early breast updates
TRANSCRIPT
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Early Breast Cancer Updates
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Why
Effect of adjuvant therapy : adjuvant hormonal with Tam. (ER +ve)
• 40% decrease in risk of recurrence by 5 years.
• 34% decrease in br. cancer mortality by 5 years.
adjuvant polychemotherapy .• < 50 years old: 10% decrease in br.
cancer mortality by 15 years.• 50-69 years old: 3% decrease in risk of
br. cancer mortality by 15 years
Meta-analyses of adjuvant therapies for women with early breast cancer: the Early Breast Cancer Trialists’ Collaborative Group overview Annals of Oncology
17 (Supplement 10): x59–x62, 2006.
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Outline
•Molecular Classification.•Adjuvant Chemotherapy.•Adjuvant Hormonal.•Adjuvant Targeted Therapy.•Neoadjuvant therapy.
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Molecular Classification:•Early EBC was 2 groups only
• Now we reached to more recent approach utilizing both TNM staging Plus ER/PR status and Her2 status. Dividing EBC into 4 main groups
Node –ve
Node +ve
Luminal
AER ++
Luminal
BER +
Her 2 +veTriple –ve Basal like virulent
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Disease outcome in subgroups
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What are the lessons we achieved from molecular classification •Lumina A: more benefit in hormonal and
less in chemo.•Luminal B: grey zone: chemo, hormonal
and/or Her 2 blockade (Luminal B2)•Her 2 +ve: benefit from single and more
recently dual Her 2 blockade + chemo•Triple negative: the hidden mystery,
rapid response to chemo, but still survive poor.
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Prognostic and Predictive markers: are we there yet?• In the last decade, advances in gene expression
profiling dramatically changed our understanding of genomic and transcriptomic landscape of breast cancer, with improved our ability to prognosticate behavior and response to treatment.
• Traditional prognostic factors: Tumor size, Nodal status, Histological grade ER/PR status , Her 2 status and age. Multiparametric tools have been developed to improve the predictive value of those factors
TNM staging Nottingham Prognostic index Adjuvant online ( http://www.adjuvantonline.com)
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• Prognostic multigene classifiers in routine clinical practice: among the them, the top 3 assays in current clinical decision making are
Oncotype Dx, the 21 gene assay.Mammaprint the 70 gene signature of Van’t veer.PAM50 clinically updated version of intrinsic subtypes.
→Why Oncotype Dx in EBC:• Use paraffin embaded fixed materials• Prognostic • Predictive value for the value of chemo in those of HR+ve.
Her 2-ve, -ve Node• Validated in randomized trail : NSABP B14, B20
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The Oncotype DX
•16 BREAST CANCER RELATED GENES
Estrogen
ERPR
Bcl2SCUBE2
Proliferation
Ki-67STK15
SurvivinCyclin B1
MYBL2
HER2
GRB7HER2
Invasion
Stromelysin 3Cathepsin L2
Others
CD68
GSTM1
BAG1
• 5 REFERENCE GENES
Beta-actin GAPDH RPLPO GUS TFRC
Paik S, et al. N Engl J Med. 2004;351:2817-2826.
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• The Oncotype DX Recurrence Score is correlated with distant recurrence rate at 10 years, hormone therapy benefit, and chemotherapy benefit.
▫Low risk is up to 17▫Intermediate risk 18-30▫High risk > 30
• Validation: a study was performed to clinically validate the prespecified 21-gene RT-PCR assay and Recurrence Score algorithm as a predictor of the prospectively defined primary endpoint of distant recurrence-free survival in node-negative, estrogen receptor–positive patients treated with tamoxifen from the large multicenter study NSABP -B14.
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Distant recurrence over time
10-Year rate of recurrence = 6.8%*
95% CI: 4.0%, 9.6%
0 2 4 6 8 10 12 14 16
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Pro
port
ion
wit
hou
t d
ista
nt
recu
rren
ce
RS < 18, n = 338
RS 18-30, n = 149
RS ≥ 31, n = 181
All Patients, n = 668
P < 0.001
10-Year rate of recurrence = 14.3%
95% CI: 8.3%, 20.3%10-Year rate of recurrence = 30.5%*
95% CI: 23.6%, 37.4%
Oncotype DX Clinical Validation: NSABP B-14, Distant Recurrence
Paik S, et al. N Engl J Med. 2004;351:2817-2826.
