Central Nervous System Metastasis in Patients With HER2 ......Dec 28, 2018 · 70 Patients with...

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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

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Running title: CNS metastasis and HER2-positive MBC from SystHERs 19

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Abbreviations: 21

Research. on February 6, 2021. © 2018 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on December 28, 2018; DOI: 10.1158/1078-0432.CCR-18-2366

http://www.medschool.pitt.edu/

http://clincancerres.aacrjournals.org/

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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

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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: [email protected] 36

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Financial support: The SystHERs study was funded by F. Hoffmann-La Roche/Genentech, Inc. 38

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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

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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

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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




19

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




20

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




21

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




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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28

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




29

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




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


46 (52.9)

45 (51.7)

13 (14.9)

666 (74.8) 630 (70.8) 272 (30.6)

Trastuzumab without pertuzumab

With chemotherapy


15 (17.2) 10 (11.5)

7 (8.0)

160 (18.0) 108 (12.1)

88 (9.9)

Lapatinib

With chemotherapy


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




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




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)




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




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




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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