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Breast Cancer Mets To Brain

Potential New Drugs For The Treatment Of Bm

Brain metastases developed from HER2 postive and triple negative breast cancer

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 .

What Are The Major Risk Factors For Brain Metastasis

Scientists do not yet know why breast cancer is more likely to spread to some parts of the body than others, but some factors that increase the risk of spread to the brain have been identified:

  • Being diagnosed with breast cancer while relatively young, particularly before age 35.
  • Having a breast cancer that has already spread to the lungs.
  • Certain subtypes of breast cancer, such as HER2-positive or triple-negative.

Strides Are Being Made In The Treatment Of Brain Metastases From Breast Cancer

New drugsfor HER2-positive breast cancer are able to overcome some of the obstacles that have made brain metastases challenging to treat, according to , the Susy Yuan-Huey Hung Professor of Oncology at Stanford University School of Medicine in California, who described the promising treatment landscape at the 2022 Miami Breast Cancer Conference.1

Specifically, some monoclonal antibodies, antibody-drug conjugates, and targeted agents can penetrate the blood-brain barrier and reach metastatic sites in the central nervous system . Their brain-specific activity has led to improved quality of life and longer overall survival for patients who develop brain metastasis along with breast cancer, said Dr. Pegram, who is also Medical Director of the Clinical and Translational Research Unit and Associate Dean for Clinical Research Quality at Stanford.

As systemic control improves for treating metastatic disease, particularly for HER2-positive breast cancer, the brain is increasingly becoming a sanctuary site. Many patients develop brain metastases when they are actually responding in the extracranial space to anticancer treatments, Dr. Pegram said. Its remarkable how most of our chemotherapeutic drugs have poor penetration of the CNS. By contrast, antitumor antibodies can penetrate the blood-brain barrier and can access tumor targets on cancer cells in the brain.

Therapeutic Breakthroughs

Screening and Treatment

REFERENCES

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Targeting The Sanctuary Site: Options When Breast Cancer Metastasizes To The Brain

Brain metastasis is common in breast cancer and often has a poor prognosis, but there are several ways to manage brain metastasis in breast cancer including focal therapies as well as systemic options for specific populations, including emerging and novel therapies.

ABSTRACT: Brain metastasis is a poor prognostic factor in breast cancer progression, and traditional treatment options have shown minimal response with overall low median survival rates. The incidence of brain metastasis has been increasing despite and, in part, due to advancements in treatment as a result of prolongation of survival. Targeted therapy such anti-HER2 agents have a lower efficacy in this setting compared to metastases elsewhere however, novel therapies are emerging in this regard. In this comprehensive review, we discuss risk per subtype, special considerations for therapy selection, current focal and systemic treatments, and recent advancements and potential future targets for success. We present our treatment paradigm and multidisciplinary approach to brain metastases arising from breast cancer based on the available evidence, incorporating molecular characteristics.

Who Gets Brain Metastasis

Frontiers

While about 15-20 percent of women diagnosed with metastatic breast cancer are eventually diagnosed with brain metastasis, some have a higher risk of developing it than others. Doctors dont know why, but breast cancer that is both HER2-positive and hormone receptor-negative, or triple-negative, is more likely to spread to the brain than hormone receptor-positive breast cancer. You may also be at higher risk for brain metastasis if:

  • You are younger than 50
  • You were diagnosed with lung or liver metastasis in the pastStill, its possible for any type of breast cancer to spread to the brain, and for people of any background or age to develop brain metastasis.

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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.

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

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How Is Metastatic Breast Cancer Treated

Although metastatic breast cancer currently cant be cured, it can be treatable with hormonal therapy, chemotherapy, biologic targeted treatments, and novel drug combinations.

Treatment for brain metastases whether originating in the breast or other part of the body takes a variety of forms, including:

  • Radiation therapy
  • Systemic treatment such as chemotherapy and/or targeted therapy

Care teams at the Metastatic Breast Cancer Program at Dana-Farber develop personalized treatment approaches for each patients specific type of cancer, as well as an individual plan of care and support for them and their loved ones.

