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Update on the 2006 San Antonio Breast Cancer Symposium. Helen K. Chew, MD, FACP UC Davis Cancer Center. Objectives. To review the 4 most clinically relevant abstracts: Adjuvant trastuzumab (abstract #52) Trastuzumab combined with aromatase inhibitors in the advanced setting (abstract #3) - PowerPoint PPT Presentation
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Update on the 2006 San Antonio Breast Cancer Symposium
Helen K. Chew, MD, FACP
UC Davis Cancer Center
Objectives
• To review the 4 most clinically relevant abstracts:
• Adjuvant trastuzumab (abstract #52)• Trastuzumab combined with aromatase
inhibitors in the advanced setting (abstract #3)• Taxanes in the adjuvant setting (abstract #53)• Endocrine therapy in metastatic disease
(abstract #49)
High-risk node negative
• T > 2 cm or
• ER and PgR negative or
• Histological grade 2-3 or
• Age < 35 y/o
How does this affect clinical practice?
• Platinum doublet appears as effective as anthracycline-containing regimen in the adjuvant setting
• Toxicities of regimens distinct and acceptable
• Role of Topo II amplification unclear in this patient population
Trastuzumab prolongs progression-free survival in hormone-dependent and HER2‑positive metastatic
breast cancer
John R. Mackey MD Cross Cancer Institute, Edmonton, Canada
On behalf of the TAnDEM investigators
Cross-talk between signal transduction and endocrine pathways
Adapted from Johnston 2005
SOSRAS
RAF
Basaltranscription
machineryp160
ERE ER target gene transcription
ER CBPPP P P
ER
Pp90RSK
AktP
MAPKP
Cellsurvival
Cytoplasm
Nucleus
ER
PI3-KP
P
PPP
P
Cellgrowth
MEKP
Plasmamembrane
Anastrozole
HER2
IGFRGrowth factorEstrogen
Trastuzumab
TAnDEM study design
• Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone
HER2-positive, hormone receptor-
positive MBC (n=208a)
R
Anastrozole 1 mg daily + trastuzumab 4 mg/kg loading dose
2 mg/kg qw until disease progression
Anastrozole 1 mg daily until disease progression
aOne patient did not receive study drug and was excluded from analysesMBC, metastatic breast cancer
End points
Primary efficacy
• PFS
Secondary efficacy
• Clinical benefit rate
• Overall response rate
• TTP
• Duration of response
• OS
• 2-year survival
Safety
• AEs and SAEs
• Cardiac function
PFS, progression-free survival; TTP, time to progression; OS, overall survival; AE, adverse event; SAE, serious adverse event
Key inclusion criteria• Postmenopausal women with MBC
• HER2 positive (IHC 3+ and / or FISH+, centrally confirmed)
• ER and / or PgR positive (local testing)
• Tamoxifen allowed for adjuvant and 1st treatment of MBC
• No chemotherapy for metastatic disease
• ECOG performance status 0-1
• Baseline LVEF >50% without serious cardiac conditions
IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; ER, estrogen receptor; PgR, progesterone receptor; ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction
Baseline patient demographics
All data are median (range) unless otherwise noted; A, anastrozole; H, trastuzumab
A+H (n=103)
56 (31-85)
25.6 (0.6-419)
1.6 (0.3-67)
2 (1-5)
4 (1-14)
4232624570
6053 45
62 (50-82)
Age, years
Time from initial diagnosis, months
Duration of metastatic disease, months
No. metastatic sites/patient
No. lesions/patient
Sites of metastases, % patientslungliverbonesoft tissueother
Previous therapy, % patients hormonalchemotherapy anthracycline
LVEF, %
A (n=104)
54 (27-77)
27.3 (0.6-154)
1.2 (0.3-19)
2 (1-5)
4 (1-13)
4628514263
6660 51
63 (51-89)
Progression-free survival
103 48 31 17 14 13 11 9 4 1 1 0 0A+H
104 36 22 9 5 4 2 1 0 0 0 0 0A