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Oncotype DX Clinical Validation: NSABP B-20•Objective: Prospectively determine the
relationship between Recurrence Score result and chemotherapy benefit in node-negative, ER+ patients
Randomized
Tam + MF
Tam + CMF
Tam
Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
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1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
4.4% absolute benefit from tamoxifen +
chemotherapy
N Events
All patients
Tamoxifen + chemotherapyTamoxifen
424227
3331 P = 0.02
RS 18-30
Tamoxifen + chemotherapyTamoxifen
8945
94 P = 0.39
RS < 18Tamoxifen + chemotherapyTamoxifen
218135
84 P = 0.61
N Events
RS 18-30
Tamoxifen + chemotherapyTamoxifen
8945
94 P = 0.39
PATIENTS WITH HIGH RS28% absolute benefit from
tamoxifen + chemotherapy
RS ≥ 31
Tamoxifen + chemotherapyTamoxifen
11747
1318 P < 0.001
2 4 6 8 10 12
Years
Pro
port
ion
wit
hou
t d
ista
nt
recu
rren
ce
Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
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Adjuvant Chemotherapy
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The Oxford OverviewEarly Breast Cancer Trialists’ Collaborative Group
(EBCTCG)
• The most comprehensive analysis of the adjuvant settings
• 1984, 1990, 1995, 2000, 2005/6, 2010• 2010: cover more than 100,000 patients
among 123 randomised trails, published 2012, postulating 3 questions to be answered in meta-analysis▫ Benefit of polychemotherapy Vs non.▫ Benefit of anthracycline (A) vs CMF.▫ Benefit of Taxane + (A) vs (A) alone.
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Polychemotherapy versusNo chemotherapy
10y results in 23500 women
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• RRs were 0·69 (SE 0·04) for distant recurrence• RRs were 0·73 (SE 0·03, χ²1=70·3) for any recurrence.• RRs 0·79 (SE 0·04, χ²1=33·7) for breast cancer mortality.
• the proportional effects of anthracycline based regimens on breast cancer outcomes did not depend much on age, nodal status, ER status, or, if ER-positive, on endocrine therapy, age, nodal status, tumor differentiation, or ER level
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Anthracycline regimens vs
standard CMF
10y results in 22000 women
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•Almost equal 4 AC, vs CMF.
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• shows results from the trials with anthracycline dose per cycle at least 60 mg/m2 doxorubicin or 90 mg/m2 epirubicin and with cumulative anthracycline dosage more than 240 mg/m2 doxorubicin or 360 mg/m2 epirubicin.
• RRs were 0·89 for recurrence.• RRs were 0·80 for breast cancer mortality
ANTHRACYC
LINE
MORE
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Taxane + Anthracycline regimens vsAnthracycline regimens
5y results in 44000 women
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•Recurrence RRs were 0.85.•Mortality RRs were 0.87.
T+AVssameA
5 y results
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5 years results • Recurrence RRs were 0.83.•Mortality RRs were 0.86.
T+AVsmoreA
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Adjuvant Hormonal
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Estrogen and Breast Cancer
Estrogen
Cell Growth and Division
Estrogen Receptor
SERMS, SERDSAromatase inhibitors, ovarian suppression
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Endocrine Therapy in Breast Cancer
• Selective Estrogen Receptor Modulators▫tamoxifen ▫toremifene ▫raloxifene
• Aromatase inhibitors (postmenopausal)▫anastrozole▫letrozole ▫exemestane
• Medical or surgical oophorectomy (premenopausal)
• Selective Estrogen Receptor Downregulators▫fulvestrant
• Others: Progestins, Estrogens, Androgens
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Selective Estrogen Receptor ModulatorsEBCTCG 2000 (Oxford Overview)
Tamoxifen vs. Nil: Disease-free Survival
ER Negative ER Positive
5 years of adjuvant tamoxifen became standard in ER+ patients
tamoxifen
nil
ER status matters!!
