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Central Nervous System Metastasis in Patients With HER2-Positive Metastatic Breast Cancer: Patient 1
Characteristics, Treatment, and Survival From SystHERs 2
Sara A Hurvitz1, Joyce O'Shaughnessy2, Ginny Mason3, Denise A Yardley4, Mohammad Jahanzeb5, Adam 3
Brufsky6, Hope S. Rugo7, Sandra M Swain8, Peter A Kaufman9, Debu Tripathy10, Laura Chu11, Haocheng 4
Li12, Vincent Antao11, Melody Cobleigh13 5
1David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Baylor 6
University Medical Center, Texas Oncology and US Oncology, Dallas, TX, USA; 3Inflammatory Breast 7
Cancer Research Foundation, West Lafayette, IN, USA; 4Breast Cancer Research Program, Sarah Cannon 8
Research Institute and Tennessee Oncology, Nashville, TN, USA; 5Sylvester Comprehensive Cancer 9
Center, University of Miami, Deerfield Campus, Deerfield Beach, FL, USA; 6University of Pittsburgh 10
Cancer Institute, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; 7Helen Diller Family 11
Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; 8Lombardi 12
Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA; 9Norris 13
Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 10The University of 14
Texas MD Anderson Cancer Center, Houston, Texas, USA; 11Genentech, Inc., South San Francisco, CA, 15
USA; 12F. Hoffmann-La Roche, Mississauga, ON, Canada; 13Department of Internal Medicine, Rush 16
University Medical Center, Chicago, IL, USA 17
18
Running title: CNS metastasis and HER2-positive MBC from SystHERs 19
20
Abbreviations: 21
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BMI, body mass index; CI, confidence interval; CNS, central nervous system; DFI, disease-free interval; 22
EBC, early breast cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ER, 23
estrogen receptor; FACT-B, Functional Assessment of Cancer Therapy-Breast; FACT-B TOI, FACT-B Trial 24
Outcome Index; IQR, interquartile range; HER2, human epidermal growth factor receptor 2; HR, hazard 25
ratio; MBC, metastatic breast cancer; MDASI-BT, MD Anderson Symptom Inventory–Brain Tumor 26
Module; NE, not estimable; OS, overall survival; PFS, progression-free survival; PR, progesterone 27
receptor; PRO, patient-reported outcome; RSC-ALS, Rotterdam Symptom Checklist–Activity Level Scale; 28
SystHERs, Systemic Therapies for HER2-positive Metastatic Breast Cancer Study; T-DM1, trastuzumab 29
emtansine. 30
31
Correspondence to: 32
Dr Sara A Hurvitz, Associate Professor of Medicine, David Geffen School of Medicine, University of 33
California Los Angeles, 10945 Le Conte Avenue, PVUB Suite 3360, Los Angeles, CA, 90095, USA 34
Telephone: 310-829-5471 35
E-mail: SHurvitz@mednet.ucla.edu 36
37
Financial support: The SystHERs study was funded by F. Hoffmann-La Roche/Genentech, Inc. 38
39
CONFLICTS OF INTEREST 40
SAH has received personal fees from F. Hoffmann-La Roche, Boehringer Ingelheim, Novartis, Lilly, Pfizer, 41
Bayer, Macrogenics, Daiichi Sankyo, Ambryx, Pieris, and Seattle Genetics. Her institution has received 42
research funding from F. Hoffmann-La Roche/Genentech, Novartis, GlaxoSmithKline, Boehringer 43
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Ingelheim, Sanofi, Pfizer, Amgen, OBI Pharma, Puma Biotechnology, Dignitana, Bayer, BioMarin, Lilly, 44
and Merrimack. 45
JO has received consulting fees from AstraZeneca, Lilly, Novartis, Pfizer, and F. Hoffmann-La 46
Roche/Genentech. 47
GM has participated in the Avon Foundation for Women Scientific Advisory Board. 48
DAY has received fees for services from Novartis and Genentech. Her institution has received research 49
funding from and F. Hoffmann-La Roche/Genentech and Novartis. 50
MJ has received consulting fees from F. Hoffmann-La Roche/Genentech and participated in the Data and 51
Safety Monitoring Board for Puma. 52
AB has received consulting fees and travel support from F. Hoffmann-La Roche/Genentech, Novartis, 53
Pfizer, Sandoz, AstraZeneca, Amgen, and Lilly. 54
HSR has received travel support from Merck, Mylan, Puma, Lilly, and Pfizer. Her institution has received 55
research funding from F. Hoffmann-La Roche/Genentech, Pfizer, Novartis, Lilly, OBI Pharma, 56
Macrogenics, and Merck. 57
SMS has received consulting fees from F. Hoffmann-La Roche/Genentech, Novartis, Pieris 58
Pharmaceuticals, Lilly, Daichi-Sanyo, and Inivata, and has received travel reimbursement from F. 59
Hoffmann-La Roche/Genentech, Caris, Lilly, and Daichi-Sanyo. Her institution has received research 60
funding from F. Hoffmann-La Roche/Genentech, Pfizer, Merrimack, and Lilly. 61
PAK has received consulting fees from F. Hoffmann-La Roche/Genentech. His institution has received 62
research funding from F. Hoffmann-La Roche/Genentech. 63
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DT has received personal fees from Pfizer and Novartis. His institution has received research funding 64
from Novartis. 65
LC, and VA are employees of, and own stock in, F. Hoffmann-La Roche/Genentech. 66
HL is an employee of F. Hoffmann-La Roche/Genentech. 67
MC has received fee reimbursement from F. Hoffmann-La Roche/Genentech. 68
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TRANSLATIONAL RELEVANCE 69
Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer 70
(MBC) and central nervous system (CNS) metastasis generally have a poor prognosis, but there are 71
limited data to describe treatments and clinical outcomes in this population since the introduction of 72
modern HER2-targeted therapies. SystHERs, a prospective, observational, US-based registry of 977 73
patients enrolled from 2012–2016, provided a unique opportunity to assess contemporary treatment 74
patterns and outcomes. We found disparities in first-line MBC treatment between patients with versus 75
without CNS metastasis at MBC diagnosis, and shorter median survival associated with CNS metastasis 76
