Toward Precision Medicine in Brain Metastases

Anna S. Berghoff; Priscilla K. Brastianos

doi:10.1055/s-0038-1627469

Seminars in Neurology, Table of Contents

Semin Neurol 2018; 38(01): 095-103
DOI: 10.1055/s-0038-1627469

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Toward Precision Medicine in Brain Metastases

Authors

Anna S. Berghoff

¹Clinical Cooperation Unit Neuro-Oncology, German Cancer Research Center, Heidelberg, Germany

²Clinical Unit for Experimental Oncology Therapy, Thoraxklinik, University of Heidelberg, Heidelberg, Germany
Priscilla K. Brastianos

³Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

⁴Division of Neuro-Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

⁵Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

⁶Broad Institute, Boston, Massachusetts

Abstract

Brain metastases (BMs) reflect an area of high clinical need, as up to 40% of patients with metastatic cancer will develop this morbid and highly fatal complication. Historically, treatment strategies have relied on local approaches including radiosurgery, whole-brain radiotherapy, and neurosurgical resection. Recently, targeted and immune-modulating therapies have shown promising responses and have been introduced in the clinical management of patients with BMs. Recent improvements in genomic technologies have enriched our understanding of BMs and have demonstrated that BMs present with significant genetic divergence from the originating primary tumor, such that potentially targetable genetic alterations are detected only in the BMs. However, this genetic divergence also results in genetic alterations associated with resistance to targeted therapies. A deeper insight on the genetic alterations of BMs and the interaction with the brain microenvironment will likely reveal new treatment targets, moving toward more precision therapies for patients with BMs.

