Brain Mets From Breast Cancer

How Are Metastatic Brain Tumors Diagnosed

Metastatic brain and spine tumors are not usually diagnosed until symptoms appear. Here are some ways doctors may diagnose a metastatic brain tumor:

• Physical exam: After gathering information about your symptoms and personal and family health history, the doctor proceeds with a physical exam and vision and reflex tests.
• Magnetic resonance imaging
• Diffusion tensor imaging is a type of MRI that visualizes how water molecules pass through parts of the brain. It reveals microscopic differences of tissue structure, including very early infiltration of cancer cells.

Neurosurgery For Brain Metastasis From Breast Cancer

Yusuke Tomita, Kazuhiko Kurozumi, Kentaro Fujii, Yosuke Shimazu, Isao Date

Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , , Japan

Contributions: Conception and design: Y Tomita, K Kurozumi Administrative support: K Kurozumi Provision of study materials or patients: Y Tomita, K Kurozumi Collection and assembly of data: Y Tomita Data analysis and interpretation: Y Tomita Manuscript writing: All authors Final approval of manuscript: All authors.

Correspondence to:

Keywords: Metastatic brain tumor breast cancer neurosurgical technique

Submitted Oct 20, 2019. Accepted for publication Mar 13, 2020.

doi: 10.21037/tcr.2020.03.68

Cancer In The Tissue Around The Brain And Spinal Cord

Sometimes breast cancer spreads to tissues and fluid that surround the brain and spinal cord. This is known as leptomeningeal metastases.

Symptoms are similar to those of secondary breast cancer in the brain, but may be less obvious and more difficult to diagnose.

Its usually diagnosed using an MRI scan, but you may also have a lumbar puncture to take a sample of fluid to be looked at under a microscope.

Treatment can include steroids, radiotherapy and chemotherapy. Chemotherapy or targeted therapy drugs may be given directly into the fluid surrounding the brain and spinal cord to treat the cancer.

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What Are Brain Metastases

Brain metastases are areas of cancer that develop when breast cancer cells travel to the brain and form tumors. Because the brain controls our movements, senses, and more, the affected area in the brain can affect different parts of your life.

You may hear your doctor or others refer to brain metastases as lesions.

Metastatic Brain Tumor Surgery

Surgery provides fast relief of mass effect pressure inside the skull resulting from a growing metastatic tumor and swelling of the brain. Some patients may find improvement of symptoms as early as within hours of surgery if mass effect is what is causing your symptoms.

The goal of surgery is to minimize the amount of space the tumor takes up by debulking, which means removing as much of the tumor as possible while maintaining neurological function.

In general, doctors recommend surgery for metastatic brain cancer when:

• There is a clear link between the symptoms and the tumors location.
• The primary cancer is treatable and under control.
• The tumor can be safely removed.

The most common type of surgery to remove metastatic brain tumors is called a craniotomy, which can be performed through a variety of approaches, including the keyhole craniotomy.

Learn more about brain tumor surgery and recovery.

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Consider A Clinical Trial

Doctors and scientists continue to research new approaches for treating cancer, including brain metastases. These new approaches are tested in clinical trials.

If youre interested in trying an experimental treatment option, talk with your oncology care team about clinical trials that you may be eligible for. You can also find a searchable database of NCI-supported clinical trials

What Causes Brain Metastasis

Right now, doctors dont know exactly how breast cancer cells travel to the brain and begin to grow. The small blood vessels in the brain have a protective inner lining known as the blood-brain barrier, which keeps harmful toxins from getting into the brain. How breast cancer cells break through this barrier isnt well understood. But it is the subject of ongoing research. Some researchers believe certain genetic pathways may help breast cancer cells cross through the blood-brain barrier to cause brain mets.

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Resection Of Cystic Tumors

Cystic brain metastasis of breast cancer is associated with a poor prognosis . In the surgical treatment of cystic tumors, entire removal of the cyst wall is necessary to achieve GTR because of the higher risk of leptomeningeal dissemination . Cyst puncture is sometimes performed to decompress the tumor during surgery, but the boundary between the tumor and the surrounding brain tissue becomes indistinct by cyst shrinkage. Tomita et al. introduced a technique for visualization of the inner cyst wall by injection of pyoktanin blue solution diluted in 0.3% saline. Although tumor dissemination is a potential concern when performing cyst puncture, solidification with fibrin glue might prevent dissemination and enable easier dissection of the tumor from the surrounding brain tissue .

