Treatments of brain metastases in breast cancer include whole brain radiotherapy, surgery, stereotactic radiosurgery, and systemic chemotherapy. The aim of this study was to investigate the clinicopathological factors which were associated with brain metastases-related survival, and to evaluate the efficacy of systemic chemotherapy.
A total of 106 breast cancer patients with brain metastases who were treated at the Seoul St. Mary’s Hospital were retrospectively analyzed. The brain metastases-free survival (BMFS) was defined as the time from first systemic metastases to detection of the brain metastases. Overall survival after brain metastases (OS) was measured from the detection of the brain metastases to death. The patient’s clinicopathological factors which were associated with BMFS and OS and role of systemic chemotherapy on brain metastases were evaluated.
The median BMFS was 30.7 months. In univariate analyses, age >50 years, stages I/II, tumor size <5 cm, positive lymph node ≤3, no vascular invasion, positive estrogen receptor, use of adjuvant chemotherapy, solitary brain lesion, and brain metastases as an initial recurrence site were associated with longer BMFS. The median OS after brain metastases was 5.0 months. In univariate analyses, nuclear grade I/II, mitotic activity indices <10, non-triple negative receptor, solitary brain lesion, and administration of local and systemic treatment on brain metastases were associated with longer OS. In multivariate analyses, systemic chemotherapy after brain metastases was the only significant prognostic factor associated with better OS and was effective regardless of blood-brain barrier (BBB) permeability.
A systemic chemotherapy after brain metastases improved OS regardless of BBB permeability in breast cancer patients.
Breast cancer is the second most common cause of brain metastases [
In most cases, breast cancer patients progressed to brain metastases after metastases had appeared systemically in the lung, liver, bone, and other organs [
Several factors increased the risk of brain metastases, including young age, negative hormone receptors, large tumor sizes, positive lymph node status, previous lung, liver, or bone metastases, and increased numbers of metastatic sites [
Treatment of brain metastases consists of whole brain radiotherapy(WBRT), surgery, stereotactic radiosurgery (SRS), and systemic chemotherapy [
in addition to WBRT, improved the median survival from 3 to 6months to 14 to 16 months [
The primary purpose of our study was to investigate the clinicopathological factors associated with brain metastases-free survival (BMFS) and overall survival after brain metastases in breast cancer patients. The second purpose was to investigate the efficacy of systemic chemotherapy, especially to determine whether BBB-crossing chemotherapeutic agents improved the overall survival rates.
Among the patients diagnosed with breast cancer, between May 1986 and June 2007, at the Seoul St. Mary’s Hospital, the Catholic University of Korea, 168 patients with brain metastases were reviewed for this retrospective study. Among these patients, 106 patients with nearly complete medical records and pathological data were included in this study. Computed tomography or magnetic resonance imaging of the brain was used to diagnose brain metastases. Histological examination of the brain tumors was not performed for any patient. Age, tumor type, stage, proliferative index, estrogen receptor(ER) levels, progesterone receptor (PR) levels, HER2 status, local and systemic treatments, interval between first diagnosis of breast cancer and occurrence of brain metastases, and survival thereafter were analyzed from the patient database of our hospital. BMFS was defined as the time from first systemic metastases of breast cancer to detection of the brain metastases. Overall survival after brain metastases(OS) was measured from the time of detection of the brain metastases to the time of death. Univariate survival analysis was estimated using the Kaplan-Meier method and the log-rank test was used to assess survival differences between prognostic factors. Multivariate analysis was performed using the Cox proportional hazards regression model. A P-value less than 0.05 was considered statistically significant.
This study was approved by the institutional review committee of Seoul St. Mary’s Hospital (KC10RISI0358).
