This review summarizes the most up-to-date approach to the multidisciplinary management of patients with breast cancer brain metastases. A brief overview of the epidemiology and biology of breast cancer brain metastasis is provided. The perspectives of radiation oncology, neurosurgery, and medical oncology—and landmark studies from each discipline—are all discussed. We also offer practical tips to help guide the treating physician, including data on antiseizure medications. Finally, we introduce the concept of a multidisciplinary clinic that combines input from medical and radiation oncology, neurosurgery, and support services, which we developed at the University of North Carolina as a coordinated and optimal approach to the management of patients with this complex disease.
Brain metastases are a challenging consequence of advanced cancer. It is estimated that there are over 150,000 cases of brain metastases diagnosed annually across all tumor types. Breast cancer is among the solid tumors that most commonly metastasize to the brain, along with lung cancer, kidney cancer, colorectal cancer, and melanoma. While brain metastases associated with various solid tumors do share some similarities in presentation and management, it is important to recognize that there are innate differences between the metastases of the varying tumor histologies. These differences include, but are not limited to, host demographics, the presence and/or control of extracranial disease, systemic therapy options, and unique prognosis. Even among breast cancer brain metastases, inherent differences between the breast cancer subtypes exist and should be considered when counseling patients on treatment decisions and discussing long-term prognosis. Moreover, many clinical trials, particularly trials of local therapy, have historically enrolled patients with brain metastases from a variety of cancer types. Recognizing the differences in treatment options and outcomes as the field moves forward will help individualize the multidisciplinary management of patients diagnosed with breast cancer brain metastases. Here we review the most up-to-date management of brain metastases arising from breast cancer, including both local therapy—neurosurgery and radiation—and systemic therapy. We also review the evolving knowledge surrounding the biology of breast cancer brain metastases and the many ongoing clinical trials that are evaluating novel therapies for treating this aggressive disease.
Epidemiology and Biology
Six distinct molecular subtypes of breast cancer have been identified by genetic analyses: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, basal-like, claudin-low, and normal breast–like. Clinically, the luminal A and B subtypes express hormone receptors (HRs; estrogen receptors and/or progesterone receptors), while the HER2-enriched subtype often demonstrates HER2 receptor mutational activation and/or genetic amplification (HER2-positive clinical subtype). Breast tumors that lack expression of any of the foregoing receptors are considered triple-negative breast cancer (TNBC). Each subtype exhibits a different metastatic pattern. Luminal tumors tend to metastasize to the bones and lungs.[4-7] HER2-enriched primary tumors often metastasize to the liver, brain, lungs, and bone, with one-third of patients with advanced HER2-enriched disease developing brain metastases.[4-8] Metastatic TNBC spreads to the brain in up to one-half of patients with advanced disease, as well as to the lungs.[4-7,9] Moreover, once brain metastases occur, prognosis varies by subtype. Niwinska et al showed that the average survival of breast cancer patients with brain metastases following whole-brain radiotherapy (WBRT) and systemic therapy across all subtypes was 10 months, ranging from ~12 months for those with luminal or HER2-positive cancer to only 4 months in patients with TNBC. More recent data from the era of evolving HER2-targeted therapies demonstrate survival following a diagnosis of HER2-positive brain metastases to be greater than 3 years.[11,12] Different rates of necrosis and immune cell infiltration among the subtypes of breast cancer brain metastases may contribute to the differences in outcomes.
These differences in metastatic patterns and prognosis across breast cancer subtypes suggest an innate biological characteristic within some primary tumors, or in a certain population of cells within some tumors, that may drive or enhance brain metastases. Less differentiated, more stem cell–like breast cancer cells and tumors are correlated with brain metastatic potential and brain relapse in patients. Breast cancer brain metastases are genetically distinct from primary breast cancer and extracranial metastases; breast cancer brain metastases show chromosomal alterations, including amplification of 5q and deletions on 17p, 21p, and Xq, which may be specific drivers of breast cancer brain metastases. Dozens of proteins involved in several key signaling pathways regulating cell motility, extravasation, blood-brain barrier disruption, and brain seeding have been shown to enhance brain metastatic potential in breast cancer cells and to correlate with brain metastases in patients.[16-18] Compared with primary breast tumors, breast cancer brain metastases demonstrate increased activation of several important oncogenic pathways, including the phosphoinositide 3-kinase (PI3K)/AKT[15,19] and MAPK/ERK pathways.