Systematic Screening For The Detection Of Bm

Due to the lack of data demonstrating a clinical benefit, brain screening for patients with MBC is not currently recommended in the US NCCN and ESMO guidelines. Nevertheless, patients at high risk of developing BM could potentially benefit from screening strategies, as an earlier diagnosis could lead to a reduction in WBRT use and enable localised, less toxic and more effective BM treatment in a higher proportion of cases.,, Four studies are exploring the value of systematic radiological screening.

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Chemotherapy For Metastatic Brain Tumors

Because traditional chemotherapy cannot cross the blood-brain barrier, newer treatments called targeted therapy are used as the primary type of chemotherapy for treating metastatic brain tumors.

These drugs identify and attack cancer cells with minimal harm to normal cells while preventing the growth and spread of cancer cells. Targeted therapy can be administered after surgery or in conjunction with radiation therapy to destroy remaining cancer cells.

Targeted therapies used to treat metastatic brain tumors include:

• Trastuzumab for breast cancer that has spread to the brain
• Erlotinib for the most common type of lung cancer that has spread to the brain

Chemotherapy For Treatment Of Breast Cancer Brain Metastases

Until recently, clinical trials for patients with CNS recurrence have typically included administration of standard chemotherapy agents, as single agents or in combination, to patients with a variety of solid tumors or to women with breast cancer in a nonsubtype-specific manner. Past treatment trials for women with breast cancer brain metastases have examined efficacy of treatments such as temozolomide , capecitabinetemozolomide , topotecan , liposomal doxorubicintemozolomide , cisplatinetoposide , and cisplatintemozolomide . Response rates in these studies have ranged from 0% to 38%, with progression-free survival times of 0 to 6 months . One additional study in Singapore attempted to administer liposomal doxorubicin to patients with breast cancer and recurrent CNS disease but terminated prematurely due to slow accrual. Case series and case reports in breast cancer brain metastases have also described mixed results with combination therapies such as cyclophosphamidemethotrexate5-fluorouracil , cyclophosphamidedoxorubicin5-fluorouracil , cyclophosphamide5-fluorouracilprednisone , doxorubicincyclophosphamide , paclitaxel , and carmustinemethotrexate . However, the small sample sizes and tumor heterogeneity included in these studies have limited their impact and applicability in clinical practice.

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Support For Living With Secondary Breast Cancer In The Brain

Everyones experience of being diagnosed with secondary breast cancer is different, and people cope in their own way.

For many people, uncertainty can be the hardest part of living with secondary breast cancer.

You may find it helpful to talk to someone else whos had a diagnosis of secondary breast cancer.

• Chat to other people living with secondary breast cancer on our online Forum.
• Meet other women with a secondary diagnosis and get information and support at a Living with Secondary Breast Cancer meet-up.
• Live Chat is a weekly private chat room where you can talk about whatevers on your mind.

You can also call Breast Cancer Nows Helpline free on 0808 800 6000.

Surgical Strategy For Metastatic Brain Tumors

Complete removal of metastatic brain tumors, termed gross total resection , is the ideal goal in surgical treatment. According to the latest guidelines published by the Congress of Neurological Surgeons, GTR is recommended over subtotal resection to improve overall survival and prolong the time to recurrence . However, recurrence affects about 20% of patients even after treatment with GTR followed by SRS . In contrast to diffusely invading tumors such as gliomas, metastatic brain tumors are more often well demarcated masses surrounded by gliotic tissue . Several reports have shown that supramarginal resection achieved by additional 5-mm surrounding tissue resection from the tumor edge improved the local control rate compared with conventional GTR . Even for brain metastasis in eloquent areas, supramarginal resection can be achieved with awake surgery in many cases . However, supramarginal resection cannot prevent temporary deficits such as supplementary motor area syndrome even with intraoperative neurophysiological monitoring or awake surgery . Therefore, deliberative planning for maximal safe resection with minimal tissue trauma is ideal for both surgeons and patients.

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Potential New Drugs For The Treatment Of Bm

According to the ClinicalTrial.gov site , there are 108 studies on BCBM, of which 24 are recruiting to test new drugs, including poly-ADP ribose polymerase inhibitors , immuno-oncology therapy , CDK4/6 inhibitors , TKIs , phosphatidylinositol 3-kinase inhibitors , ATM inhibitors and BBB disruptors .