Local and systemic treatment of brain metastases (
Median BMFS was 30.7 months and median OS after brain metastases was 5.0 months. The BMFS and OS were analyzed according to the patient and tumor characteristics (
Overall survival of patients with triple negative receptors was significantly shorter than for those with non-triple negative receptors (3.5 months vs. 5.4 months, P=0.011). Survival of patients with single metastases was significantly longer than for those with multiple metastases (11.1 months vs. 4.1 months, P=0.005). Patients who received combined local treatment (WBRT and SRS/surgery) had a longer survival than the patients who did not (17.4 months vs. 1.3 months, P=0.05). Survival of patients who received chemotherapy after brain metastases was significantly longer than for those who did not receive chemotherapy (10.1 months vs. 2.4 months, P<0.001). NG I and NG II (P=0.046), MAI less than 10 (P=0.008), non-triple receptor negative status (P=0.011), presence of solitary metastatic brain lesion (P=0.005), and if local (P=0.05) and systemic chemotherapeutic drug treatment was given (P<0.001) for brain metastases, were associated with longer OS (
In most reports, brain metastases occurred in the late stages of metastatic breast cancer and were already found in lung, liver, or bone by the time brain metastases was diagnosed. In breast cancer, the brain was rarely the first metastatic site [
Tham et al. [
Local treatment modalities were associated with better outcomes. In previous studies, overall survival of patients with brain metastases, treated with supportive care alone, was 1 to 2 months, and WBRT improved the median survival to 3 to 6 months [
The role of systemic chemotherapy in patients with brain metastases is still unclear. Many patients with brain metastases have been heavily pretreated with chemotherapy directed at their systemic metastatic disease. Development of brain metastases is a later event in the natural history of most tumors, and this could reflect the failure of several prior chemotherapeutic regimens, and would suggest that the recurrent tumor histology is inherently more drug resistant [
Our study had several limitations. It was a retrospective design, had no control group, and responses to systemic chemotherapy were determined from the medical charts rather than by a rigorous evaluation of radiologic studies and protocol response criteria. In some cases, patient data were not complete. Another limitation was the small number of patients. As in other studies, treatment of breast cancer consisted of multimodality treatments, including hormonal therapy and radiotherapy. Most metastatic breast cancer patients received many chemotherapeutic agents before brain metastases were diagnosed. These variables may have an influence as confounding factors on overall survival.
This study did not analyzed other significant prognostic factors, such as performance status at brain metastasis diagnosis, the first systemic metastasis site before brain metastasis, and treatment after the first systemic metastasis.
So, even though systemic chemotherapy after brain metastases was a significant factor associated with better overall survival times in multivariate analysis, we should interpret the results with care.
Nevertheless, in contrast to previous studies, we classified patients who were given the BBB-crossing agents and the non-crossing agents. In this regard, our study is significant, because we found that there was no survival benefit to the patients who received the agents that crossed the BBB.
In this study, we identified the clinicopathological factors associated the overall survival rate after brain metastases in breast cancer patients. Among these factors, systemic chemotherapy after brain metastases was identified as the most important factor. Although survival of breast cancer patients with brain metastases was generally poor, overall survival seemed to be affected by aggressive systemic chemotherapy after brain metastases. Our results differ from previous studies, which found a survival benefit only from agents which were able to cross the BBB. Therefore, it is important to use an agent known to be active against breast cancer regardless of whether it crosses the BBB. In the future, extensive prospective randomized trials are still needed to fully assess the efficacy of BBB-crossing and non-crossing chemotherapeutic agents in breast cancer with brain metastases.
No potential conflict of interest relevant to this article was reported.
Kaplan-Meier overall survival curves according to (A) triple negative receptor status, (B) number of metastatic brain lesion, (C) brain metastases local treatment modalities, and (D) systemic chemotherapy after brain metastases. TN, triple negative; Tx, treatment; WBRT, whole brain radiation therapy; SRS, stereotactic radiosurgery.
Kaplan-Meier overall survival curves after brain metastases according to used the BBB crossing agents. BBB, blood-brain barrier; Yes, BBB-crossing agents; No, BBB impermeable agents.