In addition to the innate biologic predilection of certain breast cancer cells for colonizing the brain, both breast cancer brain metastasis cells and normal brain cells in the surrounding microenvironment continue to evolve during the growth and progression of metastases. Breast cancer brain metastasis cells change and adapt to their new brain niche by expressing neural genes, which enable the utilization of the neurotransmitter γ-aminobutyric acid (GABA) as a brain-specific oncometabolite.[21,22] Overexpression of HER family receptors, particularly HER3, may permit breast cancer brain metastasis cells to use members of the neuregulin family of neural growth factors to enhance their growth and survival through activation of the PI3K and MAPK pathways.[20,23] Breast cancer brain metastasis cells also signal to neighboring normal brain cells, including neural progenitor cells and astrocytes, to create a permissive microenvironment to enhance the growth and survival of breast cancer brain metastases.[24-27] The findings just discussed regarding the biology of breast cancer brain metastases demonstrate that although these metastases are complicated and unique, even relative to other breast cancer metastases, there are several potential therapeutic strategies worth pursuing.
Diagnosis and Initial Management
Brain metastases should be suspected in a patient with a history of breast cancer of any stage who presents with unexplained neurologic symptoms. Initial symptoms could be vague, including difficulty with word finding, executive function, or headache—or they could be more profound, such as loss of motor function or seizures. Prompt neuroimaging, specifically gadolinium-enhanced magnetic resonance imaging (MRI) of the brain, should be obtained, assuming there are no contraindications. If brain metastases are confirmed by imaging, the immediate goal is to stabilize neurologic symptoms with corticosteroid treatment (dexamethasone) prior to initiation of definitive treatment. The European Federation of Neurological Societies (EFNS) has recommended doses of dexamethasone of between 4 mg and 8 mg orally daily; however, the authors recommend a starting dose of 16 mg divided into 3 or 4 doses per day, with a taper as tolerated. The role of antiepileptic medications in the initial management of brain metastases has shifted over the decades. Historically, antiepileptics, including phenytoin, carbamazepine, valproic acid, and more recently, levetiracetam, were prescribed to all patients at diagnosis of brain metastases, regardless of seizure activity. The EFNS has updated this approach and now only recommends anticonvulsants for patients who have experienced a seizure. To avoid interactions with systemic therapies, it is recommended that non–enzyme-inducing agents (eg, levetiracetam) be prescribed if possible.
Surgical resection has an important role in the treatment of brain metastasis, but with the efficacy and availability of radiosurgery, the indications for surgery have evolved. The main indication for surgery is removal of a tumor mass that is large and causing neurologic symptoms. Surgery quickly reduces these symptoms, both because of the removal of the tumor itself, and because of the rapid reduction in edema that follows successful tumor resection. Surgery can lead to improved neurocognitive function as compared with a patient’s own presurgical neurocognitive state, and can be performed with low mortality and morbidity. Cysts associated with tumors, and intratumoral hemorrhage, such as that often seen in metastases from melanoma, complicate radiosurgery by increasing effective treatment volume—but paradoxically they can make surgery easier, as rapid decompression of a cyst or clot reduces intraoperative swelling. As a very general guideline, lesions larger than 3 cm are usually better treated with resection. A second key indication for surgery is the need for tissue diagnosis of malignancy. Two common time points in the course of disease where such tissue is needed are at first presentation of the cancer (brain metastasis with unknown primary; synchronous presentation of primary and brain metastasis with symptomatic brain lesion) or at first apparent occurrence of any metastasis. This is especially true if the primary was low-risk or remote. With increasing frequency, discussions are held regarding the need for tissue from the metastasis to investigate tissue-based and molecular markers. Location can also play a role in the decision for surgery, particularly for lesions in the posterior fossa, where there is less room for edema or tumor growth prior to development of significant symptoms. Finally, in the postradiosurgery setting, surgery may be indicated both to differentiate radiation necrosis from true progression and as definitive treatment for radiosurgery failures.
The role of surgery is most clearly defined for single metastases (Figure). Early studies clearly showed that in patients with a reasonable life expectancy, surgical resection preceding radiation prolonged survival compared with fractionated WBRT alone (40 weeks vs 15 weeks).[30,31] More recent studies suggest that surgery used alone is associated with relatively high local recurrence rates (46% at 1 year, 59% at 2 years),[32,33] which has led to increased use of surgery followed by some form of radiation, with a growing trend toward surgery-radiosurgery rather than surgery-WBRT. The role of surgical resection for multiple metastases is less well defined, but it appears that surgery that resects all existing brain metastases can have an outcome similar to that of surgery for a single lesion. Whenever possible, en bloc resection is preferred to piecemeal resection, since the latter may be associated with increased recurrence rates. Because it provides tissue for pathology and investigation of molecular markers, and because it can most rapidly reverse neurologic deficits associated with tumor mass, edema, and/or hemorrhage, surgery remains a valuable treatment for metastases to the brain.
1. Ewend MG, Morris DE, Carey LA, et al. Guidelines for the initial management of metastatic brain tumors: role of surgery, radiosurgery, and radiation therapy. J Natl Compr Canc Netw. 2008;6:505-13; quiz 14.
2. Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer. 1996;78:1781-8.
3. Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5:5-23.
4. Niwinska A, Murawska M, Pogoda K. Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT). Ann Oncol. 2010;21:942-8.
5. Kennecke H, Yerushalmi R, Woods R, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28:3271-7.
6. Harrell JC, Prat A, Parker JS, et al. Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res Treat. 2012;132:523-35.
7. Smid M, Wang Y, Zhang Y, et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res. 2008;68:3108-14.
8. Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972-7.
9. Lin NU, Claus E, Sohl J, et al. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer. 2008;113:2638-45.
10. Niwinska A, Murawska M, Pogoda K. Breast cancer subtypes and response to systemic treatment after whole-brain radiotherapy in patients with brain metastases. Cancer. 2010;116:4238-47.
11. McKee MJ, Keith K, Deal AM, et al. A multidisciplinary breast cancer brain metastases clinic: the University of North Carolina Experience. Oncologist. 2016;21:16-20.
12. Mounsey L, Deal AM, Benbow JM, et al. A changing natural history of HER2-positive breast cancer metastatic to the brain in the era of new, targeted therapies. J Clin Oncol. 2016;34(suppl):abstr 584.
13. McKee MJ, Trembath DG, Deal AM, et al. Histopathological markers at craniotomy and outcome in breast cancer brain metastases. J Clin Oncol. 2015;33(suppl):abstr 2027.
14. Salhia B, Kiefer J, Ross JT, et al. Integrated genomic and epigenomic analysis of breast cancer brain metastasis. PLoS One. 2014;9:e85448.
15. Brastianos PK, Carter SL, Santagata S, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 2015;5:1164-77.
16. Malin D, Strekalova E, Petrovic V, et al. alphaB-Crystallin: a novel regulator of breast cancer metastasis to the brain. Clin Cancer Res. 2014;20:56-67.
17. Bos PD, Zhang XH, Nadal C, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459:1005-9.
18. Tayyeb B, Parvin M. Pathogenesis of breast cancer metastasis to brain: a comprehensive approach to the signaling network. Mol Neurobiol. 2016;53:446-54.
19. Adamo B, Deal AM, Burrows E, et al. Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases. Breast Cancer Res. 2011;13:R125.
20. Da Silva L, Simpson PT, Smart CE, et al. HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer. Breast Cancer Res. 2010;12:R46.
21. Neman J, Termini J, Wilczynski S, et al. Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc Natl Acad Sci USA. 2014;111:984-9.
22. Van Swearingen AED, Siegel MB, Anders CK. Breast cancer brain metastases: evidence for neuronal-like adaptation in a ‘breast-to-brain’ transition? Breast Cancer Res. 2014;16:304.
23. Mendes O, Kim HT, Lungu G, Stoica G. MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2. Clin Exp Metastasis. 2007;24:341-51.
24. Neman J, Choy C, Kowolik CM, et al. Co-evolution of breast-to-brain metastasis and neural progenitor cells. Clin Exp Metastasis. 2013;30:753-68.
25. Fitzgerald DP, Palmieri D, Hua E, et al. Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin Exp Metastasis. 2008;25:799-810.
26. Gril B, Palmieri D, Qian Y, et al. Pazopanib inhibits the activation of PDGFRbeta-expressing astrocytes in the brain metastatic microenvironment of breast cancer cells. Am J Pathol. 2013;182:2368-79.
27. Witzel I, Oliveira-Ferrer L, Pantel K, et al. Breast cancer brain metastases: biology and new clinical perspectives. Breast Cancer Res. 2016;18:8.
28. Soffietti R, Cornu P, Delattre JY, et al. EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force. Eur J Neurol. 2006;13:674-81.
29. Brem S, Meyers CA, Palmer G, et al. Preservation of neurocognitive function and local control of 1 to 3 brain metastases treated with surgery and carmustine wafers. Cancer. 2013;119:3830-8.
30. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322:494-500.
31. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33:583-90.
32. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280:1485-9.
33. 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;29:134-41.
34. Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg. 1993;79:210-6.
35. Patel AJ, Suki D, Hatiboglu MA, et al. Factors influencing the risk of local recurrence after resection of a single brain metastasis. J Neurosurg. 2010;113:181-9.
36. Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol. 2012;2:210-25.
37. Chao JH, Phillips R, Nickson JJ. Roentgen-ray therapy of cerebral metastases. Cancer. 1954;7:682-9.
38. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745-51.
39. 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;30:419-25.
40. Grubb CS, Jani A, Wu CC, et al. Breast cancer subtype as a predictor for outcomes and control in the setting of brain metastases treated with stereotactic radiosurgery. J Neurooncol. 2016;127:103-10.
