molecular subtyping of brain metastases and implications for therapy

Current Treatment Options in OncologyDOI 10.1007/s11864-013-0248-2

Neuro-oncology (GJ Lesser, Section Editor)

Molecular Subtyping of BrainMetastases and Implicationsfor TherapyJaclyn J. Renfrow, MD1

Glenn J. Lesser, MD, FACP2*

Address1Department of Neurosurgery, Wake Forest Baptist Medical Center,Medical Center Boulevard, Winston-Salem, NC 7157-1082, USA2, *Department of Internal Medicine, Section on Hematology and Oncology,Comprehensive Cancer Center of Wake Forest University,Medical Center Boulevard, Winston-Salem, NC 27157-1082, USAEmail: [email protected]

* Springer Science+Business Media New York 2013

Keywords Targeted therapy I Cancer I Brain metastases I Small-molecule inhibitor

Opinion statement

Molecular subtyping of tumors and treatment with specifically targeted therapy is a rapidly de-veloping trend in oncology. Genetic and protein biomarkers impact biological behavior, patientprognosis, and inform treatment options. Select examples include EGFR mutations in primarynon-small cell lung cancers, Her2 overexpression in breast cancer, and BRAF mutations in mel-anoma. Systemic benefit is emphasized in targeted therapies; yet lung cancer, breast cancer,andmelanoma comprise themost commondiagnoses in patientswith brainmetastasesmakingthe effectiveness of targeted therapies in the treatment and/or prevention of brain metastasesrelevant.Emerging evidence suggests efficacy for targeted therapy in the setting of brain me-tastases. Randomized, phase III clinical trials indicate targeted HER2 treatment with lapatiniband capecitabine in brain metastases from breast cancer increases the time to progression anddecreases the frequency of CNS involvement at progression. Phase II trials and retrospectivereviews for gefitinib and erlotinib demonstrate these agents may have a role in both the che-moprevention of brainmetastases and, in combinationwithWBRT, treatment for non-small celllung cancer (NSCLC) brain metastases. Dabrafenib and other BRAF inhibitors have demonstrat-ed improved survival in patientswith brainmetastases frommelanoma in a recent phase II clin-ical trial. Further data that support the use of these agents are the subject of several activeclinical trials. Challenges and future directions for targeted therapies in brain metastases in-clude both better characterization and drug design with respect to central nervous system dis-tribution. Limited published data demonstrate suboptimal CNS distribution of currentlyavailable targeted chemotherapeutic agents. Increasing systemic dosing, alternate deliverymethods, and new compounds with improved CNS distribution are being pursued. Additionally,eventual resistance to targeted therapies poses a challenge; however, research is showing re-

sistance mutations are conserved and relatively predictable creating opportunities for second-line therapies with additional targeted drugs. Newer targeted therapies represent an additionalchemotherapeutic option for the treatment and/or prevention of brain metastases in patientswith an appropriate molecular profile.

IntroductionUp to 40 % of all cancer patients will develop meta-static disease in the brain [1]. This percentage con-tinues to increase with improvements in brainimaging and systemic disease control [2]. Primary his-tology most commonly found in the brain, in decreas-ing order of incidence, is lung, breast, unknownprimary, and melanoma. The incidence of single vs.multiple sites of CNS metastasis is approximatelyequal. The majority of metastasis are supratentorial(80 %) with the cerebellum and brain stem compris-ing 15 % and 5 % respectively [3].