Clinicopathologic characteristics of 106 breast cancer patients with brain metastases
Variable | Number (%) |
---|---|
Age (yr, range) | 50(27-73) |
Operation type (n=106) | |
Mastectomy | 84 (79) |
Breast conservation surgery | 10 (9) |
Non-operation | 12 (12) |
T stage (n=104) | |
1 | 31 (30) |
2 | 48 (46) |
3 | 16 (15) |
4 | 9 (9) |
N stage (n=106) | |
0 | 24 (23) |
1 | 27 (25) |
2 | 18 (17) |
3 | 37 (35) |
TNM stage (n=106) | |
I | 12 (11) |
II | 35 (33) |
III | 49 (46) |
V | 10 (10) |
Histology (n=106) | |
Invasive ductal carcinoma | 103 (97) |
Invasive lobular carcinoma | 3 (3) |
Histologic grade (n=78) | |
I | 8 (10) |
II | 25 (32) |
III | 45 (58) |
Nuclear grade (n=78) | |
I | 4 (5) |
II | 39 (50) |
III | 35 (45) |
Lymphatic invasion (n=79) | |
Present | 63 (80) |
Absent | 16 (20) |
Vascular invasion (n=89) | |
Present | 11 (12) |
Absent | 68 (86) |
Mitotic activity index (n=79) | |
<10 | 35 (44) |
≥10 | 44 (56) |
Estrogen receptor (n=77) | |
Positive | 29 (38) |
Negative | 48 (62) |
Progesteron receptor (n=77) | |
Positive | 32 (42) |
Negative | 45 (58) |
HER2 (n=70) | |
Positive | 29 (41) |
Negative | 41 (59) |
Triple negative (n=76) | |
Yes | 23 (30) |
No | 53 (70) |
p53 (n=58) | |
Positive | 36 (62) |
Negative | 22 (38) |
Prior adjuvant chemotherapy (n=106) | |
Yes | 103 (96) |
No | 3 (4) |
TNM, tumor node metastasis; HER2, human epidermal growth factor receptor 2.
The clinical characteristics and treatment of brain metastases
Variable | Number (%) |
---|---|
Presenting neurologic symptoms | |
Headache | 64 (60.4) |
Nausea and vomiting | 35 (33.0) |
Dizziness | 27 (25.5) |
Seizure | 9 (8.5) |
Hemiplegia/paresis | 27 (25.5) |
Memory loss | 1 (0.9) |
Asymptomatic | 5 (4.7) |
No. of metastatic brain lesion | |
Single | 27 (25) |
Multiple | 79 (75) |
Extracranial metastases at brain metastases diagnosis | |
Yes | 86 (81) |
No | 20 (19) |
Extracranial metastatic sites | |
Lung | 45 (42.5) |
Liver | 15 (14.2) |
Bone | 60 (56.6) |
Lymph node | 36 (34.0) |
Skin | 11 (10.4) |
Brain metastases local treatment modalities | |
WBRT | 71 (67) |
SRS and Surgery | 9 (9) |
Combine treatment | 12 (11) |
None | 14 (13) |
Systemic chemotherapy after brain metastases | |
Yes | 55 (52) |
No | 51 (48) |
WBRT, whole brain radiation therapy; SRS, stereotactic radiosurgery.