at or after MBC diagnosis (30.2 and 38.3 months, respectively) versus no CNS metastasis (median not 77
reached). However, we observed that survival in all subgroups improved over the past decade. 78
Development of new HER2-targeted treatments, and optimization of treatment regimens and 79
management, may continue to improve outcomes in patients with HER2-positive MBC and CNS 80
metastasis. 81
82
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ABSTRACT 83
Background 84
Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer 85
(MBC) with central nervous system (CNS) metastasis have a poor prognosis. We report treatments and 86
outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for 87
HER2-positive Metastatic Breast Cancer Study (SystHERs). 88
Methods 89
SystHERs (NCT01615068) was a prospective, US-based, observational registry of patients with newly 90
diagnosed HER2-positive MBC. Study endpoints included treatment patterns, clinical outcomes, and 91
patient-reported outcomes (PROs). 92
Results 93
Among 977 eligible patients enrolled (2012–2016), CNS metastasis was observed in 87 (8.9%) at initial 94
MBC diagnosis and 212 (21.7%) after diagnosis, and was not observed in 678 (69.4%) patients. White 95
and younger patients, and those with recurrent MBC and hormone receptor–negative disease, had 96
higher risk of CNS metastasis. Patients with CNS metastasis at diagnosis received first-line lapatinib more 97
commonly (23.0% vs. 2.5%), and trastuzumab less commonly (70.1% vs. 92.8%), than patients without 98
CNS metastasis at diagnosis. Risk of death was higher with CNS metastasis observed at or after diagnosis 99
(median overall survival [OS] 30.2 and 38.3 months from MBC diagnosis, respectively) versus no CNS 100
metastasis (median OS not estimable; hazard ratio 2.86 [95% confidence interval 2.05–4.00] and 1.94 101
[95% confidence interval 1.52–2.49]). Patients with versus without CNS metastasis at diagnosis had 102
lower quality of life at enrollment. 103
Conclusions 104
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Despite advances in HER2-targeted treatments, patients with CNS metastasis continue to have a poor 105
prognosis and impaired quality of life. Observation of CNS metastasis appears to influence HER2-106
targeted treatment choice. 107
108
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INTRODUCTION 109
Human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) is 110
associated with a high incidence of central nervous system (CNS) metastasis,(1–6) a development 111
typically associated with poor survival and a negative impact on quality of life.(7) Diagnoses of CNS 112
metastasis have increased over time in patients with HER2-positive MBC, likely due to improved 113
detection and longer survival associated with the advent of HER2-targeted therapies over the past two 114
decades.(8) The first HER2-targeted treatment, trastuzumab, was approved in the United States in 1998. 115
An analysis of data from registHER, a prospective, observational study that enrolled patients with HER2-116
positive MBC, found that trastuzumab-based regimens were significantly associated with increased 117
overall survival (OS) in patients with CNS metastasis.(3) 118
In the time since registHER completed enrollment, several additional HER2-targeted therapies have 119
been approved for HER2-positive MBC in the US, including lapatinib, a small-molecule tyrosine kinase 120
inhibitor, in 2007; pertuzumab, a HER2-targeted antibody, in 2012; and trastuzumab emtansine (T-121
DM1), an antibody–drug conjugate, in 2013. On the basis of results from the pivotal phase III 122
CLEOPATRA trial,(9–11) the combination of pertuzumab with trastuzumab and a taxane became a 123
standard of care for the first-line treatment of HER2-positive MBC soon after the approval of 124
pertuzumab. In addition to significantly prolonging progression-free survival (PFS) and OS,(9–11) the 125
addition of pertuzumab (vs. placebo) to trastuzumab and docetaxel has been suggested to delay the 126
onset of CNS metastasis.(12) 127
Patients with CNS metastasis are commonly excluded from enrollment in clinical trials, providing an 128
incomplete understanding of its natural history and management in the real world. Hence, limited data 129
are available regarding the incidence, treatment, risk factors, and outcomes associated with CNS 130
metastasis in the era of modern HER2-targeted therapies. Furthermore, while guidelines for treatment 131
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have been developed based on the limited available data,(13) the level of guideline implementation is 132
unknown. 133
The Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) was a fully 134
enrolled, US-based, prospective, observational registry study designed to explore real-world treatment 135
patterns and outcomes in patients with recently diagnosed HER2-positive MBC. Here, we report baseline 136
characteristics and clinical outcomes in three key cohorts: patients with CNS metastasis observed at 137
initial MBC diagnosis, patients with CNS metastasis observed after MBC diagnosis, and patients with no 138
reported CNS metastasis by the data cutoff for this analysis. Additionally, systemic treatment patterns 139
and patient-reported outcomes (PROs) are presented in patient cohorts with versus without CNS 140
metastasis at MBC diagnosis. 141
142
MATERIALS AND METHODS 143
Study design and participants 144
SystHERs (NCT01615068) was a US-based, multicenter, prospective, observational cohort study. Patients 145
were recruited from academic sites (defined as those including one or more health profession schools 146
and with research, training, education, and clinical care functions) and community sites (typically 147
privately owned practices, including group practices, which do not have associated health profession 148