Outcomes for patients with brain metastases areheterogeneous. Treatment choice and goals varywith prognosis and are informed through the useof clinical grading scales. Recursive PartitioningAnalysis (RPA) divides patients into three catego-ries based on Karnofsky Performance Status(KPS), age, and primary tumor control with pa-tients in Group I having a better prognosis thanpatients in Group III [4•]. Multiple studies havestratified patients using RPA analysis and demon-strate Group III patients may not survive longenough to benefit from aggressive measures. Ofthe variables considered in the RPA score, perfor-mance status is strongly correlated with outcomeand should be evaluated consistently and docu-mented. An updated assessment tool, the GradedPrognostic Assessment (GPA), evaluates the prog-nosis of patients with brain metastases while alsotaking consideration of the primary tumor diagno-sis [5•]. Histology also carries prognostic signifi-cance along with subcategories that are histologydependent. Age and extracranial disease are prog-nostic in lung cancer patients, whereas number ofmetastases is prognostic for melanoma patients.Tumor subtype based on HER2/ER/PR status andage are prognostic for breast cancer and is expand-ed upon with a specific Breast-GPA, currently inuse for Radiat ion Therapy Oncology Group(RTOG) trials [6].

Treatment options usually include a combina-tion of steroids, radiation, and surgery. Chemother-apy has historically had a limited role in thetreatment of brain metastases. Few chemotherapeu-tic agents are able to achieve good blood brainbarrier (BBB) penetration. Additionally, manybrain metastases arise from heavily pretreated sys-temic tumors and may be intrinsically resistant tochemotherapeutics. Patients with symptomaticbrain metastases on average survive 1 month with-out therapy, whereas the addition of systemic ste-roids affords an additional month of survival [7].Whole-brain radiotherapy (WBRT) and steroids fur-ther extend median survival to 3-6 months [8].Multimodal treatment including surgery or radio-surgery for local tumor control combined withWBRT for regional CNS tumor control results inmedian survival on the order of 9-14 months inselected patients. Of these modalities, treatmentstrategies are patient-specific and informed throughtreatment goal discussions along with clinical grad-ing scale prognostic categories.

With the advent of tumor molecular profiling,established cancer-specific biomarkers help to elu-cidate underlying tumor biology. Cancer common-ly shows activation, dysregulation, and addictionto oncogenic signaling pathways. Interruption ofaberrant signaling through targeted therapy hasshown success in systemic treatment and representsanother treatment option for patients with brainmetastases. Some targeted agents act on commonlyimplicated oncogenic pathways without biomarkerscreening; an example is multitargeted tyrosine ki-nase inhibitors: sorafenib and sunitinib. Othertargeted agents are clinically indicated only afterscreening for a known molecular marker. Ideally,molecular marker analysis serves to divide the can-cer into subtypes with distinct outcomes and/or re-sponsiveness to specific chemotherapies. Important


breast cancer markers include HER2, estrogen recep-tor, and progesterone receptor status. Non-smallcell lung cancer subtypes include EGFR mutatedand ALK rearranged. BRAF mutation detection se-lects a population of patients with melanoma re-

sponsive to a specific drug class. The discussionbelow includes evidence for agents active againstscreened biomarkers in brain metastases from sys-temic breast, non-small cell lung, and melanomamalignancies.

TreatmentInterventional procedures

Radiotherapy is the primary treatment modality for the treatment ofbrain metastases. Both whole brain radiotherapy and stereotactic radio-surgery are therapeutic options. Both modalities also are used in combi-nation with surgery.

Whole Brain Radiotherapy (WBRT)Doses vary between 20 and 40 Gy delivered in 5-20 fractions.& As a single modality, local tumor control rate of 48% [9] but up to half

of patients die from intracranial progression with a median survival of3-6 months [7, 8, 10].

& Shown to improve neurological symptoms in 64-85 % of patientswith minimal morbidity [11].

& No improvement in overall survival or neurologic symptoms withalternative dose-fractionation schedules as compared to 3000 cGy in10 daily fractions.

& Six radiosensitizer trials have failed to confer additional benefit toWBRT.

Stereotactic Radiosurgery (SRS)Marginal doses of 24, 18, or 15 Gy according to the tumor volume.& Early studies were designed to add SRS in combination with the

existing standard of WBRT and demonstrated median survival ad-vantage (6.5 months vs. 4.9 months, p=0.0393) and KPSimprovement for patients with a single, unresectable brainmetastases [12].