5 yrs
15 yrs
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Aromatase InhibitorsAdrenal Hormones
Cortisol Androstenedione Aldosterone
Estradiol
TestosteroneEstrone
Aromatase inhibitors block post-menopausal estrogen production
AnastrozoleLetrozoleExemestane
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Adjuvant Aromatase Inhibitors
AIs asInitial Therapy
AIs After2-3 Yrs of TAM
AIs After5 Years of TAM
TAM X 5 Yrs
AI X 5 Yrs TAM X 2-3 AI X 2-3
TAM X 5 YrsTAM X 5 Yrs
PLAC X 5 Yrs
AI X 5 Yrs
Three Strategies
Survival benefit for AI arm
ATAC and BIG1-98 studiesReduction in recurrences
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Upfront Use of Aromatase Inhibitors vs. Tamoxifen
ATAC Trial: Anastrozole vs. Tamoxifen Howell A et al, Lancet 365:60-62, 2005
BIG 1-98 Trial: Letrozole vs. Tamoxifen Thurlimann B et al, NEJM 353: 2747-57, 2005
68 months follow-up:17% relative reduction in events for A vs T (3% absolute difference)
26 months follow-up:19% relative reduction in events for L vs. T(3% absolute difference)
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Extended Adjuvant Hormonal Therapy Trials
MA17 Trial: Letrozole vs. Placebo After Completing 5 Years of Tamoxifen Goss P et al, J Natl Cancer Inst 97: 1262-71, 2005
30 months of follow-up:42% decrease in breast cancer eventsNode positive patients show statistically significant improvement in survival
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Letrozole + Zoledronic Acid 4 mg
q6m
Letrozole + Delayed* Zoledronic Acid 4 mg
q6m
Stage I-IIIa breast cancer Postmenopausal or
amenorrheic due to cancer treatment
ER+ and/or PgR+ T-score ≥ -2 SD N = 1065
Treatment duration 5 yrs
De Boer R, et al. SABCS 2011. Abstract S1-3.
ZO-FAST: 5-Yr Final AnalysisTreatment duration 5 yrs
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ZO-FAST: Conclusions
•Immediate initiation of ZOL at start of letrozole significantly prolonged DFS vs delayed initiation of ZOL in postmenopausal women with endocrine-responsive EBC▫Continued to improve BMD after 5 yrs of
follow-up▫34% improvement in DFS
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Adjuvant Targeted Therapy
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37
HER-2 as a Target for Therapy
cell division
HER-2
nucleus
cancer cell
Trastuzumab (Herceptin) Anti-HER-2 Antibody
HER-2 Oncogene: amplified and overexpressed in 20-25%
of breast cancer
Lapatinib (Tykerb) Dual HER-1/HER-2 Tyrosine Kinase Inhibitor
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Adjuvant trastuzumab trials: >13,000 patients
NCCTG N9831 (USA)
HERA (ex-USA) BCIRG 006 (global)
NSABP B-31 (USA)
Piccart-Gebhart et al 2005;Romond et al 2005;
Slamon et al 2006
IHC orFISH
(n=5090)2 years Herceptin
Observation
Standard chemotherapy
1 year Herceptin
IHC orFISH
(n=2030)
Herceptin 1 year
IHC orFISH
(n=3505)
Herceptin 1 year
FISH(n=3222)
Herceptin 1 year
IHC or FISH
(n=5090)
Docetaxel Docetaxel + carboplatin
Doxorubicin + cyclophosphamide Paclitaxel
FISH (n=3222)
IHC or FISH
(n=3505)
IHC or FISH
(n=2030)
Herceptin 1 yr
Herceptin 1 yr
Herceptin 1 yr
Herceptin 1 yr
Herceptin 2 yr
Observation
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aBased on small subgroups of patients with HER2-positive breast cancer; brelapse-free survival; V, vinorelbine CEF, cyclophosphamide, epirubicin, 5-fluorouracil
DFS benefit across 5 out of 6 trials
4
2
3
4
Joensuu et al 2006; Slamon et al 2006 Perez et al 2007; Smith et al 2007
Spielmann et al 2007
3
3
Median follow-up, years
0 1 2FavoursHerceptin
Favours noHerceptin
HR
DFS benefit
B-31 / N9831 ACPH
HERA CTxH 1 year
FinHera VH / DHCEFb
