ORIGINAL ARTICLE
Population-based Analysis of Treatment and Survival in Women Presenting With Brain Metastasis at Initial Breast Cancer Diagnosis Bradley Wiksyk, BSc,* David H. Nguyen, MD,w Cheryl Alexander, CHIM,* and Pauline T. Truong, MD, CM*z
Purpose: Brain metastasis at initial breast cancer diagnosis is rare. This study aims to evaluate the clinical characteristics of these patients and identify prognostic and treatment factors associated with improved survival. Methods: Subjects were 35 women referred from 1996 to 2005 with newly diagnosed breast cancer with synchronous brain metastasis. Overall survival (OS) and brain progression-free survival were examined using Kaplan-Meier methods and compared between subgroups with different clinicopathologic and treatment characteristics using log-rank tests. Results: Median age was 65 years. Whole-brain radiotherapy (WBRT) alone was used in 25 patients, surgical resection and postoperative WBRT in 5 patients, and no or unknown treatment in 5 patients. Patients who underwent cranial resection were more likely to have solitary brain metastasis (P = 0.003) and no visceral involvement (P = 0.006). Overall, median OS was 6.8 months and median brain progression-free survival was 6.5 months (range, 0.7 to 54 mo). Median OS were 15 months with surgery and postoperative WBRT, 5 months with WBRT alone, and 3 months with no brain treatment. Longer OS was observed with age below 65 years versus 65 years and above (11 vs. 5 mo, P = 0.046), 0 to 1 versus Z2 sites of extracranial metastasis (10 vs. 3 mo, P = 0.047), and diagnosis from 2001 to 2005 versus 1996 to 2000 (10 vs. 3 mo, P = 0.018). A trend toward improved OS was observed in patients with no visceral involvement (11 vs. 4 mo, P = 0.09). Conclusions: In this unique cohort presenting with breast cancer and synchronous brain metastasis, longer survival were observed with young age, limited extracranial metastasis, and no visceral disease. These characteristics may be used to select candidates for more aggressive treatment. Key Words: breast cancer, brain metastasis, de novo stage IV breast cancer, treatment, survival
(Am J Clin Oncol 2016;39:255–260)
B
rain metastasis may develop in approximately 20% to 40% of all patients with breast cancer during the trajectory of their disease.1–3 The vast majority of these cases occur after an From the *Radiation Therapy Program, British Columbia Cancer Agency, Vancouver Island Centre, Victoria; zDepartment of Radiation Oncology, University of British Columbia, Vancouver, BC; and wDepartment of Radiation Oncology, Maisonneuve Rosemont Hospital, University of Montreal, Montreal, QC, Canada. The authors declare no conflicts of interest. Reprints: Pauline T. Truong, MD, CM, BC Cancer Agency, Vancouver Island Centre, 2410 Lee Avenue, Victoria, BC, Canada V8R 6V5. E-mail: [email protected]. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/16/3903-0255 DOI: 10.1097/COC.0000000000000055
American Journal of Clinical Oncology
initial diagnosis of primary breast cancer, representing systemic recurrence or distant disease dissemination. Brain metastasis is often associated with neurological symptoms and cognitive deficits that can adversely affect function and quality of life.3,4 The majority of patients have limited overall survival (OS),1,4–12 but prognostic factors have been identified in several studies including age, performance status, extent of intracranial and extracranial disease, and time interval between the initial breast cancer diagnosis and the development of brain metastasis.9–15 Although distant metastasis most often occurs as systemic recurrence or dissemination after an initial diagnosis of primary breast cancer, distant disease at the time of initial breast cancer diagnosis is less common, occurring in approximately 5% of all breast cancer cases.1,16,17 Within this population, a unique subset exists who present with brain metastasis at the time of initial diagnosis of breast cancer. There is a lack of study focusing on the characteristics and outcomes of these patients. This population-based study aims to evaluate the clinical characteristics, treatment, and outcomes of patients with newly diagnosed breast cancer with synchronous brain metastasis and to identify prognostic factors associated with improved survival in these subjects.
METHODS Study Cohort The British Columbia Cancer Agency is a Canadian cancer care institution providing universal access to its services throughout the province of British Columbia. Between January 1, 1996 and December 31, 2005, 22,592 women were referred with a new diagnosis of breast cancer. Of these, 733 (3.2%) women had clinical or pathologic stage IV or distant metastatic disease at diagnosis. Within this cohort, 35 patients with brain metastasis at the same time as or within 4 months from the initial diagnosis of primary breast cancer were identified, comprising the current study cohort. Initial brain metastasis and brain progression were confirmed with cranial computed tomography or magnetic resonance imaging. Brain imaging was not routinely performed as a part of staging workup in asymptomatic patients18 but was obtained only in patients with neurological signs or symptoms. Women whose brain metastasis were identified more than 4 months after the initial breast cancer diagnosis were excluded.
