Epidemiology. Definition Biology “Basal-Like” The “Triple Negative” Breast Cancer Estrogen...
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Transcript of Epidemiology. Definition Biology “Basal-Like” The “Triple Negative” Breast Cancer Estrogen...
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Epidemiology
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DefinitionBiology
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“Basal-Like”
The “Triple Negative” Breast Cancer
Estrogen Receptor (ER) negativeProgesterone receptor (PR) negative
Her2neu (HER2) negative
ER/PR/HER2 -ER/PR/HER2 -
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Clinical features
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“Triple-Negative” Breast Cancer: Clinical Features and Patterns of
Recurrence• HBBC database (1987-1997)
• 1601 (80%) of patients had details on hormone receptors/HER2 and were eligible for the study
• 180 (12%) of the 1601 patients were defined as “triple negative” breast cancers
• Mean follow up was 8.1 years
Dent, R. et al. Clin Cancer Res 2007
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Characteristics of “Triple Negative” vs. Other Breast Cancers
CharacteristicOther
(N=1421)number (percent)
“Triple Negative”(N=180)
number (percent)
Significancep value *
Mean Age at Diagnosis (yrs) 57.7 53 p < 0.0001
Mean Tumor Size 2.1 cm 3.0 cm p < 0.0001
Tumor Size
T1 (≤ 2 cm) 880 (62.7) 65 (36.5) p < 0.0001
T2 (>2cm to ≤ 5cm) 461 (32.8) 99 (55.6)
T3 (>5cm) 64 (4.6) 14 (7.9)
Missing 16 2
Lymph Node Status
Positive 510 (45.6) 87 (54.4) p = 0.02
Negative 609 (54.4) 70 (44.6)
Missing or Not Tested 302 23
Tumor Grade
I 237 (19.9) 15 (9.8) p < 0.0001
II 616 (51.8) 37 (24.2)
III 336 (28.3) 101 (66.0)
Missing
* p values were calculated with the use of the chi-square test
Dent, R. et al. Clin Cancer Res 2007
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Tumor Size by Nodal Status according to “Basal-Like” Group
Non “Basal-like” Group(N=1421)
“Basal-like” Group(N=180)
Tumour Size Lymph Node PositiveNumber (percent)
Lymph Node PositiveNumber (percent)
<1.0 cm 38 (19.3) 5 (55.6)
1 - 2 cm 180 (39.3) 25 (55.6)
2.1- 5 cm 238 (59.5) 43 (48.9)
>5.1 cm 53 (91.4) 12 (92.3)
p<0.0001 p=0.042
* p values were calculated with the use of the chi-square test
Dent, R. et al. Clin Cancer Res 2007
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Distant Recurrence
Dent, R. et al. Clin Cancer Res 2007;13:4429-4434
Prob
abili
ty o
f bei
ng re
curr
ence
-fre
e
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Years after diagnosis
p<0.0001 (log-Rank test)
Other (290 of 1421) “Triple-negative” (61 of 180)
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Overall Survival
Dent, R. et al. Clin Cancer Res 2007;13:4429-4434
Prob
abili
ty o
f sur
viva
l
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Years after diagnosis
p<0.0001 (log-Rank test)
Other (261 of 1420) “Triple-negative” (62 of 180)
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Non-random distribution X² statistic 42.78p 0.0003
Subtype
Smid et al, Cancer Res, in press
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Patterns of Metastatic Spread• More likely to spread to brain, lung and possibly liver