PACS-04a CTxH 1 year
BCIRG 006 ACDH
BCIRG 006 DCarboH
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0 1 2Favours
HerceptinFavours noHerceptin
HR
Adjuvant Trastuzumab trials: proven OS benefit
B-31 / N9831 ACPH
BCIRG 006 ACDH
HERA H 1 year
BCIRG 006 DCarboH
FinHer VH / DHa
4
3
2
Median follow-up,years
3
Joensuu et al 2006; Perez et al 2007;Slamon et al 2006; Smith et al 2006
3
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Cumulative incidence of cardiac events: N9831/NSABP B31 updated analysis
• Longer follow-up showed no additional concerns regarding the cardiac safety profile Cardiac events occurred early No evidence of increased toxicity or late toxicity
• In NSABP B 31 the following factors were shown to be predictive for CHF: Age (p=0.03) Hypertensive medications (p=0.02) Baseline LVEF (p=0.0003)
• The incidence of cardiac events reach a plateau at around 1 year
• Cardiac effects of trastuzumab were largely reversible
Perez et al Abs 512 ASCO 2007Perez et al Abs 512 ASCO 2007
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Slamon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008
Incidence of trastuzumab-related cardiac events in EBC trials
3.0
NR
NR
18.0
8.6
Asymptomatic LVEF decline,
%aH 1 year
ACPH
ACPH
ACDH
DCarboH
Arm
HERA
NSABP B-31
NCCTG N9831
BCIRG 006
1,678
947
570
1,068
1,056
nSevere CHF, %
0.6
3.8cum (5 yr)
3.3cum (3 yr)
1.9
0.4
Cardiac death, n
0
0
0
0
0
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Surgery & ChemoComplete
Randomize
Trastuzumab 1
Lapatinib 2
Lapatinib + Trastuzumab 4
Lapatinib 3Trastuzumab
Taxane
Taxane
Taxane
Taxane
Wash out
52 Weeks
All Patients: Radiotherapy, if indicated
Hormone receptor-positive patients:Endocrine therapy for at least 5
yrs
34 Weeks6 Weeks12 WeeksConsent &Send Blocks for Central Path Review
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Neoadjuvant Therapy
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Goals of Neoadjuvant Theapy in Early Breast Cancer• Make tumours more operable, increase the rate of breast conserving
surgeries
• Improve prognosis of certain disease subtypes (i.e. HER2+)
• Have a better idea of prognosis based on response to neoadjuvant treatment
• Allow patients to start treatment earlier
• Reduce the extent of surgery required in breast and axilla
• Improve DFS and OS using pathological response rate for selection of subsequent treatment in individual patients
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Definition of pCR
Different definition of pCR are in use: - Absence of invasive cancer in the breast - Absence of invasive cancer in the breast and in the
axillary lymph nodes. - Absence of invasive and in situ cancer cells in the
breast and in the axillary nodes There is high degree of concordance between the
different definition With very definition pCR identifies cases with
favorable disease
Marchiò C. & Sapino A. JNCI Monogr 2011;43:86–90
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There was no significant difference in overall survival (OS) between the treatment arms (data not shown). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR 0.33; P .0001).
Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.
Disease free-survival
Overall Survival
pCR to Neoadjuvant Chemotherapy is correlated with improved DFS & OS (NSABP B-27)
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Intrinsic sub-types have different prognosis and different response to Neoadjuvant therapy.
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Impact of treatment characteristics on the pCR
Untch M. et al J Nat Cancer Inst
Monogr 2011.