Study Variables Patient demographics, tumor, treatment, and outcomes data were abstracted from the BCCA Breast Cancer Outcomes Unit Database that prospectively records this information. Chart review was performed to obtain information regarding
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the characteristics of brain metastasis that were not available in the database. Patient and clinicopathologic characteristics of the primary breast disease analyzed were age at diagnosis, year of diagnosis (1996 to 2000 vs. 2001 to 2005), Karnofsky performance status (KPS), Charlson comorbidity index,19 T stage, N stage, histologic grade, estrogen receptor status, and human epidermal growth factor 2 status. Characteristics of the brain metastasis analyzed were neurological symptoms, number of brain lesions, size of the largest brain lesion, location of brain metastasis, presence of extracranial metastasis, sites of extracranial metastatic involvement (bone, soft tissue, or viscera), number of subsites of extracranial metastasis, and Radiation Therapy Oncology Group recursive partitioning analysis risk classification (class 1: KPSZ70, age 2 cm (89%) and neurological symptoms (100%). The number of brain lesions were 1 to 3 in 40%, >3 in 43%, and unknown in 17%. The size of the largest brain lesion was r3 cm in 69% of cases. Extracranial metastasis was present in 66% and visceral disease was present in 54% of the cases. Treatment of brain metastasis was surgical resection followed by WBRT in 5 patients, external beam WBRT alone in 25 patients, and no or unknown treatment in 5 patients. In patients receiving WBRT, the mean total dose was 20 Gy (range, 5 to 30 Gy) in 5 fractions (range, 1 to 10 fractions). Table 2 compares the characteristics of patients who underwent surgical resection of brain metastasis to those who underwent WBRT alone. Patients who underwent cranial resection were more likely to have solitary brain metastasis (P = 0.003) and no visceral involvement (P = 0.006). No patient in this cohort received stereotactic radiosurgery or gamma knife treatment. Systemic therapy used included chemotherapy in 20%, hormone therapy in 37%, both in 20%, and none in 23% of patients. Locoregional therapy with surgery or radiation therapy to the primary breast tumor was used in 31% of cases. In the study cohort, median OS was 6.8 months (range, 0.7 to 54 mo) and median time to brain progression was 6.5 months (range, 0.7 to 54 mo). Survival outcomes stratified by
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clinicopathologic and treatment characteristics are summarized in Table 1. The median OS times were 15 months with surgery, 5 months with WBRT, and 3 months with no brain treatment (P = 0.475). Longer OS was observed with age below 65 years versus 65 years of age and above (11 vs. 5 mo, P = 0.046; Fig. 1A), 0 to 1 versus Z2 sites of extracranial metastasis (10 vs. 3 mo, P = 0.047; Fig. 1B), and diagnosis from 2001 to 2005 versus 1996 to 2000 (10 vs. 3 mo, P = 0.018; Fig. 1C). A trend toward improved OS was observed in patients with no visceral involvement (11 vs. 4 mo, P = 0.09, Fig. 1D).
DISCUSSION The available data on the management of brain metastasis from breast cancer have been predominantly derived from patients in whom brain metastasis occurred as recurrent disease after the primary breast cancer diagnosis. There are few data examining the less common setting in which brain metastasis is detected at the initial diagnosis of breast cancer. The current population-based study confirmed that this presentation is rare, occurring in 3 Unknown P No. brain metastases 1 >1 Unknown P Size of largest brain lesion r3 cm > 3 cm Unknown P Location of brain metastases Parenchymal Leptomeningeal Unknown P Site(s) of extracranial metastatic Bone involvement Present