and less likely to spread to bone and soft tissues– Tsuda et al. 2000 Am J of Surgical Pathology– Rodriguez-Pinilla et al. Clinical Cancer Research 2006– Fulford et al. Breast Cancer Research and Treatment 2007– Hicks et al. 2006 Am J of Surgical Pathology
• More likely to present with visceral metastases versus bone metastases as first site of metastases
– 70% vs 37%, p < 0.001 (Dent et al. SABCS 2007)
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Median Time from Distant Relapse to Death
0 5 10 15 20 25
22 months
9 months
Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007
“Triple Negative” Breast CA
Other Breast CA
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Treatment
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Days
0 20 40 60 80 100
Tum
or
Volu
me
(m
m3 )
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Control5mg Doxorubicin1.25mg Doxorubicin3mg Cisplatin1.25mg Cisplatin6mg Cisplatin (non-average)
Response of Brca1/p53 Mammary Tumors to Doxorubicin or Cisplatin/Carboplatin in vivo
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Characteristics of retrieved studies Characteristics of retrieved studies - I- I
Study ComparisonHER2 status
determined (%)
NSABP B11 Paik S et al, JNCI 1998
PF vs PAF 638/682 (94%)
NSABP B15Paik S et al, JNCI 2000
CMF vs AC 2.034/2.295 (89%)
GUN 3 De Laurentiis M et al, ASCO 2001
CMF vs CMF/EV 123/220 (56%)
BelgianDi Leo A et al, Clin Cancer Res 2002
CMF vs HEC/EC 354/777 (46%)
Milan Moliterni A et al, J Clin Oncol 2003
CMF vs CMF→ A 506/552 (92%)
DanishKnoop AS et al, J Clin Oncol 2005
CMF vs FEC 805/980 (82%)
NCIC MA5 Pritchard KI et al, NEJM 2006
CMF vs CEF 628/710 (88%)
Gennari et al, JNCI 2008
Total (determined/randomised)Total (determined/randomised) 5.088/6.216 (82%)5.088/6.216 (82%)
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Characteristics of studies - IICharacteristics of studies - II
Study MethodHER2
positive/screened
%
NSABP B11 IHC 239/638 37%
NSABP B15 IHC 599/2.034 29%
GUN 3 IHC 30/123 24%
Belgian FISH 73/354 21%
Milan IHC 95/506 19%
Danish IHC/FISH 246/805 33%
NCIC MA5 IHC/FISH/PCR 163/628 (FISH) 26%
Total (positive/screened)Total (positive/screened) 1.445/5.0881.445/5.088 28%28%
Gennari et al, JNCI 2008
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Adjuvant Anthracyclines and HER2:Adjuvant Anthracyclines and HER2:Disease Free SurvivalDisease Free Survival
Anthra betterStudy HER2 status HR (95% CI)
+ 0.60 (0.44 to 0.82)- 0.96 (0.75 to 1.23)
+ 0.84 (0.65 to 1.08)- 1.02 (0.86 to 1.20)
+ 0.65 (0.34 to 1.26)- 1.35 (0.93 to 1.97)
+ 0.83 (0.46 to 1.49)- 1.22 (0.91 to 1.64)
+ 0.75 (0.53 to 1.06)- 0.79 (0.60 to 1.05)
+ 0.52 (0.34 to 0.80)- 0.91 (0.71 to 1.17)
Overall 0.90 (0.82 to 0.98)+ 0.71 (0.61 to 0.83)- 1.00 (0.90 to 1.11)
NSABP B11
NSABP B15
Belgian
Milan
DBCG 89D
NCIC MA5
HER2 specific
0.00 0.50 1.00 1.50 2.00
Test for interaction: 2 13.7, p< .001
Non anthra better
Gennari A. et al. JNCI 2008Gennari A. et al. JNCI 2008
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Adjuvant Anthracyclines and HER2 :Adjuvant Anthracyclines and HER2 :Overall SurvivalOverall Survival
Study HER2 status HR (95% CI)