schools) and were treated and assessed in accordance with their treating physician’s standard practice. 149
The primary study endpoint was treatment patterns; secondary endpoints included clinical outcomes 150
and PROs. Additional study design details are available in the previously published study protocol.(14) 151
Eligible patients were ≥18 years old and within 6 months of HER2-positive MBC diagnosis at enrollment. 152
HER2-positivity was locally determined based on the status of the primary tumor or biopsy of 153
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recurrence, per the standards of the patients’ physicians and their institutions. Enrolled patients 154
provided written informed consent to use their medical records. The study was conducted in accordance 155
with US FDA regulations, the International Conference on Harmonisation E6 Guidelines for Good Clinical 156
Practice, the Declaration of Helsinki, and applicable local laws. Each participating study site obtained 157
approval of the study protocol by the site’s ethics committee or institutional review board. 158
Evaluations and follow-up 159
Baseline patient and disease characteristics, disease history, previous cancer-related treatment data, 160
and PROs were collected at enrollment. MBC treatments, disease progression, and clinical outcomes 161
were captured quarterly from patient charts, clinical notes, diagnostic tests, and laboratory findings; 162
PROs were reported quarterly by patients. Metastatic sites were identified at MBC diagnosis and on 163
study by treating physicians; screening for CNS metastasis was not required and was based on each 164
physician’s standard clinical practices. Patients who discontinued the study had the option to participate 165
in quarterly survival follow-up. 166
PRO measurements quantified in this study included Functional Assessment of Cancer Therapy-Breast 167
(FACT-B, a sum of five subscales measuring physical, social, emotional, functional, and breast cancer–168
related well-being on an overall scale of 0–148),(15) FACT-B Trial Outcome Index (FACT-B TOI; a sum of 169
the FACT-B physical, functional, and breast subscales on a scale of 0–96), Rotterdam Symptom 170
Checklist–Activity Level Scale (RSC-ALS; measuring the impact of cancer on activities of daily living on a 171
scale of 0–100),(16) and the MD Anderson Symptom Inventory–Brain Tumor Module (MDASI-BT, 172
measuring brain tumor-related symptom severity and impact on cognitive function [scale of 0–10] and 173
interference in daily life [scale of 0–10]).(17) 174
Analyses and statistical methods 175
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Patient characteristics were tabulated by cohorts defined by CNS metastasis observed at initial MBC 176
diagnosis, CNS metastasis observed after MBC diagnosis, or no CNS metastasis over the study follow-up 177
period. Calculation of p-values comparing baseline characteristics between these cohorts were 178
performed using Fisher's exact test for categorical variables and the Kruskal-Wallis non-parametric test 179
for continuous variables. 180
Multivariate and univariate logistic regression was also used to examine the association of baseline 181
demographic and clinical characteristics in patients with CNS metastasis at any time versus those 182
without CNS metastasis. A forest plot was prepared to present adjusted odds ratios and their 95% 183
confidence intervals (CI) for a multivariate analysis of six variables selected on the basis of clinical 184
significance (ethnicity, race, age, ECOG status, MBC diagnosis type, and hormone receptor status). The 185
other multivariate regression and a univariate logistic regression were carried out based on the wider 186
collection of baseline characteristics presented in this report, with the exception of “duration from EBC 187
diagnosis to MBC diagnosis” (as this variable is only applicable to patients with recurrent disease). The 188
multivariate logistic regression analysis included all covariates in one regression model, and the 189
univariate logistic regression considered each variable in the regression model separately. 190
First-line treatment, defined as any therapy received for MBC up to first disease progression, was 191
analyzed in patients with versus without CNS metastasis at MBC diagnosis. Treatments administered to 192
patients with CNS metastasis observed after diagnosis were also summarized before versus after the 193
detection of CNS lesions, regardless of line of treatment. 194
PRO scores at enrollment were compared between patients with versus without CNS metastasis at MBC 195
diagnosis. P-values comparing baseline PRO scores between these groups were calculated using the 196
Wilcoxon rank-sum non-parametric test. 197
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Median follow-up was calculated as the median observation time in each CNS cohort and overall. PFS 198
was defined as the time from MBC diagnosis to first investigator-assessed disease progression or death, 199
whichever came first. OS was defined as the time from MBC diagnosis to death. PFS and OS were 200
estimated by the Kaplan–Meier product-limit method and compared across cohorts using a log-rank 201
test. Cox regressions were used to estimate hazard ratios (HRs) and their 95% CI. 202
203
RESULTS 204
Patients 205
Out of a total of 1028 patients who met the SystHERs study inclusion criteria, 1005 patients were 206
enrolled between June 2012 and June 2016. There were 23 refusals among patients meeting inclusion 207
criteria over the 4-year enrollment period. Among 977 eligible patients enrolled from 135 study sites, 208
197 (20.2%) were from a total of 17 academic centers and 780 (79.8%) were from a total of 118 209
community centers. The remaining 28 patients did not meet eligibility criteria, most commonly due to 210