Copyright
r
Brain Disease Progression-free Survival
N (%)
Median (mo)
1-y KM Rates (%)
Median (mo)
1-y KM Rates (%)
35 (100)
6.8
31.4
6.5
20.0
8 (22.9) 27 (77.1)
3.0 10.4 0.018
12.5 37.0 0.018
3.0 7.2 0.031
0 25.9 0.031
17 (48.6) 18 (51.4)
10.5 5.3 0.046
41.2 22.2 0.046
7.2 3.9 0.148
29.4 7.4 0.148
16 (45.7) 16 (45.7) 3 (8.6)
2.6 8.7 13.1 0.162
18.8 37.5 66.7 0.162
2.6 6.6 13.1 0.128
12.5 18.8 66.7 0.128
27 (77.1) 8 (22.9)
7.7 4.6 0.457
29.6 37.5 0.457
6.6 4.6 0.551
18.5 15.0 0.551
3 (8.6) 31 (88.6) 1 (2.9)
4.6 7.7 1.2 0.688
33.3 32.3 0 0.688
4.6 6.6 1.2 0.980
33.3 19.4 0 0.980
22 (62.9) 9 (25.7) 4 (11.4)
8.7 5.3 1.2 0.067
40.9 22.2 0 0.067
7.2 3.0 1.2 0.105
22.7 22.2 0 0.105
13 (37.1) 13 (37.1) 9 (25.7)
8.7 4.6 10.5 0.191
38.5 15.4 44.4 0.191
7.2 3.5 10.5 0.237
23.1 7.7 33.3 0.237
11 (31.4) 18 (51.4) 6 (17.1)
7.7 5.3 10.5 0.582
27.3 27.8 50.0 0.582
4.6 4.6 10.5 0.300
27.3 11.1 33.3 0.300
6 (17.1) 9 (25.7) 20 (57.1)
11.6 8.7 3.1 0.781
50.0 22.2 30.0 0.781
6.6 7.5 3.1 0.948
33.3 22.2 15.0 0.948
14 (40.0) 15 (42.9) 6 (17.1)
10.4 5.3 8.7 0.809
42.9 26.7 16.7 0.809
6.6 3.9 7.5 0.856
21.4 20.0 16.7 0.856
11 (31.4) 18 (51.4) 6 (17.1)
11.6 5.3 8.7 0.685
45.5 27.8 16.7 0.685
6.6 3.9 7.5 0.741
27.3 16.7 16.7 0.741
24 (68.6) 3 (8.6) 8 (22.9)
4.6 7.7 10.5 0.715
29.2 33.3 37.5 0.715
4.6 3.9 10.5 0.878
12.5 33.3 37.5 0.878
29 (82.9) 5 (14.3) 1 (2.9)
6.5 10.5 3.1 0.744
34.5 20.0 0 0.744
4.6 10.5 3.1 0.532
20.7 20.0 0 0.532
involvement 17 (48.6)
3.0
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23.5
2.9
23.5
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TABLE 1. (continued) Overall Survival Characteristics
N (%)
Median (mo)
Absent 18 (51.4) P Soft tissue involvement Present 5 (14.3) Absent 30 (85.7) P Visceral Involvement Present 19 (54.3) Absent 16 (45.7) P No. subsites of extracranial metastasis 0-1 20 (57.1) Z2 15 (42.9) P RTOG RPA risk class 1 1 (2.9) 2 16 (45.7) 3 15 (42.9) Unknown 3 (8.6) P Systemic therapy use None 8 (22.9) Chemotherapy 7 (20.0) Hormone therapy 13 (37.1) Both 7 (20.0) P Use of locoregional therapy to the primary tumor Yes 11 (31.4) No 24 (68.6) P Brain treatment Surgery 5 (14.3) Whole-brain radiotherapy 25 (71.4) None 4 (11.4) Unknown 1 (2.9) P
Brain Disease Progression-free Survival
1-y KM Rates (%)
Median (mo)
1-y KM Rates (%)
8.7 0.383
38.9 0.383
7.2 0.590
16.7 0.590
10.5 5.3 0.777
40.0 30.0 0.777
8.3 4.6 0.914
20.0 20.0 0.914
3.5 11.1 0.090
21.1 43.8 0.090
3.0 7.2 0.236
21.1 18.8 0.236
10.4 3.0 0.047
40.0 20.0 0.047
7.2 2.9 0.123
20.0 20.0 0.123
13.9 7.7 3.0 13.1 0.514
100.0 31.3 20.0 66.7 0.514
13.1 6.4 2.6 13.1 0.370
100.0 12.5 13.3 66.7 0.370
4.6 6.5 2.6 13.4 0.375
25.0 28.6 23.1 57.1 0.375
4.6 6.5 2.6 11.8 0.273
12.5 14.3 15.4 42.9 0.273
11.6 3.5 0.240
45.5 25.0 0.240
7.2 3.1 0.292
27.3 16.7 0.292
14.7 5.3 3.1 11.6 0.475
80.0 28.0 21.7 0 0.475
11.8 4.6 3.1 6.6 0.489
40.0 20.0 0 0 0.489
*Test statistics applied to known values only. KM indicates Kaplan-Meier; RTOG RPA, Radiation Therapy Oncology Group Recursive Partitioning Analysis.
resection was used in only 5 subjects. Consistent with data from studies that report on cranial resection for brain metastasis,11 the current study also observed that patients with solitary metastasis and without visceral disease were significantly more likely to be treated with surgical resection. TABLE 2. Comparison of Clinicopathologic Characteristics Between Patients Treated With Surgery Plus WBRT Versus WBRT Alone
N (%) Surgery + WBRT WBRT Alone (n = 5) (n = 25) Median age (y) KPSZ70 Solitary brain lesion Size of largest brain lesion r3 cm No visceral involvement
P
67 3 (60.0) 5 (100.0) 4 (80.0)
63 10 (45.5) 5 (22.7) 19 (76.0)
0.542 0.648 0.003 0.367
5 (100.0)
7 (28.0)
0.006
KPS indicates Karnofsky performance status; WBRT, whole-brain radiation therapy.