Modern Approaches To Brain Cancer Metastases In Breast Cancer

Prognosis and treatment recommendations for patients with breast cancer and brain metastases rely heavily on the tumor subtype however, evolving evidence demonstrates that receptor expression and subtype grouping may change during the course of the patients disease.

The development of brain metastases represents a common complication of a diagnosis of cancer occurring more frequently than primary tumors, with approximately 97,000 to 170,000 new cases diagnosed annually in the United States. In fact, approximately 10% to 30% of all patients with cancer will develop brain metastases at some point during the course of their systemic disease.1 The incidence of brain metastases has increased over the past 10 years as a result of heightened screening in patients who are asymptomatic but deemed high-risk, improvements in diagnostic imaging, the increased availability and efficacy of systemic therapies, and improved survival of patients with cancer. These principles are especially important for patients with breast cancer who represent the second-highest proportion of patients with brain metastases, second to only lung cancer.2

Further, the addition of systemic therapies, such as lapatinib may improve the control rates over SRS alone. In results from a retrospective study, investigators observed a reduction in the risk of local failure as well as a trend to decreased risk of distant intracranial failure with the addition of lapatinib to SRS.

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Crosstalk Between Tumor And Brain Microenvironment

Breast cancer cells also adapt to the local microenvironment in the brain and co-opt neurons, astrocytes and microglial cells to proliferate and establish metastases.

Metastatic breast cells have been shown to develop neuronal characteristics, expressing the GABAA receptor, GABA transporter, GABA transaminase, parvalbumin, and reelin, allowing them to take up GABA, shunt it to nicotinamide adenine dinucleotide phosphate production and facilitate proliferation of the tumor cells in the brain microenvironment . Kim et al. showed that murine astrocytes co-cultured in direct cell-to-cell contact with human breast cancer cells caused up-regulation of survival genes in the tumor cells, thus protecting them from the toxic effects of chemotherapy.

Zhang et al. demonstrated that microRNAs from astrocytes cause human and mouse tumor cells with normal expression of PTEN, to downregulate PTEN expression in the brain environment. The loss of this tumor suppressor gene expression allows proliferation of brain metastases. Subsequent blockade of astrocyte secretion restored PTEN and suppressed brain metastasis in vivo. Loss of PTEN is associated TNBC subtype and portends a shorter survival time. Hohensee et al. showed that upregulation of PTEN in a TNBC cell line led to reduced migration and invasion to the brain. Autocrine and paracrine activation of GM-CSF/CSF2RA and AKT/PTEN pathway on both astrocytes and tumor cells mediated this crosstalk.

Oncolytic Virus Therapy And Gene Therapy

Oncolytic virus therapy has been described as a prospective treatment option that selectively targets cancer. Various types of oncolytic viruses have been engineered to increase the effectiveness of this treatment and have been shown to improve the therapeutic effect in preclinical research . We have also evaluated combination therapy with genetically engineered oncolytic viruses and systemic treatments such as molecular targeting drugs in mouse glioma models . Administration of talimogene laherparepvec into the tumor improved the durable response rates in a randomized phase III clinical trial , for which the FDA approved the use of this oncolytic virus for patients with recurrent melanoma. Moreover, phase I and II trials of HF10 in patients with malignant tumors, including recurrent metastatic breast carcinoma, have been successfully conducted . Although no oncolytic viruses have been approved for the treatment of brain tumors, we are now starting a phase I/II study evaluating the safety and effectiveness of Ad-SGE-REIC in patients with recurrent malignant glioma as gene therapy. Several recent reports have shown the effectiveness of oncolytic viruses against brain metastasis in preclinical models . Therefore, oncolytic viruses and gene therapy can be a clinically applicable therapeutic platform to target metastatic brain tumors from breast cancer.

Figure 2in vitroin vivoet al

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Special/molecular Considerations For Therapy Selection

HER 2 positive breast cancer

Approximately 25% of patients with HER2-positive breast cancer will develop brain metastases. Those with HER2-positive disease have demonstrated a significant survival benefit with the use of systemic anti-HER2 therapy. One proposed mechanism behind the propensity of HER2-positive disease to metastasize to the brain is the inability of trastuzumab to cross the BBB.

