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.
Breast cancer has the second highest incidence of brain metastasis among all malignancies. There are few systemic therapies that penetrate the blood-brain barrier BBB. The risk of developing brain metastases arising from breast cancer varies by subtype as a result of the natural history of each. HER2 -directed therapies for breast cancer can be classified into three subgroups: monoclonal antibodies such as trastuzumab and pertuzumab, small-molecule tyrosine kinase inhibitors TKIs such as lapatinib and neratinib, and the antibody-drug conjugate ado-trastuzumab emtansine T-DM1.
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. Trastuzumab was the first developed recombinant monoclonal antibody directed against the HER2 oncoprotein.
The brain is increasingly reported as the first site of distant relapse in HER2 -positive patients, especially those who are treated with trastuzumab. The exact mechanism is unclear but is possibly linked to the increased survival in this subset of patients since the emergence of HER2 -targeted therapy.
It is speculated that there is sufficient opportunity to develop brain metastasis as a result of prolongation of survival. Although pertuzumab is also unable to cross the BBB, dual HER2 targeting appears to delay the onset of brain metastases. Table 2 highlights some of the key clinical trials upon which systemic therapy recommendations for the treatment of brain metastases in breast cancer are based.
It was analyzed with capecitabine in a phase II trial in the first-line setting to delay whole-brain radiotherapy WBRT. This study enrolled 45 patients with metastatic breast cancer and brain metastases; 29 patients had a partial response to treatment. The most common grade 3 or 4 toxicities included diarrhea and hand-foot syndrome. Lapatinib with capecitabine is considered a treatment option for progressive brain metastasis after trastuzumab and T-DM1 failure 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.
T-DM1 is an antibody-drug conjugate of trastuzumab and a cytotoxic agent, DM1. Crossover was allowed. This study demonstrated a significant improvement in the T-DM1 arm in terms of median progression-free survival PFS 6.
The backbone of therapy in this subset of triple-negative breast cancer TNBC is cytotoxic chemotherapy, as there are no targetable receptors. There is some evidence of CNS response with chemotherapy. Agents demonstrating efficacy include cisplatin-based regimens and single-agent capecitabine. Although recent developments in the field have shown promising results, there is a need for new therapeutics with BBB penetration to improve CNS control. In Figure 2 and Figure 3, we outline our recommendations on systemic therapy for the various subgroups.
Olaparib was studied in first or second progression, compared with standard therapy. Median PFS benefit was 2. 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. Randomized trials are lacking in this area and only low-level evidence exists in the form of case reports to support the activity of endocrine therapy in brain metastases. The overall incidence of brain metastasis in the hormone receptor HR positive subtype is much less frequent.
Case report data suggest responses to tamoxifen[35] and aromatase inhibition[36]. Patients with HR positive brain metastases have shown significant responses to cytotoxic chemotherapy. Niwinska et al. Focal treatment including surgery, WBRT, and stereotactic radiosurgery SRS 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.
In the case of a solitary brain metastasis, preferred treatment options include surgical resection or SRS, although surgical resection may be limited by anatomic site. Neurosurgical resection is also helpful in relieving mass effect in patients with large symptomatic lesions. Brain metastases adult. Mayo Clinic; Niederhuber JE, et al. Brain metastases and neoplastic meningitis. In: Abeloff's Clinical Oncology. Elsevier; Accessed Sept. Central nervous system cancers.
National Comprehensive Cancer Network. Metastatic cancer. National Cancer Institute. Loeffler JS. Overview of the treatment of brain metastases. Treatments and side effects. American Brain Tumor Association. Types of complementary therapies. Le Rhun E, et al. Leptomeningeal metastases of solid cancer. Current Opinion in Neurology. Rades D, et al. A new scoring tool to assess overall survival in patients with intracerebral metastases from gynecological cancers.
International Journal of Gynecological Cancer. Klos KJ, et al. Brain metastases. The Neurologist. O'Neill BP, et al. Brain metastatic lesions. Mayo Clinic Proceedings. Heim JB, et al. Studies are currently looking at methods to increase the permeability of the blood-brain barrier. In addition to steroids and systemic or local treatments for brain metastases, it's important to address the other symptoms related to metastatic cancer, such fatigue, loss of appetite, depression, and more.
Your oncologist may recommend a palliative care consult , and this can be frightening if you are not familiar with the field. Palliative care is not the same as hospice, but is a treatment approach used to treat the physical, emotional, and spiritual symptoms that go along with a diagnosis of cancer. Systemic treatment options are those used to address your breast cancer no matter where it is located in your body.
Whether or not you have local treatments for your brain metastases, the mainstay of treatment is usually these therapies. Systemic treatments for metastatic breast cancer may include:. Chemotherapy is often used for metastatic breast cancer, usually using different drugs than you had if you had chemotherapy previously. There are many different options or "lines" of therapy which can be used. As noted, many chemotherapy agents do not penetrate the blood-brain barrier, but frequently metastases to other regions are present along with brain metastases.
