al. JCO 2011;29:2144-2149
©2011 by American Society of Clinical Oncology
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Progression-free survival.
Gennari A et al. JCO 2011;29:2144-2149
©2011 by American Society of Clinical Oncology
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June 26, 2007 42
New(er) Agents in Metastatic Breast Cancer
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• Locally recurrent or MBC• 2-5 prior chemotherapies
• Progression ≤6 months of last chemotherapy
• Neuropathy ≤grade 2• ECOG ≤2
Eribulin mesylate1.4 mg/m2, 2-5 min IV
Day 1, 8 q21 days
Treatment of Physician’s Choice (TPC)
Any monotherapy (chemotherapy, hormonal, biological)* or
supportive care only†
Randomization 2:1
• PFS• ORR• Safety
•Overall survival
Primary endpoint
Secondary endpoints
EMBRACE study design
Stratification:– Geographical region, prior capecitabine, HER2/neu status
Global, randomized, open-label Phase III trial (Study 305)
Patients (N=762)
− ≥2 for advanced disease− Prior anthracycline and
taxane
* Approved for treatment of cancer
†Or palliative treatment or radiotherapy administered according to local practice, if applicable
ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival;HER2/neu, human epidermal growth factor receptor 2
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EMBRACE Design Features• Strengths:
– Heavily pre-treated patient population (median 4 prior regimens), a setting of clear unmet need
– Treatment choices reflect real-world options– Large trial with “all comers” design– Powered to look for OS with two-sided log-rank test
• Limitations:– Not a blinded study– Patients in TPC arm could receive treatments they have
been exposed to previously– If many patients elected BSC, then it becomes a trial of
“1 vs 0” additional lines of therapy– Does schema invite investigator bias in considering
subsequent lines of therapy beyond progression?
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Overall survival (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 282624222018161412108642
Su
rviv
al p
rob
abili
tyOverall survival
EribulinMedian 13.12 months
TPCMedian 10.65 months
HR* 0.81 (95% CI 0.66, 0.99)p-value†=0.041
2.47 months
TPC (n=254)
Eribulin (n=508) 53.9%
1 year survival
43.7%
ITT population; *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata†p value from stratified log-rank test (pre-defined primary analysis); HR, hazard ratio; CI, confidence intervals
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Does 3rd Line Chemotherapy Palliate Refractory Breast Cancer?h 3rd line chemotherapy:
h 30% had improvement in emotional status
h 34% had major improvement in HRQL scores
h 6% had objective clinical response
h Tumor response correlated with more energy, diminished distress, and functional improvement
h Not all “benefit” was seen in responders, and not all “responders” benefit
McLachlan SA, Pintilie M, Tannock IF. Breast Cancer Res Treatment 1999;54:213
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Clinical Trials are Often Appropriate
• PARP inhibitors• Stem cell targeted agents
– Notch pathway– Hedgehog pathway– CXCR1/2
• MEK• AKT/PI3K• Other anti-angiogenic
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Measuring treatment benefit – clinical trial methodologies focus on tumor “response”
• Plain films• CT scan• Bone scan• MRI• PET scan• MUC-1 based tumor antigens• CEA, CA 125• Circulating Tumor Cells• Other biological markers of response
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%P
rob
abil
ity
of
Pro
gre
ssio
n F
ree
Su
rviv
al
0 5 10 15 20 25 30 35 40 45 55 60 65 70 75 80
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
50
~7 mos~2.1 mos
CTC at 1st Follow-up predict PFS
1st Follow-up (3 - 4 wk)N = 163Log rank p < 0.0001
Time from Baseline (Weeks)
<5 CTC (n=114)
≥5 CTC (n=49)~7-8 mos
~5-6 WEEKS
First F
ollowup
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S0500 Trial SchemaMetastatic Breast Cancer
Starting 1st Line ChemotherapyN = 350
Metastatic Breast CancerStarting 1st Line Chemotherapy
N = 350
End 1st cycle / blood draw 5-7 days prior to next cycleEnd 1st cycle / blood draw 5-7 days prior to next cycle
Group B - RandomizedN = 104
Group B - RandomizedN = 104
End Therapy / Final Blood drawEnd Therapy / Final Blood draw
Analysis & Report1º End Points = PFS (Progression / RECIST) & OS (12 month follow-up)2º End point = QOL (SWOG Method)
Analysis & Report1º End Points = PFS (Progression / RECIST) & OS (12 month follow-up)2º End point = QOL (SWOG Method)
Arm 2 – Δ TherapyN = 52
Arm 2 – Δ TherapyN = 52
Arm 1- same therapyN = 52
Arm 1- same therapyN = 52
Group A – Same Therapy N = 246
Group A – Same Therapy N = 246
<5CTC ≥5CTC
*2 x 8ml CellSave tubes 1 x 10mL EDTA Processed at:
• Immunicon• Impath Labs
*2 x 8ml CellSave tubes 1 x 10mL EDTA Processed at:
• Immunicon• Impath Labs*Baseline blood draw / begin new therapy*Baseline blood draw / begin new therapy
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The Goals of “Active Therapy”
• Prolonged survival• Relief of symptoms primarily by
decreasing disease bulk• Not cure in the vast majority of patients
• “To cure sometimes, to relieve often, to comfort always” - Anonymous
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Palliative Care
• At some point, “active treatment” goals are unrealistic
• Drop the goal “prolongation of survival”• Focus only on “relief” and “comfort”
– Pain and symptom management– Family involvement/planning– Spiritual needs– May be best served by hospice
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In memory of….You can shed tears that she is gone,
or you can smile because she has lived.
You can close your eyes and pray that she'll come back,
or you can open your eyes and see all she's left.
Your heart can be empty because you can't see her,
or you can be full of the love you shared.
You can turn your back on tomorrow and live yesterday,
or you can be happy for tomorrow because of yesterday.
You can remember her only that she is gone,
or you can cherish her memory and let it live on.
You can cry and close your mind, be empty and turn your back.
or you can do what she'd want:
smile, open your eyes, love and go on.
---David Harkins
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