& A meta-analysis of trials investigating combined WBRT plus SRS orWBRT alone for single or multiple brain metastases did not support asurvival benefit from the combined treatment; however, KPS andlocal control were significantly better with WBRT plus SRS [13].

& Later studies evaluated SRS as a single modality, omitting WBRT.& As a single modality, SRS local tumor control rates range between 74-

94 % at 1 year; however, approximately 50 % of patients will developnew intracranial metastases within one year [14•] demonstrating theneed for surveillance imaging and follow-up.

Therapy for Molecularly Defined Brain Metastases Renfrow and Lesser

& Three randomized controlled trials investigated SRS alone versusWBRT plus SRS [3]. Two trials demonstrated no difference inoverall survival (hazard ratio (HR) 0.98, 95 % confidence interval(CI) 0.71-1.35, p=0.88), yet the addition of WBRT significantlyimproved local (HR 2.61, 95 % CI 1.68-4.06, pG0.0001) anddistant (HR 2.15, 95 % CI 1.55-2.99, pG0.00001) control [15••,16]. The third trial closed and did not report overall survival databut concluded patients treated with WBRT plus SRS were morelikely to show a decline in learning and memory; however, thiswas assessed at only one time point (4 months) [17].

& These studies suggest no survival disadvantage for SRS as a single mo-dality. In combinationwith concern for cognitive side effects fromWBRT,SRS is a commonly employed treatment strategy for brain metastases.

SurgeryThe surgical literature reveals surgery can be beneficial in treating up to threebrain metastases with the strongest evidence for single metastases. Other ben-efits of surgery include the ability to establish a tissue diagnosis, decreasemass effect immediately (especially in posterior fossa lesions), improveCSF flow, and decrease the disease burden for adjuvant therapies. Studies al-so have shown surgery in combination with radiation can improve survivaland preserve functional independence.

Surgical resection& Used in combination with either whole brain or stereotactic radiation.& Three Phase III studies address surgery in the treatment of single brain

metastases [18–20]. Two of the studies found a statistically significantincrease in median overall survival when surgery was added to WBRT.The third study did not find a significant difference but included pa-tients with more advanced systemic disease and lower performancestatus.

& Two Phase III studies demonstrated a preservation of functional in-dependence when surgery was added to WBRT [18, 20].

& Three retrospective reviews investigated the role of surgery in the case ofmultiple brain metastases (three or fewer) [21–23]. Gross total resec-tion of all metastases improved survival over subtotal resections andwas equivalent to survival achieved in the resection of singlemetastases.

& Patient selection including tumor location, medical comorbidities,and functional/performance status impact each individual case forconsideration of surgical resection.

Pharmacologic treatment – breast cancerCNSmetastases frombreast cancer occur in approximately 15%of patientswithincreased risk in young patients, HER2-positive disease, triple-negative disease(estrogen receptor/progesterone receptor/HER2 receptor), and estrogen receptor(ER)-negative pathology.


HER2 is overexpressed in up to 30 % of breast cancers [24]. A retrospec-tive analysis of 9,524 women in the pretrastuzumab era identified HER2 ex-pression as a risk factor for brain metastases [25]. The incidence of brainmetastases in HER2-positive patients is twice that of unselected breast cancerpatients at 27-31 % [26–30]. Additionally, an increasing percentage of pa-tients develop brain metastases, whereas their systemic disease is controlledusing HER2 directed therapies [29]. A retrospective case series from Claytonet al. reported 23 of 93 (25 %) patients developed brain metastasesposttrastuzumab therapy and of those patients 78 % of them had stable orbetter systemic disease.

HER2 status is assessed at the protein level by immunohistochemistry and("interpreted as 0, 1+, 2+, or 3.") Tumors with 0 and 1+ staining areHER2-negativeand tumors with 3+ staining are HER2-positive. Tumors with 2+ staining are con-sidered indeterminate and generally are sent for FISH (fluorescent in situ hybridiza-tion) analysis to determine the presence of HER2 amplification at the genetic level.

