Introduction
Methods
Study design and patient selection
Standard pathology biomarkers
Evaluation of pathologic response
RNA analysis
DNA analysis
Statistical analysis
Results
Patient characteristics
Characteristics | I-SPY trial evaluable (n = 221) | Profiled with agilent microarray (n = 149) | Profiled with agilent microarray without any trastuzumab (n = 120) |
---|---|---|---|
Age (years) | |||
Median (range) | 49 (26–68) | 48 (27–65) | 47 (28–65) |
Premenopausal | 48% (106) | 49% (72) | 47% (56) |
Race | |||
Caucasian | 75% (165) | 76% (114) | 77% (93) |
African American | 19% (42) | 18% (27) | 18% (21) |
Asian | 4% (9) | 5% (7) | 4% (5) |
Other | 2% (5) | 1% (1) | 1% (1) |
Clinical tumor size (cm) | |||
Median (range) | 6.0 (0–25) | 5.5 (0–25) | 5.5 (0–18) |
Tumor longest diameter on baseline MRI (cm) | |||
Median (range) | 6.8 (0–18.4) | 6.5 (0–18.4) | 6.45 (2.0–16.6) |
Clinically node positive at diagnosis | 65% (143) | 66% (99) | 63% (76) |
Histologic grade (baseline) | |||
Low | 8% (18) | 7% (10) | 7% (9) |
Intermediate | 43% (96) | 42% (63) | 40% (48) |
High | 47% (103) | 50% (75) | 52% (62) |
Indeterminate | 2% (4) | 1% (1) | 1% (1) |
Clinical stage (baseline) | |||
I | 1% (3) | 2% (3) | 2% (3) |
IIA | 19% (43) | 21% (32) | 25% (30) |
IIB | 28% (61) | 26% (38) | 26% (31) |
IIIA | 35% (78) | 34% (51) | 33% (40) |
IIIB | 5% (11) | 5% (8) | 7% (8) |
IIIC | 3% (7) | 3% (5) | 2% (2) |
Inflammatory | 8% (17) | 7% (11) | 4% (5) |
Indeterminate | <1% (1) | 1% (1) | 1% (1) |
Hormone receptors (baseline) | |||
ER-positive | 56% (124) | 55% (82) | 58% (70) |
PR-positive | 46% (102) | 44% (66) | 49% (59) |
HR-positive (ER or PR) | 59% (130) | 58% (86) | 62% (74) |
Her-2 positive (baseline) | 30% (67) | 30% (45) | 15% (18) |
HR-negative/Her-2 negative (baseline) (triple negative) | 24% (53) | 25% (37) | 30% (36) |
Neoadjuvant treatment | |||
AC only | 5% (11) | 3% (4) | 3% (4) |
AC + T | 85% (187) | 87% (129) | 95% (114) |
AC + T + trastuzumab | 9% (20) | 9% (14) | – |
AC + T + other | 1% (3) | 1% (2) | 1% (2) |
Surgery type | |||
Mastectomy | 56% (123) | 57% (84) | 54% (65) |
Lumpectomy | 41% (92) | 40% (60) | 43% (51) |
No Surgery | 3% (6) | 3% (5) | 3% (4) |
Post-operative adjuvant therapy | 58% (128) | 56% (84) | 45% (54) |
Any hormonal therapy | 34% (75) | 34% (52) | 38% (46) |
Tamoxifen | 43% (95) | 44% (61) | 43% (52) |
Aromatase inhibitor | 12% (27) | 12% (20) | 12% (15) |
Ovarian suppression or ablation | 3% (7) | 3% (6) | 4% (5) |
Trastuzumab | 16% (35) | 16% (25) | – |
Institutions participating in the I-SPY trial | ||
---|---|---|
Total accrual 237 | ||
Institution name | Accrual | Biomarker tests performed* |
Georgetown University Hospital | 4 | |
Memorial Sloan-Kettering Cancer Center | 20 | |
National Cancer Institute/George Mason University | N/A | Reverse phase phosphoprotein arrays |
University of Alabama at Birmingham | 50 | |
University of California, San Francisco | 67 | Frozen tissue, DNA and RNA processing, cDNA arrays |
