central nervous system metastasis in patients with her2...

Precision Medicine and Imaging

Central Nervous System Metastasis in Patientswith HER2-Positive Metastatic Breast Cancer:Patient Characteristics, Treatment, and Survivalfrom SystHERsSara A. Hurvitz1, Joyce O'Shaughnessy2, Ginny Mason3, Denise A. Yardley4,Mohammad Jahanzeb5, Adam Brufsky6, Hope S. Rugo7, Sandra M. Swain8,Peter A. Kaufman9, Debu Tripathy10, Laura Chu11, Haocheng Li12, Vincent Antao11,and Melody Cobleigh13

Abstract

Purpose: Patients with HER2-positive metastatic breastcancer (MBC) with central nervous system (CNS) metastasishave a poor prognosis. We report treatments and outcomes inpatients with HER2-positive MBC and CNS metastasis fromthe Systemic Therapies for HER2-positive Metastatic BreastCancer Study (SystHERs).

Experimental Design: SystHERs (NCT01615068) was aprospective, U.S.-based, observational registry of patients withnewly diagnosed HER2-positive MBC. Study endpointsincluded treatment patterns, clinical outcomes, and patient-reported outcomes (PRO).

Results: Among 977 eligible patients enrolled (2012–2016), CNS metastasis was observed in 87 (8.9%) at initialMBC diagnosis and 212 (21.7%) after diagnosis, and was notobserved in 678 (69.4%) patients. White and youngerpatients, and those with recurrent MBC and hormone recep-

tor–negative disease, had higher risk of CNS metastasis.Patients with CNS metastasis at diagnosis received first-linelapatinibmore commonly (23.0%vs. 2.5%), and trastuzumabless commonly (70.1% vs. 92.8%), than patients without CNSmetastasis at diagnosis. Risk of death was higher with CNSmetastasis observed at or after diagnosis [median overallsurvival (OS) 30.2 and 38.3 months from MBC diagnosis,respectively] versus no CNS metastasis [median OS not esti-mable: HR 2.86; 95% confidence interval (CI), 2.05–4.00 andHR 1.94; 95% CI, 1.52–2.49]. Patients with versus withoutCNS metastasis at diagnosis had lower quality of life atenrollment.

Conclusions:Despite advances inHER2-targeted treatments,patients with CNSmetastasis continue to have a poor prognosisand impaired quality of life. Observation of CNS metastasisappears to influence HER2-targeted treatment choice.

IntroductionHER2-positive metastatic breast cancer (MBC) is associated

with a high incidence of central nervous system (CNS) metasta-sis (1–6), a development typically associated with poor survivaland a negative impact on quality of life (7). Diagnoses of CNSmetastasis have increased over time in patients with HER2-pos-itive MBC, likely due to improved detection and longer survivalassociated with the advent of HER2-targeted therapies over thepast two decades (8). The first HER2-targeted treatment, trastu-zumab, was approved in the United States in 1998. An analysis ofdata from registHER, a prospective, observational study thatenrolled patients with HER2-positive MBC, found that trastuzu-mab-based regimens were significantly associated with increasedoverall survival (OS) in patients with CNS metastasis (3).

In the time since registHER completed enrollment, severaladditional HER2-targeted therapies have been approved forHER2-positive MBC in the United States, including lapatinib, asmall-molecule tyrosine kinase inhibitor, in 2007; pertuzumab, aHER2-targeted antibody, in 2012; and trastuzumab emtansine(T-DM1), an antibody–drug conjugate, in 2013. On the basis ofresults from the pivotal phase III CLEOPATRA trial (9–11), the

1David Geffen School of Medicine, University of California Los Angeles, LosAngeles, California. 2Baylor University Medical Center, Texas Oncology and USOncology, Dallas, Texas. 3Inflammatory Breast Cancer Research Foundation,West Lafayette, Indiana. 4Breast Cancer Research Program, Sarah CannonResearch Institute and Tennessee Oncology, Nashville, Tennessee. 5SylvesterComprehensive Cancer Center, University of Miami, Deerfield Campus, DeerfieldBeach, Florida. 6University of Pittsburgh Cancer Institute, University of Pitts-burgh Cancer Institute, Pittsburgh, Pennsylvania. 7Helen Diller Family Compre-hensive Cancer Center, University of California San Francisco, San Francisco,California. 8Lombardi Comprehensive Cancer Center, Georgetown UniversityMedical Center,Washington, District of Columbia. 9Norris Cotton Cancer Center,Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. 10The Univer-sity of Texas MD Anderson Cancer Center, Houston, Texas. 11Genentech, Inc.,South San Francisco, California. 12F. Hoffmann-La Roche, Mississauga, ON,Canada. 13Department of Internal Medicine, Rush University Medical Center,Chicago, Illinois.

Note: Supplementary data for this article are available at Clinical CancerResearch Online (http://clincancerres.aacrjournals.org/).

Corresponding Author: Sara A. Hurvitz, University of California at Los Angeles,10945 Le Conte Avenue, PVUB Suite 3360, Los Angeles, CA 90095. Phone: 310-829-5471; Fax: 310-829-6192; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-18-2366

�2018 American Association for Cancer Research.

ClinicalCancerResearch

www.aacrjournals.org 2433

on July 12, 2019. © 2019 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst December 28, 2018; DOI: 10.1158/1078-0432.CCR-18-2366

http://crossmark.crossref.org/dialog/?doi=10.1158/1078-0432.CCR-18-2366&domain=pdf&date_stamp=2019-3-22

http://clincancerres.aacrjournals.org/

combination of pertuzumab with trastuzumab and a taxanebecame a standard of care for the first-line treatment of HER2-positive MBC soon after the approval of pertuzumab. In additionto significantly prolonging progression-free survival (PFS) andOS (9–11), the addition of pertuzumab (vs. placebo) to trastu-zumab and docetaxel has been suggested to delay the onset ofCNS metastasis (12).

Patients with CNS metastasis are commonly excluded fromenrollment in clinical trials, providing an incomplete understand-ing of its natural history and management in the real world.Hence, limited data are available regarding the incidence, treat-ment, risk factors, and outcomes associated with CNS metastasisin the era ofmodernHER2-targeted therapies. Furthermore, whileguidelines for treatment have been developed based on thelimited available data (13), the level of guideline implementationis unknown.

The Systemic Therapies for HER2-positive Metastatic BreastCancer Study (SystHERs) was a fully enrolled, U.S.-based, pro-spective, observational registry study designed to explore real-world treatment patterns and outcomes in patients with recentlydiagnosed HER2-positive MBC. Here, we report baseline char-acteristics and clinical outcomes in three key cohorts: patientswith CNS metastasis observed at initial MBC diagnosis, patientswith CNS metastasis observed after MBC diagnosis, and patientswith no reported CNS metastasis by the data cutoff for thisanalysis. Additionally, systemic treatment patterns and patient-reported outcomes (PRO) are presented in patient cohorts withversus without CNS metastasis at MBC diagnosis.