Although no patient in our cohort underwent stereotactic radiosurgery as a component of brain metastasis treatment, a systematic review of 9 randomized controlled trials with 1420 patients reported that radiosurgery was not associated with improvement in OS among patients with multiple lesions, but that it may improve OS for patients with solitary brain metastasis.12 Patients with brain metastasis, whether diagnosed de novo or as distant relapse, are a heterogenous population with varying survival outcomes. The current study shows that in this cohort with de novo brain metastasis, prognostic factors associated with improved survival include younger age, limited extracranial disease, and no visceral involvement. Consistent with these findings, several studies of patients with brain relapse have similarly found the number of extracranial subsites, visceral involvement, and age to be significant factors associated with survival.11–15 Other studies have also identified performance status, number of brain metastasis, and systemic therapy use as additional prognostic factors for survival that may be used in individualizing therapeutic decisions.9–13,15,21,22 In the current study, patients diagnosed in the later time period from 2001 to 2005 were observed to have longer survival compared with the older era from 1996 to
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Breast Cancer With Synchronous Brain Metastasis
FIGURE 1. Kaplan-Meier overall survival according to: age (A); number of subsites of extracranial metastasis (B); year of diagnosis (C); and visceral involvement (D).
2000. Although it is difficult to attribute this difference to evolved treatment over time in our small cohort, similar trends in improved survival over time have been reported and attributed to advances in systemic therapy for women with metastatic disease.23 The Radiation Therapy Oncology Group Graded Prognostic Assessment has shown KPS, breast cancer subtype, and age to be prognostic factors for breast cancer patients with brain metastasis.24 The current study similarly identified age as an important prognostic factor but lacked subtype information in the current cohort. In the current series, approximately one third of patients underwent locoregional treatment of their primary breast tumor Copyright
r
with either surgery or radiation therapy, with nonsignificant trends toward longer observed survival. This finding is likely related to the selection of patients who were likely more fit or with more limited distant disease. Prospective trials are ongoing to examine the role of locoregional therapy with surgery or radiation therapy to the primary breast tumor in women with distant metastasis at initial breast cancer diagnosis. Although these trials vary in their inclusion/exclusion criteria with respect to brain metastasis, most trials generally require potential subjects to have an anticipated survival of at least 6 months.25–27 The current study provides populationbased outcomes data to support that selected women with brain
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metastasis at diagnosis may reasonably be considered for enrolment in such trials given their more favorable observed survival. Limitations of the current study include its retrospective design that is subject to inherent biases in patient and treatment selection. The small number of patients with the rare presentation of newly diagnosed breast cancer with synchronous brain metastasis also limits our ability to conduct robust multivariable analysis. Acknowledging these limitations, the study contributes outcomes information in a contemporary cohort treated in a universal access cancer care system with institutional treatment guidelines and availability of multidisciplinary conference to discuss management of individual cases. The findings suggest that even among women presenting with brain metastasis at initial breast cancer diagnosis, there are specific patient and disease characteristics that may be used to individualize treatment decisions.
11.
12. 13.
14. 15. 16.
CONCLUSIONS In this unique cohort of women presenting with brain metastasis at initial breast cancer diagnosis, not all patients have poor prognosis. A trend toward improved survival over time suggests that more modern treatment strategies may contribute to better outcomes in this cohort. Trends for longer survival were also observed in patients with young age, fewer than 2 sites of extracranial metastasis, and no visceral disease. These characteristics may be used to select candidates for more aggressive treatment or for enrolment into clinical trials.
17. 18. 19. 20.
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breast cancer brain metastasis. Zhonghua Wai Ke Za Zhi. 2013;1:30–34. Hart MG, Grant R, Walker M, et al. Surgical resection and whole brain radiation therapy versus whole brain radiation therapy alone for single brain metastases. Cochrane Database Syst Rev. 2011;3. Tsao MN, Lloyd N, Wong RK, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012;4. Gerdan L, Segedin B, Nagy V, et al. The number of involved extracranial organs: a new predictor of survival in breast cancer patients with brain metastasis. Clin Neurol Neurosurg. 2013;115: 2108–2110. Tarhan MO, Demir L, Somali I, et al. The clinicopathological evaluation of the breast cancer patients with brain metastases: predictors of survival. Clin Exp Metastasis. 2013;30:201–213. Jaboin JJ, Ferraro DJ, Dewees TA, et al. Survival following gamma knife radiosurgery for brain metastasis from breast cancer. Radiat Oncol. 2013;8:131–138. Dawood S, Broglio K, Ensor J, et al. Survival differences among women with de novo stage IV and relapsed breast cancer. Ann Oncol. 2010;21:2169–2174. Blanchard DK, Shetty PB, Hilsenbeck SG, et al. Association of surgery with improved survival in stage IV breast cancer patients. Ann Surg. 2008;247:732–738. Ravaioli A, Tassinari D, Pasini G, et al. Staging of breast cancer: what standards should be used in research and clinical practice? Ann Oncol. 1998;9:1173–1177. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–383. Gaspar LE, Scott C, Murray K, et al. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys. 2000;47: 1001–1006. Antoni D, Clavier JB, Pop M, et al. Institutional, retrospective analysis of 777 patients with brain metastases: treatment outcomes and diagnosis-specific prognostic factors. Int J Radiat Oncol Biol Phys. 2013;86:630–637. Anders CK, Deal AM, Miller CR, et al. The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases. Cancer. 2011;117:1602–1611. Chia SK, Speers CH, D’yachkova Y, et al. The impact of new chemotherapeutic and hormone agents on survival in a populationbased cohort of women with metastatic breast cancer. Cancer. 2007;110:973–979. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosisspecific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30:419–425. Eastern Cooperative Oncology Group (ECOG). A randomized phase III trial of the value of early local therapy for the intact primary tumor in patients with metastatic breast cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT01242800?term = Stage + IV + breast + cancer + early + surgery&rank = 1. Accessed February 17, 2014. Shien T, Nakamura K, Shibata T, et al. A randomized controlled trial comparing primary tumour resection plus systemic therapy with systemic therapy alone in metastatic breast cancer (PRIMBC): Japan Clinical Oncology Group Study JCOG1017. Jpn J Clin Oncol. 2012;42:970–973. Ruiterkamp J, Voogd AC, Tjan-Heijnen VC, et al. SUBMIT: systemic therapy with or without up front surgery of the primary tumor in breast cancer patients with distant metastases at initial presentation. BMC Surg. 2012;12:5–12.
