*For medical professionals only
Interpretation of the treatment strategy of brain metastases for HER2-positive breast cancer under MDT.
Breast cancer is prone to brain metastases, with 30 to 55 percent of central nervous system (CNS) metastases in patients with HER2-positive breast cancer [1]. Although anti-HER2 targeted therapy has prolonged the survival time of breast cancer patients and improved the control rate of extracranial lesions, the presence of the blood-brain barrier has greatly weakened the killing effect of most systemic therapeutic drugs on brain tumors, making brain metastasis of breast cancer a clinical treatment problem. Once her2-positive breast cancer has brain metastases, the prognosis is poor, and the effective management of such patients has become a major clinical challenge [2]. Recently, ESMO Open, the official journal of the European Society of Oncology (ESMO), published a review titled "How we treat HER2-positive brain metastases"[3], which provides an overview of the treatment of brain metastases for HER2-positive breast cancer.
Characteristics and course of brain metastases in HER2-positive breast cancer
The incidence of brain metastases varies by breast cancer subtype and stage, especially in patients with advanced breast cancer, where HER2 overexpression is associated with an increased risk of brain metastasis. On the one hand, overexpression or abnormal expansion of HER2 makes breast cancer cells more aggressive and therefore more susceptible to metastasis to the brain. On the other hand, in the era of anti-HER2 targeted therapy, the application of antiHER2 therapy in patients with HER2-positive breast cancer has greatly improved the survival of patients, and CNS may become a "refuge" for HER2 overexpressed breast cancer cells due to its biological specificity (blood-brain barrier) [3].
In patients with HER2-positive early-stage breast cancer who receive breast-conserving therapy and systemic therapy, the risk of developing brain metastases within 10 years is about 12%. In patients with HER2-positive advanced breast cancer, about 50% develop brain metastases during the disease. In the HERA trial, after 4 years of median follow-up, the risk of CNS events as the site of initial recurrence was low (2% in both trastuzumab and observation groups, P=0.55).
Among patients who died in the HERA trial, there was a trend toward a decrease in CNS events (47% vs. 57%), but this difference was still not statistically significant (P=0.06), and the incidence of CNS events was very high in both groups of these deaths. The findings suggest that the incidence of brain metastases may increase in patients with metastatic HER2-positive breast cancer as the course progresses. This finding also led to reflections on the risk of brain metastases under anti-HER2 treatment for HER2-positive breast cancer [3].
Currently, no adjuvant therapy (including trastuzumab, paltozumab, lapatinib, or T-DM1) has been shown to prevent CNS recurrence. For example, in the ALLTO trial, no difference in the incidence of CNS as the first site of recurrence was observed (2% in both the lapatinib plus trastuzumab and monoclonal antibody groups).
Similarly, in the KATHERINE trial, 1486 patients who still had residual lesions after neoadjuvant anti-HER2 therapy were randomly assigned to continue trastuzumab or switch to T-DM1 treatment. Although metastatic events in the T-DM1 group were significantly reduced, the risk of CNS as the first site of recurrence was not reduced, occurring in 5% of both groups of patients, and brain metastases accounted for more than half of the distant recurrence events in the T-DM1 group. In the T-DM1 group, 4.8% of patients had THE only site of recurrence, compared with 2.8% in the trastuzumab group. In the ExteNET trial, data from an 8-year follow-up of neratinib adjuvant therapy for early HER2-positive breast cancer showed that the incidence of CNS metastases in the Niratinib group was 1.3% and 1.8% in the placebo group. Together, these findings suggest that anti-HER2 adjuvant therapy does not prevent brain metastases [3].
Treatment of brain metastases in HER2-positive breast cancer
The treatment of breast cancer brain metastases should follow a multidisciplinary diagnosis and treatment model, and the purpose of treatment is to control the metastatic lesions, improve the patient's symptoms, improve the quality of life, and maximize the survival time of the patient. Treatment of brain metastases for breast cancer includes surgery, radiation therapy, medication, and symptomatic supportive care. The overarching principle of treatment is to prioritize surgery and/or radiation therapy for brain metastases, with reasonable consideration for systemic therapy,[4] with adequate assessment of the systemic condition [4].