41. Dyer MA, Kelly PJ, Chen YH, et al. Importance of extracranial disease status and tumor subtype for patients undergoing radiosurgery for breast cancer brain metastases. Int J Radiat Oncol Biol Phys. 2012;83:e479-e486.
42. Sahgal A, Aoyama H, Kocher M, et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2015;91:710-7.
43. Sperduto PW, Kased N, Roberge D, et al. Effect of tumor subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases. Int J Radiat Oncol Biol Phys. 2012;82:2111-7.
44. Subbiah IM, Lei X, Weinberg JS, et al. Validation and development of a modified breast graded prognostic assessment as a tool for survival in patients with breast cancer and brain metastases. J Clin Oncol. 2015;33:2239-45.
45. Yang TJ, Oh JH, Folkert MR, et al. Outcomes and prognostic factors in women with 1 to 3 breast cancer brain metastases treated with definitive stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2014;90:518-25.
46. Akyurek S, Chang EL, Mahajan A, et al. Stereotactic radiosurgical treatment of cerebral metastases arising from breast cancer. Am J Clin Oncol. 2007;30:310-4.
47. Tsao MN, Lloyd N, Wong RK, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012:CD003869.
48. Kordbacheh T, Law WY, Smith IE. Sanctuary site leptomeningeal metastases in HER-2 positive breast cancer: a review in the era of trastuzumab. Breast. 2016;26:54-8.
49. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363:1665-72.
50. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295:2483-91.
51. Sanghavi SN, Miranpuri SS, Chappell R, et al. Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys. 2001;51:426-34.
52. Park HS, Wang EH, Rutter CE, et al. Changing practice patterns of Gamma Knife versus linear accelerator-based stereotactic radiosurgery for brain metastases in the US. J Neurosurg. 2016;124:1018-24.
53. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10:1037-44.
54. Brown PD, Asher AL, Ballman KV, et al. NCCTG N0574 (Alliance): a phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. J Clin Oncol. 2015;33(suppl):abstr LBA4.
55. Minniti G, Scaringi C, Paolini S, et al. Repeated stereotactic radiosurgery for patients with progressive brain metastases. J Neurooncol. 2016;126:91-7.
56. Kaidar-Person O, Zagar TM, Ewend M, et al. Frameless LINAC-based stereotactic radiation therapy to brain metastasis resection cavity without whole-brain radiation therapy: a systematic review. Pract Radiat Oncol. 2016;6:324-30.
57. Robbins JR, Ryu S, Kalkanis S, et al. Radiosurgery to the surgical cavity as adjuvant therapy for resected brain metastasis. Neurosurgery. 2012;71:937-43.
58. Ahmed KA, Freilich JM, Abuodeh Y, et al. Fractionated stereotactic radiotherapy to the post-operative cavity for radioresistant and radiosensitive brain metastases. J Neurooncol. 2014;118:179-86.
59. Jairam V, Chiang VL, Yu JB, Knisely JP. Role of stereotactic radiosurgery in patients with more than four brain metastases. CNS Oncol. 2013;2:181-93.
60. Serizawa T, Hirai T, Nagano O, et al. Gamma knife surgery for 1-10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria. J Neurooncol. 2010;98:163-7.
61. Tannock IF, Ahles TA, Ganz PA, Van Dam FS. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol. 2004;22:2233-9.
62. Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group study 91-04. Int J Radiat Oncol Biol Phys. 2001;51:711-7.
63. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15:1429-37.
64. Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32:3810-6.
65. Lin NU, Dieras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15:1452-9.
66. Lin NU, Eierman W, Greil R, et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol. 2011;105:613-20.
67. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-91.
68. Keith KC, Lee Y, Ewend MG, et al. Activity of trastuzumab-emtansine (TDM1) in HER2-positive breast cancer brain metastases: a case series. Cancer Treat Commun. 2016;7:43-6.
69. Kalsi R, Feigenberg S, Kwok Y, et al. Brain metastasis and response to ado-trastuzumab emtansine: a case report and literature review. Clin Breast Cancer. 2015;15:e163-e166.
70. Bartsch R, Berghoff AS, Vogl U, et al. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin Exp Metastasis. 2015;32:729-37.
71. Freedman RA, Gelman RS, Wefel JS, et al. Translational Breast Cancer Research Consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2016;34:945-52.
72. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520-9.
73. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25-35.
74. Anders CK, Adamo B, Karginova O, et al. Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer. PLoS One. 2013;8:e61359.
75. Tang SC, Bates S, Kesari S, et al. A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases. Cancer Res. 2016;76(suppl):abstr P6-17-04.
76. Karginova O, Siegel MB, Van Swearingen AE, et al. Efficacy of carboplatin alone and in combination with ABT888 in intracranial murine models of BRCA-mutated and BRCA-wild-type triple-negative breast cancer. Mol Cancer Ther. 2015;14:920-30.