Introduction
Background and significance
Receptor status from IHC and one single gene
Adding co-genes
Objectives regarding patient benefit
Results
Predictive co-genes
Receptor | Receptor gene | Co-gene |
---|---|---|
Estrogen receptor (ER) |
ESR1
|
AGR3
|
Progesterone receptor (PGR) |
PGR
|
ESR1
|
Human epidermal growth factor receptor 2 (HER2) |
ERBB2
|
PGAP3
|
Predicting receptor status separately from genes and co-genes
Joint prediction of receptor status from IHC, genes and co-genes
Probabilistic view on IHC estimates
Joint prediction from IHC, expression of genes and co-genes
Overall improvement of receptor diagnostics based on joint assessment
Flow-label | Flow-category | IHC category | IHC & GE & CO category | |
---|---|---|---|---|
(a) | Confirmed + | Definite + | → | Definite + |
(b) | Confirmed − | Definite − | → | Definite − |
(c) | Allocated + | Inconclusive | → | Definite + |
(d) | Allocated − | Inconclusive | → | Definite − |
(e) | Corrected to − | Definite + | → | Definite − |
(f) | Corrected to + | Definite − | → | Definite + |
(g) | Rejected + | Definite + | → | Inconclusive |
(h) | Rejected − | Definite − | → | Inconclusive |
(i) | Undetermined | Inconclusive | → | Inconclusive |
Estrogen receptor assessment
Progesterone receptor assessment
HER2 assessment
Discussion
Selection of co-genes
Rank | Gene | Probe set |
t-value |
---|---|---|---|
1 |
ESR1
| 205225_at | 75.2026 |
2 |
AGR3
| 228241_at | 64.9077 |
3 |
CA12
| 204508_s_at | 60.0012 |
4 |
CA12
| 214164_x_at | 58.8398 |
5 |
CA12
| 215867_x_at | 58.3216 |
6 |
CA12
| 203963_at | 56.0489 |
7 |
TBC1D9
| 212956_at | 55.7256 |
8 |
PSAT1
| 223062_s_at | 55.4939 |
9 |
GATA3
| 209603_at | 55.0988 |
10 |
GATA3
| 209602_s_at | 53.5509 |
Concordance of estrogen and progesterone receptor status
\({\text{PGR}}_{{{\text{IHC}}}}^{+}\)
|
\({\text{PGR}}_{{{\text{IHC}}}}^{{{\text{inc}}}}\)
|
\({\text{PGR}}_{{{\text{IHC}}}}^{ - }\)
| |
---|---|---|---|
\({\text{ER}}_{{{\text{IHC}}}}^{+}\)
| 901 | 518 | 240 |
\({\text{ER}}_{{{\text{IHC}}}}^{{{\text{inc}}}}\)
| 0 | 216 | 1 |
\({\text{ER}}_{{{\text{IHC}}}}^{ - }\)
| 23 | 347 | 995 |
Rank | Gene | Probe set |
t-value |
---|---|---|---|
1 |
PGR
| 228554_at | 50.9031 |
2 |
ESR1
| 205225_at | 43.0697 |
3 |
AGR3
| 228241_at | 41.2904 |
4 |
CA12
| 204508_s_at | 40.7144 |
5 |
CA12
| 214164_x_at | 39.7163 |
6 |
CA12
| 215867_x_at | 39.3184 |
7 |
CA12
| 203963_at | 38.6599 |
8 |
GREB1
| 205862_at | 38.5008 |
9 |
SCUBE2
| 219197_s_at | 38.2929 |
10 |
GFRA1
| 230163_at | 37.2852 |
Rank | Gene | Probe set |
t-value |
---|---|---|---|
1 |
PGAP3
| 55616_at | 56.6386 |
2 |
ERBB2
| 234354_x_at | 55.7404 |
3 |
PGAP3
| 221811_at | 54.9610 |
4 |
MIEN1
| 224447_s_at | 52.7986 |
5 |
STARD3
| 202991_at | 47.7318 |
6 |
ERBB2
| 216836_s_at | 44.4821 |
7 |
GRB7
| 210761_s_at | 40.9352 |
8 |
ERBB2
| 210930_s_at | 33.7941 |
9 |
ORMDL3
| 223259_at | 32.7630 |
10 |
CDK12
| 225691_at | 32.2625 |
Impact of false positive hormone receptor assessment on outcome
Probe set | Logistic regression parameters | Logistic regression quality | |||||
---|---|---|---|---|---|---|---|
\(\beta _{0}^{{{\text{GE}}}}\)
|
\(\beta _{1}^{{{\text{GE}}}}\)
| AUC | Dev of fit DoF | No. of samples | |||
ER | |||||||
Gene |
ESR1
| 205225_at | 8.98 | − 0.99 | 0.95 | 1654.9 | 3024 |
Co-gene |
AGR3
| 228241_at | 4.64 | − 0.60 | 0.92 | 2071.4 | |
PGR | |||||||
Gene |
PGR
| 228554_at | 6.25 | − 0.87 | 0.92 | 1522.1 | 2160 |
Co-gene |
ESR1
| 205225_at | 7.67 | − 0.76 | 0.88 | 1715.1 | |
HER2 | |||||||
Gene |
ERBB2
| 216836_s_at | 13.20 | − 1.23 | 0.90 | 1491.4 | 2444 |
Co-gene |
PGAP3
| 221811_at | 9.69 | − 1.68 | 0.91 | 1374.1 |
Possibly lacking versus unnecessary anti-HER2 therapy
Enhanced precision of receptor status: impact on outcome
Setting the precision threshold
Different clinical weights of false positive and false negative assessments
Materials and methods
Study selection, normalization and co-genes
GSM-ID | GSE-ID | |
---|---|---|
GSM124996 | GSE5460 | Series GSE5460 |
GSM125003 | GSE5460 | |
GSM125005 | GSE5460 | |
GSM125007 | GSE5460 | |
GSM125022 | GSE5460 | |
GSM125023 | GSE5460 | |
GSM125039 | GSE5460 | |
GSM125042 | GSE5460 | |
… | … | |
GSM151259 | GSE6532 | Series GSE6532 |
GSM151260 | GSE6532 | |
GSM151261 | GSE6532 | |
GSM151262 | GSE6532 | |
GSM151263 | GSE6532 | |
… | … |