Breast Cancer Metastasis To The Brain

HER2+ Breast Cancer: Brain Metastasis Prevalence & Later-Line Therapy

Breast cancer sometimes metastasizes to the brain. This condition is commonly referred to as “secondary breast cancer in the brain.” Brain metastases occur in approximately 10%-15% of women with stage 4 breast cancer. In some cases, the breast cancer metastasizes directly to the brain in others, the breast cancer metastasizes to another area of the bodysuch as the lungs, liver or bonesbefore it reaches the brain.

Some people assume that a brain metastasis is brain cancer. However, thats not the case. The distinction between brain cancer and brain metastases lies in where the cancer originatedbrain cancer involves tumors made up of cancerous brain cells, while brain metastases involve tumors made up of cancerous cells from elsewhere in the body .

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What Is The Role Of Estrogen In The Brain

Estrogen is used in the brain to help modulate several functions. For example, there are estrogen receptors on astrocytes, which are helper cells for the neurons. And certain parts of the brain have increased estrogen activity over others. That seems to be part of the reason metastases are drawn to the brain in breast cancer more frequently than other places, and its also why breast cancer spreads more frequently to the brain than some other cancers. Prostate cancer, for example, only rarely goes to the brain.

Radiation Therapy For Metastatic Brain Tumors

Radiation therapy treats metastatic brain tumors by using X-rays and other forms of radiation to destroy cancer cells or prevent a tumor from growing. It is also called radiotherapy.

These painless treatments involve passing beams of radiation through the brain, which can treat cancers in areas that are difficult to reach through surgery. Procedures may include any one or a combination of the following:

  • External beam radiation therapy delivers radiation from a machine and through the body to reach metastatic tumors.
  • Whole-brain radiation targets the entire brain to hit multiple tumors or any metastatic disease that hides from an MRI scan.
  • Stereotactic radiosurgery directs a high dose of radiation targeted to the specific shape of the tumor, sparing surrounding healthy tissue from unnecessary radiation exposure.
  • Proton therapy uses protons to treat metastatic brain tumors. Like stereotactic radiosurgery, proton therapy minimizes harm to healthy tissue surrounding a tumor.
  • Brachytherapy is radioactive material implanted within a tumor to prevent further growth.
  • These procedures may be performed after surgery to prevent tumors from recurring at the surgical site and growing into other brain tissue.

    Because radiation therapy has been so successful in treating brain metastases and because many live long lives after treatment studies are now looking at how to manage the long-term effects of treatment.

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    Surgery Followed By Radiotherapy

    The use of surgery is most often reserved for patients with good performance status, few lesions or large symptomatic lesions . Surgery followed by radiation therapy has been shown to improve OS and symptom control vs radiation therapy alone., Patchell et al. demonstrated that, in patients with a single BM , WBRT after complete surgical resection reduced the rate of recurrence at both the initial metastatic site and other brain sites , and reduced death due to intracranial progression . However, OS was similar between the WBRT and the control arm. In addition, WBRT has short- and long-term toxicities, including neurocognitive side effects and decreased quality of life.,

    Two randomised clinical trials compared post-operative WBRT to post-operative stereotactic radiosurgery , a precise form of radiotherapy that delivers highly conformal high-dose radiation to restricted areas to kill small groups of cells with minimal damage to the surrounding normal tissues., One of these studies included patients with up to three lesions. In both studies, local control was equivalent or better with SRS and there was a lower risk of cognitive impairment no differences in OS were seen between the radiotherapeutic approaches. Therefore, after surgical resection, the use of SRS is the recommended option whenever feasible.,

    Brain Metastases Vs Leptomeningeal Metastases

    Single brain metastasis from breast cancer

    While brain metastases refer to cancer that has spread to the brain, leptomeningeal metastases refer to cancer that has spread to the tissues and fluid surrounding the brain and spinal cord. Although the symptoms of leptomeningeal metastases are similar to those of brain metastases, they are often less obvious and thus more challenging to diagnose. Physicians often confirm a diagnosis using MRI scans, but in some cases they may also order a lumbar puncture, which involves inserting a needle into the spine and collecting a fluid sample to be examined by a pathologist in a laboratory.

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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 .