Clinicopathologic features of the patient groups in regard to survival outcomes
Variable | BMFS (median, mo) | P-value | OS (median, mo) | P-value |
---|---|---|---|---|
Age (yr) | 0.002 | 0.259 | ||
<50 | 24.6 | 5.4 | ||
≥50 | 35.8 | 4.3 | ||
TNM stage | 0.024 | 0.76 | ||
I, II | 36.6 | 5.4 | ||
III, IV | 28.5 | 4.9 | ||
T stage | 0.026 | 0.217 | ||
1 | 31.2 | 4.7 | ||
2 | 35.5 | 4.8 | ||
3 | 14.2 | 5 | ||
4 | 24.6 | 7.4 | ||
N stage | 0.034 | 0.847 | ||
0, 1 | 33.5 | 5.4 | ||
2, 3 | 29.3 | 4.9 | ||
Histologic grade | 0.187 | 0.84 | ||
I, II | 29.8 | 4.3 | ||
III | 32.5 | 4.1 | ||
Nuclear grade | 0.224 | 0.046 | ||
I, II | 33.5 | 5 | ||
III | 26 | 2.5 | ||
Lymphatic invasion | 0.810 | 0.655 | ||
Present | 29.8 | 4 | ||
Absent | 39.5 | 5.3 | ||
Vascular invasion | 0.017 | 0.063 | ||
Present | 28.1 | 2.9 | ||
Absent | 32.7 | 4.7 | ||
Mitotic activity index | 0.304 | 0.008 | ||
<10 | 32.5 | 5.8 | ||
≥10 | 31.4 | 2.6 | ||
Estrogen receptor | 0.043 | 0.119 | ||
Positive | 34.8 | 5 | ||
Negative | 29.2 | 5.1 | ||
Progesteron receptor | 0.106 | 0.406 | ||
Positive | 33.9 | 5.2 | ||
Negative | 30.9 | 4.3 | ||
HER2 | 0.619 | 0.245 | ||
Positive | 24.5 | 4.8 | ||
Negative | 36.6 | 4.7 | ||
Triple negative | 0.150 | 0.011 | ||
Yes | 32.8 | 3.5 | ||
No | 31.2 | 5.4 | ||
p53 | 0.127 | 0.243 | ||
Positive | 26.6 | 3.9 | ||
Negative | 36 | 4.8 | ||
Prior adjuvant chemotherapy | 0.015 | 0.943 | ||
Yes | 30.9 | 4.9 | ||
No | 14 | 12.7 | ||
No. of metastatic | 0.024 | 0.005 | ||
brain lesion | ||||
Single | 33 | 11.1 | ||
Multiple | 28.5 | 4.1 | ||
Extracranial metastasis at brain metastasis diagnosis | 0.001 | 0.342 | ||
Yes | 33.1 | 4.8 | ||
No | 20.4 | 6.4 | ||
Brain metastasis local treatment modality | 0.05 | |||
WBRT | - | - | 4.8 | |
SRS/surgery | - | - | 8.3 | |
Combine treatment | - | - | 17.4 | |
None | - | - | 1.3 | |
Systemic chemotherapy after brain metastasis | < 0.001 | |||
Yes | - | - | 10.1 | |
No | - | - | 2.4 |
BMFS, brain metastases-free survival; OS, overall survival after brain metastases; TNM, tumor node metastasis; HER2, human epidermal growth factor receptor 2; WBRT, whole brain radiation therapy; SRS, stereotactic radiosurgery.
Multivariate analysis of prognostic factor for overall survival after brain metastases
Variable | P-value | Hazard ratio | 95% Confidence interval |
---|---|---|---|
Nuclear grade (I, II vs. III) | 0.832 | 0.933 | 0.494-1.764 |
Mitotic activity index (<10 vs. ≥10) | 0.891 | 0.958 | 0.515-1.781 |
Triple negative receptor (no vs. yes) | 0.143 | 0.588 | 0.289-1.196 |
No. of brain metastases (single vs. multiple) | 0.835 | 1.113 | 0.407-3.043 |
Local treatment modalities | 0.411 | ||
Combine treatment vs. SRS/surgery | 0.643 | 1.422 | 0.321-6.301 |
Combine treatment vs. WBRT | 0.923 | 1.050 | 0.391-2.825 |
Combine treatment vs. none | 0.348 | 0.517 | 0.130-2.053 |
Systemic chemotherapy after brain metastases (yes vs. no) | 0.000 | 8.091 | 3.700-17.697 |
SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy.