The development of brain metastases represents a common complication of cancer detection occurring more frequently than primary tumors, with approximately 97,000 to 170,000 new cases diagnosed each year in the United States. In fact, about 10% to 30% of patients with cancer develop brain metastasis at some point during their systemic disease.1 The frequency of brain metastasis has increased in the last 10 years as a result of higher screening in asymptomatic but considered high-risk patients, improvements in diagnostic imaging, increased accessibility and effectiveness of systemic therapies. , and improved survival in cancer patients. These principles are particularly important for patients with breast cancer who represent the second highest proportion of patients with brain metastases, second only to lung cancer.2
The overall incidence of patients with brain metastases associated with breast cancer is 15%; about 5% of patients diagnosed with breast cancer develop brain metastases.2 Some subgroups of patients, such as those with triple negative disease, are at higher risk than those with HER2disease. In patients with breast cancer who develop brain metastases, the highest rate of diagnosis occurs in those between 50 and 59 years.
The diagnostic-specific graded prognostic assessment (DS-GPA) was developed as a targeted method to estimate the survival of patients with newly diagnosed brain metastases. The prognostic criteria vary according to tumor subtype. Specifically for patients with breast cancer, prognostic traits include age, performance status, and tumor subtype.3 Overall, the prognosis of patients with breast cancer who develop brain metastases has improved significantly over the past 20 years. The 5-year survival rate was around 1.3% in 2000 compared to 12% in 2020.4,5 During this period, the DS-GPA has continued to stratify patients into prognostic groups, with moderate survival lasting from 6 to 36 months.
Prognosis and treatment recommendations for patients with breast cancer and brain metastases are highly dependent on the tumor subtype; however, emerging evidence indicates that receptor sensitivity and subtype accumulation may change during the course of the patient’s disease. Whole exome layers of brain metastasis compared to primary breast tumors as well as other visceral metastases have shown that approximately 50% of brain metastases may detect functional mutations not found in primary.2
Patterns of tumor subtype change have been observed in several studies; the most common disorders are estrogen receptor loss, progesterone receptor loss, and proliferation HER2 in brain metastasis.2 As more systemic therapies are available with the potential for intracranial intervention, a more complete understanding of the biology of brain metastases has developed. This will be important for personalization and tailoring treatment for patients during intracranial progression.
There are a number of management issues to note for a patient diagnosed with brain metastasis, including performance status, number of brain metastases, size and location of injuries, presence of neurologic deficits, age, stage of primary tumor. or extracranial disease, complete persistence of systemic therapy, and patient admission.
Similarly, there is a range of treatment strategies for this patient population, from corticosteroids and medical management only, to whole brain radiation therapy with or without hippocampal bypass, stereotactic radiosurgery (SRS), resection, or mixing techniques. Evidence has shown that there is a risk of neurocognitive decline in a whole brain radiation therapy setting and so there has been a paradigm shift towards offering SRS for the majority of patients with metastases brain including those with multiple diseases or larger brain metastases. In addition, SRS before or after surgery should be considered for patients requiring resection, or as an incentive to reduce the incidence of leptomeningeal disease in those patients receiving intrathecal systemic therapy.
Primary SRS is an effective local treatment with many benefits for patients with brain metastases, including its ability to target inaccessible areas of the brain; shorter recovery time compared to resection; shorter treatment schedules that allow rapid treatment between systemic cycles for patients receiving conventional cytotoxic chemotherapy; an effective management strategy for patients who develop metachronous lesions; and possibly synergistic treatment combined with targeted therapy or immunotherapy in selected patients. In particular, the response to SRS for patients with brain metastases in various breast cancer subtypes reflects the outcomes of obstructive-treated patients and infectious radiation therapy for early-stage disease. For example, results showed that patients with luminal B or HER2-positive subtypes had the highest risk for local failure compared with those with luminal A disease.5
It is important to consider the timing and order of systemic treatment around the time of radiosurgery for patients receiving treatment for the metastatic disease as well as local treatment with SRS. Several systemic treatment agents have been safely combined with SRS and the results of postoperative studies have revealed favorable safety profiles with concomitant immunotherapy, capecitabine, temozolomide, trastuzumab (Herceptin), hormonal agents, and lapatinib (Tykerb).6 Results of a study of 445 patients with brain metastasis treated with SRS and concomitant systemic therapy showed a frequency of radiographic radiation necrosis of about 8%, which was compared with those treated with radiosurgery alone.7
Further, systemic medications, such as lapatinib may be added to control levels over SRS alone. In results from a retrospective study, researchers observed a reduction in the risk of local failure as well as a shift to a lower risk of distant intracranial failure with the addition of lapatinib to SRS.
The RTOG test 1119 (NCT01622868), which evaluated radiation therapy with or without concomitant lapatinib for HER2-positive breast cancer patients with brain metastases, yielded results at the 2020 Society for Neuro-Oncology Virtual Meeting (Table8). Although concomitant lapatinib improved the 4-week overall response rate, concurrent treatment did not improve the 12-week overall response rate, the primary endpoint of the study. In addition, use of the central nervous system (CNS) – combined therapy, reduced presence of injuries, and a higher DS-GPA score were associated with a higher overall 12-week response rate. Finally, fewer injuries and receiving CNS-penetrating systemic treatment were also associated with survival without CNS progression. We await publication here and other studies to determine the benefits of consensual treatment.
Although several agents for breast cancer patients can be safely combined with radiosurgery, there is growing concern about the use of ado-trastuzumab emtansine (Kadclya; T-DM1) for those with HER2-positive disease with metastases brain that received prior stereotactic radiation therapy. . Researchers have found that patients who receive either follow-up or follow-up radiosurgery with T-DM1 are at a much higher risk of radiation necrosis. Therefore, this patient population needs to be alerted until additional data is collected.
Finally, advances in radiotherapy and systemic therapy have allowed improved survival and quality of life for patients with breast cancer and brain metastases. Further research is needed to increase personalized management based on the biology of brain metastasis.
Rupesh R. Kotecha, MD, is the head of radiosurgery and the director of central nervous system metastasis at the Miami Cancer Institute at Baptist Health South Florida.