Breast cancer – HER2 inhibitors

Trastuzumab 4 mg/kg IV loading dose followedby 2 mg/kg weekly

& Trastuzumab is a humanized monoclonal antibody that targets theextracellular domain of HER2. Trastuzumab is FDA-approved for theadjuvant treatment of breast cancer alone or in combination with che-motherapy for patients with tumors that overexpress theHER2 receptor.

& Patterns of relapse in trastuzumab-treated patients, specifically the de-velopment of brainmetastases, have been thoroughly investigated. Datafrom three retrospective studies are inconclusive [31–33]. A meta-anal-ysis using data from three large phase III trials indicated the incidence ofCNS disease was significantly higher in the trastuzumab treated patientscompared with the nontrastuzumab treated patients [34].

& Although HER2-positive tumors demonstrate a tropism for CNSspread, it also has been noted that the superior survival from HER2-targeted therapy may permit more time for brain metastases to de-velop. The average incidence of brain metastases in nonselected pa-tients is 33 months postdiagnosis [35]. In a retrospective review of201 patients with HER2-positive metastatic breast cancer, treatmentwith trastuzumab improved median overall survival 41 vs.13 months (pG0.001) [36] extending survival in these patients pastthe median time of brain metastasis incidence.

& Trastuzumab’s high molecular weight, approximately 700 times thatpermitted by the BBB, also may create a sanctuary site in the CNS forHER2-positive tumors and its limited CSF bioavailability hindersefficacy in treating brain metastases [37].

Pertuzumab 8 mg/kg IV loading dose followedby 6 mg/kg every 21 days

& Pertuzumab is an intravenously delivered monoclonal anti-HER2 an-


tibody that inhibits the dimerization of HER2with other HER receptors(including EGFR, HER3, and HER4). Pertuzumab is FDA-approved incombination with trastuzumab and docetaxel for patients with HER2-positive, metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

& In the pivotal Phase III trial, trastuzumab plus docetaxel were com-pared with trastuzumab plus docetaxel plus pertuzumab for first-linetreatment of HER2 metastatic breast cancer. Median overall survivalfor the pertuzumab group was 18.5 months vs. 12.4 months in theplacebo group (pG0.001) [38]. The presence of CNS metastases metexclusion criteria and little is known about potential central nervoussystem activity at present. The molecular weight of pertuzumab is148 kDa. Although several factors ultimately contribute to the abilityof a substance to cross the blood brain barrier selectivity is likely formolecules greater than 200-400 Da.

Trastuzumab-Emtansine (TDM1/Kadcyla) 3.6 mg/kg IVevery 21 days

& TDM1 is an intravenously delivered antibody-drug conjugate incor-porating anti-HER2 properties of trastuzumab with the cytotoxicanti-microtubule properties of DM1. TDM1 is FDA-approved forHER2-positive, metastatic breast cancer.

& Data on TDM1 in patients with brain metastases are lacking as cur-rent clinical trials exclude symptomatic or recently treated brainmetastases. However, TDM1 was compared to lapatinib pluscapecitabine in the pivotal phase III clinical trial and demonstrated asuperior progression-free survival of 9.6 months vs. 6.4 months (pG0.001) [39]. This may pose an interesting treatment decision forpatients with known brain metastases where lapatinib pluscapecitabine may be beneficial yet the efficacy of TDM1 is indeter-minate. The molecular weight of TDM1 is approximately 150 kDa.

Breast cancer - Tyrosine Kinase Inhibitors (TKI)

Lapatinib 1,250 mg/day

& Lapatinib is an orally available dual HER1 and HER2 inhibitor.Lapatinib is FDA approved for the treatment of HER2 overexpressingmetastatic breast cancer in combination with capecitabine in patientswho have received prior therapy, including an anthracycline, ataxane, and trastuzumab. Lapitinib also is FDA-approved in combi-nation with letrozole for postmenopausal hormone receptor andHER2-positive metastatic breast cancer patients.