At present, topical therapy including surgery, stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) is still the main treatment for breast cancer, and the choice of treatment is mainly determined by the prognosis of the patient, whether there are neurological symptoms, the number, size, distribution of metastatic lesions, and what previous treatment has been received. How these treatment options are chosen and how to line up the troops requires an experienced multidisciplinary team to discuss and decide. In general, surgery is appropriate for patients with no extracranial lesions or a single lesion with controlled brain metastases, and the brain lesions are large or involve swelling. For patients who have not previously had a confirmed metastatic disease, surgery may also provide focal tissue to confirm the status of metastatic disease.
During the perioperative period, radiation therapy for the surgical site is generally recommended to improve local control. For single, small, and unreachable brain lesions, first-line SRS is an alternative to surgery. For patients with multiple metastases in the brain, SRS is well suited for patients with limited lesions. Controlled study data showed that SRS was superior to WBRT in patients with brain metastases with up to 4 lesions.
In an ongoing randomized controlled study comparing the efficacy of SRS and WBRT in patients with 5-20 brain lesions, there are currently no results. Given its acute and chronic toxicity, WBRT avoidance is generally considered first, but in cases where there are many intracranial lesions and multiple large lesions, the WBRT regimen is usually required. Systemic therapy may also be considered as first-line therapy in newly diagnosed HER2-positive patients if brain metastases are limited and asymptomatic or mild. Systemic therapy is also considered if CNS progression is developed after topical therapy [3].
When patients with brain metastases need to consider systemic therapy, there are several treatment strategies depending on the clinical situation (Figures 1 and Table 1).
Table 1. Systemic treatment options for HER2-positive brain metastases[3]
Figure 1. Treatment pathways for HER2-positive brain metastases[3]
01
Patients who do not have any symptoms of systemic disease but have a recurrence of THE CNS
In patients with CNS metastases without signs of extracranial disease, CNS progression is primarily treated by surgery and/or radiotherapy, and there is a lack of prospective studies to guide treatment options other than topical treatment. However, trastuzumab or trastuzumab plus patozumab is usually used clinically after topical treatment of CNS disease (and endocrine therapy in patients with estrogen receptor-positive disease) [3].
02
Patients with stable systemic disease but local CNS progression
For patients with stable systemic disease but local progression of the CNS, SRS is usually used to treat progressive CNS lesions and continue existing systemic therapy. Anti-HER2 monoclonal antibodies can be sustained throughout the course of radiotherapy, if the patient is receiving chemotherapy, the chemotherapy is suspended and resumed 1-2 weeks after the completion of radiotherapy. If patients have repeated CNS progression events over shorter time intervals, they tend to delay SRS and switch to systemic therapy, which both helps control systemic lesions and has potential efficacy for micrometastatic disease.
In general, the use of this drug is recommended for patients who have not yet received T-DM1. Second, for patients who had previously progressed during T-DM1 treatment, the preference for a triple therapy with tucatanib plus capecitabine + trastuzumab in patients with brain metastases increased the rate of CNS response, progression-free survival (PFS) and overall survival (OS), which was mainly based on the 1-year PFS rate of 24.9% in the tukatinib triple treatment group compared with only 0% in the placebo group (HR = 0.48, 95% in the HER2CLIMB trial for 291 patients with brain metastases) compared with only 0% in the placebo group (HR = 0.48, 95% CI 0.34-0.69，P
Other systemic therapies (e.g., trastuzumab plus carboplatin or doxorubicin liposomes, or high-dose trastuzumab plus paltozumab) may be considered in patients whose CNS is progressing despite T-DM1 and HER2-targeted TKI therapy, but the evidence is usually based on small, nonsortized studies or case reports. Although both tucatanib and neratinib respond to treatment in patients treated with HER2-targeted TKI, overall, the efficacy of HER2-targeted TKI sequential therapy has not been fully validated [3].