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Population-based Analysis of Treatment and Survival in Women Presenting With Brain Metastasis at Initial Breast Cancer Diagnosis Bradley Wiksyk, BSc,* David H. Nguyen, MD,w Cheryl Alexander, CHIM,* and Pauline T. Truong, MD, CM*z
Purpose: Brain metastasis at initial breast cancer diagnosis is rare. This study aims to evaluate the clinical characteristics of these patients and identify prognostic and treatment factors associated with improved survival. Methods: Subjects were 35 women referred from 1996 to 2005 with newly diagnosed breast cancer with synchronous brain metastasis. Overall survival (OS) and brain progression-free survival were examined using Kaplan-Meier methods and compared between subgroups with different clinicopathologic and treatment characteristics using log-rank tests. Results: Median age was 65 years. Whole-brain radiotherapy (WBRT) alone was used in 25 patients, surgical resection and postoperative WBRT in 5 patients, and no or unknown treatment in 5 patients. Patients who underwent cranial resection were more likely to have solitary brain metastasis (P = 0.003) and no visceral involvement (P = 0.006). Overall, median OS was 6.8 months and median brain progression-free survival was 6.5 months (range, 0.7 to 54 mo). Median OS were 15 months with surgery and postoperative WBRT, 5 months with WBRT alone, and 3 months with no brain treatment. Longer OS was observed with age below 65 years versus 65 years and above (11 vs. 5 mo, P = 0.046), 0 to 1 versus Z2 sites of extracranial metastasis (10 vs. 3 mo, P = 0.047), and diagnosis from 2001 to 2005 versus 1996 to 2000 (10 vs. 3 mo, P = 0.018). A trend toward improved OS was observed in patients with no visceral involvement (11 vs. 4 mo, P = 0.09). Conclusions: In this unique cohort presenting with breast cancer and synchronous brain metastasis, longer survival were observed with young age, limited extracranial metastasis, and no visceral disease. These characteristics may be used to select candidates for more aggressive treatment. Key Words: breast cancer, brain metastasis, de novo stage IV breast cancer, treatment, survival
(Am J Clin Oncol 2016;39:255–260)
B
rain metastasis may develop in approximately 20% to 40% of all patients with breast cancer during the trajectory of their disease.1–3 The vast majority of these cases occur after an From the *Radiation Therapy Program, British Columbia Cancer Agency, Vancouver Island Centre, Victoria; zDepartment of Radiation Oncology, University of British Columbia, Vancouver, BC; and wDepartment of Radiation Oncology, Maisonneuve Rosemont Hospital, University of Montreal, Montreal, QC, Canada. The authors declare no conflicts of interest. Reprints: Pauline T. Truong, MD, CM, BC Cancer Agency, Vancouver Island Centre, 2410 Lee Avenue, Victoria, BC, Canada V8R 6V5. E-mail: [email protected]. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/16/3903-0255 DOI: 10.1097/COC.0000000000000055
American Journal of Clinical Oncology
initial diagnosis of primary breast cancer, representing systemic recurrence or distant disease dissemination. Brain metastasis is often associated with neurological symptoms and cognitive deficits that can adversely affect function and quality of life.3,4 The majority of patients have limited overall survival (OS),1,4–12 but prognostic factors have been identified in several studies including age, performance status, extent of intracranial and extracranial disease, and time interval between the initial breast cancer diagnosis and the development of brain metastasis.9–15 Although distant metastasis most often occurs as systemic recurrence or dissemination after an initial diagnosis of primary breast cancer, distant disease at the time of initial breast cancer diagnosis is less common, occurring in approximately 5% of all breast cancer cases.1,16,17 Within this population, a unique subset exists who present with brain metastasis at the time of initial diagnosis of breast cancer. There is a lack of study focusing on the characteristics and outcomes of these patients. This population-based study aims to evaluate the clinical characteristics, treatment, and outcomes of patients with newly diagnosed breast cancer with synchronous brain metastasis and to identify prognostic factors associated with improved survival in these subjects.