lack of distant metastatic disease upon review. Eighty-seven patients (8.9%) had CNS metastasis 211
reported at initial MBC diagnosis, 212 (21.7%) had CNS metastasis detected after MBC diagnosis, and 212
678 (69.4%) had no observed CNS metastasis as of the October 3, 2017 data cutoff date. Median follow-213
up duration was 27.8 months from MBC diagnosis for all patients, and 21.0, 29.6, and 27.9 months in 214
patients with CNS metastasis at diagnosis, CNS metastasis after diagnosis, and no observed CNS 215
metastasis, respectively. Patients alive and remaining on study at data cutoff included 35.6% (31/87), 216
43.4% (92/212), and 59.6% (404/678) in the respective cohorts. 217
Of the 977 patients in the overall population, median age was 56 years at MBC diagnosis. Most patients 218
were white (78.4% [n=766]) and non-Hispanic (86.5% [n=845]), and had a body-mass index <30 (59.5% 219
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[n=581]), ECOG performance status of 0 or 1 (84.4% [n=825]), hormone receptor–positive disease 220
(70.1% [n=685]), and <3 metastatic sites (69.1% [n=675]) (Table 1, Supplemental Table 1). CNS 221
metastasis was detected at MBC diagnosis in 4.3% (21/487) and 13.5% (66/490) of patients with de novo 222
and recurrent MBC, respectively. Patients with CNS metastasis at or after diagnosis had hormone 223
receptor–negative disease more commonly than those with no CNS metastasis (34.5% [30/87] and 224
38.7% [82/212] vs. 26.5% [180/678]) (Table 1). 225
Of 87 patients with CNS metastasis at MBC diagnosis, 28 (32.2%) had CNS-only metastasis, and 59 226
(67.8%) had both CNS and non-CNS metastasis. Bone and liver metastasis at MBC diagnosis were 227
observed less frequently in patients with CNS metastasis at diagnosis (bone: 40.2% [35/87]; liver: 20.7% 228
[18/87]) versus patients with CNS metastasis observed after diagnosis (bone: 56.6% [120/212]; liver: 229
50.5% [107/212]) and those without CNS metastasis at data cutoff (bone: 51.3% [348/678]; liver: 35.5% 230
[241/678]), while lung metastasis was observed more commonly in patients with CNS metastasis at or 231
after diagnosis (36.8% [32/87] and 38.7% [82/212], respectively) versus those without CNS metastasis 232
(28.9% [196/678]) (Supplemental Fig. 1). 233
Of patients with recurrent disease and available treatment data for early breast cancer (EBC, n=430), the 234
majority of patients in all three cohorts received neoadjuvant and/or adjuvant trastuzumab (CNS 235
metastasis at MBC diagnosis: 80.0% [48/60]; CNS metastasis after MBC diagnosis: 68.4% [65/95]; no CNS 236
metastasis: 61.8% [170/275]) (Supplemental Fig. 2). Of note, among the 318 patients with known HER2 237
status in both primary (EBC) and metastatic tissue in the SystHERs study, 15.7% (50/318) had HER2-238
negative primary tumors, and 12.3% (39/318) had HER2-equivocal primary tumors. As such, these 239
patients are not likely to have received (neo)adjuvant HER2-targeted treatment. 240
Association between baseline characteristics and risk of CNS metastasis 241
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We performed a multivariate logistic analysis of baseline characteristics selected based on their clinical 242
importance to identify risk factors associated with the development of CNS metastasis at any time. Of 243
these characteristics, younger age showed the strongest association with CNS metastasis (odds ratio 244
[OR] 3.128, 95% CI 1.852–5.284 for patients <50 vs. ≥70 years old) (Fig. 1). Other characteristics 245
associated with CNS metastasis included white race (OR 1.619, 95% CI 1.072–2.444 vs. black/African 246
American race), ECOG status ≥2 (OR 1.900, 95% CI 1.125–3.210 vs. ECOG status of 0), recurrent MBC (OR 247
1.650, 95% CI 1.239–2.196 vs. de novo MBC), and hormone receptor–negative status (OR 1.841, 95% CI 248
1.359–2.494 vs. hormone receptor–positive status). Multivariate and univariate logistic regression 249
analyses considering all baseline characteristics shown in Table 1 (with the exception of “duration from 250
EBC diagnosis to MBC diagnosis”, as this variable is only applicable to patients with recurrent disease) 251
produced similar conclusions (Supplemental Table 2). 252
Treatment patterns 253
Among patients with CNS metastases at MBC diagnosis, 80.5% (70/87) received brain radiotherapy 254
(local, n=35; whole brain, n=52) and 44.8% (39/87) received brain surgery, including 10 patients who 255
received surgery without radiotherapy (Supplemental Table 3). In patients with CNS metastasis observed 256
after MBC diagnosis, 79.2% (168/212) and 20.8% (44/212) had received brain radiotherapy (local, n=60; 257
whole brain, n=131) and brain surgery by data cutoff, respectively, including eight patients who received 258
surgery without radiotherapy. 259
At data cutoff, 97.0% of all patients (948/977) had received first-line systemic treatment for MBC, 260
including 88.5% (77/87) of those with CNS metastasis at MBC diagnosis (of whom nine patients were still 261
in first-line treatment) and 97.9% (871/890) of those without CNS metastasis at diagnosis (of whom 217 262
were still in first-line treatment). The most common first-line HER2-targeted agent was trastuzumab, 263
although it was administered less frequently to patients with CNS metastasis at diagnosis (70.1% 264
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[61/87]) compared with patients without CNS metastasis at diagnosis (92.8% [826/890]) (Table 2). 265
Trastuzumab was used in combination with pertuzumab in 52.9% (46/87) of patients with and 74.8% 266
(666/890) of patients without CNS metastasis at diagnosis. The most common first-line treatment 267
regimen was trastuzumab + pertuzumab + taxane, with or without hormonal therapy, administered to 268
48.3% (42/87) and 68.3% (608/890) of patients with and without CNS metastasis at diagnosis, 269
respectively (Supplemental Table 4). 270