Materials and MethodsStudy design and participants

SystHERs (NCT01615068) was a U.S.-based, multicenter, pro-spective, observational cohort study. Patients were recruited fromacademic sites (defined as those including one or more healthprofession schools and with research, training, education, andclinical care functions) and community sites (typically privatelyowned practices, including group practices, which do not have

associated health profession schools) and were treated andassessed in accordance with their treating physician's standardpractice. The primary study endpoint was treatment patterns;secondary endpoints included clinical outcomes and PROs. Addi-tional study design details are available in the previously pub-lished study protocol (14). Eligible patients were �18 years oldand within 6 months of HER2-positive MBC diagnosis at enroll-ment. HER2-positivity was locally determined based on the statusof the primary tumor or biopsy of recurrence, per the standards ofthe patients' physicians and their institutions. Enrolled patientsprovided written informed consent to use their medical records.The study was conducted in accordance with US FDA regulations,the International Conference on Harmonisation E6 Guidelinesfor Good Clinical Practice, the Declaration of Helsinki, andapplicable local laws. Each participating study site obtainedapproval of the study protocol by the site's ethics committee orinstitutional review board.

Evaluations and follow-upBaseline patient and disease characteristics, disease history,

previous cancer-related treatment data, and PROs were collectedat enrollment. MBC treatments, disease progression, and clinicaloutcomes were captured quarterly from patient charts, clinicalnotes, diagnostic tests, and laboratory findings; PROs werereported quarterly by patients. Metastatic sites were identified atMBC diagnosis and on study by treating physicians; screening forCNS metastasis was not required and was based on each physi-cian's standard clinical practices. Patients who discontinuedthe study had the option to participate in quarterly survivalfollow-up.

PRO measurements quantified in this study included Func-tional Assessment ofCancer Therapy-Breast (FACT-B, a sumoffivesubscales measuring physical, social, emotional, functional, andbreast cancer–related well-being on an overall scale of 0–148;ref. 15), FACT-B Trial Outcome Index (FACT-B TOI; a sum of theFACT-B physical, functional, and breast subscales on a scale of 0–96), Rotterdam Symptom Checklist–Activity Level Scale (RSC-ALS;measuring the impact of cancer on activities of daily living ona scale of 0–100; ref. 16), and the MD Anderson SymptomInventory–Brain Tumor Module [MDASI-BT, measuring braintumor-related symptom severity and impact on cognitive func-tion (scale of 0–10) and interference in daily life (scale of 0–10);ref. 17].

Analyses and statistical methodsPatient characteristics were tabulated by cohorts defined by

CNSmetastasis observed at initialMBCdiagnosis, CNSmetastasisobserved after MBC diagnosis, or no CNS metastasis over thestudy follow-up period. Calculation of P values comparing base-line characteristics between these cohorts were performed usingFisher's exact test for categorical variables and the Kruskal–Wallisnonparametric test for continuous variables.

Multivariate and univariate logistic regression was also used toexamine the association of baseline demographic and clinicalcharacteristics in patients with CNS metastasis at any time versusthose without CNS metastasis. A forest plot was prepared topresent adjusted odds ratios (OR) and their 95% confidenceintervals (CI) for a multivariate analysis of six variables selectedon the basis of clinical significance [ethnicity, race, age, EasternCooperative Oncology Group (ECOG) status, MBC diagnosistype, and hormone receptor status]. The other multivariate

Translational Relevance

PatientswithHER2-positivemetastatic breast cancer (MBC)and central nervous system (CNS) metastasis generally have apoor prognosis, but there are limited data to describe treat-ments and clinical outcomes in this population since theintroduction of modern HER2-targeted therapies. SystHERs,a prospective, observational, U.S.-based registry of 977patients enrolled from 2012 to 2016, provided a uniqueopportunity to assess contemporary treatment patterns andoutcomes. We found disparities in first-line MBC treatmentbetween patients with versus without CNS metastasis at MBCdiagnosis, and shorter median survival associated with CNSmetastasis at or after MBC diagnosis (30.2 and 38.3 months,respectively) versus no CNS metastasis (median not reached).However, we observed that survival in all subgroups improvedover the past decade. Development of new HER2-targetedtreatments, and optimization of treatment regimens andmanagement, may continue to improve outcomes in patientswith HER2-positive MBC and CNS metastasis.

Hurvitz et al.

Clin Cancer Res; 25(8) April 15, 2019 Clinical Cancer Research2434




regression and a univariate logistic regression were carried outbased on the wider collection of baseline characteristics presentedin this report, with the exception of "duration from early breastcancer (EBC) diagnosis toMBC diagnosis" (as this variable is onlyapplicable to patients with recurrent disease). The multivariatelogistic regression analysis included all covariates in one regres-sionmodel, and the univariate logistic regression considered eachvariable in the regression model separately.

First-line treatment, defined as any therapy received forMBCupto first disease progression, was analyzed in patients with versuswithout CNS metastasis at MBC diagnosis. Treatments adminis-tered to patients with CNS metastasis observed after diagnosiswere also summarized before versus after the detection of CNSlesions, regardless of line of treatment.

PRO scores at enrollment were compared between patientswith versus without CNS metastasis at MBC diagnosis. Pvalues comparing baseline PRO scores between these groupswere calculated using the Wilcoxon rank-sum nonparametrictest.

Median follow-up was calculated as the median observationtime in each CNS cohort and overall. PFS was defined as the timefromMBC diagnosis to first investigator-assessed disease progres-sion or death, whichever came first. OS was defined as the timefrom MBC diagnosis to death. PFS and OS were estimated by theKaplan–Meier product-limit method and compared acrosscohorts using a log-rank test. Cox regressions were used toestimate HRs and their 95% CI.

ResultsPatients

Out of a total of 1,028 patients who met the SystHERs studyinclusion criteria, 1,005patientswere enrolledbetween June2012and June 2016. There were 23 refusals among patients meetinginclusion criteria over the 4-year enrollment period. Among 977eligible patients enrolled from 135 study sites, 197 (20.2%) werefrom a total of 17 academic centers and 780 (79.8%) were from atotal of 118 community centers. The remaining 28 patients didnotmeet eligibility criteria, most commonly due to lack of distantmetastatic disease upon review. Eighty-seven patients (8.9%) hadCNS metastasis reported at initial MBC diagnosis, 212 (21.7%)had CNS metastasis detected after MBC diagnosis, and 678(69.4%) had no observed CNS metastasis as of the October 3,2017, data cutoff date. Median follow-up duration was 27.8months from MBC diagnosis for all patients, and 21.0, 29.6, and27.9 months in patients with CNS metastasis at diagnosis, CNSmetastasis after diagnosis, and no observed CNS metastasis,respectively. Patients alive and remaining on study at data cutoffincluded 35.6% (31/87), 43.4% (92/212), and 59.6% (404/678)in the respective cohorts.