METHODS Study Cohort The British Columbia Cancer Agency is a Canadian cancer care institution providing universal access to its services throughout the province of British Columbia. Between January 1, 1996 and December 31, 2005, 22,592 women were referred with a new diagnosis of breast cancer. Of these, 733 (3.2%) women had clinical or pathologic stage IV or distant metastatic disease at diagnosis. Within this cohort, 35 patients with brain metastasis at the same time as or within 4 months from the initial diagnosis of primary breast cancer were identified, comprising the current study cohort. Initial brain metastasis and brain progression were confirmed with cranial computed tomography or magnetic resonance imaging. Brain imaging was not routinely performed as a part of staging workup in asymptomatic patients18 but was obtained only in patients with neurological signs or symptoms. Women whose brain metastasis were identified more than 4 months after the initial breast cancer diagnosis were excluded.
Study Variables Patient demographics, tumor, treatment, and outcomes data were abstracted from the BCCA Breast Cancer Outcomes Unit Database that prospectively records this information. Chart review was performed to obtain information regarding
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the characteristics of brain metastasis that were not available in the database. Patient and clinicopathologic characteristics of the primary breast disease analyzed were age at diagnosis, year of diagnosis (1996 to 2000 vs. 2001 to 2005), Karnofsky performance status (KPS), Charlson comorbidity index,19 T stage, N stage, histologic grade, estrogen receptor status, and human epidermal growth factor 2 status. Characteristics of the brain metastasis analyzed were neurological symptoms, number of brain lesions, size of the largest brain lesion, location of brain metastasis, presence of extracranial metastasis, sites of extracranial metastatic involvement (bone, soft tissue, or viscera), number of subsites of extracranial metastasis, and Radiation Therapy Oncology Group recursive partitioning analysis risk classification (class 1: KPSZ70, age 2 cm (89%) and neurological symptoms (100%). The number of brain lesions were 1 to 3 in 40%, >3 in 43%, and unknown in 17%. The size of the largest brain lesion was r3 cm in 69% of cases. Extracranial metastasis was present in 66% and visceral disease was present in 54% of the cases. Treatment of brain metastasis was surgical resection followed by WBRT in 5 patients, external beam WBRT alone in 25 patients, and no or unknown treatment in 5 patients. In patients receiving WBRT, the mean total dose was 20 Gy (range, 5 to 30 Gy) in 5 fractions (range, 1 to 10 fractions). Table 2 compares the characteristics of patients who underwent surgical resection of brain metastasis to those who underwent WBRT alone. Patients who underwent cranial resection were more likely to have solitary brain metastasis (P = 0.003) and no visceral involvement (P = 0.006). No patient in this cohort received stereotactic radiosurgery or gamma knife treatment. Systemic therapy used included chemotherapy in 20%, hormone therapy in 37%, both in 20%, and none in 23% of patients. Locoregional therapy with surgery or radiation therapy to the primary breast tumor was used in 31% of cases. In the study cohort, median OS was 6.8 months (range, 0.7 to 54 mo) and median time to brain progression was 6.5 months (range, 0.7 to 54 mo). Survival outcomes stratified by
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clinicopathologic and treatment characteristics are summarized in Table 1. The median OS times were 15 months with surgery, 5 months with WBRT, and 3 months with no brain treatment (P = 0.475). Longer OS was observed with age below 65 years versus 65 years of age and above (11 vs. 5 mo, P = 0.046; Fig. 1A), 0 to 1 versus Z2 sites of extracranial metastasis (10 vs. 3 mo, P = 0.047; Fig. 1B), and diagnosis from 2001 to 2005 versus 1996 to 2000 (10 vs. 3 mo, P = 0.018; Fig. 1C). A trend toward improved OS was observed in patients with no visceral involvement (11 vs. 4 mo, P = 0.09, Fig. 1D).