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Pre and Post-operative Chemotherapy plus Trastuzumab Improve DSF
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Women with operable or
locally advanced
breast cancer
(N = 2072)
TAC-NX*(4 cycles NX)
(n = 301)
TAC x 6(4 additional cycles TAC)
(n = 321)
TAC x 6(4 additional cycles TAC)
(n = 704)
TAC x 8(6 additional cycles TAC)
(n = 686)
TAC*(2 cycles)
Assessresponse†
Minimalresponse‡
(n = 622)
CR or PR(n = 1390)
*TAC regimen: docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 all on Day 1 q21d. NX regimen: vinorelbine 25 mg/m2 on Days 1 and 8, capecitabine 1000 mg/m2 on Days 1-14 q21d.†Response assessed by ultrasound/palpation.‡< 50% tumor reduction.
Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
GeparTrio Trial: Study Design
Not working? Try another type of chemotherapy
Working? Give more of the same
chemotherapy
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GeparTrio Trial: DFS and OS• Median follow-up: 62 mos
• DFS benefit in early responding and nonresponding patients who received response-guided vs conventional chemotherapy
Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
Endpoint HR for Response-Guided vsConventional Chemotherapy (95% CI)
P Value
DFS 0.71 (0.60-0.85) < .001
OS 0.79 (0.63-0.99) .048
Patient Subgroup
Treatment Comparison
HR for DFS (95% CI)
P Value
Responders TAC x 8 vs TAC x 6 0.78 (0.62-0.97) .026
Nonresponders TAC-NX vs TAC x 6 0.59 (0.49-0.82) .001
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GeparTrio Trial: DFS by Patient Subgroup
Response-guided treatments better
Conventional treatments better
0.2 0.4 0.6 0.8 1.0 1.2 1.4
SubgroupOverallAge (yrs)
<40≥ 40
cT-stagecT1-3cT4
cT-size< 40 mm≥ 40 mm
cN statusNegativePositive
Histological typeDuctal or
otherLobular
Grade1 or 23
Hormone receptor status
NegativePositive
HER2 statusNegativePositive
Breast cancer phenotype
Luminal ALuminal B
(HER2-)Luminal B
(HER2+)HER2+
(nonluminal)Triple
negative
N patients2012
3531659
1737267
7751212
894NR
1571270
1176725
7171295
1145486
572211281178362
Test for Interaction
0.67
0.66
0.22
0.19
0.71
0.25
0.008
0.54
0.12-0.01
HR (95% CI)
0.74 (0.60-0.85)
0.66 (0.42-1.03)0.73 (0.60-0.88)
0.70 (0.56-0.85)0.79 (0.54-1.17)
0.62 (0.44-0.85)0.79 (0.63-0.98)
0.84 (0.61-1.14)0.66 (0.53-0.82)
0.73 (0.60-0.88)0.61 (0.37-1.03)
0.79 (0.61-1.01)0.65 (0.49-0.85)
0.94 (0.73-1.22)0.56 (0.44-0.73)
0.63 (0.49-0.81)0.72 (0.51-1.04)
0.55 (0.37-0.82)0.40 (0.20-0.79)0.56 (0.33-0.96)1.01 (0.61-1.67)0.87 (0.61-1.25)
Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
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GeparTrio Trial: pCR by Breast Cancer Subtype
Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
pC
R (
%)
40
35
30
25
20
15
10
5
0Luminal A (n = 572)
Luminal B (HER2-)
(n = 211)
Luminal B (HER2+)(n = 281)
HER2+ (Nonluminal)
(n = 178)
Triple Negative (n =
362)
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GeparTrio Trial: Conclusions
•Adapting neoadjuvant chemotherapy based on early response significantly improved DFS and OS vs conventional chemotherapy
•Response-guided chemotherapy most effective in patients with luminal A or luminal B tumors▫Low pCR rates in these tumors▫pCR not prognostic
•No DFS benefit with response-guided chemotherapy in patients with HER2-positive or triple-negative tumors
Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
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Baselga J et al. Lancet 2012
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• pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1—59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4—37·5]; difference 21·1%, 9·1—34·2, p=0·0001).•no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1—32·3]) and the trastuzumab (difference −4·8%, −17·6 to 8·2, p=0·34) groups.
Baselga J et al. Lancet 2012
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