University of Chicago | 2 | |
University of North Carolina | 38 | Paraffin-based IHC; p53 gene chip; expression profiling |
University of Pennsylvania Medical Center | 36 | Paraffin-based IHC |
University of Texas, Southwestern | 14 | |
University of Washington, Seattle | 6 |
Early outcomes: residual disease measured at the time of surgical resection
Recurrence-free and OS
Correlation coefficient | |||||
---|---|---|---|---|---|
Concordance (P value) | |||||
p53 wt | 70-Gene low | Luminal | Wound-quiescent | ROR-S low | |
HR+, HER2− | 0.44 | 0.26 | 0.62 | 0.34 | 0.40 |
0.72 | 0.63 | 0.81 | 0.68 | 0.71 | |
(<0.001) | (0.002) | (<0.001) | (<0.001) | (<0.001) | |
p53 wt | ⇓ | 0.32 | 0.65 | 0.55 | 0.56 |
⇒ | 0.59 | 0.83 | 0.73 | 0.74 | |
(<0.001) | (<0.001) | (<0.001) | (<0.001) | ||
70-Gene low | ⇓ | 0.33 | 0.41 | 0.54 | |
⇒ | 0.61 | 0.82 | 0.83 | ||
(<0.001) | (<0.001) | (<0.001) | |||
Luminal | ⇓ | 0.40 | 0.55 | ||
⇒ | 0.68 | 0.75 | |||
(<0.001) | (<0.001) | ||||
Wound-quiescent | ⇓ | 0.63 | |||
⇒ | 0.86 | ||||
(<0.001) |
Pathological complete response (pCR) | Recurrence-free survival | |||
---|---|---|---|---|
Rate of pCR (n) | Odds ratio (P value) | Hazard ratio (95% CI) | Hazard ratio, pCR vs. no PCR (95% CI within subgroup) | |
All patients with surgery | 27% (215) | – | – | 0.41* (0.18–0.82) |
Population without any trastuzumab | 22% (180) | – | – | 0.23 * (0.06–0.63) |
HR+/HER2− (Yes vs. other) | Yes: 9% (8/93) | 0.15 (<0.001) | 0.50* (0.27–0.89) | Yes: 0.00 (–) |
Other: 38% (30/79) | Other: 0.17* (0.04–0.51) | |||
p53 (Wt vs. Mut) | Wt: 9% (5/58) | 0.18 (<0.001) | 0.34* (0.15–0.69) | Wt 0.00 (–) |
Mut: 34% (20/58) | Mut: 0.22* (0.05–0.65) | |||
70-Gene (low vs. high) | Low: 0% (0/11) | 0.00 (0.02) | 0.00* (–) | Low: 0.00 (–) |
High: 24% (25/105) | High: 0.29* (0.07–0.82) | |||
Luminal PAM50 (luminal vs. other) | Luminal: 8% (5/61) | 0.16 (<0.001) | 0.47* (0.23–0.93) | Luminal: 0.00 (–) |
Other: 36% (20/55) | Other: 0.26* (0.06–0.79) | |||
Wound healing (quiescent vs. activated) | Quiescent: 7% (2/29) | 0.21 (0.02) | 0.16* (0.03–0.51) | Quiescent: 0.00 (–) |
Activated: 26% (23/87) | ||||
Activated: 0.25* (0.06–0.71) | ||||
ROR-S (low vs. med/HIGH) | Low: 6% (2/32) | 0.18 (0.006) | 0.22* (0.05–0.61) | Low: 0.00 (–) |
Med/high: 27% (23/84) | Med/high: 0.26* (0.06–0.74) |
Univariate hazard ratio (95% CI) | Multivariate hazard ratio adjusting for predefined HR/HER2 contribution (95% CI) | |
---|---|---|
P53 (Wt vs. Mt) | 0.33* (0.16–0.70) | 0.46* (0.22–0.96) |
70-Gene (low vs. high) | 0.00a
(–) | 0.00a
(–) |
Luminal PAM50 (luminal vs. other) | 0.47* (0.23–0.94) | 0.73 (0.37–1.48) |
Wound healing (quiescent vs. activated) | 0.16* (0.04–0.65) | 0.20* (0.05–0.78) |
ROR-S (low vs. med/high) | 0.22* (0.07–0.72) | 0.29* (0.09–0.96) |
Clinical stage (<stage 3 vs. not) | 0.20* (0.10–0.42) | 0.21* (0.10–0.43) |
Ki67 (low/med vs. high) | 0.77 (0.42–1.42) | 1.14 (0.62–2.10) |