Neuro-oncology perspective of treatment options in metastatic breast cancer.

Breast cancer (BC) is a heterogeneous disease. Different subtypes of BC exhibit a peculiar natural history, metastatic potential and outcome. Stereotactic radiosurgery is the most used treatment for brain metastases (BM), while surgery is reserved for large and symptomatic lesions. Whole-brain radiotherapy is employed in multiple BM not amendable to radiosurgery or surgery, and it is not employed any more following local treatments of a limited number of BM. A critical issue is the distinction from pseudoprogression or radionecrosis, and tumor regrowth. Considering the increase of long-term survivors after combined or novel treatments for BM, cognitive dysfunctions following whole-brain radiotherapy represent an issue of utmost importance. Neuroprotective drugs and innovative radiotherapy techniques are being investigated to reduce this risk of cognitive sequelae. Leptomeningeal disease represents a devastating complication, either alone or in association to BM, thus targeted therapies are employed in HER2-positive BC brain and leptomeningeal metastases.

[1]  V. Prasad,et al.  Frequency and level of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond approvals of the US Food and Drug Administration: retrospective observational study , 2018, British Medical Journal.

[2]  Edward S. Kim,et al.  Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  R. Soffietti,et al.  Imaging and clinical end points in brain metastases trials. , 2017, CNS oncology.

[4]  W. Curran,et al.  Single-Fraction Stereotactic Radiosurgery (SRS) Alone Versus Surgical Resection and SRS for Large Brain Metastases: A Multi-institutional Analysis. , 2017, International journal of radiation oncology, biology, physics.

[5]  A. Akabane,et al.  A Multi-institutional Prospective Observational Study of Stereotactic Radiosurgery for Patients With Multiple Brain Metastases (JLGK0901 Study Update): Irradiation-related Complications and Long-term Maintenance of Mini-Mental State Examination Scores. , 2017, International journal of radiation oncology, biology, physics.

[6]  J. Buckner,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. , 2017, The Lancet. Oncology.

[7]  P. Wen,et al.  Brain Metastases in Newly Diagnosed Breast Cancer: A Population-Based Study , 2017, JAMA oncology.

[8]  Nicholas B. Levine,et al.  Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. , 2017, The Lancet. Oncology.

[9]  N. Turner,et al.  Targeting PIK3CA-mutant advanced breast cancer in the clinical setting. , 2017, The Lancet. Oncology.

[10]  M. Robson,et al.  OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). , 2017 .

[11]  E. Perez,et al.  Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial , 2017, Breast Cancer Research and Treatment.

[12]  E. Winer,et al.  TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). , 2017 .

[13]  A. Seidman,et al.  Characteristics and Outcomes of Patients With Breast Cancer With Leptomeningeal Metastasis , 2017, Clinical breast cancer.

[14]  S. Chia,et al.  Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC) , 2017, Clinical Cancer Research.

[15]  Sung-Bae Kim,et al.  Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial. , 2016, JAMA oncology.

[16]  C. Anders,et al.  Multidisciplinary Management of Breast Cancer Brain Metastases. , 2016, Oncology.

[17]  E. Winer,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. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  H. Lanfermann,et al.  Radiation injury versus malignancy after stereotactic radiosurgery for brain metastases: impact of time-dependent changes in lesion morphology on MRI , 2016, Neuro-oncology.

[19]  H. Steiger,et al.  5-ALA fluorescence of cerebral metastases and its impact for the local-in-brain progression , 2016, Oncotarget.

[20]  W. Curran,et al.  Comparing Preoperative With Postoperative Stereotactic Radiosurgery for Resectable Brain Metastases: A Multi-institutional Analysis. , 2016, Neurosurgery.

[21]  Volker W Stieber,et al.  Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. , 2016, JAMA.

[22]  V. Esposito,et al.  Single-Fraction Versus Multifraction (3 × 9 Gy) Stereotactic Radiosurgery for Large (>2 cm) Brain Metastases: A Comparative Analysis of Local Control and Risk of Radiation-Induced Brain Necrosis. , 2016, International journal of radiation oncology, biology, physics.

