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Metastatic Breast Cancer To Brain

What You Need To Know

Program for Patients with Breast Cancer Brain Metastases | Dana-Farber Cancer Institute
  • Metastatic breast cancer is serious, but the diagnosis does not always mean the end of life.
  • The most common place for breast cancer to spread is to the bones. The liver and the lungs are other areas where breast cancer can metastasize.
  • In about 15% of cases, metastatic breast cancer can be detected at the time of diagnosis. It can affect people who had breast cancer without seeking treatments, patients with aggressive breast cancer types and those with breast cancer not detected by screening.

Brca Mutated Breast Cancer

BRCA mutations, particularly BRCA1, increase the likelihood of developing brain metastases. Up to 5% of patients with breast cancer harbor a germline BRCA mutation. Poly polymerase inhibitors that disrupt DNA repair mechanisms have been developed as an effective therapy in germline BRCA-mutated breast cancers. The OlympiAD and EMBRACA trials for PARP inhibition in patients with germline BRCA mutation demonstrated a significant survival advantage with olaparib and talazoparib, respectively. Olaparib was studied in first or second progression, compared with standard therapy. Median PFS benefit was 2.8 months with a decrease of 42% in disease progression and a more favorable safety profile. Similarly, talazoparib was shown to have a 3-month PFS benefit compared to standard therapy. Another indication for PARP inhibition in most malignancies includes a germline deficiency or somatic loss of function of genes responsible for DNA repair. Repair of both single-strand and double-strand DNA breaks can be blocked using PARP inhibitors, making them particularly useful in those with homologous recombination deficiency.

Enhancing The Penetration Of Bc Cells

Not only can the permeability of the BBB be increased, but a number of mediators can also enhance the ability of BC cells to penetrate the BBB. The interaction between CXCL12, a chemokine secreted by CAFs and epithelial BC cells, and its receptor CXCR4 on MDA-MB-231 breast cancer cells promotes the penetration by MDA-MB-231 cells of a monolayer of human brain microvascular endothelial cells , as well as increasing the permeability of these cells. The expression by BC cells of cyclo-oxygenase-2 , the epidermal growth factor receptor ligand HBEGF, and 2,6-sialyltransferase has been shown to mediate passage across the BBB unlike COX-2 and HBEGF, however, ST6GALNAC5 is regarded as a specific mediator that contributes to metastasis towards the brain rather than to any other organ. Other genes overexpressed in BCBM cells, such as ADAM8 and SEMA4D, have also been shown to be regulators of BBB transmigration. ADAM8 upregulates MMP-9, while SEMA4D interacts with overexpressed Plexin-B1 in brain ECs, which contributes to the increased penetration of CTCs.

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What Is Secondary Breast Cancer

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,

Brain Metastases Vs Leptomeningeal Metastases

Breast Cancer Metastases to the Neural Axis

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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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.

Research Models For Bcbm

The paucity of optimal and clinically relevant models presents a huge obstacle to the study of the mechanisms underlying BCBM and thus the development of possible treatments. However, several models, including cell, murine and PDX models , have been widely implemented, providing a theoretical basis and methodological guides for further BCBM studies.

Table 1 Models in BCBM research.

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Additional Cell Types Involved In Bbb Transmigration

As well as the interaction of tumour cells with brain ECs, additional cell types are also likely to be involved during migration across the BBB. For example, T lymphocytes upregulates the expression of guanylate-binding protein 1 in BC cells to facilitate the BBB transmigration. CAFs were proved to enhance the BBB permeability. In addition, novel pathways such as endothelialmesenchymal transition are involved in BBB transmigration. These provide additional perspectives on the mechanism of extravasation during BCBM.

Ongoing Trials And Future Prospects

Brain metastases developed from HER2 postive and triple negative breast cancer

Current trials include a focus on immunotherapy. From clinical trials in melanoma and lung cancer, we are aware that immunotherapy does have an impact on brain metastases. Hoping to unleash an abscopal effect using radiation in addition to immunotherapy, there are ongoing trials combining the two. Investigators are pursuing a phase II trial with the programmed death ligand 1 inhibitor atezolizumab in combination with SRS in TNBC with brain metastasis . Another phase II clinical trial is evaluating neratinib with capecitabine in HER2-positive patients. Subsequently, another arm in this trial has been added to include neratinib plus T-DM1 .