+ 0.66(0.42 to 1.01)- 0.90(0.69 to 1.18)+ 0.82(0.63 to 1.06)- 1.07(0.88 to 1.30)+ 0.85(0.27 to 2.69)- 1.64(0.85 to 3.15)+ 0.61(0.32 to1.16)- 1.26(0.89 to 1.79)+ 0.73(0.50 to 1.05)- 0.82(0.59 to 1.13)
+ 0.65(0.42 to 1.01)- 1.06(0.80 to1.40)+ 0.71(0.32 to 1.55)- 1.25(0.58 to 2.67)
Overall 0.91(0.79 to 1.04)+ 0.73(0.62 to 0.85)- 1.03(0.92 to 1.16)
NSABP B11
NSABP B15
GUN
Milan
DBCG 89D
NCIC MA5
HER2 specific
GOIRC
0.00 0.50 1.00 1.50 2.00 2.50 3.003.50
Test for interaction: 2 12.6, p< .001
Anthra betterNon anthra better
Gennari A. et al. JNCI 2008Gennari A. et al. JNCI 2008
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Efficacy summaryEfficacy summary
•Risk of relapse
29%
HR 0.71 (0.61-0.83)
•Risk of death
27%
HR 0.73 (0.62-0.85)
HER2 positiveHER2 positive
Risk of relapse anthra ≈ non anthra HR 1.00 (0.90-1.11)
Risk of death anthra ≈ non anthra
HR 1.03 (0.92-1.16)
HER2 negativeHER2 negative
p <0.001p <0.001
p <0.001p <0.001
Gennari et al, JNCI 2008
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Highly hormon-sensitive
Moderately hormon-sensitive
HER-2 amplified
Triple negative
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Pathological Complete Response to Chemotherapy Differs by Subtipes
AC → TCarey CCR 07
T → FACRouzier CCR 05
Luminal A/B 4/62 (7%) 2/30 (7%)
Normal-like NA 0/10 (0)
HER2+ and ER- 4/11 (36%) 9/20 (45%)
Triple negative 9/34 (27%) 10/22 (45%)
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Neoadjuvant Chemotherapy in Triple Negative Patients. MD Anderson Experience
• The largest date set available (1118 pts) 23% TNBC, pCR 15%
Regimens pts TNBC non-TNBC
FAC/FEC/AC 308 20% 5%
TFAC/TFEC 588 28% 17%
Taxanes 58 12% 2%
Other 164 14% 7%
Total 1118 22% 11%p 0.034
Liedtke, M. et al. J Clin Oncol; aheadof print on Febr 4, 2008
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Neoadjuvant Chemotherapy in TNBCSurvival by Pathological Response
Liedtke, M. et al. J Clin Oncol; aheadof print on Febr 4, 2008
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Ixabepilone+Capecitabine a Phase III TrialIxabepilone+Capecitabine a Phase III Trial
MetastaticMetastaticbreast cancerbreast cancer
N = 752N = 752
IxabepiloneIxabepilone++
CapecitabineCapecitabine
N = 375N = 375
CapecitabineCapecitabine
N = 377N = 377
Previous AnthraPrevious Anthra
Taxane ResistantTaxane Resistant
Vahdat LTVahdat LT et al: et al: ASCO2007ASCO2007
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1.01.0
0.00.0
Prop
ortio
n Pr
ogre
ssio
n Fr
eePr
opor
tion
Prog
ress
ion
Free
MonthsMonths
0.60.6
0.80.8
0.40.4
0.20.2
00
MedianMedian
5.8 mo5.8 mo
4.2 mo4.2 mo
95 % Cl95 % Cl
(5.5 - 7.0)(5.5 - 7.0)
(3.8 - 4.5)(3.8 - 4.5)
HR: 0.75 (0.64-0.88)HR: 0.75 (0.64-0.88)p = 0.0003p = 0.0003
44 88 1212 1616 2020 2424 2828 3232 3636
IxabepiloneIxabepilone++ Capecitabine Capecitabine
CapecitabineCapecitabine
Vahdat LTVahdat LT et al: et al: ASCO2007ASCO2007
Ixabepilone+Capecitabine a Phase III TrialIxabepilone+Capecitabine a Phase III Trial
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Ixabepilone+Capecitabine a Phase III TrialIxabepilone+Capecitabine a Phase III Trial
RugoRugo et al: et al: SABCS 2007SABCS 2007
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Perspectives
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Basal-like Breast Cancer and BRCA1
= BRCA1+
Sorlie T et al. PNAS 03