Background
Methods
Design
Patients
Objectives
Clinical and biological data
Analysis of serum biomarkers
Statistical analysis
Ethical considerations
Results
Patients’ characteristics
Initial characteristics | |
Tumor biology group, n (%) | |
HER2+ HR+ | 58 (23.2) |
HER2+ HR- | 61 (24.4) |
HER2- HR+ | 64 (25.6) |
Triple negative | 67 (26.8) |
ER status, n (%)
| |
Negative | 128 (51.2) |
Positive | 122 (48.8) |
PR status, n (%)
| |
Negative | 186 (74.7) |
Positive | 63 (25.3) |
Missing | 1 |
HER2 status, n (%)
| |
Negative | 131 (52.4) |
Positive | 119 (47.6) |
Histological subtype, n (%)
| |
Ductal carcinoma | 203 (82.9) |
Other subtypesa | 42 (17.1) |
Missing | 5 |
Histological grade (SBR), n (%)
| |
1 or 2 | 103 (45.8) |
3 | 122 (54.2) |
Missing | 25 |
Inflammatory BC, n (%)
| |
No | 216 (90.8) |
Yes | 22 (9.2) |
Missing | 12 |
Metastatic status at BC diagnosis, n (%)
| |
M0 | 174 (71.3) |
M1 | 70 (28.7) |
Mx | 6 |
Patients’ characteristics at the time of the serum sample | |
Median age in years (range)
| 58.4 (26.4–87.2) |
Age group, n (%)
| |
< 50 | 77 (30.8) |
50 to 70 | 132 (52.8) |
> 70 | 41 (16.4) |
Median number of lines of CT (range)
| 1 (0–9) |
Number of lines of CT, n (%)
| |
0 line | 61 (24.4) |
1 or 2 line(s) | 113 (45.2) |
> 2 lines | 76 (30.4) |
Previous anti-HER2 treatment, n (%)
| |
No | 149 (59.6) |
Yes | 101 (40.4) |
Brain metastases, n (%)
| 88 (35.2) |
Liver metastases, n (%)
| 152 (60.8) |
Bone metastases, n (%)
| 142 (56.8) |
Lung metastases, n (%)
| 125 (50.0) |
Lymph node metastases, n (%)
| 134 (53.6) |
Subcutaneous metastases, n (%)
| 43 (17.2) |
Pleural metastases, n (%)
| 55 (22.0) |
Metastases of other sites, n (%)
| 109 (43.6) |
ECOG status, n (%)
| |
0 | 70 (30.2) |
1 | 106 (45.7) |
2 | 34 (14.7) |
3 | 22 (9.5) |
Missing | 18 |
Anemia, n (%)
| |
No | 38 (25.9) |
Yes | 109 (74.1) |
Missing | 103 |
Leucopenia, n (%)
| |
No | 118 (82.5) |
Yes | 25 (17.5) |
Missing | 107 |
Neutropenia, n (%)
| |
No | 129 (89.0) |
Yes | 16 (11.0) |
Missing | 105 |
Lymphopenia, n (%)
| |
No | 82 (59.4) |
Yes | 56 (40.6) |
Missing | 112 |
Thrombopenia, n (%)
| |
No | 128 (88.3) |
Yes | 17 (11.7) |
Missing | 105 |
Elevated LDH, n (%)
| |
No | 51 (56.7) |
Yes | 39 (43.3) |
Missing | 160 |
Elevated serum CEA, n (%)
| |
No | 154 (66.4) |
Yes | 78 (33.6) |
Missing | 18 |
Elevated serum CA 15-3, n (%)
| |
No | 92 (39.7) |
Yes | 140 (60.3) |
Missing | 18 |
Elevated serum HER2 ECD (cut-off 15 ng/mL)
| |
No | 107 (42.8) |
Yes | 143 (57.2) |
Missing | 0 |
Elevated serum HER2 ECD (cut-off 30 ng/mL)
| |
No | 187 (74.8) |
Yes | 63 (25.2) |
Missing | 0 |
Elevated serum NSE (cut-off 12.5 μg/L)
| |
No | 76 (30.5) |
Yes | 173 (69.5) |
Missing | 1 |
Elevated serum MMP9 (cut-off 50 ng/mL)
