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Classification of Breast Cancer&
Update on Triple-Negative Breast Cancer
W. Fraser Symmans, M.D.Department of Pathology
UT M.D. Anderson Cancer Center
HER2
Proliferation Estrogen Dependence
DIFFERENTIATION
Endocrine Therapies
Chemotherapies
Progenitor cell
DNA Repair
Cell cycle control
Signal transduction Cell survival
Cell survival
Cell cycle control
Signal transduction
Gene Expression Profiles Might Augment Pathology
Images courtesy of Affymetrix, Inc.
Molecular Classification Of Breast Cancer
Perou et al. Nature 2000;406:747-52
Basal c-erbB-2 Normal breast Luminal epithelialER-positive
Unsupervised Hierarchical Clustering (500 Intrinsic Genes) - “Cell Types”
Test not cleared by the FDA for sale in the U.S. For Investigational Use Only
Pathwork™ Tissue of Origin Example Report
M48
5M
120
M28
7M
464
M23
0M
407B
W07
M31
0M
576
M11
1M
302
M18
6M
239
M12
6M
159
M49
9M
627
M13
0M
215
M40
6M
444
M23
5M
382
M40
2M
121
M43
9M
580
M61
7M
332
M50
3M
113
M20
5M
605
M59
4M
443
M61
1M
154
M62
8M
321
M13
6M
636
M60
8M
255
M14
6M
282
M49
7M
193B
W02
M44
2M
458
M18
0M
418
M30
4M
145
M14
1M
251
M40
3BW
06M
399
M10
8M
220
M13
9M
466
M22
8M
194
M38
6M
238
M56
9M
434
M26
6M
384
M46
9M
421
M50
6M
385
M18
1M
536
M10
7M
575
M17
6M
523
M27
0M
231
M15
5M
117
M32
2M
366
M16
5M
157
M34
1M
565
M41
9M
246
M25
7M
196
M12
8M
508
M26
4M
201
M48
4
0
2000
4000
6000
8000
Threshold of 500 is shown
PE
RU
11P
ER
U31
US
154
US
181
US
071
PE
RU
29U
S14
1U
S17
3U
S10
0U
S08
4G
M14
US
088
US
016
US
032
GM
16U
S16
4U
S12
7U
S05
4U
S14
2U
S02
4U
S12
8U
S07
4U
S16
6U
S14
8U
S11
1U
S08
9U
S09
0U
S04
7U
S18
2U
S02
6U
S06
0U
S05
9U
S06
7U
S11
5G
M11
US
168
US
104
PE
RU
17-1
9U
S15
8M
L44
US
108
ML5
4P
ER
U09
US
117
US
080
US
149
US
151
US
093
US
085
US
186
US
087
US
163
US
134
US
144
PE
RU
07P
ER
U28
PE
RU
02U
S01
4U
S04
9P
ER
U06
US
096
PE
RU
01
0
2000
4000
Threshold of 500 is shown
B38
FA37
B05
B13
F A09
FA01
F A14
B10
F A13
jox0
588
B26
B17
j ox0
890
FA39
B28
jox1
168
B35
B24
jox1
177
B16
jox0
928
B29
B11
j ox2
002
jox0
876
j ox0
706
jox0
779
j ox0
511
B32
jox1
525
B15
jox1
982
j ox1
097
FA43
j ox1
331
jox1
579
B40
FA50
j ox0
055
jox0
837
j ox0
742
B14
j ox0
676
jox2
027
jox2
069
j ox1
181
B08
j ox0
427
jox1
167
j ox1
766
jox0
209
B22
jox1
103
j ox0
192
jox1
432
j ox0
114
jox1
889
j ox4
904
B30
jox0
595
j ox1
107
jox1
125
j ox1
804
jox0
555
j ox1
127
jox2
175
j ox1
397
jox1
156
j ox0
550
jox1
769
j ox1
981
jox0
596
j ox0
638
jox2
341
jox0
738
B12
0
2000
4000
6000
Threshold of 500 is shown
ESR1
ESR1
ESR1
M39
9M
314
M15
3M
228
M52
1M
234
M61
1M
636
M31
0M
226
M55
3M
434
M21
1M
580
M60
3M
497
M37
3M
227
M48
5M
139
M46
3M
111
M34
1M
129
M20
7M
473
M19
6M
385
M28
6M
180
M45
8M
313
M15
8M
246
M23
1M
523
M33
7M
270
M12
8M
357
M37
5M
366
M53
4M
256
M62
0M
201
M62
8M
442
M14
1M
245
M60
5M
567
M14
5M
371
M18
6M
199
M59
4M
251
M38
2M
194
M31
6M
418
M25
8M
235
M23
9
0
3000
6000
9000
12000
15000
Threshold of 1150 is shown
US
118
GM
11
GM
03
ML2
0
US
080
US
082
US
019
US
154
ML7
0
US
057
US
067
US
110
US
111
US
071
PE
RU
31
US
135
US
112
US
160
PE
RU
01
US
165
US
032
US
107
US
011
GM
05
US
033
PE
RU
12-1
4
ML4
4
PE
RU
02
PE
RU
16-1
8
PE
RU
05
US
151
US
038
PE
RU
09
US
085
US
084
US
149
US
182
US
148
GM
14
US
137
US
102
US
179
US
145
PE
RU
17-1
9
US
169
US
101
PE
RU
10
US
020
US
016
PE
RU
15-1
7
US
180
US
170
0
3000
6000
9000
12000
Threshold of 1150 is shown
B02
B40
B10
B13
B33
B41
B31
B30
B38
B35
B26
B32
B15
B07
B01
B06
B29
B08
B19
B28
B16
B25
B42
B24
B36
B11
B37
B23
B18
B27
B22
B04
B09
B03
B17
B14
B39
B05
0
3000
6000
9000
12000
Threshold of 1150 is shown
ERBB2
ERBB2
ERBB2
N = 193 N = 151N = 123
N = 104 N = 38N = 195
FNA FNA Tissue
Single Gene Measurements of ER and HER2 are Accurate