Of the 977 patients in the overall population, median age was56 years at MBC diagnosis. Most patients were White (78.4%, n¼766) and non-Hispanic (86.5%, n ¼ 845), and had a body massindex <30 (59.5%, n¼ 581), ECOG performance status (PS) of 0or 1 (84.4%, n ¼ 825), hormone receptor–positive disease(70.1%,n¼685), and<3metastatic sites (69.1%,n¼675; Table1;Supplementary Table S1). CNS metastasis was detected at MBCdiagnosis in 4.3% (21/487) and 13.5% (66/490) of patients withde novo and recurrent MBC, respectively. Patients with CNSmetastasis at or after diagnosis had hormone receptor–negativedisease more commonly than those with no CNS metastasis

[34.5% (30/87) and 38.7% (82/212) vs. 26.5% (180/678)](Table 1).

Of 87 patients with CNS metastasis at MBC diagnosis, 28(32.2%) had CNS-only metastasis and 59 (67.8%) had both CNSand non-CNS metastasis. Bone and liver metastasis at MBCdiagnosis were observed less frequently in patients with CNSmetastasis at diagnosis [bone: 40.2% (35/87); liver: 20.7% (18/87)] versus patients with CNSmetastasis observed after diagnosis[bone: 56.6% (120/212); liver: 50.5% (107/212)] and thosewithout CNS metastasis at data cutoff [bone: 51.3% (348/678); liver: 35.5% (241/678)], whereas lung metastasiswas observed more commonly in patients with CNS metastasisat or after diagnosis [36.8% (32/87) and 38.7% (82/212),respectively] versus those without CNS metastasis [28.9%(196/678)] (Supplementary Fig. S1).

Of patients with recurrent disease and available treatment datafor EBC (n ¼ 430), the majority of patients in all three cohortsreceived neoadjuvant and/or adjuvant trastuzumab [CNS metas-tasis atMBCdiagnosis: 80.0% (48/60); CNSmetastasis afterMBCdiagnosis: 68.4% (65/95); no CNSmetastasis: 61.8% (170/275)](Supplementary Fig. S2). Of note, among the 318 patients withknown HER2 status in both primary (EBC) and metastatic tissuein the SystHERs study, 15.7% (50/318) had HER2-negative pri-mary tumors, and 12.3% (39/318) had HER2-equivocal primarytumors. As such, these patients are not likely to have received(neo)adjuvant HER2-targeted treatment.

Association between baseline characteristics and risk of CNSmetastasis

We performed a multivariate logistic analysis of baseline char-acteristics selected based on their clinical importance to identifyrisk factors associated with the development of CNSmetastasis atany time. Of these characteristics, younger age showed the stron-gest association with CNS metastasis (OR 3.128; 95% CI, 1.852–5.284 for patients <50 vs. �70 years old; Fig. 1). Other character-istics associated with CNS metastasis included White race (OR1.619; 95% CI, 1.072–2.444 vs. Black/African American race),ECOG status �2 (OR 1.900; 95% CI, 1.125–3.210 vs. ECOGstatus of 0), recurrent MBC (OR 1.650; 95% CI, 1.239–2.196 vs.de novoMBC), and hormone receptor–negative status (OR 1.841;95% CI, 1.359–2.494 vs. hormone receptor–positive status).Multivariate and univariate logistic regression analyses consider-ing all baseline characteristics shown in Table 1 (with the excep-tion of "duration from EBC diagnosis to MBC diagnosis," as thisvariable is only applicable to patients with recurrent disease)produced similar conclusions (Supplementary Table S2).

Treatment patternsAmong patients with CNSmetastases atMBC diagnosis, 80.5%

(70/87) received brain radiotherapy (local, n ¼ 35; whole brain,n ¼ 52) and 44.8% (39/87) received brain surgery, including 10patients who received surgery without radiotherapy (Supplemen-tary Table S3). In patients with CNS metastasis observed afterMBC diagnosis, 79.2% (168/212) and 20.8% (44/212) hadreceived brain radiotherapy (local, n ¼ 60; whole brain, n ¼131) andbrain surgery by data cutoff, respectively, including eightpatients who received surgery without radiotherapy.

At data cutoff, 97.0% of all patients (948/977) had receivedfirst-line systemic treatment forMBC, including 88.5% (77/87) ofthose with CNS metastasis at MBC diagnosis (of whom ninepatients were still in first-line treatment) and 97.9% (871/890) of

CNS Metastasis and HER2-Positive MBC from SystHERs

www.aacrjournals.org Clin Cancer Res; 25(8) April 15, 2019 2435




those without CNS metastasis at diagnosis (of whom 217 werestill in first-line treatment). The most common first-line HER2-targeted agentwas trastuzumab, although it was administered lessfrequently to patients with CNS metastasis at diagnosis [70.1%(61/87)] compared with patients without CNS metastasis atdiagnosis [92.8% (826/890); Table 2]. Trastuzumab was used incombination with pertuzumab in 52.9% (46/87) of patients withand 74.8% (666/890) of patients without CNS metastasis atdiagnosis. The most common first-line treatment regimen wastrastuzumab þ pertuzumab þ taxane, with or without hormonaltherapy, administered to 48.3% (42/87) and 68.3% (608/890) ofpatients with and without CNS metastasis at diagnosis, respec-tively (Supplementary Table S4).

First-line lapatinib was administered to a higher proportionof patients with CNS metastasis at diagnosis [23.0% (20/87),of whom 11 patients received lapatinib þ trastuzumab]compared with patients without CNS metastases at diagnosis[2.5% (22/890), of whom 12 patients received lapatinib þtrastuzumab; Table 2; Supplementary Fig. S3]. Patients withCNS-only metastasis at MBC diagnosis received regimens withlapatinib more commonly, and regimens with trastuzumab þpertuzumab less commonly, than those with CNS and non-CNSmetastasis at diagnosis [lapatinib: 35.7% (10/28) vs. 16.9% (10/59), respectively; trastuzumab þ pertuzumab: 17.9% (5/28) vs.69.5% (41/59); Supplementary Table S5]. Among patientswith CNS metastasis at diagnosis (both CNS-only and CNS and

Table 1. Baseline demographics, patient characteristics, and disease characteristics

All eligible patients(n ¼ 977)

CNS metastasis atdiagnosis (n ¼ 87)

CNS metastasis afterdiagnosis (n ¼ 212)

No CNS metastasis(n ¼ 678) P-value

DemographicsMedian 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 94 (9.6) 10 (11.5) 16 (7.5) 68 (10.0) 0.490Not Hispanic or Latino 845 (86.5) 74 (85.1) 186 (87.7) 585 (86.3)Not reported/unknown 38 (3.9) 3 (3.4) 10 (4.7) 25 (3.7)

Race, n (%)White 766 (78.4) 71 (81.6) 175 (82.5) 520 (76.7) 0.288Black or African American 151 (15.5) 9 (10.3) 29 (13.7) 113 (16.7)Asian 13 (1.3) 1 (1.1) 1 (0.5) 11 (1.6)Other 29 (3.0) 5 (5.7) 6 (2.8) 18 (2.7)Not reported/unknown 18 (1.8) 1 (1.1) 1 (0.5) 16 (2.4)

