Introduction
Methods
Patient population
The HERmark™ Breast Cancer Assay
Central HER2 immunohistochemistry (IHC) retesting
Local HER2 testing results
Statistical analysis
Results
Patient and tumor characteristics
Parameter
|
No.
|
% (range)
|
---|---|---|
Sample size
| 194 | |
Median length of follow-up (months)
| 193 | 67.1 (14.8 - 302.8) |
Median age (years)
| 51 (27 - 84) | |
<40 | 21 | 11% |
40-49 | 66 | 34% |
50-59 | 50 | 26% |
≥60 | 57 | 29% |
Menopausal status
| ||
Premenopausal | 75 | 39% |
Perimenopausal | 8 | 4% |
Postmenopausal | 96 | 49% |
Not reported | 15 | 8% |
Tissue source
| ||
Primary breast | 187 | 96% |
Other*
| 7 | 4% |
Tumor histology
| ||
Invasive ductal carcinoma | 172 | 89% |
Invasive lobular carcinoma | 14 | 7% |
Other histologic type**
| 8 | 4% |
Median tumor size (cm)
| 185 | 2.1 (0.4 - 14) |
Not reported | 9 | |
Tumor grade
| ||
Grade 1 (well) | 17 | 9% |
Grade 2 (moderate) | 49 | 25% |
Grade 3 (poor) | 93 | 48% |
Not reported | 35 | 18% |
Stage at initial diagnosis
| ||
I | 46 | 24% |
II | 91 | 47% |
III | 40 | 21% |
IV | 13 | 7% |
Not reported | 4 | 2% |
Nodal status at initial diagnosis
| ||
Node positive | 89 | 46% |
Node negative | 66 | 34% |
Not reported | 39 | 20% |
HER2 status (reported)
| ||
Positive | 83 | 43% |
Negative | 110 | 57% |
Equivocal | 1 | 1% |
HER2 IHC (reported)
| ||
3+ | 73 | 38% |
2+ | 30 | 16% |
IHC 2+/FISH positive
|
2
|
7%
|
IHC 2+/FISH negative
|
18
|
60%
|
IHC 2+/FISH not reported
|
10
|
33%
|
1+ | 32 | 17% |
0 | 56 | 29% |
HER2 FISH (reported)
| ||
Positive | 23 | 36% |
Negative | 41 | 64% |
Hormone receptor (ER/PR) status
| ||
Positive | 141 | 73% |
Negative | 53 | 27% |
ER and PR status
| ||
ER (+), PR (+) | 110 | 57% |
ER (+), PR (−) | 30 | 15% |
ER (−), PR (+) | 1 | 1% |
ER (−), PR (−) | 53 | 27% |
HER2 targeted therapy
#
| ||
No | 174 | 90% |
Yes | 20 | 10% |
Comparison of HER2 results and various testing methods
Local HER2 IHC
|
Central HER2 IHC
|
Local HER2 FISH
|
Local clinical HER2 status
| |||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Negative
|
Equivocal
|
Positive
|
Total IHC
|
Negative
|
Equivocal
|
Positive
|
Total IHC
|
Non-amplified
|
Amplified
|
Total FISH
|
Negative
|
Equivocal
|
Positive
|
Total HER2
| ||||||||||||||||||
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
| |||
HERmark | Negative | 69 | 71% | 14 | 14% | 14 | 14% | 97 | 51% | 86 | 86% | 13 | 13% | 1 | 1% | 100 | 52% | 27 | 90% | 3 | 10% | 30 | 45% | 83 | 83% | 1 | 1% | 16 | 16% | 100 | 52% | |
HERmark | Equivocal | 10 | 38% | 9 | 35% | 7 | 27% | 26 | 14% | 17 | 71% | 5 | 21% | 2 | 8% | 24 | 13% | 11 | 92% | 1 | 8% | 12 | 18% | 17 | 65% | 0 | 0% | 9 | 35% | 26 | 13% | |
