Breast joint clinic ( tumor board) Oct 1 , 2016
 
Case presentation : Management of breain metastasis in breast cancer

  41yrs Female , history of breast cancer 1393(T2N0) BCT & ALND  

Pathology:  IDC , ER+ , PR+, LN 11/11 positive

Chemotherapy/RTx/HR therapy -Tamoxifen

 CC: convulsion-frontal mass

Brain mass Excision-metastatic carcinoma ER-/PR-/Her2-/Ki67 10%

Joint recommendation:   Brain XRT/ Chemotherapy
 
Discussion:
Specialized treatment options are available for patients with breast cancer with metastases to selective anatomic sites.(1) Breast cancer represents the second most frequent cause of brain metastases after lung cancer, with metastases occurring in 10–16 % of patients . In addition, autopsy studies have demonstrated another 10 % which were asymptomatic . (2)  The diagnosis of breast cancer brain metastases (BCBMs) is associated with the shortest survival time compared with other sites of metastatic spread. Incidence rates of brain metastasis are highest in those with human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC; defined as estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative disease) and lowest in ER-positive disease(3).

Current Treatment Strategies for BCBMs
 Improvements in survival in metastatic breast cancer achieved through chemotherapy and trastuzumab-based treatment have led to an increase in the incidence of central nervous system metastases, especially those with HER2-overexpressing or hormone receptor–negative tumors.(1)Patients with leptomeningeal disease may achieve symptomatic improvement with WBI or, in some cases, intrathecal chemotherapy with methotrexate or cytarabine. Very limited clinical experience suggests that some systemic therapies, including endocrine treatments, chemotherapy agents including anthracyclines, alkylators, and capecitabine, and lapatinib, may have antitumor activity in the brain. However, none of these are a substitute for local therapy to the brain(1).
Treatment options for patients with breast cancer brain metastases are limited and include surgical resection, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), chemotherapy and targeted therapy. Surgical resection of the brain metastasis is an important treatment option in patients  with single or few (≤3)lesions. Particularly when the systemic disease is well controlled and when the brain metastases are symptomatic. Three non-randomized studies have also confirmed improvements in survival, brain recurrence and neurological outcomes with surgical resection in addition to WBRTIn patients with limited brain metastases who are deemed poor candidates for surgical resection or who have lesions in difficult anatomic locations, SRS has been proposed as an alternative treatment option.(2) When a patient has a small number of tumors or a large tumor that is significantly compressing surrounding tissue, or when obtaining a tissue sample for diagnosis is critical, surgical resection and stereotactic radiosurgery (SRS) are usually considered. SRS is typically used in patients with surgically inaccessible metastases and in those who are not surgical candidates. (3) This approach delivers a high-precision photon radiation to a small target volume while sparing most normal brain tissues. In patients with solitary metastases who are treated with surgical resection plus WBRT, the addition of SRS to the tumor bed can improve local control. One of the most important treatments available for brain metastases is WBRT, particularly in the setting of multiple brain lesions. This approach has two main goals—the control of macroscopic metastases, and the eradication of microscopic seeding of the brain. The majority of patients are given conventional WBRT, a total dose of 30 Gy in 10 fractions with daily fractions of 3–4 Gy. The mainstay of systemic treatment for breast cancer brain metastases is cytotoxic chemotherapy; however, there are currently additional options for targeted therapy.(2) Key determinants in the management of symptomatic BCBMs include the number, size, and site of lesions; the status of extracranial metastases; and the performance status of the patient. (3) For patients with a single brain metastasis, surgical resection can improve overall survival, particularly in symptomatic patients when systemic disease is well controlled. The addition of SRS to the tumor bed or WBRT improve local control.(2)  For patients with one to four brain metastases, SRS with or without WBRT should be considered to improve local control. If WBRT is added, we recommend to delay its administration as much as possible to prevent neurocognitive decline, which is particularly important in the absence of overall survival benefit. For patients with progressive systemic disease at the time of development of brain metastases, a change in systemic therapy should be considered based on the tumor subtype. For patients with non-progressive systemic disease at the time of development of brain metastases, systemic therapy should not be changed. For each patient, the choice of systemic therapy should be considered based on the tumor subtype. For patients with poor prognosis, options include WBRT and/or best supportive care.(2)
Most chemotherapy agents and HER2 targeted therapies do not cross the intact BBB or are pumped out of the central nervous system (CNS) by P-glycoproteins present in the BBB, therefore they may not reach sufficient therapeutic levels to eradicate metastatic cells. Patients with brain metastases from triple-negative breast cancer unfortunately lack targeted therapies and chemotherapy is currently their only systemic option.(2) Also, several clinical studies have shown that the combination of chemotherapy with trastuzumab improved survival, even after the development of brain metastases . This benefit is presumed to be mainly due to improved control of systemic disease. The efficacy of anti-HER2 therapy to control systemic disease for longer periods of time has exposed the ability of the HER2-positive breast cancer cells to seed the brain parenchyma and develop brain metastases. Lapatinib, a small molecule with potential ability to cross the BBB, has been extensively tested in the treatment of HER2-positive brain metastases. As a single agent, lapatinib has shown response rates in the brain ranging from 2.6 to 6 % in heavily pre-treated patients. However, when added to capecitabine, response rates increase to 20 to 33% . (2) Newer in vivo positron emission tomography (PET) imaging data in a limited number of patients using 89Zr-trastuzumab have demonstrated CNS uptake of trastuzumab into brain metastases, indicating that at least in some patients, trastuzumab can cross a disrupted BBB(3).  
In the setting of ER-positive BCBMs, key determinants of outcome from the time of CNS recurrence are the overexpression of the HER2 receptor and treatment with HER2-directed therapies. Median survival times from time of diagnosis of BCBMs in the ER-positive/HER2-negative and ER-positive/HER2-positive subsets were 10 months and 22.7 months, respectively, with the former outcome similar to that in the TNBC subset (median survival time, 7 months). A likely explanation is that many of these patients have hormone-refractory disease by the time CNS metastases appear, therefore rendering this class of treatment of limited value when used alone(3).

Novel Therapies for BCBMs
The ideal systemic therapy for BCBMs should specifically target ligands that are expressed by tumor cells and are responsible for the tumorigenic phenotype, should adequately penetrate the BBB, should effectively control extracranial disease, and should be relatively well tolerated. Although a therapy that is designed specifically for BCBMs and fulfills all these criteria has not yet been developed, the majority of novel approaches to therapy for BCBMs build on promising efficacy demonstrated in the context of extracranial metastasis. PI3K pathway–directed therapy: BKM120 is an oral, pan-PI3K inhibitor that penetrates the BBB. A phase I/II study of the combination of trastuzumab and BKM120 in patients who have relapsed on trastuzumab is underway, with an expansion cohort in patients with HER2-positive BCBMs. VEGF inhibitors and PARP inhibitors are other therapies under investigation(3).

References:
1-DeVita, Hellman, and Rosenberg’s Cancer Principles & Practice of Oncology 10th Edition-1152
2-Breast cancer brain metastases: the last frontierLeone and Leone Exp Hematol Oncol (2015) 4:33 DOI 10.1186/s40164-015-0028-8
3-Updates on the Management of Breast Cancer Brain MetastasesPublished on Cancer Network http://www.cancernetwork.com) 



 




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