03
Patients with stable systemic disease but PROGRESSION OF THE CNS (e.g., multiple tiny lesions of the CNS)
When the patient's systemic disease is stable or remission, but the CNS progresses with many small CNS lesions that are not suitable for SRS, WBRT (if not already given) is recommended with systemic therapy. If patients have not been treated with tucatanib plus capecitabine + trastuzumab, consider using this combination therapy and follow up closely with a view to delaying the occurrence of WBRT and its associated toxicities. For patients who have received WBRT, systemic therapy is considered if tucatanib, clinical trials, or other regimens listed above and table 1 are considered [3].
04
Patients with extensive progression of CNS
Although WBRT is clinically avoided for safety reasons, WBRT is effective in controlling morbidity and mortality in patients with widespread PROGRESSION of CNS and tends to have a good response to treatment [3].
05
Patients with simultaneous CNS and extracranial progression
For patients with simultaneous CNS and systemic progression, it is recommended to follow guidelines for the treatment of advanced HER2-positive breast cancer, but prefer regimens with CNS therapeutic activity [3].
Other handling opinions
In view of the poor overall prognosis of patients with brain metastases, the overall incidence of radiation brain necrosis in breast cancer was low, especially symptomatic brain necrosis, which occurred only 6% to 11%. However, in the context of comprehensive treatment, the survival of HER2-positive breast cancer has been significantly prolonged, and the reports of radiation brain necrosis have gradually increased. Clinicians should note that in some cases, radiation after SRS that shows progressive CNS disease may be radiation necrosis. If radionecrosis is suspected, clinical follow-up will be performed by interval imaging.
If symptomatic cerebral necrosis occurs, because it often presents symptoms of intracranial hypertension, glucocorticoids represented by dexamethasone are currently the classic first-line treatment. In addition, antivascular endothelial growth factor drugs theoretically prevent the destruction of the blood-brain barrier, thereby alleviating angioedema and associated symptoms, and some clinical studies have shown that these drugs can improve the imaging manifestations of radiation cerebral necrosis [3].
Clinical trial methods
With the deepening of understanding of the biological properties of HER2-positive brain metastases, there are currently a number of clinical trials exploring new approaches to the management of HER2-positive CNS metastases, encouraging participation in such trials if feasible. Although the blood-brain barrier makes the delivery of certain systemic therapeutic drugs challenging, most drugs appear to be able to penetrate the CNS in cases where the barrier is broken, although sometimes drug concentrations are lower. In addition, genetic differences in brain metastases in breast cancer and differences in the MICROEN OF CNS tumors are also worth exploring, which will help to explore more effective treatment options [3].
summary
Treatment of HER2-positive brain metastases is complex and requires the involvement of an experienced multidisciplinary team. A series of clinical studies have been conducted to explore the activity of existing treatment options in patients with brain metastases, and novel drugs with therapeutic potential are being developed. As the occurrence of brain metastases from breast cancer becomes more common and the need to improve the prognosis of brain metastases from breast cancer becomes more urgent clinically, it is particularly important to develop more effective treatment strategies to manage and ultimately prevent CNS diseases in the future [3].
bibliography:
[1] Lin NU, Amiri-Kordestani L, Palmieri D, et al. CNS metastases in breast cancer: old challenge, new frontiers[J]. Clin Cancer Res, 2013, 19(23): 6404-6418.
Ma Li, Wang Hui, She Chunhua, et al. Research progress of brain metastasis in breast cancer[J]. Chinese Journal of Breast Diseases: Electronic Edition, 2015, 9(3):6.
[3] Stavrou E, Winer EP, Lin NU. How we treat HER2-positive brain metastases. ESMO Open. 2021 Oct;6(5):100256.
4] 2021 CSCO Breast Cancer Diagnosis and Treatment Guidelines
* This article is supported by AstraZeneca and is intended for medical professionals only
Approval number: CN-90915 valid until: 2023-1-20
*This information is for medical and scientific reference only and does not constitute a recommendation or promotion of any drug or treatment regimen. The information contained in this article should not be a substitute for medical advice provided by healthcare professionals.