HERmark | Positive | 9 | 13% | 7 | 10% | 52 | 76% | 68 | 36% | 4 | 6% | 23 | 34% | 41 | 60% | 68 | 35% | 5 | 20% | 20 | 80% | 25 | 37% | 10 | 15% | 0 | 0% | 58 | 85% | 68 | 35% | |
Total | 88 | 46% | 30 | 16% | 73 | 38% | 191 | 100% | 107 | 56% | 41 | 21% | 44 | 23% | 192 | 100% | 43 | 64% | 24 | 36% | 67 | 100% | 110 | 57% | 1 | 1% | 83 | 43% | 194 | 100% | ||
Overall concordance | 68%, (69 + 9 + 52)/191 | 69%, (86 + 5 + 41)/192 | NA#
| 73%, (83 + 0 + 58)/194 | ||||||||||||||||||||||||||||
Kappa (CI 95%), overall | 0.475 (0.373 to 0.578); weighted Kappa = 0.545 | 0.481 (0.386 to 0.576); weighted Kappa = 0.631 | 0.510 (0.409 to 0.610); weighted Kappa = 0.583 | |||||||||||||||||||||||||||||
Concordance, excluding Eqv.*
| 84%, (69 + 52)/(69 + 9 + 14 + 52) | 96%, (86 + 41)/(86 + 4 + 1 + 41) | 85%, (27 + 20)/(27 + 5 + 3 + 20) | 84%, (83 + 58)/(83 + 10 + 16 + 58) | ||||||||||||||||||||||||||||
Kappa (CI 95%), excluding Eqv. | 0.676 (0.550 to 0.797) | 0.914 (0.841 to 0.988) | 0.705 (0.516 to 0.893) | 0.682 (0.570 to 0.794) |
Kaplan-Meier overall survival analyses by HER2 status as stratified by different HER2 testing methods
Concordant negative
|
Concordant positive
|
Discordant low
|
Discordant high
| |||||
---|---|---|---|---|---|---|---|---|
HER2 -, H2T low
|
HER2 +, H2T high
|
HER2 +, H2T low
|
HER2 -, H2T high
| |||||
Parameter
|
No.
|
%
|
No.
|
%
|
No.
|
%
|
No.
|
%
|
Tumor size (cm)
| ||||||||
<2 | 45 | 51% | 30 | 49% | 9 | 47% | 6 | 43% |
>2 | 43 | 49% | 31 | 51% | 10 | 53% | 8 | 57% |
Tumor grade
| ||||||||
Grade 1 and Grade 2 | 41 | 54% | 10 | 19%*
| 6 | 40% | 8 | 62% |
Grade 3 | 35 | 46% | 43 | 81% | 9 | 60% | 5 | 38% |
Stage at initial diagnosis
| ||||||||
I and II | 73 | 83% | 40 | 65% | 14 | 74% | 8 | 47% |
III and IV | 15 | 17% | 22 | 35%*
| 5 | 26% | 9 | 53% |
Nodal status at diagnosis
| ||||||||
Node negative | 40 | 55% | 15 | 28% | 7 | 47% | 3 | 25% |
Node positive | 33 | 45% | 38 | 72% | 8 | 53% | 9 | 75% |
Hormone receptor (ER/PR) status
| ||||||||
Negative | 19 | 21% | 23 | 37%*
| 6 | 32% | 4 | 24% |
Positive | 72 | 79% | 40 | 63%*
| 13 | 68% | 13 | 76% |
Overall survival
| ||
---|---|---|
HR
|
P
value
| |
Model A
| ||
HERmark positive vs. negative*
| 3.1 | 0.034 |
Grade 3 vs. 1 or 2 | 2.0 | 0.26 |
Stage III or IV vs. I or II | 0.93 | 0.89 |
Node positive vs. negative | 1.7 | 0.38 |
Hormone receptor positive vs. negative | 0.43 | 0.071 |
Model B
| ||
H2T high vs. low#
| 3.9 | 0.0061 |
Grade 3 vs. 1 or 2 | 1.7 | 0.30 |
Stage III or IV vs. I or II | 0.91 | 0.84 |
Node positive vs. negative | 1.9 | 0.26 |
Hormone receptor positive vs. negative | 0.54 | 0.15 |