Some of the other noteworthy trials in HER2-positive disease include a phase II randomized controlled trial of a new oral HER2 inhibitor, tucatinib, in combination with trastuzumab and capecitabine . Some other interesting future prospects include phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors and cyclin-dependent kinase 4/6 inhibitors.

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Can Breast Cancer Spread To The Brain

Sometimes breast cancer can spread to the brain. This is known as secondary breast cancer in the brain. It can also be called brain metastases or brain mets. Its not the same as having cancer that starts in the brain. The cancer cells that have spread to the brain are breast cancer cells. For most people with secondary breast cancer in

What Are The Risk Factors For Breast Cancer

Risk factors. Younger womenespecially those younger than 35 at the time of their breast cancer diagnosisare at a greater risk for developing brain metastases. Other risk factors include having a breast tumor thats larger than 2 cm in diameter and having positive lymph nodes at the time of the initial diagnosis.

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Current Therapeutic Strategies And Challenges In The Management Of Bcbm

Traditional therapeutic strategies for BCBM involve multimodality approaches, such as whole-brain radiotherapy , stereotactic radiosurgery , surgery, chemotherapy and palliative therapy,, while treatment options for intra-cerebrospinal fluid administration for leptomeningeal metastases are limited to methotrexate, cytarabine and thio-TEPA these agents show poor efficacy, and survival after diagnosis is disappointingly short . Multidisciplinary comprehensive therapy has become the current preferred treatment. For example, results from a randomised open-label Phase 3 study suggested that intrathecal liposomal cytarabine plus systemic therapy significantly decreased the risk of leptomeningeal metastases progression or death, and prolonged progression free survival from 2.2 to 3.8 months and median overall survival from 4 to 7.3 months. However, the prognosis of patients with BCBM is far from satisfactory. This frustrating outcome can be partly attributed to our incomplete understanding of the brain structure as well as difficulties in generating research models during BCBM investigation. Several additional challenges also limit the success of current BCBM treatment approaches.

Focal Treatment Of Brain Metastases

Breast Cancer Metastases to the Neural Axis

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.

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Symptoms Of Metastatic Breast Cancer

Symptoms depend on where the cancer has metastasized. According to Habibi, common areas include the bones of the spine, the lungs and the liver. The symptoms can be back pain, shortness of breath, cough and fatigue.

Some types, including triple negative breast cancer, can also spread to the brain. The patient can experience headache, convulsions, changes in mood, and difficulty with speech or field of vision, Habibi says.

People who have been treated for breast cancer should be on the lookout for symptoms such as:

  • Back or neck pain

Reporting these symptoms is important, says Habibi. Patients are usually the first and best people to notice something is not right, and can ask for guidance from their physicians.

After completion of the active phase of cancer care, and in the absence of specific symptoms, we usually do not recommend routine metastatic workup.

Doing a lot of unnecessary testing can harm the patient, he explains. Small abnormalities in one test can lead to additional test and biopsies, which can be very stressful to the patient, and repeated testing without symptoms has not been shown to improve outcomes.

However, patients should continue with their routine follow-ups as prescribed by their surgeon, medical oncologist and primary care doctor, the latter of whom plays a very important role in the survivorship phase.

What Is The Risk Of Brain Metastasis In Stage 4 Breast Cancer

About 10% to 15% of people with stage IV breast cancer have brain metastases. The risk of brain metastasis is usually highest for people with more aggressive subtypes of breast cancer, such as HER2-positive or triple-negative breast cancer. About 10% to 15% of people with stage IV breast cancer have brain metastases.

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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.

Who Gets Brain Metastasis

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

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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Overall Survival Of Patients With Her2+ Mbc By Presence Of Cns Metastases3

  • No CNS metastasis
  • CNS metastasis after MBC diagnosis
  • CNS metastasis at MBC diagnosis
  • No CNS metastasis
  • CNS metastasis after MBC diagnosis
  • CNS metastasis at MBC diagnosis

Adapted from Clinical Cancer Research, 2019, Volume 25, Issue 8, 2433-2441, Hurvitz, Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs, with permission from AACR.

