Introduction
Methods
Patients and material
Immunohistochemistry
DNA isolation and PIK3CAmutation analysis
Statistics
Results
Associations between molecular alterations in PI3K/AKT/mTOR pathway and known prognostic factors and downstream-activated proteins
PIK3CAmutation status | ||||||
---|---|---|---|---|---|---|
Wild-type | Exon 9 mutanta | Exon 20 mutanta | ||||
n(%) | n(%) | Pvalueb | n(%) | P value b | ||
Age
|
<65
| 166 (51) | 30 (39) | 0.10 | 39 (44) | 0.28 |
≥65
| 161 (49) | 46 (61) | 50 (56) | |||
Lymph node status
|
Negative
| 177 (54) | 39 (51) | 0.70 | 55 (62) | 0.23 |
Positive
| 150 (46) | 37 (49) | 34 (38) | |||
T stage
|
T1-2
| 293 (90) | 69 (91) | 1.00 | 79 (89) | 0.85 |
T3-4
| 34 (10) | 7 (9) | 10 (11) | |||
Grade
|
Grade 1-2
| 198 (61) | 59 (78) | 0.005 | 65 (73) | 0.04 |
Grade 3
| 129 (39) | 17 (22) | 24 (27) | |||
Progesterone receptor
|
Negative
| 164 (50) | 35 (46) | 0.70 | 34 (38) | 0.05 |
Positive
| 159 (49) | 38 (50) | 54 (61) | |||
Missing
| 4 (1) | 3 (4) | 1 (1) | |||
HER2
|
Negative
| 282 (86) | 71 (93) | 0.03 | 80 (90) | 0.39 |
Positive
| 29 (9) | 1 (1) | 5 (6) | |||
Missing
| 16 (5) | 4 (5) | 4 (4) | |||
Histologic subtype
|
Ductal
| 236 (72) | 56 (73) | 1.00c | 63 (71) | 0.84c |
Lobular
| 36 (11) | 8 (11) | 8 (9) | |||
Other
| 55 (17) | 12 (16) | 18 (20) |
HER2 status | PTEN | IGF-1-R | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Negative | Positive | Negative | Positive | Low (0–2) | High (3) | |||||
n(%) | n(%) | Pvalue | n(%) | n(%) | Pvalue | n(%) | n(%) | P-value | ||
Age
|
<65
| 233 (48) | 18 (44) | 0.75 | 39 (48) | 164 (46) | 0.90 | 190 (47) | 19 (49) | 1.00 |
≥65
| 256 (52) | 23 (56) | 43 (52) | 190 (54) | 210 (53) | 20 (51) | ||||
Lymph node status
|
Negative
| 276 (56) | 16 (39) | 0.03 | 42 (51) | 189 (53) | 0.81 | 211 (53) | 22 (56) | 0.74 |
Positive
| 213 (44) | 25 (61) | 40 (49) | 165 (47) | 189 (47) | 17 (44) | ||||
T stage
|
T1-2
| 437 (89) | 34 (83) | 0.20 | 70 (85) | 317 (89) | 0.33 | 354 (89) | 31 (80) | 0.12 |
T3-4
| 52 (11) | 7 (17) | 12 (15) | 37 (11) | 46 (11) | 8 (20) | ||||
Grade
|
Grade 1-2
| 342 (70) | 9 (22) | <0.001 | 45 (55) | 226 (64) | 0.16 | 250 (63) | 26 (67) | 0.73 |
Grade 3
| 147 (30) | 32 (78) | 37 (45) | 128 (36) | 150 (37) | 13 (33) | ||||
Progesterone receptor
a
|
Negative
| 222 (45) | 30 (73) | 0.001 | 49 (60) | 163 (46) | 0.03 | 194 (49) | 18 (46) | 1.00 |
Positive
| 261 (53) | 11 (27) | 32 (39) | 190 (54) | 205 (51) | 20 (51) | ||||
Missing
| 6 (1) | 0 (0) | 1 (1) | 1 (0) | 1 (0) | 1 (3) | ||||
HER2
a
|
Negative
| 489 (100) | 0 (0) | na | 77 (94) | 313 (88) | 0.08 | 357 (89) | 36 (92) | 0.56 |
Positive
| 0 (0) | 41 (100) | 3 (4) | 36 (10) | 36 (9) | 2 (5) | ||||
Missing
| na | na | 2 (2) | 5 (1) | 7 (2) | 1 (3) |
PIK3CA mutations, loss of PTEN, and overexpression/amplification of HER2 and/or IGF-1R do not predict resistance to tamoxifen
Number | adjusted HRcfor tamoxifen versus control (95% confidence interval) | Adjusted Pvalue for interaction | ||
---|---|---|---|---|
PIK3CA
|
Wild type
| 308 | 0.51 (0.30-0.88) | |
Exon 20 mutant
a
| 82 | 0.77 (0.25-2.36) | 0.51 | |
Exon 9 mutant
a
| 71 | 0.82 (0.22-3.04) | 0.51 | |
PTEN
|
Negative
| 78 | 0.44 (0.15-1.28) | 0.63 |
Positive
| 348 | 0.58 (0.34-0.98) | ||
HER2
|
Negative
| 479 | 0.52 (0.33-0.80) | 0.52 |
Positive
| 41 | 0.85 (0.19-3.95) | ||
IGF-1R
|
Low (0–2)
| 390 | 0.55 (0.33-0.91) | 0.90 |
High (3)
| 38 | 0.60 (0.20-1.76) | ||
Any molecular alteration
|
Absent
| 206 | 0.48 (0.22-1.02) | 0.36 |
Present
b
| 151 | 0.76 (0.38-1.53) |
PIK3CA mutations have no prognostic effect in patients randomized to the control arm
N(events) | Hazard ratioa | 95% confidence interval | Pvalue | |
---|---|---|---|---|
PIK3CA exon 9 mutant vs PIK3CA wt | 111 (28) | 0.49 | 0.11-2.25 | 0.36 |
PIK3CA exon 20 mutant vs PIK3CA wt | 111 (28) | 0.72 | 0.24-2.19 | 0.56 |
PIK3CA mutant (exon 9 or exon 20) vs PIK3CA wt | 111 (28) | 0.62 | 0.25-1.59 | 0.32 |
IGF-1R (3 versus 0–2) | 96 (27) | 1.81 | 0.67-4.87 | 0.24 |
PTEN positive versus negative | 94 (25) | 0.97 | 0.29-3.26 | 0.96 |
HER2 positive versus negative | 121 (33) | 0.60 | 0.13-2.76 | 0.51 |