Insurance status, n (%)Private 372 (38.1) 30 (34.5) 96 (45.3) 246 (36.3) 0.103Public 201 (20.6) 13 (14.9) 38 (17.9) 150 (22.1)Both 115 (11.8) 7 (8.0) 17 (8.0) 91 (13.4)None 36 (3.7) 3 (3.4) 10 (4.7) 23 (3.4)Missing 253 (25.9) 34 (39.1) 51 (24.1) 168 (24.8)

Patient characteristicsBMI, n (%)<30 581 (59.5) 48 (55.2) 137 (64.6) 396 (58.4) 0.265�30 385 (39.4) 38 (43.7) 75 (35.4) 272 (40.1)Missing 11 (1.1) 1 (1.1) 0 10 (1.5)

ECOG PS, n (%)0 460 (47.1) 26 (29.9) 106 (50.0) 328 (48.4) <0.0011 365 (37.4) 34 (39.1) 82 (38.7) 249 (36.7)2 67 (6.9) 15 (17.2) 11 (5.2) 41 (6.0)3 8 (0.8) 5 (5.7) 0 3 (0.4)Unknown/missing 77 (7.9) 7 (8.0) 13 (6.1) 57 (8.4)

Disease characteristicsMBC diagnosis typea, n (%)De novo 487 (49.8) 21 (24.1) 107 (50.5) 359 (52.9) <0.001Recurrent 490 (50.2) 66 (75.9) 105 (49.5) 319 (47.1)

Median duration from EBC diagnosis n ¼ 487 n ¼ 66 n ¼ 105 n ¼ 316 0.063to MBC diagnosisb, months (range) 42.8 (4–452) 39.9 (12–332) 40.4 (5–369) 48.7 (4–452)Hormone receptor status, n (%)ER- and/or PR-positive 685 (70.1) 57 (65.5) 130 (61.3) 498 (73.5) 0.002ER- and PR-negative 292 (29.9) 30 (34.5) 82 (38.7) 180 (26.5)

Visceral diseasec, n (%) 603 (61.7) 41 (47.1) 160 (75.5) 402 (59.3) <0.001Number of metastatic sites atdiagnosis, n (%)1 417 (42.7) 28 (32.2) 72 (34.0) 317 (46.8) <0.0012 258 (26.4) 14 (16.1) 54 (25.5) 190 (28.0)�3 302 (30.9) 45 (51.7) 86 (40.6) 171 (25.2)

Abbreviations: BMI, body mass index; ER, estrogen receptor; IQR, interquartile range; PR, progesterone receptor.aRecurrent (as opposed to de novo) MBC indicates �90 days between EBC and MBC diagnoses.bIn patients with recurrent disease.cIncludes nonhepatic abdominal, ascites, liver, lung, or pleural effusion sites of metastasis (excludes CNS).

Hurvitz et al.





non-CNS), patients who received radiotherapy also received regi-mens containing lapatinib or trastuzumab þ pertuzumab morecommonly compared with the small group of patients who didnot receive radiotherapy [lapatinib: 27.1% (19/70) vs. 5.9% (1/17), respectively; trastuzumab þ pertuzumab: 55.7% (39/70) vs.41.2% (7/17)].

In patients with CNS metastasis observed after MBC diagnosis,treatment data were available for 211 patients prior to the detec-tion of CNS lesions and 128 patients following diagnosis of CNSmetastasis. Similar to observations in patients with CNS metas-tasis atMBCdiagnosis, administration of lapatinib in any linewasmore common following the detection of CNS lesions [prior toCNS metastasis: 6.2% (13/211), of whom 12 patients alsoreceived trastuzumab; following CNS metastasis: 34.4% (44/128), of whom 18 patients also received trastuzumab; Supple-mentary Fig. S4]. T-DM1 was administered to 26.1% (55/211)and 51.6% (66/128) of patients before versus after the diagnosisof CNS metastasis, respectively.

Patient-reported outcomesPROquestionnaire completion rates at enrollment were 79.4%

(776/977) for FACT-B (15), 79.6% (778/977) for FACT-B TOI,80.3% (785/977) for RSC-ALS, 77.3% (755/977) for MDASI-BT:cognitive symptoms, and 77.1% (753/977) for MDASI-BT: inter-ference in daily life. Rates of completion were similar betweenCNS cohorts. Patients with CNS metastases at MBC diagnosisreported lower quality of life at enrollment compared withpatients without CNS metastasis at diagnosis, as measured byFACT-B (median score 94.5 vs. 103.5 out of a possible 148, P ¼0.002) and FACT-B TOI (median score 56.5 vs. 62.0 out of 96, P¼0.009; Supplementary Fig. S5A and S5B). Greater impairment indaily activities was also observed in the cohort with CNS metas-tases at diagnosis (versus without CNS metastases at diagnosis)per RSC-ALS (median score 77.1 vs. 87.5 out of 100,P¼ 0.002), aswell as greater severity of cognitive dysfunction per MDASI-BT(cognitive symptoms, median score 2.3 vs. 0.8 out of 10, P <0.001; brain tumor-related interference in daily life, median score3.9 vs. 2.0 out of 10, P ¼ 0.004; Supplementary Fig. S5C–S5E).

Clinical outcomesEstimated median first-line PFS and OS from MBC diagnosis

weremarkedly shorter in patientswithCNSmetastases at any timecompared with patients with no CNS metastasis (Fig. 2). MedianPFS was 9.2, 9.9, and 19.1 months in patient cohorts with CNSmetastasis at diagnosis, CNS metastasis observed after diagnosis,and no CNS metastasis, respectively. By the data cutoff date,50.6% (44/87), 49.5% (105/212), and 23.6% (160/678) patientsin each cohort haddied, respectively.MedianOSwas30.2months(HR 2.86; 95% CI, 2.05–4.00; P < 0.0001) in patients with CNSmetastasis at diagnosis, 38.3 months (HR 1.94; 95% CI, 1.52–2.49; P < 0.0001) in patients with CNS metastasis observed afterdiagnosis, and was not yet estimable in patients with no CNSmetastasis.

Patients with CNS-only metastasis at MBC diagnosis (n ¼ 28)had a median PFS of 9.2 months and median OS of 20.1 months

Ethnicity1.181 (0.718–1.943)

0 1 2 3 4 5

Higher risk of CNS metastasisLower risk of CNS metastasis

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 status1.841 (1.359–2.494)

ECOG PS 1 vs. 0 ≥2 vs. 0

1.192 (0.876–1.622)1.900 (1.125–3.210)

OR

Figure 1.

Multivariate analysis of selected baseline characteristics and risk of CNSmetastasis at any time.