Keywords

brain metastases - branched evolution - targeted therapies - clinical trials

Full Text

References

References
1 Soffietti R, Abacioglu U, Baumert B. , et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol 2017; 19 (02) 162-174
2 Chukwueke U, Batchelor T, Brastianos P. Management of brain metastases in patients with melanoma. J Oncol Pract 2016; 12 (06) 536-542
3 Borghaei H, Paz-Ares L, Horn L. , et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373 (17) 1627-1639
4 Robert C, Long GV, Brady B. , et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372 (04) 320-330
5 Brastianos PK, Curry WT, Oh KS. Clinical discussion and review of the management of brain metastases. J Natl Compr Canc Netw 2013; 11 (09) 1153-1164
6 Osswald M, Blaes J, Liao Y. , et al. Impact of blood-brain barrier integrity on tumor growth and therapy response in brain metastases. Clin Cancer Res 2016; 22 (24) 6078-6087
7 Kienast Y, von Baumgarten L, Fuhrmann M. , et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 2010; 16 (01) 116-122
8 Berghoff AS, Schur S, Füreder LM. , et al. Descriptive statistical analysis of a real life cohort of 2419 patients with brain metastases of solid cancers. ESMO Open 2016; 1 (02) e000024
9 Yamamoto M, Kawabe T, Sato Y. , et al. Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2-9 versus 10 or more tumors. J Neurosurg 2014; 121 (Suppl): 16-25
10 Brown PD, Ballman KV, Cerhan JH. , et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2017; 18 (08) 1049-1060
11 Kocher M, Soffietti R, Abacioglu U. , et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011; 29 (02) 134-141
12 Tsai PF, Yang CC, Chuang CC. , et al. Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: a prospective study. Radiat Oncol 2015; 10: 253
13 Bachelot T, Romieu G, Campone M. , et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol 2013; 14 (01) 64-71
14 Liu W, Laitinen S, Khan S. , et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med 2009; 15 (05) 559-565
15 Lu YW, Zhang HF, Liang R. , et al. Colorectal cancer genetic heterogeneity delineated by multi-region sequencing. PLoS One 2016; 11 (03) e0152673
16 Brastianos PK, Carter SL, Santagata S. , et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 2015; 5 (11) 1164-1177
17 Chen G, Chakravarti N, Aardalen K. , et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin Cancer Res 2014; 20 (21) 5537-5546
18 Bos PD, Zhang XH, Nadal C. , et al. Genes that mediate breast cancer metastasis to the brain. Nature 2009; 459 (7249): 1005-1009
19 Haueis SA, Kränzlin P, Mangana J. , et al. Does the distribution pattern of brain metastases during BRAF inhibitor therapy reflect phenotype switching?. Melanoma Res 2017; 27 (03) 231-237
20 Duchnowska R, Dziadziuszko R, Trojanowski T. , et al; Polish Brain Metastasis Consortium. Conversion of epidermal growth factor receptor 2 and hormone receptor expression in breast cancer metastases to the brain. Breast Cancer Res 2012; 14 (04) R119
21 Gow CH, Chang YL, Hsu YC. , et al. Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer. Ann Oncol 2009; 20 (04) 696-702
22 Capper D, Berghoff AS, Magerle M. , et al. Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. Acta Neuropathol 2012; 123 (02) 223-233
23 Preusser M, Berghoff AS, Ilhan-Mutlu A. , et al. ALK gene translocations and amplifications in brain metastases of non-small cell lung cancer. Lung Cancer 2013; 80 (03) 278-283
24 Berghoff AS, Bartsch R, Wöhrer A. , et al. Predictive molecular markers in metastases to the central nervous system: recent advances and future avenues. Acta Neuropathol 2014; 128 (06) 879-891
25 Hanssen A, Wagner J, Gorges TM. , et al. Characterization of different CTC subpopulations in non-small cell lung cancer. Sci Rep 2016; 6: 28010
26 Wrage M, Ruosaari S, Eijk PP. , et al. Genomic profiles associated with early micrometastasis in lung cancer: relevance of 4q deletion. Clin Cancer Res 2009; 15 (05) 1566-1574
27 Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 2002; 3 (01) 53-57
28 Berghoff AS, Preusser M. The inflammatory microenvironment in brain metastases: potential treatment target?. Linchuang Zhongliuxue Zazhi 2015; 4 (02) 21
29 Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in immune privilege of the CNS. Nat Immunol 2017; 18 (02) 123-131
30 Mansfield AS, Aubry MC, Moser JC. , et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol 2016; 27 (10) 1953-1958
31 Berghoff AS, Fuchs E, Ricken G. , et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. OncoImmunology 2015; 5 (01) e1057388
32 Berghoff AS, Ricken G, Widhalm G. , et al. Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology 2015; 66 (02) 289-299
33 Goldberg SB, Gettinger SN, Mahajan A. , et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016; 17 (07) 976-983
34 Margolin K, Ernstoff MS, Hamid O. , et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012; 13 (05) 459-465
35 Chen Q, Boire A, Jin X. , et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 2016; 533 (7604): 493-498
36 Osswald M, Jung E, Sahm F. , et al. Brain tumour cells interconnect to a functional and resistant network. Nature 2015; 528 (7580): 93-98
37 Hohensee I, Chuang HN, Grottke A. , et al. PTEN mediates the cross talk between breast and glial cells in brain metastases leading to rapid disease progression. Oncotarget 2017; 8 (04) 6155-6168
38 Zhang L, Zhang S, Yao J. , et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 2015; 527 (7576): 100-104
39 Lyle LT, Lockman PR, Adkins CE. , et al. Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer. Clin Cancer Res 2016; 22 (21) 5287-5299
40 Morikawa A, Peereboom DM, Thorsheim HR. , et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro Oncol 2015; 17 (02) 289-295