& As a single agent in breast cancer patients with brain metastases,lapatinib produced a low rate of radiographic response andprompted alternative treatment strategies to be utilized [40, 41].

& A single-arm Phase II trial (LANDSCAPE) [42] evaluated the activity


of lapatinib plus capecitabine in 45 patients with HER2-positivebreast cancer and brian metastases. The CNS-objective response ratewas 67 % with a median time to progression (TTP) of 5.5 months.

& A Phase III trial [43], including 399 women with HER2-positive,locally advanced, or metastatic breast cancer previously treated withanthracycline-, taxane-, and trastuzumab-containing regimens wererandomized to either lapatinib plus capecitabine or capecitabine. Theaddition of lapatinib prolonged TTP with a HR of 0.57 (95 % CI0.43-0.77; pG0.001) and fewer patients had CNS involvement at firstprogression (4 vs. 13, p=0.045).

Neratinib (HKI-272) 240-340 mg/day

& Neratinib is an orally available potent irreversible pan-ErbB tyrosinekinase inhibitor with antitumor activity in advanced HER2-positivebreast cancer [44].

& A phase II trial is currently underway for patients with HER2-positivebreast cancer and brain metastases (NCT01494662) with recruitmentending in February 2014.

Breast cancer – other targeted agents

Iniparib 8 mg/kg IV twice-weekly on Days 1, 4, 8,and 11 every 21 days

& Iniparib was originally classified as a Poly(adenosine diphosphate-ribose)polymerases (PARPs) inhibitor but later shown to act through adifferent unknownmechanism [45]. Clinical interest lies in its reportedactivity in triple negative breast cancer.

& A Phase Ib of Iniparib and 125 mg/m2 irinotecan in 34 patients withmetastatic breast cancer reported an overall response rate of 31.8 %.Sixty-five percent of the patients in this cohort were triple-negative(HER2/ER/PR) [46].

& Results are pending from the recently closed Phase II trial(NCT01173497) investigating iniparib in combination with irinotecanin triple-negative breast cancer patients with brain metastasis.

Pharmacologic treatment – Non-Small Cell Lung Cancer (NSCLC)CNS metastases occur in approximately 40 % of patients with lung cancerwith up to 10 % present at the time of initial diagnosis [47, 48]. Chemother-apy, radiation, and surgical measures in patients with stage III NSCLC haveimproved survival and systemic disease control with a 5-year relative survivalof 26.1 %. The prognosis for patients with stage IV lung cancer remains chal-lenging with a 1-year survival rate of 10 % [49]. Surviving patients who had acomplete response after neoadjuvant chemotherapy or chemoradiotherapycommonly experience CNS failure with an incidence of brain metastases in40-55 % of surviving patients at 3 years [50]. The high rate of CNS failureindicates a particular need for improved therapies for brain metastases in


lung cancer patients.EGFR mutations are present in 10-25 % of NSCLC, with the highest prev-

alence (up to 55 %) found in never-smoking women of East Asian descent[50]. EGFR mutations in patients with brain metastases may be more com-mon with two reports analyzing patients with NSCLC and brain metastasesfinding EGFR mutations to be present in 63 % and 50 % of patients, raisingthe question whether patients with EGFR mutations have an increased risk ofdeveloping brain metastases [51, 52]. EGFR mutation analysis is performedby Sanger dideoxy terminator sequencing of exons 18-21 with sensitizingmutations commonly including deletions in exon 19, duplications in exon19, deletion-insertions of exon 19, L858R point mutation, L861Q point mu-tation, and G719 missense point mutation [51, 52].

Activation of the ALK oncogene occurs in approximately 8 % of patients withNSCLC and is due to the inversion of chromosome band 2p23 resulting in fusionof the anaplastic lymphoma kinase (ALK) and the echinodermmicrotubule-asso-ciated protein-like 4 (EML4) genes. This fusionmost frequently occurs in youngerpatients (52 vs. 60 yr), adenocarcinomas (often with signet cells) and never/lightsmokers [53•]. Patients with ALK activation had no increased risk of brainmetas-tasis but did show a higher frequency of liver metastases (23% vs. 10%). Testingfor ALK gene activation is done through FISH.