Table 2. First-line HER2-targeted therapy by CNS metastasis cohort

HER2-targeted therapya

by patients with anyfirst-line exposure, n (%)

CNS metastasisat diagnosis(n ¼ 87)

No CNS metastasisat diagnosis(n ¼ 890)

Trastuzumab 61 (70.1) 826 (92.8)With chemotherapy 55 (63.2) 738 (82.9)With hormonal therapy 20 (23.0) 360 (40.4)

Trastuzumab þ pertuzumab 46 (52.9) 666 (74.8)With chemotherapy 45 (51.7) 630 (70.8)With hormonal therapy 13 (14.9) 272 (30.6)

Trastuzumab without pertuzumab 15 (17.2) 160 (18.0)With chemotherapy 10 (11.5) 108 (12.1)With hormonal therapy 7 (8.0) 88 (9.9)

Lapatinib 20 (23.0) 22 (2.5)With chemotherapy 14 (16.1) 18 (2.0)With hormonal therapy 7 (8.0) 8 (0.9)

Lapatinib þ trastuzumab 11 (12.6) 12 (1.3)T-DM1 10 (11.5) 61 (6.9)aTreatments are not mutually exclusive.






from MBC diagnosis. In patients with CNS metastasis observedafter MBC diagnosis, median time to diagnosis of CNSmetastasiswas 15.1 (95% CI, 13.7–16.6) months.

Among patients with CNS-only metastasis at diagnosis, 46.4%(13/28)hadCNS-only progression at their next progression event,10.7% (3/28) had non-CNS progression, and no patients had

both CNS and non-CNS progression. In the 59 patients with bothCNS and non-CNS metastasis at MBC diagnosis, 33.9% (20/59)had CNS-only progression at their next progression event, 35.6%(21/59) had non-CNS progression, and 5.1% (3/59) had bothCNS and non-CNS progression. In each group, respectively,42.9% (12/28) and 25.4% (15/59) of patients did not have a

0

1.0A

0.8

0.6

0.4

0.2

0.0

CNS metastasis at diagnosis

No 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

2.49 (1.93–3.20), log-rank P < 0.0001

2.52 (2.13–2.99), log-rank P < 0.0001

1.919.92.9

CNS metastasisat MBC diagnosis

n = 87

CNS metastasis

n = 212No CNS metastasis

n = 678

CNS metastasis at MBC diagnosis (n = 87)

No CNS metastasis (n = 678)Censored +

0

1.0

0.8

0.6

0.4

0.2

0.0

CNS metastasis at diagnosis

No 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

2.86 (2.05–4.00), log-rank P < 0.0001

1.94 (1.52–2.49), log-rank P < 0.0001

EN3.832.03

CNS metastasisat MBC diagnosis

n = 87

CNS metastasis

n = 212No CNS metastasis

n = 678

CNS metastasis at MBC diagnosis vs.

CNS metastasis at MBC diagnosis (n = 87)

No CNS metastasis (n = 678)Censored +

B

HR (95% CI)

HR (95% CI)

HR (95% CI)

HR (95% CI)

Prop

or�o

n w

ith P

FS

Figure 2.

(A) Progression-free survival and (B) overall survival by CNSmetastasis cohort. NE, not estimable.

Hurvitz et al.





progression event by the timeof data cutoff, whether due to death,loss of follow-up, or study closure.

DiscussionIn this real-world analysis of patients with HER2-positive MBC

from the SystHERs study, we found that development of CNSmetastasis was associated with race, age, hormone receptor status,and MBC diagnosis type. Patients with CNS metastasis at MBCdiagnosis reported poorer quality of life at enrollment, andreceived first-line lapatinib more commonly and first-line trastu-zumab less commonly, than patients with CNS metastasisobserved after diagnosis or those with no CNS metastasis whileon study. Of the three CNS metastasis cohorts, prognosis waspoorest in patients with CNS metastasis at diagnosis and mostfavorable in patients without CNS metastasis.

Breast cancer is associated with a high incidence of CNSmetastasis, a risk that rises significantly in patients with HER2-positive disease (1–6). Other previously identified risk factorsincluded high tumor grade or disease burden, hormone receptor–negative MBC, and younger age (3, 18). Routine magnetic reso-nance imaging for CNS metastasis is currently not recommendedin the absence of suggestive symptoms (13), limiting our ability toassess whether early detection and treatment of asymptomaticCNS disease improves outcomes. In a multivariate analysis ofSystHERs data, we found CNS metastasis was more common inWhite and younger patients, and in those with recurrentMBC andhormone receptor–negative disease. Data from SystHERs andother studies may help identify a particularly high-risk cohort ofpatients for further study.

Because of the presumed inability of certain pharmacologictreatments to cross the blood–brain barrier and limited historicaldata regarding the efficacy of these therapies against CNS lesions,management of CNS metastasis has typically involved the use oflocal treatments, including surgery and whole-brain or stereotac-tic radiotherapy. However, optimizing control of systemic diseaseis needed to prolong survival. As such, ASCO guidelines forpatients with HER2-positive MBC and CNS metastasis recom-mend that in addition to local treatments, patients with progres-sive disease should receive systemic therapy according to standardalgorithms for HER2-positive MBC (13). In this analysis, wefound that only 48.3% of patients with CNS metastasis at MBCdiagnosis were treated with the first-line standard of care, trastu-zumabþpertuzumabþ taxane, comparedwith 68.3%of patientswithout CNS metastasis at diagnosis, although part of this dis-parity could potentially be attributed to differences in CNS-independent baseline characteristics between the two groups.Patients with CNS metastasis at diagnosis preferentially receivedfirst-line regimens containing lapatinib (23.0% vs. 2.5% ofpatients without CNS metastasis at diagnosis), presumably dueto evidence that lapatinib may have activity in the CNS. A meta-analysis of patients with HER2-positive breast cancer and brainmetastasis treated with lapatinib � capecitabine indicated anoverall response rate of 21.4% in the CNS, which increased to29.2% when lapatinib monotherapy was excluded (19). In thephase II LANDSCAPE study, lapatinib þ capecitabine demon-strated a volumetric response rate of 65.9% against CNS lesions,although the regimen was associated with a high rate of grade 3and 4 toxicities (20). However, a retrospective analysis of datafrom the phase III EMILIA trial showed significantly improvedOSin patients with MBC and brain metastasis treated with T-DM1

versus lapatinib þ capecitabine (21). Furthermore, a study byGelmon and colleagues indicated thatfirst-line lapatinibþ taxaneis associated with lower PFS than trastuzumabþ taxane (22). It ispossible that the use of lapatinib-based first-line treatment regi-mens in patients with CNS metastasis at MBC diagnosis, at thepossible expense of targeting systemic disease, may contribute tothe poorer outcomes observed in that cohort. The use of first-lineregimens containing lapatinib versus other HER2-targeted treat-ments should be further examined in randomized clinical trials toassess their overall impact on survival in patients with CNSmetastasis at diagnosis.