CI, confidence intervalPFS = time from randomisation to date of progressive disease or death
Probability 1.0
0.8
0.6
0.4
0.2
0 5 10 15 20 25 30 35 40 45 50 55 60Months
95% CI
3.7, 7.02.0, 4.6
p value
0.0016
Median PFS
4.8 months2.4 months
Events
8799
0.0
No. at risk2.4 months
Patients(%)
0
10
20
30
40
50
60p=0.026
Clinical benefit
A+H (n=103)
A (n=104)
Clinical benefit rate in all patients
42.7
27.9
Overall survival
73 / 104 patients (70%) received H later during the course of disease
103 91 83 76 63 49 36 24 12 4 3 0 0A+H
104 96 87 73 58 42 34 22 5 2 1 1 0A
No. at risk
0 5 10 15 20 25 30 35 40 45 50 55 60Months
95% CI
22.8, 42.418.2, 37.4
p value
0.325
Median OS
28.5 months23.9 months
Events
5864
Probability 1.0
0.8
0.6
0.4
0.2
0.0
Most common AEs (>10%)
FatigueVomitingDiarrhoeaPyrexiaNasopharyngitisNauseaArthralgiaBack painChillsCoughHeadacheDyspnoeaConstipationBone pain
2121201717171515151414131211
1058725
107–66956
Patients, %
AE A+H (n=103) A (n=104)
Safety profile
Cardiac disorders
asymptomatic CHF (NYHA class I)
symptomatic CHF (NYHA class II)
myocardial infarction, ischaemia
dysrythmia
>1 AE
>1 SAE
Death due to AE
Grade 3/4 AEs
13
4a
1
2
7
87
23
0
25
2
0
0
1
1
65
6
2b
15
Patients, %
a1 patient had a myocardial infarction and subsequent CHF class I
b1 event occurred after crossover to A+H
A+H(n=103)
A(n=104)
CHF, congestive heart failure; NYHA, New York Heart Association
Conclusions
• Trastuzumab added to anastrozole significantly improves PFS for women with HER2 and HR co-positive MBC
• >15% of patients receiving A + H did not progress for at least 2 years; thus chemotherapy can be delayed
• Despite 70% of patients receiving H after progression on A alone OS seems to be improved
• Treatment with A + H was manageable, with no new or unexpected AEs
How does this affect clinical practice?
• In patients with HER-2/neu positive and hormone receptor positive advanced breast cancer, the combination of trastuzumab and anastrazole is well tolerated
• Small study (n=207), underpowered?• Does not address whether sequential
therapy may be optimal in this uncommon patient population
A Randomized Trial of CEF vs. Dose Dense EC followed by
Paclitaxel vs. AC followed by Paclitaxel in Women with Node
Positive or High Risk Node Negative Breast Cancer
NCIC CTG MA21
Results of an Interim Analysis
Background• Milan Cancer Institute: 15 yr DFS 42% (CMF) vs.
28% (no Rx)• NSABP B - 15: 3yr DFS 62% (4 cycles AC) vs. 68%
(AC delayed CMF) vs. 63% (6 cycles CMF) • NCIC CTG MA5: 5yr DFS 63% (CEF) vs. 53%
(CMF)• EORTC, NCIC CTG, SAKK: PFS 34m (CEF) vs.
34m (12 weeks dose dense EC) in LABC • CALGB 9344: 3 yr DFS 77% (AC/T) vs. 73% (AC)
Patient Population: Inclusion
• ≤ 60 years
• Histologically confirmed operable breast cancer
• Axillary node +ve, high risk node –ve (tumor ≥ 1cm, grade III or ER –ve, or LVI)
• Able to start protocol Rx within 12 weeks of surgery
NCIC CTG MA 21
ECF
AC → T
EC →T
Stratification: No. of nodes +ve (0,1-Stratification: No. of nodes +ve (0,1-3, 4-10, >10); Surgery (partial vs. 3, 4-10, >10); Surgery (partial vs. mastectomy), ER (+ vs. -) mastectomy), ER (+ vs. -)
Regimens
• CEF:6 cycles of C 75 mg/m2 po days 1-14, E 60mg/m2 and 5FU 500mg/m2 both iv Days 1 & 8 plus antibiotics (cotrimoxazole or cipro)
• Dose dense EC: 6 cycles every 2 weeks of E 120mg/m2 and C 830mg/m2 both iv, plus filgrastim and epoetin alfa followed by 4 cycles of T 175 mg/m2 every 3 weeks
• AC/T: 4 cycles of A 60mg/m2 and C 600mg/m2 both iv every 3 weeks followed by T 175 mg/m2 every 3 weeks
Other Therapy