[23]  Kwang Hee Kim,et al.  Eribulin Mesylate Combined with Local Treatment for Brain Metastasis from Breast Cancer: Two Case Reports , 2016, Journal of breast cancer.

[24]  L. Carey,et al.  Changing Natural History of HER2–Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies , 2016, Clinical breast cancer.

[25]  S. Tolaney,et al.  Assessment of concentrations of abemaciclib and its major active metabolites in plasma, CSF, and brain tumor tissue in patients with brain metastases secondary to hormone receptor positive (HR+) breast cancer. , 2016 .

[26]  G. Romieu,et al.  Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases , 2016, Breast Cancer Research and Treatment.

[27]  A. Viale,et al.  Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  D. Vordermark,et al.  Radiotherapy of brain metastases from breast cancer: Treatment results and prognostic factors. , 2016, Oncology letters.

[29]  Ricardo J. Komotar,et al.  The role of 5-aminolevulinic acid in brain tumor surgery: a systematic review , 2016, Neurosurgical Review.

[30]  Chien-Kuo Wang,et al.  Differentiating Radiation-Induced Necrosis from Recurrent Brain Tumor Using MR Perfusion and Spectroscopy: A Meta-Analysis , 2016, PloS one.

[31]  Robert T. Jones,et al.  Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. , 2015, Cancer discovery.

[32]  H. Steiger,et al.  Early postoperative magnet resonance tomography after resection of cerebral metastases , 2015, Acta Neurochirurgica.

[33]  Martin Bendszus,et al.  Response assessment criteria for brain metastases: proposal from the RANO group. , 2015, The Lancet. Oncology.

[34]  E. Shaw,et al.  Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  J. Olson,et al.  Hypofractionated radiosurgery has a better safety profile than single fraction radiosurgery for large resected brain metastases , 2015, Journal of Neuro-Oncology.

[36]  Akash J. Patel,et al.  Impact of surgical methodology on the complication rate and functional outcome of patients with a single brain metastasis. , 2015, Journal of neurosurgery.

[37]  Yasuyoshi Watanabe,et al.  64Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients , 2015, EJNMMI Research.

[38]  Chiun-Sheng Huang,et al.  Bevacizumab Preconditioning Followed by Etoposide and Cisplatin Is Highly Effective in Treating Brain Metastases of Breast Cancer Progressing from Whole-Brain Radiotherapy , 2015, Clinical Cancer Research.

[39]  R. Weil,et al.  Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. , 2015, Neuro-oncology.

[40]  S. Margolin,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. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  Lang Li,et al.  Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients , 2015, Journal of Neuro-Oncology.

[42]  K. Blackwell,et al.  Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[43]  Wolfgang A Tome,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. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  J. Suh Hippocampal-avoidance whole-brain radiation therapy: a new standard for patients with brain metastases? , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  P. Wen,et al.  Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials. , 2014, Neuro-oncology.

[46]  J. Baselga,et al.  Safety profile of Pertuzumab with Trastuzumab and Docetaxel in patients from Asia with human epidermal growth factor receptor 2-positive metastatic breast cancer: results from the phase III trial CLEOPATRA. , 2014, The oncologist.

[47]  Satoshi Suzuki,et al.  Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. , 2014, The Lancet. Oncology.

[48]  Walter F. Wiggins,et al.  A new treatment paradigm: neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence. , 2014, International journal of radiation oncology, biology, physics.

[49]  B. Lippitz,et al.  Stereotactic radiosurgery in the treatment of brain metastases: the current evidence. , 2014, Cancer treatment reviews.

[50]  Samuel T Chao,et al.  Challenges with the diagnosis and treatment of cerebral radiation necrosis. , 2013, International journal of radiation oncology, biology, physics.

[51]  M. Mehta,et al.  Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). , 2013, International journal of radiation oncology, biology, physics.

[52]  P. Brown,et al.  Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. , 2013, Neuro-oncology.

[53]  C. Perou,et al.  Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[54]  M. Duffy,et al.  Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer , 2013, Oncotarget.

[55]  V. Esposito,et al.  Health-related quality of life in elderly patients with newly diagnosed glioblastoma treated with short-course radiation therapy plus concomitant and adjuvant temozolomide. , 2013, International journal of radiation oncology, biology, physics.