Accumulating preclinical and clinical evidence suggest thatotherHER2-targeted therapies can also penetrate the blood–brainbarrier and delay or ameliorate CNS metastasis in patients withMBC (12, 23–30). Preliminary results from the phase III CEREBELstudy found that patients receiving lapatinib þ capecitabineversus trastuzumabþ capecitabine had similar incidences of CNSmetastases as first detected site of relapse (3% vs. 5%, respective-ly), with longer PFS and OS in the trastuzumab þ capecitabinearm (28). In the phase III CLEOPATRA trial, the addition ofpertuzumab to first-line trastuzumab þ docetaxel delayed obser-vations of CNS metastasis as the first site of disease progression,from 11.9 months in the placebo arm to 15.0 months in thepertuzumab arm (12). Preliminary evidence from the ongoingphase III KAMILLA and phase II PATRICIA studies suggest thatT-DM1 and pertuzumab þ high-dose trastuzumab, respectively,have activity against CNS lesions (26, 27). Finally, tucatinib, aninvestigational small-molecule HER2 inhibitor, has demonstrat-ed promisingCNS activity (29, 30) andhas been grantedU.S. FDAorphan drug status for patients with HER2-positive MBC withCNS metastasis. Data from these and other studies (31, 32) mayhelp identify therapeutic regimens that optimize the treatment ofboth CNS and extracranial lesions to improve OS in patients withCNS metastasis.

CNSmetastasis in patients with breast cancer has historicallybeen associated with decreased quality of life and a poorprognosis (7). As management of MBC is often consideredpalliative, PRO-assessed quality of life is an important consid-eration in this population. In this study, PRO measures cap-tured at enrollment suggested that patients with CNS metasta-ses at MBC diagnosis may carry a greater disease burden thanthose without CNS metastasis at diagnosis. Patients with CNSmetastases at MBC diagnosis reported poorer quality of life andhigher impairment in functional measures of cognition anddaily activities, although these measures may reflect compositeeffects of disease and treatments initiated prior to enrollment.Furthermore, patients with CNS metastasis at or after MBCdiagnosis had markedly shorter median PFS (9.2 and 9.9months, respectively) and median OS (30.2 and 38.3 months,respectively) compared with patients who did not develop CNSmetastasis on study (median PFS, 19.1months;medianOS, notyet estimable).

Despite these differences, OS observed in patients with CNSmetastasis notably exceeds that reported prior to the approval oflapatinib, pertuzumab, and T-DM1: in registHER, which enrolledpatients from 2003 to 2006, patients with CNSmetastasis atMBCdiagnosis had a median OS of 20.3 months (3). In patients withCNS metastasis observed after MBC diagnosis, median time todiagnosis of CNSmetastasis was 15.1 months in SystHERs versus13.3 months in registHER after similar follow-up durations forboth studies (3). Data from both registHER and SystHERs






represent substantial improvements in clinical outcomes relativeto the pre-trastuzumab era, whenmedian survival following brainmetastasis was only 4months (33). Among other variables, futurestudies should assess the contribution of different systemic treat-ments (e.g., regimens including trastuzumab þ pertuzumab vs.lapatinib) on PROs and clinical outcomes in patients with CNSmetastasis.

In the SystHERs study, CNS metastasis at MBC diagnosis wasobserved in 8.9% of patients. With a median follow-up of 27.8months from MBC diagnosis in SystHERs, CNS metastasis wasdetected in an additional 21.7% of patients (i.e., a total of 30.6%of patients with CNS metastasis). Of note, this number would beexpected to increase with longer follow-up. Additionally, screen-ing for CNS metastasis in SystHERs was not required at enroll-ment, and was conducted at the investigator's discretion. Asprevious studies have suggested a high incidence of asymptom-atic, occult CNS lesions in patients with breast cancer (34), thereported prevalence of CNSmetastasis in SystHERsmay be under-estimated due to undetected CNS disease. Our analysis was alsoconstrained by limitations inherent to registry studies. For exam-ple, because EBC data were collected retrospectively, some datawere missing, and prospectively collected data may have beenimpacted by attrition or reporting bias. Finally, similar to themethodological caveats common to other reports of real-worldstudies, clinical response data were based on investigator assess-ments with variable assessment intervals across patients in accor-dance with institutional practice norms, which may be lessreliable than standardized criteria used in randomized clinicaltrials.

In summary, data from the SystHERs registry study suggestthat while patients with CNS metastasis continue to experiencelower quality of life and a poorer prognosis than patientswithout CNS metastasis, key clinical outcomes, including timeto CNS progression and OS, have improved in this populationover time. Recent interest in the use of HER2-targeted therapiesagainst CNS lesions, along with promising preliminary resultsfrom the LANDSCAPE, KAMILLA, PATRICIA, and other studies,may lead to further improvements in the treatment, manage-ment, and prognosis of patients with HER2-positive MBC andCNS metastasis.

Disclosure of Potential Conflicts of InterestS.A. Hurvitz reports receiving commercial research grants from Ambryx,

Amgen, Bayer, Bi Pharma, Biomarin, Cascadian, Daiichi Sankyo, Dignitana,Genentech, Glaxo Smith Kline, Lilly, Macrogenics, Medivation, Merrimack,Novartis, Obi Pharma, Pfizer, Pieris, Puma, Roche, and Seattle Genetics. J.O'Shaughnessy reports receiving speakers bureau honoraria from Lilly andis a consultant/advisory board member for AstraZeneca, Novartis, Lilly,Pfizer, Genentech, and Roche. D. Yardley reports receiving commercialresearch grants from Celldex, Novartis, Astrazeneca, Janssen, Roche/Gen-entech, Bristol-Myers Squibb, Amgen, Celgene, Exelixis, Eli Lilly, GlaxoSmith Kline, Medimmune, Medivation, Pfizer, Sanofi, Tesaro, Eisai, Spec-trum Pharmaceuticals, Merck, AbbVie, Astellas, Bayer, Biomarin, BiotheraPharmaceuticals, Celldex, Clovis, Concordia, G1 Therapeutics, Genzyme,Imclone, Incyte, Ipsen Pharmaceuticals, and Merrimack Pharmaceuticals;reports receiving other commercial research support from Novartis, Roche/Genentech, Celgene, Eli Lilly, Pfizer, Abraxis, Eisai, Spectrum Pharmaceu-ticals, R-Pharm US, Merck, Nippon-Kayaku, ELM Medical Limited, andbioTheranostics; and is a consultant/advisory board member for Novartis,Genentech, Seattle Genetics, Odonate, Hengrui Therapeutics, Biotheranos-tics, and Eisai. M. Jahanzeb reports receiving commercial research grantsand speakers bureau honoraria from, and is a consultant/advisory boardmember for Genentech. A.M. Brufsky is a consultant/advisory board mem-

ber for Roche, Eisai, Celgene, Lilly, Pfizer, and Novartis. H.S. Rugo reportsreceiving commercial research grants from Pfizer, Eisai, Genentech, Novar-tis, Lilly, Macrogenics, Immunomedics, Daiichi, and Odonate, and reportsreceiving speakers bureau honoraria from Celltrion. S.M. Swain reportsreceiving commercial research grants from Genentech and is a consultant/advisory board member for Pieris Pharmaceuticals, Inivata Ltd, Tocagen,Genomic Health, Genentech/Roche, Lilly, Daiichi Sankyo, and CardinalHealth, and reports other remuneration from Novartis, AstraZeneca, Ini-vata, Caris Life Sciences, Genentech/Roche, NanoString Technologies, Lilly,and Daiichi Sankyo. P.A. Kaufman reports receiving commercial researchgrants from and is a consultant/advisory board member for Genentech. L.Chu is an employee of Genentech/Roche and holds ownership interest(including patents) in Roche. V. Antao holds ownership interest (includingpatents) in Roche. M. Cobleigh is a consultant/advisory board member forGenentech. No potential conflicts of interest were disclosed by the otherauthors.