DISCUSSION The available data on the management of brain metastasis from breast cancer have been predominantly derived from patients in whom brain metastasis occurred as recurrent disease after the primary breast cancer diagnosis. There are few data examining the less common setting in which brain metastasis is detected at the initial diagnosis of breast cancer. The current population-based study confirmed that this presentation is rare, occurring in 3 Unknown P No. brain metastases 1 >1 Unknown P Size of largest brain lesion r3 cm > 3 cm Unknown P Location of brain metastases Parenchymal Leptomeningeal Unknown P Site(s) of extracranial metastatic Bone involvement Present
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Brain Disease Progression-free Survival
N (%)
Median (mo)
1-y KM Rates (%)
Median (mo)
1-y KM Rates (%)
35 (100)
6.8
31.4
6.5
20.0
8 (22.9) 27 (77.1)
3.0 10.4 0.018
12.5 37.0 0.018
3.0 7.2 0.031
0 25.9 0.031
17 (48.6) 18 (51.4)
10.5 5.3 0.046
41.2 22.2 0.046
7.2 3.9 0.148
29.4 7.4 0.148
16 (45.7) 16 (45.7) 3 (8.6)
2.6 8.7 13.1 0.162
18.8 37.5 66.7 0.162
2.6 6.6 13.1 0.128
12.5 18.8 66.7 0.128
27 (77.1) 8 (22.9)
7.7 4.6 0.457
29.6 37.5 0.457
6.6 4.6 0.551
18.5 15.0 0.551
3 (8.6) 31 (88.6) 1 (2.9)
4.6 7.7 1.2 0.688
33.3 32.3 0 0.688
4.6 6.6 1.2 0.980
33.3 19.4 0 0.980
22 (62.9) 9 (25.7) 4 (11.4)
8.7 5.3 1.2 0.067
40.9 22.2 0 0.067
7.2 3.0 1.2 0.105
22.7 22.2 0 0.105
13 (37.1) 13 (37.1) 9 (25.7)
8.7 4.6 10.5 0.191
38.5 15.4 44.4 0.191
7.2 3.5 10.5 0.237
23.1 7.7 33.3 0.237
11 (31.4) 18 (51.4) 6 (17.1)
7.7 5.3 10.5 0.582
27.3 27.8 50.0 0.582
4.6 4.6 10.5 0.300
27.3 11.1 33.3 0.300
6 (17.1) 9 (25.7) 20 (57.1)
11.6 8.7 3.1 0.781
50.0 22.2 30.0 0.781
6.6 7.5 3.1 0.948
33.3 22.2 15.0 0.948
14 (40.0) 15 (42.9) 6 (17.1)
10.4 5.3 8.7 0.809
42.9 26.7 16.7 0.809
6.6 3.9 7.5 0.856
21.4 20.0 16.7 0.856
11 (31.4) 18 (51.4) 6 (17.1)
11.6 5.3 8.7 0.685
45.5 27.8 16.7 0.685
6.6 3.9 7.5 0.741
27.3 16.7 16.7 0.741
24 (68.6) 3 (8.6) 8 (22.9)
4.6 7.7 10.5 0.715
29.2 33.3 37.5 0.715
4.6 3.9 10.5 0.878
12.5 33.3 37.5 0.878
29 (82.9) 5 (14.3) 1 (2.9)
6.5 10.5 3.1 0.744
34.5 20.0 0 0.744
4.6 10.5 3.1 0.532
20.7 20.0 0 0.532
involvement 17 (48.6)
3.0
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23.5
2.9
23.5
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Volume 39, Number 3, June 2016
TABLE 1. (continued) Overall Survival Characteristics
N (%)
Median (mo)
Absent 18 (51.4) P Soft tissue involvement Present 5 (14.3) Absent 30 (85.7) P Visceral Involvement Present 19 (54.3) Absent 16 (45.7) P No. subsites of extracranial metastasis 0-1 20 (57.1) Z2 15 (42.9) P RTOG RPA risk class 1 1 (2.9) 2 16 (45.7) 3 15 (42.9) Unknown 3 (8.6) P Systemic therapy use None 8 (22.9) Chemotherapy 7 (20.0) Hormone therapy 13 (37.1) Both 7 (20.0) P Use of locoregional therapy to the primary tumor Yes 11 (31.4) No 24 (68.6) P Brain treatment Surgery 5 (14.3) Whole-brain radiotherapy 25 (71.4) None 4 (11.4) Unknown 1 (2.9) P
Brain Disease Progression-free Survival
1-y KM Rates (%)
Median (mo)
1-y KM Rates (%)
8.7 0.383
38.9 0.383
7.2 0.590
16.7 0.590
10.5 5.3 0.777
40.0 30.0 0.777
8.3 4.6 0.914
20.0 20.0 0.914
3.5 11.1 0.090
21.1 43.8 0.090
3.0 7.2 0.236
21.1 18.8 0.236
10.4 3.0 0.047
40.0 20.0 0.047
7.2 2.9 0.123
20.0 20.0 0.123
13.9 7.7 3.0 13.1 0.514
100.0 31.3 20.0 66.7 0.514
13.1 6.4 2.6 13.1 0.370
100.0 12.5 13.3 66.7 0.370
4.6 6.5 2.6 13.4 0.375
25.0 28.6 23.1 57.1 0.375
4.6 6.5 2.6 11.8 0.273
12.5 14.3 15.4 42.9 0.273
11.6 3.5 0.240
45.5 25.0 0.240
7.2 3.1 0.292
27.3 16.7 0.292
14.7 5.3 3.1 11.6 0.475
80.0 28.0 21.7 0 0.475
11.8 4.6 3.1 6.6 0.489
40.0 20.0 0 0 0.489
*Test statistics applied to known values only. KM indicates Kaplan-Meier; RTOG RPA, Radiation Therapy Oncology Group Recursive Partitioning Analysis.