First-line lapatinib was administered to a higher proportion of patients with CNS metastasis at diagnosis 271
(23.0% [20/87], of whom 11 patients received lapatinib + trastuzumab) compared with patients without 272
CNS metastases at diagnosis (2.5% [22/890], of whom 12 patients received lapatinib + trastuzumab) 273
(Table 2, Supplemental Fig. 3). Patients with CNS-only metastasis at MBC diagnosis received regimens 274
with lapatinib more commonly, and regimens with trastuzumab + pertuzumab less commonly, than 275
those with CNS and non-CNS metastasis at diagnosis (lapatinib: 35.7% [10/28] vs. 16.9% [10/59], 276
respectively; trastuzumab + pertuzumab: 17.9% [5/28] vs. 69.5% [41/59]) (Supplemental Table 5). 277
Among patients with CNS metastasis at diagnosis (both CNS-only and CNS and non-CNS), patients who 278
received radiotherapy also received regimens containing lapatinib or trastuzumab + pertuzumab more 279
commonly compared with the small group of patients who did not receive radiotherapy (lapatinib: 280
27.1% [19/70] vs. 5.9% [1/17], respectively; trastuzumab + pertuzumab: 55.7% [39/70] vs. 41.2% [7/17]). 281
In patients with CNS metastasis observed after MBC diagnosis, treatment data were available for 211 282
patients prior to the detection of CNS lesions and 128 patients following diagnosis of CNS metastasis. 283
Similar to observations in patients with CNS metastasis at MBC diagnosis, administration of lapatinib in 284
any line was more common following the detection of CNS lesions (prior to CNS metastasis: 6.2% 285
[13/211], of whom 12 patients also received trastuzumab; following CNS metastasis: 34.4% [44/128], of 286
whom 18 patients also received trastuzumab) (Supplemental Fig. 4). T-DM1 was administered to 26.1% 287
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(55/211) and 51.6% (66/128) of patients before versus after the diagnosis of CNS metastasis, 288
respectively. 289
Patient-reported outcomes 290
PRO questionnaire completion rates at enrollment were 79.4% (776/977) for FACT-B,(15) 79.6% 291
(778/977) for FACT-B TOI, 80.3% (785/977) for RSC-ALS, 77.3% (755/977) for MDASI-BT: cognitive 292
symptoms, and 77.1% (753/977) for MDASI-BT: interference in daily life. Rates of completion were 293
similar between CNS cohorts. Patients with CNS metastases at MBC diagnosis reported lower quality of 294
life at enrollment compared with patients without CNS metastasis at diagnosis, as measured by FACT-B 295
(median score 94.5 vs. 103.5 out of a possible 148, p=0.002) and FACT-B TOI (median score 56.5 vs. 62.0 296
out of 96, p=0.009) (Supplemental Fig. 5A, 5B). Greater impairment in daily activities was also observed 297
in the cohort with CNS metastases at diagnosis (versus without CNS metastases at diagnosis) per RSC-298
ALS (median score 77.1 vs. 87.5 out of 100, p=0.002), as well as greater severity of cognitive dysfunction 299
per MDASI-BT (cognitive symptoms, median score 2.3 vs. 0.8 out of 10, p<0.001; brain tumor-related 300
interference in daily life, median score 3.9 vs. 2.0 out of 10, p=0.004) (Supplemental Fig. 5C–5E). 301
Clinical outcomes 302
Estimated median first-line PFS and OS from MBC diagnosis were markedly shorter in patients with CNS 303
metastases at any time compared with patients with no CNS metastasis (Fig. 2). Median PFS was 9.2, 304
9.9, and 19.1 months in patient cohorts with CNS metastasis at diagnosis, CNS metastasis observed after 305
diagnosis, and no CNS metastasis, respectively. By the data cutoff date, 50.6% (44/87), 49.5% (105/212), 306
and 23.6% (160/678) patients in each cohort had died, respectively. Median OS was 30.2 months (HR 307
2.86, 95% CI 2.05–4.00, p<0.0001) in patients with CNS metastasis at diagnosis, 38.3 months (HR 1.94, 308
95% CI 1.52–2.49, p<0.0001) in patients with CNS metastasis observed after diagnosis, and was not yet 309
estimable in patients with no CNS metastasis. 310
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Patients with CNS-only metastasis at MBC diagnosis (n=28) had a median PFS of 9.2 months and median 311
OS of 20.1 months from MBC diagnosis. In patients with CNS metastasis observed after MBC diagnosis, 312
median time to diagnosis of CNS metastasis was 15.1 (95% CI 13.7–16.6) months. 313
Among patients with CNS-only metastasis at diagnosis, 46.4% (13/28) had CNS-only progression at their 314
next progression event, 10.7% (3/28) had non-CNS progression, and no patients had both CNS and non-315
CNS progression. In the 59 patients with both CNS and non-CNS metastasis at MBC diagnosis, 33.9% 316
(20/59) had CNS-only progression at their next progression event, 35.6% (21/59) had non-CNS 317
progression, and 5.1% (3/59) had both CNS and non-CNS progression. In each group, respectively, 42.9% 318
(12/28) and 25.4% (15/59) of patients did not have a progression event by the time of data cutoff, 319
whether due to death, loss of follow-up, or study closure. 320
321
DISCUSSION 322
In this real-world analysis of patients with HER2-positive MBC from the SystHERs study, we found that 323
development of CNS metastasis was associated with race, age, hormone receptor status, and MBC 324
diagnosis type. Patients with CNS metastasis at MBC diagnosis reported poorer quality of life at 325
enrollment, and received first-line lapatinib more commonly and first-line trastuzumab less commonly, 326
than patients with CNS metastasis observed after diagnosis or those with no CNS metastasis while on 327
study. Of the three CNS metastasis cohorts, prognosis was poorest in patients with CNS metastasis at 328
diagnosis and most favorable in patients without CNS metastasis. 329
Breast cancer is associated with a high incidence of CNS metastasis, a risk that rises significantly in 330
patients with HER2-positive disease.(1–6) Other previously identified risk factors included high tumor 331