[56]  M. Dimopoulos,et al.  Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis , 2013, Breast Cancer Research and Treatment.

[57]  Li Ding,et al.  Activating HER2 mutations in HER2 gene amplification negative breast cancer. , 2013, Cancer discovery.

[58]  P. Venuturumilli,et al.  Rapid clinical and radiographic improvement after intrathecal trastuzumab and methotrexate in a patient with HER-2 positive leptomeningeal metastases , 2013, Acta oncologica.

[59]  Steven D Chang,et al.  Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases. , 2012, International journal of radiation oncology, biology, physics.

[60]  S. Ambudkar,et al.  Neratinib Reverses ATP-Binding Cassette B1-Mediated Chemotherapeutic Drug Resistance In Vitro, In Vivo, and Ex Vivo , 2012, Molecular Pharmacology.

[61]  J. Joo,et al.  Risk for leptomeningeal seeding after resection for brain metastases: implication of tumor location with mode of resection. , 2012, Journal of neurosurgery.

[62]  J. Polli,et al.  Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer , 2012, Pharmaceutical Research.

[63]  Chris Twelves,et al.  Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study , 2011, The Lancet.

[64]  Mafalda Oliveira,et al.  Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab , 2011, Breast Cancer Research and Treatment.

[65]  L. Collette,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. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[66]  M. Mehta,et al.  Why avoid the hippocampus? A comprehensive review. , 2010, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[67]  Karen Gelmon,et al.  Metastatic behavior of breast cancer subtypes. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  A. Baschnagel,et al.  Surgical Resection of Brain Metastases and the Risk of Leptomeningeal Recurrence in Patients Treated With Stereotactic Radiosurgery. , 2009, International journal of radiation oncology, biology, physics.

[69]  K. Hess,et al.  Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. , 2009, The Lancet. Oncology.

[70]  R. Greil,et al.  Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer , 2009, Clinical Cancer Research.

[71]  R. Béliveau,et al.  Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep‐2 , 2008, British journal of pharmacology.

[72]  Hans-Jakob Steiger,et al.  Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial , 2008, Journal of Neuro-Oncology.

[73]  Kelly A. Harmon,et al.  The Role of Efflux and Uptake Transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions , 2008, Drug Metabolism and Disposition.

[74]  D. Kondziolka,et al.  TUMOR BED RADIOSURGERY AFTER RESECTION OF CEREBRAL METASTASES , 2008, Neurosurgery.

[75]  Akash J. Patel,et al.  Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to the posterior fossa. , 2008, Journal of neurosurgery.

[76]  M. Casey,et al.  A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses , 2008, Breast Cancer Research and Treatment.

[77]  H. Shirato,et al.  Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. , 2007, International journal of radiation oncology, biology, physics.

[78]  M. Vogelbaum,et al.  Resectable brain metastases. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[79]  Maria Werner-Wasik,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 , 2004, The Lancet.

[80]  B. Pestalozzi,et al.  Trastuzumab in CSF. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[81]  G. Duncan,et al.  A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis , 1996, Cancer.

[82]  Ronald Brand,et al.  Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery , 1993, Annals of neurology.

[83]  Y Maruyama,et al.  A randomized trial of surgery in the treatment of single metastases to the brain. , 1990, The New England journal of medicine.

[84]  L. Deangelis,et al.  Radiation‐induced dementia in patients cured of brain metastases , 1989, Neurology.

[85]  Eudocia Q Lee,et al.  Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group. , 2018, The Lancet. Oncology.

[86]  W. Gradishar,et al.  Developmental therapeutics for patients with breast cancer and central nervous system metastasis: current landscape and future perspectives. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[87]  L. Collette,et al.  A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[88]  M. Campone,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. , 2013, The Lancet. Oncology.

[89]  Kelly A. Harmon,et al.  The Role of Efflux and Uptake Transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions , 2008, Drug Metabolism and Disposition.

[90]  P. Brown,et al.  Properly Selected Patients with Multiple Brain Metastases May Benefit from Aggressive Treatment of their Intracranial Disease , 2004, Journal of Neuro-Oncology.

[91]  M. Mehta,et al.  A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. , 1996, International journal of radiation oncology, biology, physics.