| |
No | 6 (2.4) |
Yes | 244 (97.6) |
Missing | 0 |
Elevated serum S100ß (cut-off 0.12 μg/L)
| |
No | 224 (92.2) |
Yes | 19 (7.8) |
Missing | 7 |
Elevated serum S100ß (cut-off 0.072 μg/L)
| |
No | 183 (75.3) |
Yes | 60 (24.7) |
Missing | 7 |
Low protein level, n (%)
| |
No | 32 (74.4) |
Yes | 11 (25.6) |
Missing | 119 |
Low albumin level, n (%)
| |
No | 135 (85.4) |
Yes | 23 (14.6) |
Missing | 92 |
Follow-up | |
Status as last follow-up, n (%)
| |
Alive | 77 (30.8) |
Dead | 173 (69.2) |
Cause of death, n (%)
|
(174 deceased)
|
Oncological disease | 153 (87.9) |
Non-oncological | 4 (2.3) |
Toxic | 4 (2.3) |
Unknown | 13 (7.5) |
Serum CA 15-3, CEA, HER2 ECD, NSE, MMP-9 and S100ß
Prognostic factors
Parameter | Median OS in months (CI 95 %) | P-value |
---|---|---|
Initial characteristics | ||
Tumor biology group
| <0.001 | |
HER2+ HR+ | 32.1 (16.5 – NC) | |
HER2+ HR- | 28.7 (19.1–34.5) | |
HER2- HR+ | 12.5 (10.4–22.8) | |
Triple negative | 7.6 (4.6–10.4) | |
ER status
| 0.087 | |
Negative | 13.3 (10.0–19.1) | |
Positive | 20.1 (12.4–20.6) | |
PR status
| 0.035 | |
Negative | 12.5 (10.6–17.8) | |
Positive | 22.8 (16.5–35.6) | |
HER2 status
| <0.001 | |
Negative | 10.4 (8.5–12.5) | |
Positive | 31.6 (20.2–34.5) | |
Histological subtype
| 0.344 | |
Ductal carcinoma | 15.2 (11.6–20.6) | |
All other subtypes | 20.1 (10.1–35.6) | |
Histological grade (SBR)
| 0.024 | |
1 or 2 | 20.6 (14.8–31.6) | |
3 | 11.1 (9.7–15.5) | |
Inflammatory BC
| 0.523 | |
No | 15.1 (11.6–20.2) | |
Yes | 20.9 (6.8 – NC) | |
Metastatic status at BC diagnosis
| 0.012 | |
M0 | 13.6 (10.4–16.5) | |
M1 | 27.2 (13.7–32.1) | |
Characteristics at the time of the serum sample | ||
Age group
| 0.723 | |
< 50 | 15.0 (10.0–23.0) | |
50 to 70 | 16.3 (11.6–20.7) | |
> 70 | 20.2 (9.7–51.4) | |
ECOG status
| <0.001 | |
Score 0 | 34.5 (20.9–53.4) | |
Score 1 | 16.5 (12.1–22.5) | |
Score 2 | 8.5 (3.8–16.8) | |
Score 3 | 2.0 (1.4–4.6) | |
Number of lines of CT
| <0.001 | |
0 line | 17.6 (14.8–27.2) | |
1 or 2 line(s) | 22.8 (16.8–32.1) | |
> 2 lines | 6.4 (4.6–10.4) | |
Previous anti-HER2 treatment
| <0.001 | |
No | 11.7 (9.8–15.2) | |
Yes | 28.7 (20.1–33.9) | |
Metastatic-free interval
| 0.464 | |
≤ 24 months | 14.8 (10.6–20.7) | |
> 24 months | 16.5 (12.4–23.3) | |
Number of metastatic sites
| <0.001 | |
1 | 59.2 (23.0 – NC) | |
> 2 | 13.3 (11.1–16.8) | |
Location of metastatic sites
| 0.001 | |
Bone and/or subcutaneous only | 63.6 (95 % CI NC) | |
Visceral | 14.4 (11.4–19.4) | |
Brain metastases
| <0.001 | |
Absent | 30.4 (17.2–34.9) | |
Present | 9.7 (5.6–10.4) | |
Liver metastases
| <0.001 | |
Absent | 28.7 (14.9–36.8) | |
Present | 12.4 (10.6–17.6) | |
Bone metastases
| 0.639 | |
Absent | 17.8 (10.6–31.6) | |