grade or disease burden, hormone receptor–negative MBC, and younger age.(3,18) Routine magnetic 332
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resonance imaging for CNS metastasis is currently not recommended in the absence of suggestive 333
symptoms,(13) limiting our ability to assess whether early detection and treatment of asymptomatic 334
CNS disease improves outcomes. In a multivariate analysis of SystHERs data, we found CNS metastasis 335
was more common in white and younger patients, and in those with recurrent MBC and hormone 336
receptor–negative disease. Data from SystHERs and other studies may help identify a particularly high-337
risk cohort of patients for further study. 338
Due to the presumed inability of certain pharmacologic treatments to cross the blood–brain barrier and 339
limited historical data regarding the efficacy of these therapies against CNS lesions, management of CNS 340
metastasis has typically involved the use of local treatments, including surgery and whole-brain or 341
stereotactic radiotherapy. However, optimizing control of systemic disease is needed to prolong 342
survival. As such, ASCO guidelines for patients with HER2-positive MBC and CNS metastasis recommend 343
that in addition to local treatments, patients with progressive disease should receive systemic therapy 344
according to standard algorithms for HER2-positive MBC.(13) In this analysis, we found that only 48.3% 345
of patients with CNS metastasis at MBC diagnosis were treated with the first-line standard of care, 346
trastuzumab + pertuzumab + taxane, compared with 68.3% of patients without CNS metastasis at 347
diagnosis, although part of this disparity could potentially be attributed to differences in CNS-348
independent baseline characteristics between the two groups. Patients with CNS metastasis at diagnosis 349
preferentially received first-line regimens containing lapatinib (23.0% vs. 2.5% of patients without CNS 350
metastasis at diagnosis), presumably due to evidence that lapatinib may have activity in the CNS. A 351
meta-analysis of patients with HER2-positive breast cancer and brain metastasis treated with lapatinib ± 352
capecitabine indicated an overall response rate of 21.4% in the CNS, which increased to 29.2% when 353
lapatinib monotherapy was excluded.(19) In the phase II LANDSCAPE study, lapatinib + capecitabine 354
demonstrated a volumetric response rate of 65.9% against CNS lesions, although the regimen was 355
associated with a high rate of grade 3 and 4 toxicities.(20) However, a retrospective analysis of data 356
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from the phase III EMILIA trial showed significantly improved OS in patients with MBC and brain 357
metastasis treated with T-DM1 versus lapatinib + capecitabine.(21) Furthermore, a study by Gelmon et 358
al. indicated that first-line lapatinib + taxane is associated with lower PFS than trastuzumab + 359
taxane.(22) It is possible that the use of lapatinib-based first-line treatment regimens in patients with 360
CNS metastasis at MBC diagnosis, at the possible expense of targeting systemic disease, may contribute 361
to the poorer outcomes observed in that cohort. The use of first-line regimens containing lapatinib 362
versus other HER2-targeted treatments should be further examined in randomized clinical trials to 363
assess their overall impact on survival in patients with CNS metastasis at diagnosis. 364
Accumulating preclinical and clinical evidence suggest that other HER2-targeted therapies can also 365
penetrate the blood–brain barrier and delay or ameliorate CNS metastasis in patients with MBC.(12,23–366
30) Preliminary results from the phase III CEREBEL study found that patients receiving lapatinib + 367
capecitabine versus trastuzumab + capecitabine had similar incidences of CNS metastases as first 368
detected site of relapse (3% vs. 5%, respectively), with longer PFS and OS in the trastuzumab + 369
capecitabine arm.(28) In the phase 3 CLEOPATRA trial, the addition of pertuzumab to first-line 370
trastuzumab + docetaxel delayed observations of CNS metastasis as the first site of disease progression, 371
from 11.9 months in the placebo arm to 15.0 months in the pertuzumab arm.(12) Preliminary evidence 372
from the ongoing phase III KAMILLA and phase II PATRICIA studies suggest that T-DM1 and pertuzumab 373
+ high-dose trastuzumab, respectively, have activity against CNS lesions.(26,27) Finally, tucatinib, an 374
investigational small-molecule HER2 inhibitor, has demonstrated promising CNS activity (29,30) and has 375
been granted US FDA orphan drug status for patients with HER2-positive MBC with CNS metastasis. Data 376
from these and other studies (31,32) may help identify therapeutic regimens that optimize the 377
treatment of both CNS and extracranial lesions to improve OS in patients with CNS metastasis. 378
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CNS metastasis in patients with breast cancer has historically been associated with decreased quality of 379
life and a poor prognosis.(7) As management of MBC is often considered palliative, PRO-assessed quality 380
of life is an important consideration in this population. In this study, PRO measures captured at 381
enrollment suggested that patients with CNS metastases at MBC diagnosis may carry a greater disease 382
burden than those without CNS metastasis at diagnosis. Patients with CNS metastases at MBC diagnosis 383
reported poorer quality of life and higher impairment in functional measures of cognition and daily 384
activities, although these measures may reflect composite effects of disease and treatments initiated 385
prior to enrollment. Furthermore, patients with CNS metastasis at or after MBC diagnosis had markedly 386
shorter median PFS (9.2 and 9.9 months, respectively) and median OS (30.2 and 38.3 months, 387