resection was used in only 5 subjects. Consistent with data from studies that report on cranial resection for brain metastasis,11 the current study also observed that patients with solitary metastasis and without visceral disease were significantly more likely to be treated with surgical resection. TABLE 2. Comparison of Clinicopathologic Characteristics Between Patients Treated With Surgery Plus WBRT Versus WBRT Alone
N (%) Surgery + WBRT WBRT Alone (n = 5) (n = 25) Median age (y) KPSZ70 Solitary brain lesion Size of largest brain lesion r3 cm No visceral involvement
P
67 3 (60.0) 5 (100.0) 4 (80.0)
63 10 (45.5) 5 (22.7) 19 (76.0)
0.542 0.648 0.003 0.367
5 (100.0)
7 (28.0)
0.006
KPS indicates Karnofsky performance status; WBRT, whole-brain radiation therapy.
Although no patient in our cohort underwent stereotactic radiosurgery as a component of brain metastasis treatment, a systematic review of 9 randomized controlled trials with 1420 patients reported that radiosurgery was not associated with improvement in OS among patients with multiple lesions, but that it may improve OS for patients with solitary brain metastasis.12 Patients with brain metastasis, whether diagnosed de novo or as distant relapse, are a heterogenous population with varying survival outcomes. The current study shows that in this cohort with de novo brain metastasis, prognostic factors associated with improved survival include younger age, limited extracranial disease, and no visceral involvement. Consistent with these findings, several studies of patients with brain relapse have similarly found the number of extracranial subsites, visceral involvement, and age to be significant factors associated with survival.11–15 Other studies have also identified performance status, number of brain metastasis, and systemic therapy use as additional prognostic factors for survival that may be used in individualizing therapeutic decisions.9–13,15,21,22 In the current study, patients diagnosed in the later time period from 2001 to 2005 were observed to have longer survival compared with the older era from 1996 to
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American Journal of Clinical Oncology
Volume 39, Number 3, June 2016
Breast Cancer With Synchronous Brain Metastasis
FIGURE 1. Kaplan-Meier overall survival according to: age (A); number of subsites of extracranial metastasis (B); year of diagnosis (C); and visceral involvement (D).
2000. Although it is difficult to attribute this difference to evolved treatment over time in our small cohort, similar trends in improved survival over time have been reported and attributed to advances in systemic therapy for women with metastatic disease.23 The Radiation Therapy Oncology Group Graded Prognostic Assessment has shown KPS, breast cancer subtype, and age to be prognostic factors for breast cancer patients with brain metastasis.24 The current study similarly identified age as an important prognostic factor but lacked subtype information in the current cohort. In the current series, approximately one third of patients underwent locoregional treatment of their primary breast tumor Copyright
r
with either surgery or radiation therapy, with nonsignificant trends toward longer observed survival. This finding is likely related to the selection of patients who were likely more fit or with more limited distant disease. Prospective trials are ongoing to examine the role of locoregional therapy with surgery or radiation therapy to the primary breast tumor in women with distant metastasis at initial breast cancer diagnosis. Although these trials vary in their inclusion/exclusion criteria with respect to brain metastasis, most trials generally require potential subjects to have an anticipated survival of at least 6 months.25–27 The current study provides populationbased outcomes data to support that selected women with brain
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metastasis at diagnosis may reasonably be considered for enrolment in such trials given their more favorable observed survival. Limitations of the current study include its retrospective design that is subject to inherent biases in patient and treatment selection. The small number of patients with the rare presentation of newly diagnosed breast cancer with synchronous brain metastasis also limits our ability to conduct robust multivariable analysis. Acknowledging these limitations, the study contributes outcomes information in a contemporary cohort treated in a universal access cancer care system with institutional treatment guidelines and availability of multidisciplinary conference to discuss management of individual cases. The findings suggest that even among women presenting with brain metastasis at initial breast cancer diagnosis, there are specific patient and disease characteristics that may be used to individualize treatment decisions.
11.
12. 13.
14. 15. 16.
CONCLUSIONS In this unique cohort of women presenting with brain metastasis at initial breast cancer diagnosis, not all patients have poor prognosis. A trend toward improved survival over time suggests that more modern treatment strategies may contribute to better outcomes in this cohort. Trends for longer survival were also observed in patients with young age, fewer than 2 sites of extracranial metastasis, and no visceral disease. These characteristics may be used to select candidates for more aggressive treatment or for enrolment into clinical trials.
17. 18. 19. 20.
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