It may also help reduce the risk of further metastases to the brain. Hormonal therapy. Hormonal therapies for metastatic breast cancer may be recommended if your tumor is estrogen receptor positive. The use of these drugs depends on whether you were on hormonal therapy previously, and if so, which medication you were taking. When breast cancer metastasizes it's not uncommon for the receptor status to change, for example, a previously estrogen receptor positive tumor may be estrogen receptor negative and vice versa.
It's usually assumed that if you were on a particular hormonal therapy when your cancer metastasized, that the tumor is resistant to that drug. Unlike many treatment options, tamoxifen and aromatase inhibitors do appear to cross the blood-brain barrier.
Targeted therapies. Treatment options for metastatic HER2 positive breast cancer depend on what, if any, medication you were on when your tumor metastasized.
For those who have not previously received HER2 targeted therapy, treatment with either Herceptin trastuzumab or Perjecta pertuzumab can improve survival. If brain metastases develop while someone is taking Herceptin or within 12 months of stopping the drug , the drug T-DM1 trastuzumab emtansine was found to significantly improve survival.
The combination of Tykerb lapatinib and Xeloda capecitabine may also be used, but seems to lead to only modest improvement with considerable toxicity even though these drugs do appear to cross the blood-brain barrier. It appears that Tykerb might work better when combined with Xeloda than when used alone. Clinical trials. Combinations of the above treatments, as well as newer categories of drugs such as immunotherapy drugs and PARP inhibitors, are being studied in clinical trials for stage 4 breast cancer.
Local treatments are those designed to treat the brain metastases specifically and are most often recommended if brain metastases are causing significant symptoms, or if only a few metastases are present with the goal to eradicate the metastases. When many metastases are present, the goal is to reduce symptoms palliative.
With only a few metastases, eradication of the metastases may be attempted with a goal of improving survival with a curative intent. In general, it's felt that more intensive local treatments such as SBRT and metastasectomy should be considered primarily for those people who are expected to survive more than 6 to 12 months. Whole brain radiotherapy has fallen out of favor in recent years because of the side effects. It is most often recommended now for people who have widespread brain metastases which are causing significant symptoms.
Cognitive changes, such as problems with memory, immediate recall, and verbal fluency are very common, and frustrating for those who have to cope with these symptoms. Since a good quality of life is often the most important goal in treating metastatic breast cancer, the use of WBRT needs to be carefully weighed with regard to benefits and risks. Recently, the use of Namenda memantine along with WBRT has been found to reduce the cognitive decline often seen.
Surgery Metastasectomy. Surgery to remove a single or only a few metastases called a metastasectomy has been used in recent years and may improve survival when used for people who are good candidates for the procedure have only a few metastases and are in otherwise good health.
Unlike SBRT, surgery has immediate results which can reduce brain swelling. There is, however, a greater risk of neurological damage, as well as the risk of "tumor spill" spreading the cancer cells through the brain with surgery. Also referred to as "Cyberknife" or "gamma knife," stereotactic body radiotherapy or SBRT uses a high dose of radiation to a small area of tissue to attempt to eradicate metastases.
It is usually used when only a few metastases are present, but some centers have treated people with up to 10 metastases at a time. The procedure can also be repeated to treat additional metastases which are present or which occur over time. SBRT can be a better option than surgery for metastases which are deep in the brain, or in sensitive regions where surgery would cause too much damage to healthy brain tissue.
It is most effective with small metastases, and surgery may be a better option for metastases greater than 3 cm in diameter. There is less cognitive decline seen with SBRT than with whole brain radiotherapy, although some side effects, such as radiation necrosis, may occur.
Other Possible Options. Other potential treatments for brain metastases that have not been well established include radiofrequency ablation RFA and hyperthermia. Metastases in More Than One Region.
While in the past, local treatment of brain metastases was most often considered if there were not other sites of metastasis, some believe that treatment of oligometastases in more than one site may also result in improved survival. Such treatments, referred to as "radical radiation" therapy for oligometastatic breast cancer, are now being evaluated in clinical trials.
Thus far, it's thought that, for appropriately selected people, long-term progression-free survival with minimal toxicity may be possible for some people with only a few metastases to different sites including the brain, lungs, bones, and liver. The prognosis for stage 4 breast cancer which has spread to the brain is not what we would wish, especially if extensive metastases are present.
That said, brain metastases due to breast cancer have a better prognosis than brain metastases due to several other solid cancers. Historically, survival with brain metastases was only around 6 months but this is changing. A study found that overall survival for breast cancer with brain metastases all types combined was a little over 2 years, with a life expectancy of 3 years for those with HER2 positive tumors.
0コメント