respectively) compared with patients who did not develop CNS metastasis on study (median PFS, 19.1 388
months; median OS, not yet estimable). 389
Despite these differences, OS observed in patients with CNS metastasis notably exceeds that reported 390
prior to the approval of lapatinib, pertuzumab, and T-DM1: in registHER, which enrolled patients from 391
2003 to 2006, patients with CNS metastasis at MBC diagnosis had a median OS of 20.3 months.(3) In 392
patients with CNS metastasis observed after MBC diagnosis, median time to diagnosis of CNS metastasis 393
was 15.1 months in SystHERs versus 13.3 months in registHER after similar follow-up durations for both 394
studies.(3) Data from both registHER and SystHERs represent substantial improvements in clinical 395
outcomes relative to the pre-trastuzumab era, when median survival following brain metastasis was 396
only four months.(33) Among other variables, future studies should assess the contribution of different 397
systemic treatments (e.g., regimens including trastuzumab + pertuzumab vs. lapatinib) on PROs and 398
clinical outcomes in patients with CNS metastasis. 399
In the SystHERs study, CNS metastasis at MBC diagnosis was observed in 8.9% of patients. With a 400
median follow-up of 27.8 months from MBC diagnosis in SystHERs, CNS metastasis was detected in an 401
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additional 21.7% of patients (i.e., a total of 30.6% of patients with CNS metastasis). Of note, this number 402
would be expected to increase with longer follow-up. Additionally, screening for CNS metastasis in 403
SystHERs was not required at enrollment, and was conducted at the investigator’s discretion. As 404
previous studies have suggested a high incidence of asymptomatic, occult CNS lesions in patients with 405
breast cancer,(34) the reported prevalence of CNS metastasis in SystHERs may be underestimated due 406
to undetected CNS disease. Our analysis was also constrained by limitations inherent to registry studies. 407
For example, because EBC data were collected retrospectively, some data were missing, and 408
prospectively collected data may have been impacted by attrition or reporting bias. Finally, similar to the 409
methodological caveats common to other reports of real-world studies, clinical response data were 410
based on investigator assessments with variable assessment intervals across patients in accordance with 411
institutional practice norms, which may be less reliable than standardized criteria used in randomized 412
clinical trials. 413
In summary, data from the SystHERs registry study suggest that while patients with CNS metastasis 414
continue to experience lower quality of life and a poorer prognosis than patients without CNS 415
metastasis, key clinical outcomes, including time to CNS progression and OS, have improved in this 416
population over time. Recent interest in the use of HER2-targeted therapies against CNS lesions, along 417
with promising preliminary results from the LANDSCAPE, KAMILLA, PATRICIA, and other studies, may 418
lead to further improvements in the treatment, management, and prognosis of patients with HER2-419
positive MBC and CNS metastasis. 420
421
ACKNOWLEDGMENTS 422
The authors are grateful to the patients, families, and investigators who participated in SystHERs. We 423
would also like to thank Musa Mayer for her work as part of the SystHERs steering committee; the 424
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22
SystHERs team, including clinical operations leads Michelle Usher (F. Hoffmann-La Roche/Genentech, 425
Inc.) and Sandy Lam (F. Hoffmann-La Roche/Genentech, Inc.); Bongin Yoo (F. Hoffmann-La 426
Roche/Genentech, Inc.) for his contributions to the statistical analysis and manuscript review; Allen Lee 427
(Everest Clinical Research Services, Inc.) for his assistance with the statistical analysis; Bokai Xia (F. 428
Hoffmann-La Roche/Genentech, Inc.) for his statistical programming expertise; and Susan Mathias and 429
Ross Crosby (Health Outcomes Solutions) for their analysis of patient-reported outcomes. Support for 430
third-party writing assistance was provided by Sabrina Hom, PhD, of CodonMedical, an Ashfield 431
Company, part of UDG Healthcare plc, and funded by F. Hoffmann-La Roche/Genentech, Inc. F. 432
Hoffmann-La Roche/Genentech, Inc. funded the SystHERs study and participated in the study design, 433
data collection, data analysis, data interpretation, and writing of this report. 434
435
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Table 1. Baseline demographics, patient characteristics, and disease characteristics 544
All eligible
patients (n=977)
CNS
metastasis
at diagnosis
(n=87)
CNS
metastasis
after
diagnosis
(n=212)
No CNS
metastasis
(n=678)
P-value
Demographics
Median age at MBC diagnosis,
years (range) 56 (21–90) 57 (34–86) 53 (27–89) 57 (21–90) <0.001
Ethnicity, n (%)
Hispanic or Latino
Not Hispanic or Latino
Not reported/unknown
94 (9.6)
845 (86.5)
38 (3.9)
10 (11.5)
74 (85.1) 3 (3.4)
16 (7.5)
186 (87.7)
10 (4.7)
68 (10.0)
585 (86.3)
25 (3.7)
0.490
Race, n (%)
White
Black or African American
Asian
Other
Not reported/unknown
766 (78.4)
151 (15.5)
13 (1.3)
29 (3.0)
18 (1.8)
71 (81.6)
9 (10.3)
1 (1.1)
5 (5.7)
1 (1.1)
175 (82.5)
29 (13.7)
1 (0.5)
6 (2.8)
1 (0.5)
520 (76.7)
113 (16.7)
11 (1.6)
18 (2.7)
16 (2.4)
0.288
Insurance status, n (%) Private Public Both None Missing
372 (38.1) 201 (20.6) 115 (11.8)
36 (3.7) 253 (25.9)
30 (34.5) 13 (14.9)
7 (8.0) 3 (3.4)
34 (39.1)
96 (45.3) 38 (17.9) 17 (8.0) 10 (4.7)
51 (24.1)
246 (36.3) 150 (22.1) 91 (13.4) 23 (3.4)
168 (24.8)
0.103
Patient characteristics
BMI, n (%)
<30
≥30
Missing
581 (59.5)
385 (39.4)
11 (1.1)
48 (55.2)
38 (43.7)
1 (1.1)
137 (64.6)
75 (35.4)
0
396 (58.4)
272 (40.1)
10 (1.5)
0.265
ECOG PS, n (%)
0
1
2
3
Unknown/missing
460 (47.1)
365 (37.4)
67 (6.9)
8 (0.8)
77 (7.9)