• ER +ve or PR +ve: tamoxifen, and after 2004 aromatase inhibitors in postmenopausal women
• Radiation: post-lumpectomy breast radiation and post-mastectomy as per local institutional policy
• Trastuzumab: allowed after June 2005 if completed chemotherapy within previous 6 months
OUTCOMES• Primary: Relapse-free survival
(recurrence or death)
• Secondary: Overall survival
Toxicity
Quality of life
Statistics
• Sample size 2100• One planned interim analysis when 1/2
expected recurrences (227)• Stratified log rank test for RFS• The interim analysis (O’Brien-Fleming type
boundaries) would use global test of significance for 3-way comparison. If p<0.005, would then proceed to pair-wise comparisons
Baseline Characteristics
CEF %
n=701
EC/T %
n=701
AC/T %
n=702
Age: <50
≥50
60
40
61
39
62
38
Surgery: partial
total
51
49
50
50
50
50
ER: negative
positive
40
60
41
59
41
59
Menopause: pre
post
69
31
68
32
67
33
Baseline CharacteristicsCEF %
n=701
EC/T %
n=701
AC/T %
n=702
Axillary nodes: 0
1-3
4-10
> 10
28
43
22
7
28
43
22
6
28
44
23
6
T Status: T1
T2
T3
T4
34
56
9
1
34
54
10
2
36
55
8
1
Relapse-Free Survival: All Patients
P = 0.001 (stratified)
CEFCEF
EC-TEC-T
AC-TAC-T
CEFEC/TAC/T
701701702
451441405
125101113
2 yr 4 yr
Result: RFS Between Arms
Treatment Hazard Ratio (95% CI)
P Value
EC/T to CEF 0.89 (0.64, 1.22) 0.46
AC/T to CEF 1.49 (1.12, 1.99) 0.005
AC/T to EC/T 1.68 (1.25, 2.27) 0.0006
Test TypeTest Type Hazard Hazard P-valueP-value¹¹ Ratio (95% CI) Ratio (95% CI)
ER+ PatientsER+ PatientsEC/T to CEF EC/T to CEF 1.06 (0.65,1.72) 1.06 (0.65,1.72) 0.79 0.79AC/T to CEF AC/T to CEF 1.27 (0.80,2.01) 1.27 (0.80,2.01) 0.29 0.29 AC/T to EC/T AC/T to EC/T 1.20 (0.76,1.90) 1.20 (0.76,1.90)
0.39 0.39
ER- PatientsER- PatientsEC/T to CEF EC/T to CEF 0.78 (0.50,1.20) 0.78 (0.50,1.20) 0.23 0.23 AC/T to CEF AC/T to CEF 1.67 (1.15,2.42) 1.67 (1.15,2.42) 0.007 0.007 AC/T to EC/T AC/T to EC/T 2.15 (1.44,3.21) 2.15 (1.44,3.21)0.0002 0.0002
1Log-Rank Test, adjusted for stratification factors2Interaction Test for Treatment and ER p=0.23
Differences in RFS Between Treatment Arms
Toxicity
CEF EC/T AC/T
Febrile Neutropenia 22.9% 16.7% 4.8%
Cardiac Toxicity - delayed
Grade 1/2 34.9% 28.0% 21.5%
Grade 3/4 2.0% 0.7% 0.4%
Thromboembolic Events - acute 7.7% 7.8% 2.0%
ToxicityCEF EC/T AC/T
Leukemia/MDS 4 – AML
3 – AML
1 – ALL0
Sensory neuropathy - acute
Grade 1/2 25.7% 65.8% 64.1%
Grade 3/4 0.6% 5.9% 5.8%
Motor neuropathy - acute
Grade 1/2
Grade 3/43.9%
0.4%
7.5%
1.4%
6.3%
0.4%
Conclusion
• AC/T given every three weeks is significantly inferior to CEF or EC/T in terms of RFS in patients with high risk operable breast cancer.
• Taxane based chemotherapy may not be necessary in all women receiving adjuvant chemotherapy.
• The role of non-dose dense taxane based chemotherapy is unclear.
Conclusion
• A dose dense/dose intense approach with anthracyclines adds benefit in this setting.
• It is too early to detect any difference between CEF and dose dense EC/T.
How does this affect clinical practice?
• Adds thought-provoking data on the use of taxanes in the adjuvant setting and the benefits of therapy based on hormone-receptor status
• Unclear the role of dose-dense AC->T
EFECTEvaluation of Faslodex vs. Exemestane
Clinical Trial
William J Gradishar MDNorthwestern University Feinberg School of Medicine
Martine PiccartJules Bordet InstituteBrussels, Belgium
Stephen ChiaBritish Columbia Cancer Agency
Vancouver, Canada
Stephen ChiaBritish Columbia Cancer Agency
Vancouver, Canada
What are the options following adjuvant / What are the options following adjuvant / 1st-line non-steroidal AI?1st-line non-steroidal AI?