Non-small cell lung cancer - Tyrosine Kinase Inhibitors (TKI)

Gefitinib/Erlotinib 250-500 mg/day / 150 mg/day

& Gefitinib and Erlotinib are orally available reversible inhibitors of theintracellular domain of EGFR. Gefitinib is FDA-approved for NSCLCwith mutations with EGFR. Erlotinib is approved for locally ad-vanced or metastatic NSCLC that has failed at least one prior che-motherapy regimen or as maintenance treatment for locallyadvanced of metastatic NSCLC whose disease has not progressedafter four cycles of platinum-based first-line chemotherapy.

& There is concern over poor BBB penetration of these agents as CNS re-sponse rates are disproportional to systemic response rates. Serum toCSF comparisons for gefitinib revealed approximately 1.3 % of the se-rum dose represented in the CSF [54]. Erlotinib achieves better CSFdistribution with 2.77 % of the serum dose represented in the CSF [55].Both drugs are near the 400 Da molecular weight range with the bloodbrain barrier retaining selectivity for molecules greater than 200-400 Da.

& Despite concern for optimal bioavailability, gefitinib/erlotinib hasbeen investigated in first-line, palliative, and in combination settingsand is presented as case reports, case series, and threenonrandomized phase II trials. An inherent difficulty interpreting theTKI literature in lung cancer is the paucity of EGFR sequencing dataon patients treated with these drugs, raising the possibility of a di-lution effect by including patients without the targeted mutations.

& Two phase II trials for TKI in the first-line setting include data onpatients with brain metastases [56, 57]. Both studies do not include


sequencing data for EGFR mutations but instead use the clinical in-dicator of never-smokers. Lee et al. reported 36 never-smoker pa-tients, including 10 patients with synchronous brain metastases.Seven of ten patients demonstrated an intracranial objective responseto gefitinib, one patient had stable disease, and two patients hadprogressive disease after a median 48-week follow-up period. Kim etal. reported 23 never-smoker patients with synchronous brain me-tastases with a response rate to either gefitinib or erlotinib of 69% and adisease control rate of 82 %. The median overall survival was18.8 months, and time to salvage WBRT averaged 19.3 months.

& Further evidence for first-lineTKIuse comes froma retrospective analysis of155 patients screened for EGFR mutations [58•]. The rate of CNS pro-gressionwas lower inEGFR-mutantpatientswith advancedNSCLC treatedinitially with erlotinib or gefitinib compared with upfront chemotherapy(33%vs. 48%) at amedian follow-upof 25months, supporting a role forthese drugs in chemoprevention of BM. Median overall survival, on theorder of 30 months, was not different between the two groups.

& Two phase II trials reported on gefitinib in the palliative setting in pa-tients with NSCLC and brain metastases [49, 59]. Patients werenonselected in regards to both EGFR mutational status and clinicalcharacteristics, such as never-smokers. Ceresoli et al. reported 41 patientswith a 10% response rate and disease control rate of 27%. The durationof partial responders was 13.5 months. Median overall survival was5 months. Wu et al. reported 40 patients with a 32 % response rate anddisease control rate of 77 %. Median overall survival was 15 months.

& Erlotinib in combination with WBRT was evaluated in a prospectivephase II trial in 40 patients with brainmetastases fromNSCLC regardlessof EGFR status. The overall response rate was 86 % and the medianoverall survival was 11.8 months. Of these 40 patients EGFR status wasknown in17patients. Interestingly, patients negative for EGFRmutationshad a median overall survival of 9.3 months, whereas patients positivefor EGFR mutations had a median overall survival of 19.1 months [60].