Authors' ContributionsConception and design: S.A. Hurvitz, D.A. Yardley, M. Jahanzeb, A. Brufsky,H.S. Rugo, S.M. Swain, P.A. Kaufman, D. Tripathy, L. Chu, M. CobleighDevelopment of methodology: J. O'Shaughnessy, D.A. Yardley, M. Jahanzeb,A. Brufsky, D. Tripathy, L. Chu, M. CobleighAcquisition of data (provided animals, acquired and managed patients,provided facilities, etc.): S.A. Hurvitz, D.A. Yardley, A. Brufsky, H.S. Rugo,P.A. Kaufman, L. Chu, V. Antao, M. CobleighAnalysis and interpretation of data (e.g., statistical analysis, biostatistics,computational analysis): J. O'Shaughnessy, D.A. Yardley, M. Jahanzeb,A. Brufsky, H.S. Rugo, S.M. Swain, P.A. Kaufman, D. Tripathy, L. Chu, H. Li,V. Antao, M. CobleighWriting, review, and/or revision of the manuscript: S.A. Hurvitz,J. O'Shaughnessy, G. Mason, D.A. Yardley, M. Jahanzeb, A. Brufsky,H.S. Rugo, S.M. Swain, P.A. Kaufman, D. Tripathy, L. Chu, H. Li, V. Antao,M. CobleighAdministrative, technical, or material support (i.e., reporting or organizingdata, constructing databases): H. Li, V. AntaoStudy supervision: M. Jahanzeb, V. Antao, M. CobleighOther (I joined the SystHERs study after enrollment of patients had beeninitiated, and as such was not part of the Concept and design, and the initialdevelopment of the methodology. Since then, I've been involved in allsubsequent activities, including data analyses, interpretation of the data,writing of posters and manuscripts, etc.): V. Antao

AcknowledgmentsThe authors are grateful to the patients, families, and investigators who

participated in SystHERs. We would also like to thankMusa Mayer for her workas part of the SystHERs steering committee; the SystHERs team, includingclinical operations leads Michelle Usher (F. Hoffmann-La Roche/Genentech,Inc.) and Sandy Lam (F. Hoffmann-La Roche/Genentech, Inc.); Bongin Yoo(F. Hoffmann-La Roche/Genentech, Inc.) for his contributions to the statisticalanalysis and manuscript review; Allen Lee (Everest Clinical Research Services,Inc.) for his assistance with the statistical analysis; Bokai Xia (F. Hoffmann-LaRoche/Genentech, Inc.) for his statistical programming expertise; and SusanMathias and Ross Crosby (Health Outcomes Solutions) for their analysis ofpatient-reported outcomes. Support for third-party writing assistance wasprovided by Sabrina Hom, PhD, of CodonMedical, an Ashfield Company, partof UDG Healthcare plc, and funded by F. Hoffmann-La Roche/Genentech, Inc.F. Hoffmann-La Roche/Genentech, Inc. funded the SystHERs study and partic-ipated in the studydesign, data collection, data analysis, data interpretation, andwriting of this report. The SystHERs studywas fundedbyF.Hoffmann-LaRoche/Genentech, Inc.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.

Received July 23, 2018; revised November 19, 2018; accepted December 21,2018; published first December 28, 2018.

Hurvitz et al.





References1. Pestalozzi BC, ZahriehD, Price KN,Holmberg SB, Lindtner J, Collins J, et al.

Identifying breast cancer patients at risk for Central Nervous System (CNS)metastases in trials of the International Breast Cancer Study Group(IBCSG). Ann Oncol 2006;17:935–44.

2. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH,et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol 2010;28:3271–7.

3. Brufsky AM,MayerM, RugoHS, Kaufman PA, Tan-Chiu E, TripathyD, et al.Central nervous system metastases in patients with HER2-positive meta-static breast cancer: incidence, treatment, and survival in patients fromregistHER. Clin Cancer Res 2011;17:4834–43.

4. Musolino A, Ciccolallo L, PanebiancoM, Fontana E, Zanoni D, Bozzetti C,et al. Multifactorial central nervous system recurrence susceptibility inpatients with HER2-positive breast cancer: epidemiological and clinicaldata from a population-based cancer registry study. Cancer 2011;117:1837–46.

5. Olson EM,Najita JS, Sohl J, Arnaout A, BursteinHJ,Winer EP, et al. Clinicaloutcomes and treatment practice patterns of patients with HER2-positivemetastatic breast cancer in the post-trastuzumab era. Breast 2013;22:525–31.

6. Aversa C, Rossi V, Geuna E, Martinello R, Milani A, Redana S, et al.Metastatic breast cancer subtypes and central nervous system metastases.Breast 2014;23:623–8.

7. Leone JP, Leone BA. Breast cancer brain metastases: the last frontier.Exp Hematol Oncol 2015;4:33.

8. Rostami R, Mittal S, Rostami P, Tavassoli F, Jabbari B. Brain metastasis inbreast cancer: a comprehensive literature review. J Neurooncol 2016;127:407–14.

9. Baselga J, Cort�es J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plustrastuzumabplus docetaxel formetastatic breast cancer.NEngl JMed2012;366:109–19.

10. Swain SM, Kim SB, Cort�es J, Ro J, Semiglazov V, Campone M, et al.Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastaticbreast cancer (CLEOPATRA study): overall survival results from a rando-mised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol2013;14:461–71.

11. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al.Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastaticbreast cancer. N Engl J Med 2015;372:724–34.

12. Swain SM, Baselga J, Miles D, Im YH, Quah C, Lee LF, et al. Incidence ofcentral nervous system metastases in patients with HER2-positive meta-static breast cancer treated with pertuzumab, trastuzumab, and docetaxel:results from the randomized phase III study CLEOPATRA. Ann Oncol2014;25:1116–21.

13. Ramakrishna N, Temin S, Chandarlapaty S, Crews JR, DavidsonNE, EstevaFJ, et al. Recommendations on disease management for patients withadvanced human epidermal growth factor receptor 2-positive breast cancerand brain metastases: American Society of Clinical Oncology clinicalpractice guideline. J Clin Oncol 2014;32:2100–8.

14. TripathyD, RugoHS, Kaufman PA, Swain S, O'Shaughnessy J, JahanzebM,et al. The SystHERs registry: an observational cohort study of treatmentpatterns and outcomes in patients with human epidermal growth factorreceptor 2-positive metastatic breast cancer. BMC Cancer 2014;14:307.

15. BradyMJ, Cella DF,Mo F, Bonomi AE, TulskyDS, Lloyd SR, et al. Reliabilityand validity of the Functional Assessment of Cancer Therapy-Breast qual-ity-of-life instrument. J Clin Oncol 1997;15:974–86.