1st treatment1st treatment
2nd treatment2nd treatment
4th treatment4th treatment
3rd treatment3rd treatment
Non-steroidal AINon-steroidal AI
Fulvestrant?Fulvestrant?Exemestane?Exemestane?
ExemestaneExemestaneFulvestrantFulvestrant TamoxifenTamoxifen
TamoxifenTamoxifen TamoxifenTamoxifenExemestaneExemestaneor or
FulvestrantFulvestrant
Fulvestrant and exemestane after Fulvestrant and exemestane after progression on non-steroidal AIsprogression on non-steroidal AIs
Endocrine agentEndocrine agent
FulvestrantFulvestrant
ExemestaneExemestane
CBR (%)CBR (%)
35353030
2020
ReferenceReference
Ingle et al 2006Ingle et al 2006Perey et al 2006Perey et al 2006
LLøønning et al 2000nning et al 2000
Ingle et al. J Clin Oncol 2006; 24:1052Ingle et al. J Clin Oncol 2006; 24:1052––10561056Perey et al, Ann Oncol Advance Access published online on October 9, 2006Perey et al, Ann Oncol Advance Access published online on October 9, 2006
LLøønning et al. nning et al. Clin Oncol 2000; 18: 2234–44Clin Oncol 2000; 18: 2234–44
Progression
Fulvestrant loading dose + placebo for
exemestane (n=330)
Prior non-steroidal AI failure
Survival
Progression
Survival
Exemestane 25 mg orallydaily + placebo for
Fulvestrant (n=330)
Analysis after 580 events(progression or death)
500 mg Day 1, 250 mg Day 14 & 28,
and monthly
Endpoints in protocol
Primary: • Time to disease progression
Secondary: • Overall survival
• Objective response rate
• Clinical benefit rate (OR + SD ≥24weeks)
• Duration of response, time to response
• Tolerability
Key inclusion criteria• Postmenopausal women, ER+ and/or PgR+ positive
• Progression during NSAI treatment for ABC or recurrence on NSAI for adjuvant therapy or within 6 months of its discontinuation
• Measurable disease or bone lesions
• PS 0–2 and normal organ function
• No life-threatening visceral metastatic disease or any brain or leptomeningeal involvement
Demographic characteristicsDemographic characteristics
Median ageMedian age
RaceRaceCaucasianCaucasianBlackBlackOrientalOrientalOtherOther
Metastatic sitesMetastatic sitesBoneBoneLungLungLiverLiver
ER+ and/or PgR+ER+ and/or PgR+
FulvestrantFulvestrantn=351n=351
63 years63 years
ExemestaneExemestanen=342n=342
63 years63 years
89.2%89.2%3.1%3.1%1.1%1.1%6.6%6.6%
67.2%67.2%34.5%34.5%31.1%31.1%
99.7%99.7%
91.2%91.2%3.8%3.8%1.2%1.2%3.8%3.8%
66.4%66.4%36.3%36.3%32.2%32.2%
98.5%98.5%
Time to progression (ITT)Time to progression (ITT)Proportion Proportion of patients of patients progression-progression-freefree
MonthsMonthsAt risk:At risk:FulvestrantFulvestrantExemestaneExemestane
3.73.73.73.7Median (months)Median (months)
HR = 0.963, 95% CI (0.819, 1.133), p=0.6531HR = 0.963, 95% CI (0.819, 1.133), p=0.6531
Cox analysis, p=0.7021Cox analysis, p=0.7021
ExemestaneExemestaneFulvestrantFulvestrant
FulvestrantFulvestrant
ExemestaneExemestane
00 33 66 99 1212 1515 1818 2121 2424 2727
0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
351351 195195 9696 5050 2525 1212 44 22
342342 190190 9898 4141 2121 1212 88 66
00
11
00
00
Objective response and clinical benefit rate Objective response and clinical benefit rate (evaluable for response population)(evaluable for response population)
* Analyses are not adjusted for baseline covariates* Analyses are not adjusted for baseline covariates
OR rateOR rate
(CR + PR)(CR + PR)
CB rateCB rate
(OR + SD (OR + SD ≥≥24 wks)24 wks)