Gong et al. Lancet Oncol 2007;8:203-11
HER2 Status By mRNA Expression (Affymetrix Gene Profiles)Updated Results Using ASCO/CAP Guidelines
94%93%94%Agreement with mRNAcutoff at 1150
0.960.950.93Area under ROC curve
IHC &/or FISH (n = 393)FISH (n = 329)IHC (n = 252)ERBB2 (n = 393)
HER2 Status
21%6%Positive
3%70%Negative
PositiveNegativeERBB2 mRNAStatus
HER2 Status (IHC &/or FISH)
Predicting Endocrine Sensitivity
ER-negative ER-positive
Estrogen Dependence
Symmans, et al. SABCS 2005 Abstr 308
Symmans, et al. ASCO 2005 Abstr 546
Symmans, et al. SABCS 2006 Abstr 1027
Evaluation of Endocrine Sensitivity Index in Patients with ER+Metastatic Breast Cancer (LAB04-0093)
FNA Of ER+ MBC
Total of 323 patients eligible for hormonal Rx
239 second-line, 84 first-line
Affymetrix U133A Gene Array(Endocrine Sensitivity Index)
Compare Treatment GroupsTTPORR
Endocrine Therapy Chemotherapy
AI Receptor Modulator
Diminution of ER Genomic Signature With Advancing Stage ofDisease (n = 351)
I IIA IIB III IV
0
1
2
3
4
5
6
SET Index
STAGE
I IIA IIB III IV
5000
10000
15000
GAPDH
STAGE
Symmans et al. SABCS 2006 #1027
HER2
Proliferation Estrogen Dependence
DIFFERENTIATION
Endocrine Therapies
Chemotherapies
Progenitor cell
DNA Repair
Cell cycle control
Signal transduction Cell survival
Cell survival
Cell cycle control
Signal transduction
““Triple NegativeTriple Negative”” Breast CancerBreast Cancer
�� Basic FeaturesBasic Features�� High gradeHigh grade�� Highly aggressive phenotypeHighly aggressive phenotype�� CK 5/6 and 17 positiveCK 5/6 and 17 positive�� PP--cadherincadherin postivepostive
Breast Cancer Subtypes, Race and AgeBreast Cancer Subtypes, Race and Age
16%16%51%51%7%7%20%20%496496TOTALTOTAL
136136
164164
9999
9797
NN
16%16%58%58%6%6%16%16%PostmenopausalPostmenopausalnon Africannon African--AmericanAmerican
18%18%51%51%6%6%16%16%PremenopausalPremenopausalnon Africannon African--AmericanAmerican
16%16%59%59%7%7%14%14%Postmenopausal AfricanPostmenopausal African--AmericanAmerican
9%9%36%36%9%9%39%39%PremenopausalPremenopausalAfricanAfrican--AmericanAmerican
LuminalLuminalBB
LuminalLuminalAA
HER2+HER2+(ER(ER--))
BasalBasal--likelike
P=0.0001Carey LA et al, JAMA 2006
Treatment Choices in TripleTreatment Choices in Triple--NegativeNegativeBreast CancerBreast Cancer
�� ChemotherapyChemotherapy�� ChemotherapyChemotherapy�� ChemotherapyChemotherapy
�� BevacizumabBevacizumab
BevacizumabBevacizumab added to weeklyadded to weekly paclitaxelpaclitaxel in first linein first lineMBCMBC
RRAANNDDOOMMIIZZEE
PaclitaxelPaclitaxel ++BevacizumabBevacizumab
PaclitaxelPaclitaxel
ECOG 2100ECOG 2100
2828--day cycle:day cycle:PaclitaxelPaclitaxel 90 mg/m90 mg/m22 D1, 8 and 15D1, 8 and 15Bevacizumab 10 mg/kg D1 and 15Bevacizumab 10 mg/kg D1 and 15
Miller et al. SABCS 2005
0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
MonthsMonths
PFS
Prob
abili
tyPF
S Pr
obab
ility
00 66 1212 1818 2424 3030
Improved PFS withImproved PFS with BevacizumabBevacizumab Added toAdded toPaclitaxelPaclitaxel
HR = 0.51 (0.43HR = 0.51 (0.43--0.62)0.62)
Log Rank TestLog Rank Testp<0.0001p<0.0001
Pac. + Bev. 11.4 monthsPac. + Bev. 11.4 months
PaclitaxelPaclitaxel 6.11 months6.11 months
484 events reported484 events reportedMiller K, SABCS 05
BevacizumabBevacizumab in Clinical Subsetsin Clinical SubsetsGroup Ratio 95% Conf IntER+, PR+ER+, PR-ER-, PR-No adj chemoNon-taxaneTaxaneAge 27 - 49Age 50 - 64Age 65 - 85DFI 0 - 24 mos.DFI > 24 mos.< 3 sites3 or more sitesOverall
0.390.860.470.600.510.380.450.440.790.570.470.480.540.51
(0.29, 0.53)(0.52, 1.43)(0.35, 0.63)(0.44, 0.82)(0.39, 0.67)(0.25, 0.59)(0.32, 0.63)(0.33, 0.58)(0.53, 1.17)(0.43, 0.75)(0.37, 0.60)(0.37, 0.61)(0.41, 0.71)(0.43, 0.62)
0.0 0.5 1.0 1.5