41 Choo EF, Ly J, Chan J. , et al. Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib. Mol Pharm 2014; 11 (11) 4199-4207
42 Vaidhyanathan S, Mittapalli RK, Sarkaria JN, Elmquist WF. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab Dispos 2014; 42 (08) 1292-1300
43 Gallo JM, Li S, Guo P, Reed K, Ma J. The effect of P-glycoprotein on paclitaxel brain and brain tumor distribution in mice. Cancer Res 2003; 63 (16) 5114-5117
44 Kemper EM, Verheij M, Boogerd W, Beijnen JH, van Tellingen O. Improved penetration of docetaxel into the brain by co-administration of inhibitors of P-glycoprotein. Eur J Cancer 2004; 40 (08) 1269-1274
45 Wang F, Zhou F, Kruh GD, Gallo JM. Influence of blood-brain barrier efflux pumps on the distribution of vincristine in brain and brain tumors. Neuro Oncol 2010; 12 (10) 1043-1049
46 Iusuf D, Teunissen SF, Wagenaar E, Rosing H, Beijnen JH, Schinkel AH. P-glycoprotein (ABCB1) transports the primary active tamoxifen metabolites endoxifen and 4-hydroxytamoxifen and restricts their brain penetration. J Pharmacol Exp Ther 2011; 337 (03) 710-717
47 Poller B, Iusuf D, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Differential impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on axitinib brain accumulation and oral plasma pharmacokinetics. Drug Metab Dispos 2011; 39 (05) 729-735
48 Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther 2012; 342 (01) 33-40
49 Kort A, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Brain accumulation of the EML4-ALK inhibitor ceritinib is restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2). Pharmacol Res 2015; 102: 200-207
50 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12 (04) 252-264
51 Steeg PS. Perspective: the right trials. Nature 2012; 485 (7400): S58-S59
52 Pivot X, Manikhas A, Żurawski B. , et al. CEREBEL (EGF111438): a phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 2015; 33 (14) 1564-1573
53 Lin NU, Winer EP. Brain metastases: the HER2 paradigm. Clin Cancer Res 2007; 13 (06) 1648-1655
54 Berghoff AS, Rajky O, Winkler F. , et al. Invasion patterns in brain metastases of solid cancers. Neuro Oncol 2013; 15 (12) 1664-1672
55 Ilhan-Mutlu A, Osswald M, Liao Y. , et al. Bevacizumab prevents brain metastases formation in lung adenocarcinoma. Mol Cancer Ther 2016; 15 (04) 702-710
56 Bartsch R, Berghoff A, Pluschnig U. , et al. Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases. Br J Cancer 2012; 106 (01) 25-31
57 Bartsch R, Rottenfusser A, Wenzel C. , et al. Trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer. J Neurooncol 2007; 85 (03) 311-317
58 Lin NU, Lee EQ, Aoyama H. , et al; Response Assessment in Neuro-Oncology (RANO) group. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group. Lancet Oncol 2013; 14 (10) e396-e406
59 Sperduto PW, Kased N, Roberge D. , et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012; 30 (04) 419-425
60 Kondziolka D, Parry PV, Lunsford LD. , et al. The accuracy of predicting survival in individual patients with cancer. J Neurosurg 2014; 120 (01) 24-30
61 Berghoff AS, Wolpert F, Holland-Letz T. , et al. Combining standard clinical blood values for improving survival prediction in patients with newly diagnosed brain metastases-development and validation of the LabBM score. Neuro Oncol 2017; 19 (09) 1255-1262
62 Furtner J, Berghoff AS, Albtoush OM. , et al. Survival prediction using temporal muscle thickness measurements on cranial magnetic resonance images in patients with newly diagnosed brain metastases. Eur Radiol 2017; 27 (08) 3167-3173
63 Kumar P, Singh B, Ghai A. , et al. Preclinical evaluation of (99m)Tc labeled gefitinib as a potential scintigraphic probe for the detection of tumors expressing epidermal growth factor receptors. Appl Radiat Isot 2015; 99: 41-45
64 Kurihara H, Hamada A, Yoshida M. , et al. (64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients. EJNMMI Res 2015; 5: 8
65 Preusser M, Winkler F, Collette L. , et al. Trial design on prophylaxis and treatment of brain metastases: lessons learned from the EORTC Brain Metastases Strategic Meeting 2012. Eur J Cancer 2012; 48 (18) 3439-3447
66 Ou SH, Ahn JS, De Petris L. , et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol 2016; 34 (07) 661-668
67 Brastianos HC, Cahill DP, Brastianos PK. Systemic therapy of brain metastases. Curr Neurol Neurosci Rep 2015; 15 (02) 518
68 Brastianos PK, Cahill DP. Management of brain metastases in the era of targeted and immunomodulatory therapies. Oncology (Williston Park) 2015; 29 (04) 261-263
69 Dagogo-Jack I, Gill CM, Cahill DP, Santagata S, Brastianos PK. Treatment of brain metastases in the modern genomic era. Pharmacol Ther 2017; 170: 64-72
70 Lin NU, Wefel JS, Lee EQ. , et al; Response Assessment in Neuro-Oncology (RANO) group. Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group. Lancet Oncol 2013; 14 (10) e407-e416
71 Kim JE, Lee DH, Choi Y. , et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer 2009; 65 (03) 351-354
72 Gadgeel SM, Shaw AT, Govindan R. , et al. Pooled analysis of CNS response to alectinib in two studies of pretreated patients with ALK-positive non-small-cell lung cancer. J Clin Oncol 2016; 34 (34) 4079-4085
73 Crinò L, Ahn MJ, De Marinis F. , et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J Clin Oncol 2016; 34 (24) 2866-2873
74 Long GV, Trefzer U, Davies MA. , et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13 (11) 1087-1095
75 McArthur GA, Maio M, Arance A. , et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol 2017; 28 (03) 634-641
76 Davies MA, Saiag P, Robert C. , et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017; 18 (07) 863-873