HER2-directed therapies for breast cancer can be classified into three subgroups: monoclonal antibodies such as trastuzumab and pertuzumab, small-molecule tyrosine kinase inhibitors such as lapatinib and neratinib, and the antibody-drug conjugate ado-trastuzumab emtansine . The American Society of Clinical Oncology has recommendations on disease management for advanced HER2-positive breast cancer and brain metastases, which we have outlined in Table 1.

Lapatinib with capecitabine is considered a treatment option for progressive brain metastasis and when local therapy has failed, or re-radiation is not feasible, especially when an oral systemic treatment option is preferred. More recently, the TKI neratinib was studied in a phase II trial among 40 patients with HER2-positive breast cancer with brain metastases who had progressed after at least one line of therapy. The intracranial response rates were modest at 8% with this agent.

Current Treatment Options For Bmbc

Current therapeutic options for BM include both local and systemic treatments or a combination of several modalities.,, Regardless of the initial BC subtype, if the estimated life expectancy is greater than 3 months and extra-CNS disease is controlled, it is recommended that cases of up to 10 BM be systematically discussed by multidisciplinary staff. If the estimated life expectancy is less than 3 months, appropriate supportive care, whole-brain radiotherapy or exclusive systemic treatment will be proposed. Given that not only breast cancer but other cancer types were included in the radiotherapy studies detailed in the following paragraphs, the results cannot discard the influence of this variable in the results.

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Characteristics Of Metastatic Brain Tumors Of Breast Cancer

MRI is one of the most reliable modalities with which to evaluate metastatic brain tumors, although very few studies in the literature have reported the relationships between MRI features and the histology of tumors. Yeh et al. retrospectively analyzed the MRI features of brain metastasis from different subtypes of recurrent breast cancer for subclassification. In that study, the patients were categorized as having luminal type, HER-2-enriched type, or triple-negative breast cancers, and all MRI examinations were performed on a 1.5-Tesla MRI scanner. Both the patients with luminal type cancers and those with HER-2 enriched type cancers showed solid tumors with or without perifocal edema, whereas most patients with triple-negative breast cancers showed distinct features of cystic and necrotic lesions. Brain metastatic lesions frequently show characteristics different from those of the primary tumor histologically and genetically , indicating that MRI is a desirable modality with which to explore the tumor nature of brain metastasis .

Other Novel Agents And Ongoing Trials

Given the potential to improve outcome for women with breast cancer brain metastases through careful selection of systemic therapy in concert with established local therapies, brain permeability of many of the emerging and novel therapies pertinent to the treatment of breast cancer is of great interest, both in the preclinical and clinical arenas. Such an example includes the PARP inhibitor ABT-888 which has been shown in preclinical studies to penetrate the BBB in an intracranial glioma model . Presently, a phase I study is evaluating the maximum tolerated dose of ABT-888 in combination with conventional WBRT to treat patients with solid tumors metastatic to the brain . In addition, the efficacy and tolerability of the novel anticancer agent BSI-201 in combination with irinotecan is being examined in a phase II, multicenter study enrolling patients with progressive triple negative breast cancer brain metastases . Finally, a recent report illustrates a high rate of Phosphatidylinositol 3-Kinase pathway activation among a panel of breast cancer brain metastases tissues . Given that there are many PI3K inhibitors in clinical development, some of which cross the BBB, targeting this pathway to treat patients with breast cancer brain metastases is also of great interest.

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Indications For Surgical Treatment

Surgical resection continues to play an important role in patients with a limited number of brain metastases and a relatively good performance status. In the early 1990s, three randomized trials on single brain metastasis were conducted to evaluate the efficacy of surgical resection followed by whole-brain radiation therapy compared with whole-brain radiation therapy alone, and the data indicated that surgical resection significantly prolonged overall survival in patients without active systemic disease and with a higher Karnofsky performance status . According to the JCOG0504 trial, surgical resection followed by salvage stereotactic radiosurgery has been established as a standard therapy for patients with fewer brain metastases . SRS is also the effective alternative to surgical treatment for a single metastasis , but the higher doses of SRS increase the risk of the late effect of radiation necrosis . In addition, brain edema caused by metastatic brain tumors resolves significantly faster after surgical resection than after SRS . Moreover, in patients with neurological symptoms caused by brain lesions of > 3 cm with a mass effect or associated hydrocephalus, surgical resection can immediately alleviate these symptoms . Instead, surgical resection followed by SRS can be considered as standard treatment in patients with a few brain metastases, mainly with lesions of > 3 cm in diameter .