26 (29.9)
34 (39.1)
15 (17.2)
5 (5.7)
7 (8.0)
106 (50.0)
82 (38.7)
11 (5.2)
0
13 (6.1)
328 (48.4)
249 (36.7)
41 (6.0)
3 (0.4)
57 (8.4)
<0.001
Disease characteristics
MBC diagnosis typea, n (%)
De novo
Recurrent
487 (49.8)
490 (50.2)
21 (24.1)
66 (75.9)
107 (50.5)
105 (49.5)
359 (52.9)
319 (47.1)
<0.001
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Median duration from EBC
diagnosis to MBC diagnosisb,
months (range)
n=487
42.8 (4–452)
n=66
39.9 (12–
332)
n=105
40.4 (5–
369)
n=316
48.7 (4–
452)
0.063
Hormone receptor status, n (%)
ER- and/or PR-positive
ER- and PR-negative
685 (70.1)
292 (29.9)
57 (65.5)
30 (34.5)
130 (61.3)
82 (38.7)
498 (73.5)
180 (26.5)
0.002
Visceral diseasec, n (%) 603 (61.7) 41 (47.1) 160 (75.5) 402 (59.3) <0.001
Number of metastatic sites at
diagnosis, n (%)
1
2
≥3
417 (42.7)
258 (26.4)
302 (30.9)
28 (32.2)
14 (16.1)
45 (51.7)
72 (34.0)
54 (25.5)
86 (40.6)
317 (46.8)
190 (28.0)
171 (25.2)
<0.001
aRecurrent (as opposed to de novo) MBC indicates >90 days between EBC and MBC diagnoses. 545
bIn patients with recurrent disease. 546
cIncludes non-hepatic abdominal, ascites, liver, lung or pleural effusion sites of metastasis (excludes CNS). 547
Abbreviations: BMI, body mass index; CNS, central nervous system; DFI, disease-free interval; EBC, early breast 548
cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ER, estrogen receptor; IQR, 549
interquartile range; MBC, metastatic breast cancer; PR, progesterone receptor. 550
551
552
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30
Table 2. First-line HER2-targeted therapy by CNS metastasis cohort 553
HER2-targeted therapya by patients with any first-line exposure, n (%)
CNS metastasis at
diagnosis (n=87)
No CNS metastasis at
diagnosis (n=890)
Trastuzumab With chemotherapy
With hormonal therapy
61 (70.1) 55 (63.2) 20 (23.0)
826 (92.8) 738 (82.9) 360 (40.4)
Trastuzumab + pertuzumab
With chemotherapy
With hormonal therapy
46 (52.9)
45 (51.7)
13 (14.9)
666 (74.8) 630 (70.8) 272 (30.6)
Trastuzumab without pertuzumab
With chemotherapy
With hormonal therapy
15 (17.2) 10 (11.5)
7 (8.0)
160 (18.0) 108 (12.1)
88 (9.9)
Lapatinib
With chemotherapy
With hormonal therapy
20 (23.0) 14 (16.1)
7 (8.0)
22 (2.5) 18 (2.0) 8 (0.9)
Lapatinib + trastuzumab 11 (12.6) 12 (1.3) T-DM1 10 (11.5) 61 (6.9)
aTreatments are not mutually exclusive. 554
Abbreviations: CNS, central nervous system; HER2, human epidermal growth factor receptor 2; T-DM1, 555
trastuzumab emtansine. 556
557
558
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31
FIGURE LEGENDS 559
Figure 1. Multivariate analysis of selected baseline characteristics and risk of CNS metastasis at any 560
time 561
CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group Performance Status; MBC, metastatic 562
breast cancer. 563
564
565
Figure 2. (A) Progression-free survival and (B) overall survival by CNS metastasis cohort 566
CI, confidence interval; CNS, central nervous system; MBC, metastatic breast cancer; NE, not estimable; OS, overall 567
survival; PFS, progression-free survival. 568
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Ethnicity Not Hispanic/La�no vs. Hispanic/La�no 1.181 (0.718–1.943)
Odds ra�o (95% CI)
0 1 2 3 4 5
Higher risk of CNS metastasisLower risk of CNS metastasis
Figure 1
Age at MBC diagnosis 50–69 vs. ≥70 <50 vs. ≥70
2.042 (1.248–3.341)3.128 (1.852–5.284)
Race Others vs. Black/African American White vs. Black/African American
1.268 (0.580–2.769)1.619 (1.072–2.444)
MBC diagnosis type Recurrent vs. De novo 1.650 (1.239–2.196)
Hormone receptor status Nega�ve vs. Posi�ve 1.841 (1.359–2.494)
ECOG PS 1 vs. 0 ≥2 vs. 0
1.192 (0.876–1.622)1.900 (1.125–3.210)
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0
1.0A
0.8
0.6
Prop
or�o
n w
ith p
rogr
essio
n-fr
ee su
rviv
al
0.4
0.2
0.0
No. of pa�ents at riskCNS metastasis at diagnosis
CNS metastasis a�er diagnosisNo CNS metastasis
4 8 12 16 20 24 28 32
Time on study since MBC diagnosis (months)
36 40 44 48 52 56 60 64 68
87212678
71191604
47137515
2787
400
1755
300
935
225
825
161
513
116
45
86
24
57
21
40
21
301
12 10 5 2
Median PFS, months
Hazard ra�o (95% CI) 2.49 (1.93–3.20), log-rank p<0.0001
2.52 (2.13–2.99), log-rank p<0.0001Hazard ra�o (95% CI)
9.2 9.9 19.1
CNS metastasisat MBC diagnosis
n=87
CNS metastasisa�er MBC diagnosis
n=212No CNS metastasis
n=678
CNS metastasis at MBC diagnosis vs. no CNS metastasis at any �me
CNS metastasis a�er MBC diagnosis vs. no CNS metastasis at any �me
CNS metastasis at MBC diagnosis (n=87)CNS metastasis a�er MBC diagnosis (n=212)No CNS metastasis (n=678)Censored +
Figure 2A
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0
1.0
0.8
0.6
Prop
or�o
n su
rviv
ing
0.4
0.2
0.0
No. of pa�ents at riskCNS metastasis at diagnosis
CNS metastasis a�er diagnosisNo CNS metastasis
4 8 12 16 20 24 28 32
Time on study since MBC diagnosis (months)
36 40 44 48 52 56 60 64 68
87212678
83211657
69207628
63199590
59186552
48165481
36142401
30117338
1990
262
1671
209
1157
158
936
107
62274
31249
16
3027 1
Median OS, months
Hazard ra�o (95% CI) 2.86 (2.05–4.00), log-rank p<0.0001
1.94 (1.52–2.49), log-rank p<0.0001Hazard ra�o (95% CI)
30.2 38.3 NE
CNS metastasisat MBC diagnosis
n=87
CNS metastasisa�er MBC diagnosis
n=212No CNS metastasis
n=678
CNS metastasis at MBC diagnosis vs. no CNS metastasis at any �me
CNS metastasis a�er MBC diagnosis vs. no CNS metastasis at any �me
CNS metastasis at MBC diagnosis (n=87)CNS metastasis a�er MBC diagnosis (n=212)No CNS metastasis (n=678)Censored +
Figure 2B
B
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Published OnlineFirst December 28, 2018.Clin Cancer Res Sara A. Hurvitz, Joyce O'Shaughnessy, Ginny Mason, et al. Characteristics, Treatment, and Survival From SystHERsHER2-Positive Metastatic Breast Cancer: Patient Central Nervous System Metastasis in Patients With
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