Data from the SystHERs study, a real-world analysis of 977 patients with HER2+ MBC.3

Patients with CNS metastasis also progress more quickly than those without, requiring a faster transition to the next line of therapy3

  • Median PFS in patients with CNS metastases at MBC diagnosis: 9.2 months HR = 2.49 P< 0.0001
  • Median PFS in patients with CNS metastases after MBC diagnosis: 9.9 months HR = 2.52 P< 0.0001
  • Median PFS in patients with no CNS metastases: 19.1 months

*Based on a retrospective review of electronic medical records from 86 of 165 patients with HER2+ MBC with brain metastases.1

In 226 patients with HER2+ MBC who developed initial brain metastases after MBC diagnosis.2

Median OS in patients with CNS metastasis at diagnosis vs no CNS metastasis at any time: 30.2 months vs not reached HR = 2.86 P< 0.0001.3

§Median OS in patients with CNS metastasis after diagnosis vs no CNS metastasis at any time: 38.3 months vs not reached HR = 1.94 P< 0.0001.3

A Crisis Requires A Rapid Response

The most common type of breast cancer, called estrogen receptor positive, HER2-negative breast cancer, is often found early and usually responds well to treatment. More than 90% of women who receive standard treatment will be alive without a recurrence of their cancer 5 years later.

However, a small proportion of patients will have disease that spreads rapidly to the bones, liver, lungs, and other organs, causing symptoms or affecting organ function.

When cancer in an organ affects its ability to function, that is called a visceral crisis, explained Larissa Korde, M.D., of NCIs Division of Cancer Treatment and Diagnosis, who was not involved with the study.

Thats where theres enough tumor in another organ to be life-threatening, she said. For example, if its in the liver, the liver cant do its work of clearing toxins from the body. Or if its in the lungs, a patient may not be able to get enough oxygen.

For people at risk of or experiencing a visceral crisis, the standard treatment has been a combination of two chemotherapy drugs. The treatment usually shrinks tumors quickly but can have serious side effects, spurring researchers to look for less-toxic treatments.

Ribociclib has become a commonly used treatment for ER-positive, HER2-negative breast cancer that requires treatment beyond surgery and radiation therapy. It is a targeted therapy called a CDK4/6 inhibitor that shuts down certain processes that cancer cells need to divide.

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What Is The Best Treatment For Bone Metastases

Bone-modifying medications are a newer treatment for bone metastases and can be very effective. Bisphosphonates such as Zometa are not only effective in reducing pain from metastases but appear to have anti-cancer effects as well. These medications may also reduce the chance of further bone metastases and improve survival. Xgeva may also be effective in treating bone metastases while improving survival.

Breast Cancer And Metastasis To The Brain


Symptoms, Causes, and Treatment

What happens if your breast cancer spreads to your brain? Sometimes, brain metastases are found when breast cancer is first diagnosed, but the majority of the time, brain metastases occur as a distant recurrence of an early-stage breast cancer that was treated in the past. What symptoms may occur, and what treatment options are available if your breast cancer spreads to your brain?

Overall, brain metastases occur in 15% to 24% of women with metastatic breast cancer. As survival improves, however, this number is expected to increase.

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Outcomes Of Tucatinib Plus Trastuzumab And Capecitabine In Patients With Previously Treated Her2+ Metastatic Breast Cancer With Brain Metastases

JAMA Oncology

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  • Pooled Incidence Of Brain Metastases Among Patients With Her2+ Mbc

    Seventeen studies including 5971 patients reported brain metastasis incidence among patients with HER2+ MBC. The pooled cumulative incidence of brain metastases was 0.31 with a median follow-up of 30.7 months . Using a random effects model, the pooled incidence of brain metastases per patient-year was 0.13 . Corresponding forest and funnel plots are presented in and , respectively. An Eggers test did not find asymmetry in the funnel plot and, therefore, publication bias in this subset of data was unlikely .

    A) Forest plot of pooled incidence rate for HER2+ MBC. Random effects model presented. Incidence per year of follow-up ranged from 0.04 to 0.27. Median follow-up times ranged from 5.8 to 53.6 months. B) Funnel Plot for publication bias according to studies reporting brain metastasis in HER2+ MBC. Eggers test P = 0.30. HER2+, human epidermal growth factor receptor-2 positive MBC, metastatic breast cancer.

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