FulvestrantFulvestrant
7.4%7.4%
(20/270)(20/270)
32.2%32.2%
(87/270)(87/270)
ExemestaneExemestane
6.7%6.7%
(18/270)(18/270)
31.5%31.5%
(85/270)(85/270)
Odds ratio*Odds ratio*(95% CI)(95% CI)
1.1201.120
(0.578, 2.186)(0.578, 2.186)
1.0351.035
(0.720, 1.487)(0.720, 1.487)
p-valuep-value
0.73640.7364
0.85340.8534
Proportion Proportion of patients of patients respondingresponding
MonthsMonths
At risk:At risk:FulvestrantFulvestrantExemestaneExemestane
FulvestrantFulvestrant
ExemestaneExemestane
00 33 66 99 1212 1515 1818 2121 2424 2727
0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
2020 2020 1616 1111 88 33 00 00
1818 1818 1515 1010 55 44 33 33
FulvestrantFulvestrant
13.513.5
ExemestaneExemestane
9.89.8Median (months)Median (months)
Duration of ResponseDuration of Response (from randomisation)(from randomisation)
00 00
33 33
Duration of clinical benefitDuration of clinical benefit (Retrospective analysis)(Retrospective analysis)
Proportion Proportion of patients of patients progression-progression-freefree
FulvestrantFulvestrant
ExemestaneExemestane
MonthsMonthsAt risk:At risk:FulvestrantFulvestrantExemestaneExemestane
00 33 66 99 1212 1515 1818 2121 2424 2727
0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0 FulvestrantFulvestrant
9.39.3
ExemestaneExemestane
8.38.3Median (months)Median (months)
8787 8787 7171 4040 2020 1010 33 11 11 00
8585 8585 6969 2828 1414 1010 66 55 11 00
Adverse eventsAdverse events
Patient had an AEPatient had an AE
Drug-related AEDrug-related AE
Withdrawal due to AEWithdrawal due to AE
AE of grade 3 or higherAE of grade 3 or higher
Serious AESerious AE
Drug-related SAEDrug-related SAE
Death due to AEDeath due to AE
Death due to drug-related AEDeath due to drug-related AE
FulvestrantFulvestrantn=351n=351
ExemestaneExemestanen=340n=340
88.9%88.9%
45.9%45.9%
2.0%2.0%
21.7%21.7%
11.4%11.4%
1.1%1.1%
0.9%0.9%
0%0%
88.8%88.8%
48.8%48.8%
2.6%2.6%
22.6%22.6%
12.4%12.4%
0.6%0.6%
0.9%0.9%
0%0%
Analysis of pre-specified AE categoriesAnalysis of pre-specified AE categories(2-sided Fisher’s exact test)(2-sided Fisher’s exact test)
Weight gainWeight gain
Increased appetiteIncreased appetite
Hot flushesHot flushes
Joint disordersJoint disorders
Nausea and / or vomitingNausea and / or vomiting
DiarrheaDiarrhea
Androgenic effectsAndrogenic effects
Injection-site reactionsInjection-site reactions
FulvestrantFulvestrantn=351n=351
ExemestaneExemestanen=340n=340
p-valuep-value
4 (1.1%)4 (1.1%)
2 (0.6%)2 (0.6%)
47 (13.4%)47 (13.4%)
93 (26.5%)93 (26.5%)
88 (25.1%)88 (25.1%)
46 (13.1%)46 (13.1%)
15 (4.3%)15 (4.3%)
56 (16.0%)56 (16.0%)
3 (0.9%)3 (0.9%)
1 (0.3%)1 (0.3%)
54 (15.9%)54 (15.9%)
99 (29.1%)99 (29.1%)
84 (24.7%)84 (24.7%)
46 (13.5%)46 (13.5%)
12 (3.5%)12 (3.5%)
46 (13.5%)46 (13.5%)
>0.999>0.999
>0.999>0.999
0.3890.389
0.4460.446
0.9300.930
0.9110.911
0.6960.696
0.3920.392
Summary
• The first phase III trial in this population• Confirmed efficacy of fulvestrant in patients who
have progressed on a NSAI • Similar efficacy seen on both treatment arms• No differences were seen in reported AEs between
fulvestrant and exemestane
How does this affect clinical practice?
• The steroidal aromatase inhibitor exemestane and the estrogen receptor downregulator fulvestrant are equivalent choices after progression on a nonsteroidal AI in metastatic breast cancer
• The loading dose of fulvestrant is well tolerated