Present | 15.2 (12.1–20.2) | |
Lung metastases
| 0.096 | |
Absent | 20.7 (14.4–30.4) | |
Present | 12.4 (10.1–17.8) | |
Lymph node metastases
| 0.296 | |
Absent | 19.4 (12.4–27.7) | |
Present | 13.6 (10.5–19.1) | |
Subcutaneous metastases
| 0.006 | |
Absent | 19.4 (13.7–22.8) | |
Present | 11.3 (4.7–15.2) | |
Pleural metastases
| 0.077 | |
Absent | 16.3 (12.5–20.9) | |
Present | 13.3 (5.2–28.7) | |
Metastases of other sites
| <0.001 | |
Absent | 20.9 (16.2–30.7) | |
Present | 11.1 (7.5–13.6) | |
Anemia
| 0.134 | |
No | 15.5 (8.1–22.8) | |
Yes | 10.3 (8.1–11.7) | |
Leucopenia
| 0.363 | |
No | 10.3 (8.5–12.4) | |
Yes | 10.8 (6.4–31.6) | |
Neutropenia
| 0.908 | |
No | 10.6 (8.5–12.4) | |
Yes | 10.4 (5.2 – NC) | |
Lymphopenia
| 0.351 | |
No | 11.1 (9.4–15.5) | |
Yes | 8.4 (4.7–10.6) | |
Thrombopenia
| 0.748 | |
No | 10.6 (8.5–13.6) | |
Yes | 10.1 (2.6–20.6) | |
Serum protein level
| 0.780 | |
Normal | 9.7 (5.2–11.6) | |
Low | 6.4 (2.3–13.6) | |
Serum albumin level
| <0.001 | |
Normal | 14.4 (11.1–19.4) | |
Low | 1.6 (1.1–2.4) | |
Serum LDH
| 0.241 | |
Normal | 10.3 (5.5–13.7) | |
Elevated | 4.7 (1.9–9.8) | |
Elevated CEA
| 0.001 | |
Normal | 20.6 (16.2–28.7) | |
Elevated | 10.6 (8.7–12.5) | |
Elevated CA 15-3
| <0.001 | |
Normal | 28.7 (20.1–59.2) | |
Elevated | 11.3 (9.7–14.4) | |
Serum HER2 (cut-off 15 ng/mL)
| <0.001 | |
Normal | 22.6 (16.2–32.3) | |
Elevated | 11.3 (8.9–14.4) | |
Serum HER2 (cut-off 30 ng/mL)
| <0.001 | |
Normal | 20.2 (15.0–28.6) | |
Elevated | 10.1 (5.2–13.6) | |
Serum NSE (cut-off 12.5 μg/L)
| <0.001 | |
Normal | 20.6 (16.2–30.4) | |
Elevated | 9.9 (5.6–14.4) | |
Serum MMP9 (cut-off 50 ng/mL)
| 0.009 | |
Normal | 3.8 (1.1 – NC) | |
Elevated | 16.2 (12.5–20.7) | |
Serum S100ß (cut-off 0.12 μg/L)
| <0.001 | |
Normal | 17.2 (14.4–22.6) | |
Elevated | 4.5 (1.6–10.0) | |
Serum S100ß (cut-off 0.072 μg/L)
| <0.001 | |
Normal | 20.3 (15.1–30.4) | |
Elevated | 6.2 (4.5–12.1) |
Parameter | Hazard-ratio | 95 % CI | P-value |
---|---|---|---|
Performance status:
| |||
ECOG 0 | 1 | ||
ECOG 1 | 1.75 | 1.12–2.73 | 0.013 |
ECOG 2 | 2.62 | 1.51–4.53 | 0.001 |
ECOG 3 | 9.78 | 4.85–19.73 | <0.001 |
Tumor biology:
| |||
HER2+/HR+ | 1 | ||
HER2+/HR− | 1.19 | 0.70–2.04 | 0.514 |
HER2−/HR+ | 2.49 | 1.49–4.18 | 0.001 |
Triple negative | 5.31 | 2.97–9.47 | <0.001 |
Number of previous metastatic CT lines:
| |||
0 | 1 | ||
1 or 2 | 1.81 | 1.14–2.86 | 0.012 |
> 2 | 2.57 | 1.57–4.21 | <0.001 |
Brain metastases
| 2.26 | 1.57–3.25 | <0.001 |
Subcutaneous metastases
| 1.92 | 1.22–3.01 | 0.005 |
Elevated CA 15-3 (cut-off 30 UI/L)
| 1.95 | 1.31–2.93 | 0.001 |
Elevated HER2 ECD (cut-off 30 ng/mL)
| 2.51 | 1.53–4.12 | <0.001 |
Elevated S100ß (cut-off 0.12 μg/L)
| 1.93 | 1.05–3.54 | 0.033 |