16. de Haes JC, van Knippenberg FC, Neijt JP. Measuring psychological andphysical distress in cancer patients: structure and application of theRotterdam Symptom Checklist. Br J Cancer 1990;62:1034–8.

17. Armstrong TS, Mendoza T, Gning I, Coco C, Cohen MZ, Eriksen L, et al.Validationof theM.D. Anderson Symptom Inventory Brain TumorModule(MDASI-BT). J Neurooncol 2006;80:27–35.

18. Chow L, Suen D, Ma KK, Kwong A. Identifying risk factors for brainmetastasis in breast cancer patients: Implication for a vigorous surveillanceprogram. Asian J Surg 2015;38:220–3.

19. Petrelli F, Ghidini M, Lonati V, Tomasello G, Borgonovo K, Ghilardi M,et al. The efficacy of lapatinib and capecitabine in HER-2 positive breast

cancer with brain metastases: a systematic review and pooled analysis.Eur J Cancer 2017;84:141–8.

20. Bachelot T, Romieu G, Campone M, Di�eras V, Cropet C, Dalenc F, et al.Lapatinib plus capecitabine in patients with previously untreated brainmetastases from HER2-positive metastatic breast cancer (LANDSCAPE): asingle-group phase 2 study. Lancet Oncol 2013;14:64–71.

21. Krop IE, Lin NU, Blackwell K, Guardino E, Huober J, Lu M, et al. Trastu-zumab emtansine (T-DM1) versus lapatinib plus capecitabine in patientswith HER2-positive metastatic breast cancer and central nervous systemmetastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol2015;26:113–9.

22. Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A,et al. Lapatinib or trastuzumab plus taxane therapy for human epidermalgrowth factor receptor 2-positive advanced breast cancer: final results ofNCIC CTG MA.31. J Clin Oncol 2015;33:1574–83.

23. Dawood S, Broglio K, Esteva FJ, Ibrahim NK, Kau SW, Islam R, et al.Defining prognosis for women with breast cancer and CNS metastases byHER2 status. Ann Oncol 2008;19:1242–8.

24. Askoxylakis V, Ferraro GB, Kodack DP, BadeauxM, Shankaraiah RC, SeanoG, et al. Preclinical efficacy of ado-trastuzumab emtansine in the brainmicroenvironment. J Natl Cancer Inst 2015;108:pii: djv313. doi: 10.1093/jnci/djv313.

25. Lewis Phillips GD, Nishimura MC, Lacap JA, Kharbanda S, Mai E,Tien J, et al. Trastuzumab uptake and its relation to efficacy in ananimal model of HER2-positive breast cancer brain metastasis.Breast Cancer Res Treat 2017;164:581–91.

26. Lin NU, Stein A, Nicholas A, Kumthekar P, Ibrahim N, PegramM. Plannedinterim analysis of PATRICIA: an open-label, single-arm, phase II study ofpertuzumab (P) with high-dose trastuzumab (H) for the treatment ofcentral nervous system (CNS) progression post radiotherapy (RT) inpatients (pts) with HER2-positive metastatic breast cancer (MBC).J Clin Oncol 2017;35(suppl):abstr 2074.

27. Montemurro F, Ellis P, Delaloge S, Wuerstlein R, Anton A, Button P, et al.Safety and efficacy of trastuzumab emtansine (T-DM1) in 399patientswithcentral nervous systemmetastases: Exploratory subgroup analysis from theKAMILLA study. Cancer Res 2017;77(4 suppl):DOI: 10.1158/1538-7445.SABCS16-P1-12-10.

28. Pivot X, Manikhas A, _Zurawski B, Chmielowska E, Karaszewska B, AllertonR, et al. CEREBEL (EGF111438): a phase III, randomized, open-label studyof lapatinib plus capecitabine versus trastuzumab plus capecitabine inpatients with human epidermal growth factor receptor 2-positive meta-static breast cancer. J Clin Oncol 2015;33:1564–73.

29. Hamilton E, Borges V, Conlin A, Walker L, Moulder S. Efficacy results of aphase 1b study ofONT-380, anoralHER2-specific inhibitor, in combinationwith capecitabine (C) and trastuzumab (T) in HER2þ metastatic breastcancer (MBC), including patients (pts) with brain metastases (mets).Cancer Res 2017;77(4 suppl):DOI:10.1158/1538-7445.SABCS16-P4-21-01.

30. Ferrario C,Welch S, Chaves JM,Walker LN, Krop IE, Paige E, et al. ONT-380in the treatment of HER2þ breast cancer central nervous system (CNS)metastases (mets). J Clin Oncol 2015;33(no. 15_suppl);612.

31. Hurvitz SA, Martinez DA, Singh R, Taguchi J, Chan D, Dichmann R, et al.Phase Ib/II single-arm trial evaluating the combination of everolimus,lapatinib and capecitabine for the treatment of patients with HER2-positive metastatic breast cancer with progression in the CNS after trastu-zumab (TRIO-US B-09). Cancer Res 2017;77(4 Suppl):DOI:10.1158/1538-7445.SABCS16-P1-12-07.

32. Van Swearingen AED, Siegel MB, Deal AM, Sambade MJ, Hoyle A,Hayes DN, et al. LCCC 1025: a phase II study of everolimus,trastuzumab, and vinorelbine to treat progressive HER2-positivebreast cancer brain metastases. Breast Cancer Res Treat 2018;171:637–48.

33. Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histol-ogy, multiplicity, surgery, and survival. Cancer 1996;78:1781–8.

34. Niwi�nska A, Tacikowska M, Murawska M. The effect of early detectionof occult brain metastases in HER2-positive breast cancer patientson survival and cause of death. Int J Radiat Oncol Biol Phys 2010;77:1134–9.






2019;25:2433-2441. Published OnlineFirst December 28, 2018.Clin Cancer Res Sara A. Hurvitz, Joyce O'Shaughnessy, Ginny Mason, et al. Survival from SystHERsMetastatic Breast Cancer: Patient Characteristics, Treatment, and Central Nervous System Metastasis in Patients with HER2-Positive

Updated version

10.1158/1078-0432.CCR-18-2366doi:

Access the most recent version of this article at:

Material

Supplementary

http://clincancerres.aacrjournals.org/content/suppl/2018/12/28/1078-0432.CCR-18-2366.DC1

Access the most recent supplemental material at:

Cited articles

http://clincancerres.aacrjournals.org/content/25/8/2433.full#ref-list-1

This article cites 29 articles, 6 of which you can access for free at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected]

To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://clincancerres.aacrjournals.org/content/25/8/2433To request permission to re-use all or part of this article, use this link



http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-18-2366

http://clincancerres.aacrjournals.org/content/suppl/2018/12/28/1078-0432.CCR-18-2366.DC1

http://clincancerres.aacrjournals.org/content/25/8/2433.full#ref-list-1

http://clincancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]

http://clincancerres.aacrjournals.org/content/25/8/2433


central nervous system metastasis in patients with her2...

Documents