Non-small cell lung cancer - ALK inhibitors

Crizotinib 200-250 mg BID

& Crizotinib is an orally available protein kinase inhibitor that competi-tively binds to the ATP-binding pocket of the ALK and MET tyrosine ki-nases and inhibits phosphorylation of activated ALK. It is FDA-approvedfor locally advanced or metastatic NSCLC that is anaplastic lymphomakinase-positive.

& CNS drug distribution is not well described with low BBB penetra-tion (0.26 % CSF concentration of that in plasma) reported in selectcase reports along with inconsistent clinical responses [61, 62]. Itsmolecular weight is about twice that permitted by the BBB.

& Newer generation ALK inhibitors are in development including LDK378


which demonstrated responses in patients with brain metastases in aPhase I trial [63].

Pharmacologic treatment – melanomaCNS metastases are present in up to 20 % of patients at diagnosis of meta-static melanoma and nearly 50 % of patients develop brain metastasis duringthe course of their disease. Autopsy studies demonstrate an incidence ap-proaching 60 % [64]. Survival after diagnosis of brain metastases is typically17-22 weeks [65]. With current therapy of radiation and surgery, approxi-mately 10 % of patients have a response [66].

Activating BRAF mutations affect up to 60 % of melanoma patients;more than 95 % are the V600E mutation (substitution of valine byglutamic acid at the 600th amino acid position) with the remainderlargely substituted by a lysine (Val600Lys). Constitutive BRAF signalingactivates the MAPK pathway [67•]. Testing for BRAF mutation is assessedthrough the Cobas® 4800 BRAF V600 Mutation Test, an FDA-approvedRT-PCR assay. Of note, there is an antibody VE1 specific for theV600E mutation that will make immunohistochemical testing on paraf-fin-sections possible [68, 69].

Melanoma - BRAF inhibitors

Vemurafenib 960 mg BID

& FDA-approved for the treatment of patients with unresectable ormetastatic melanoma with BRAF V600E mutation.

& Data on patients with brain metastases treated with vemurafenib arelimited to individual cases as the presence of brain metastases hasbeen an exclusion criterion in the existing trials. New trials, includingpatients with brain metastases, are ongoing.

& One case report describes a child with metastatic melanoma to thebrain who demonstrated stable intracranial disease after 6 months oftreatment but also received treatment with steroids and stereotacticradiosurgery during the same time period [70]. Another case series ofthree adults reports vemurafenib controlled systemic disease but leftbrain metastases unabated [71].

Dabrafenib (GSK2118436) 150 mg BID

& Dabrafenib is an oral ATP-competitive inhibitor of BRAF kinase.& Phase I/II study demonstrated regression and some complete re-

sponses of previously untreated asymptomatic brain metastases in asubpopulation of ten patients [72].

& A multicenter, open-label Phase II study (BREAK-MB) evaluateddabrafenib in 172 patients both with and without prior brain ther-apy for BRAF-mutated melanoma metastatic to the brain (V600confirmed) [73•]. The primary outcome measure was overall re-sponse rate observed to be 29/74 (39.2 %) in patients without prior


brain therapy and 20/65 (30.8 %) in patients with prior brain ther-apy. Thus, dabrafenib was helpful in patients with both new andpretreated brain metastases. Duration of response was 20.1 weeks forpatients without prior brain treatment and 28.1 for patients withprior brain treatment. Median overall survival was 33 weeks in pa-tients without prior brain therapy and 31 weeks with prior braintherapy. Historically, survival is 17-22 weeks after diagnosis of brainmetastases in melanoma. The three most frequent serious adverseevents in treated patients were pyrexia (6 %), intracranial hemorrhage(6 %), and squamous cell carcinoma (6 %).

Conflicts of InterestGlenn J. Lesser is a consultant to Genentech and received honoraria from Merck.

Jaclyn J. Renfrow declares that she has no conflict of interest.

Human and Animal Rights and Informed ConsentThis article does not contain any studies with human or animal subjects performed by any of the authors.

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molecular subtyping of brain metastases and implications for therapy

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