    About The Medical Reviewer

    Dr. Lin is a medical oncologist specializing in the care of patients with all stages of breast cancer. Her research focuses upon improving the outcomes of people living with metastatic breast cancer, including a particular focus on the challenge of breast cancer brain metastases. She has led multiple clinical trials which have led to new treatment options for patients with breast cancer that has metastasized to the brain.Dr. Lin received her MD from Harvard Medical School in 1999. She completed her residency in internal medicine at Brigham and Women’s Hospital and went on to complete fellowships in medical oncology and hematology at Dana-Farber. In 2005, she joined the staff of Brigham and Women’s and Dana-Farber, where she is a medical oncologist and clinical investigator in the Breast Oncology Center.

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    Breast Cancer Spread To The Brain: What You Need To Know

    Medically Reviewed By: Nancy Lin, MD

    When breast cancer spreads, or metastasizes, its more likely to travel to some parts of the body than others. The most common sites of metastasis include the bones, brain, liver, or lungs.

    Its rare for patients with early-stage breast cancer, which has not spread beyond the breast or adjacent lymph nodes, to develop a brain metastasis: The brain is the first site where breast cancer spreads in fewer than 5% of these patients.

    Among patients diagnosed with breast cancer that has already spread, however, between 10% and 50% develop a brain metastasis, depending on the subtype of breast cancer and other factors.

    At Dana-Farber/Brigham Cancer Center, the Program for Patients with Breast Cancer Brain Metastases in the Susan F. Smith Center for Womens Cancers provides care from a team of experts including medical oncologists, radiation oncologists, neurosurgeons, neuro-oncologists, neuroradiologists, and pathologists. Patients receive a personalized treatment plan based on their unique situation and the specific nature of their disease.

    Dana-Farbers Breast Cancer Brain Metastases leadership team.

    How Often Do You Need To Test For Brain Metastasis

    Program for Patients with Breast Cancer Brain Metastases | Dana-Farber Cancer Institute

    How often you get which tests depends on your diagnosis and your doctors preferences. But its common for doctors to recommend imaging tests every 2-6 months in patients with known brain metastases. Its also likely you will need imaging tests if you switch to a new medicine, so that you can see how that new medicine is working.

    Your care team may also recommend additional tests if you experience new or more serious symptoms or side effects. Ask your doctor how often they recommend you have certain tests, and why.

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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 Are Some Of The Common Neurological Or Other Symptoms

    It can be weakness on one side of the body, difficulty speaking, or staring episodes, like having small seizures or having a stroke. Many patients get hydrocephalus, a potentially life-threatening condition where your spinal fluid doesn’t drain out of your brain properly because it’s obstructed by a tumor and/or swelling. This is much more likely in breast cancer than in lung cancer, for example. But probably the most common presenting symptom is a new, chronic, daily headache.

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    Focal Treatment Of Brain Metastases

    Focal treatment including surgery, WBRT, and stereotactic radiosurgery is indicated for the treatment of intracranial metastases across all intrinsic subtypes of breast cancer. However, the type of focal treatment strategy depends upon the extent of CNS disease and other disease- and patient-specific characteristics. An individualized approach is preferred, assimilating the above variables with clinical presentation. The approach to focal treatment of brain metastases in breast cancer is also based upon the intrinsic subtype of breast cancer and should be decided on a case-by-case basis. For example, salvage radiation is likely a first line-therapy among those with TNBC due to limited systemic options. However, a patient with HER2-positive disease may benefit from aforementioned systemic therapy options and may be able to forgo focal therapy.

    Systematic Screening For The Detection Of Bm

    Immunophenotyping of HER4/YAP axis in breast cancer brain metastasis ...

    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

    Mouse Models Of Her2+ Bcbrm

    • Is an intact immune system required for this therapeutic intervention? If yes, then a syngeneic model with mouse cancer cells is needed.
    • Is this gene/pathway of interest involved in the early metastatic process ? If yes, then direct intracranial implantation is not appropriate.
    • Is the ability to monitor/detect individual BrM cells or micrometastases necessary? If yes, then bioluminescence is not appropriate.
    Method
    • Requires specific antibodies and/or cells expressing fluorescent proteins
    • Cells expressing reporters may activate immune response

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