Brain metastases in patients with breast cancer are associated with poor prognosis and diminished quality of life. One year survival rate of patients with metastatic breast cancer to the brain was reported as only ~ 20% . Several risk factors associated with increased brain metastases have been identified, including younger age, poorly differentiated tumors (high grade), HR negative status and metastases to four or more axillary lymph nodes at the time of diagnosis . The HR positive breast cancers were significantly associated with bone metastases and were less frequently observed in patients with lung and brain metastases. In contrast, patients with HER2-positive and triple negative breast cancer had a 5.3-fold increased risk of developing brain metastasis compared with those with HR positive, HER2-negative disease . Furthermore, HR discordance in primary tumor and brain tumor is seen in 18-54% of cases [10, 11]. The reason for the discordant HR status is not clearly understood but one explanation may be genomic tumor heterogeneity that leads to treatment induced selection of resistant clones with altered hormone receptor expression . A retrospective study by Lindström et al. showed that discordant cases had worse survival . whereas a prospective trial by Amir et al. and retrospective trial Qi Shen et al. failed to demonstrate adverse effects on clinical outcome [10, 14]. Our patient had ER/PR expression and lack of HER2 over-expression in both primary tumor and metastatic brain lesion.
Solitary brain metastasis has been reported in approximately 0.8–14% in patients with breast cancer across different data sets [15, 16]. HER2 positive breast cancer patients are more likely to develop solitary brain metastasis without systemic relapse . Older age (≥ 40 years) at diagnosis of breast cancer (p = .04), larger tumor size (T2 and T3; p = .002), advanced baseline stage (III and IV; p < .0001), and HR positive HER2 positive subtype (p = .01) were more frequently found in patients who developed brain metastases as the first recurrence compared with those who had a first recurrence at other sites in the body . In the case of HR positive breast cancer patients, time to brain metastasis is longer (55 months) with a better median overall survival (OS) of about 10–23 months as compared to TNBC (time to metastasis: 27.5 months; median OS: 3–7 months). HER2 positive patients, on average, have intermediate time until brain metastasis (34–47 months), depending on ER negative or ER positive histologic status, respectively, and a median OS from time of diagnosis of brain metastases of about 17.9 months . Therefore ER, PR and HER2 expression status impact both the time from initial diagnosis of metastasis to the brain as well as median survival following this diagnosis. In retrospective survey of 420 metastatic breast cancer patients with brain metastasis, patients who survived more than 18 months had younger age, were premenopausal, and had solitary brain metastasis or HR positive status. Our index patient had all four characteristics and lived approximately 28 months after first diagnosis of brain metastasis .
This case report describes a rare pre-menopausal patient with history of operable, HR positive, HER2 negative breast cancer who experienced relapse of her disease in the form of a single metastatic lesion to the left thalamus. Over time, her metastatic disease in the brain worsened but she continued to show no radiographic evidence of metastatic disease outside of the central nervous system. Whether this isolated brain recurrence can be due to CNS serving as a sanctuary site for cancer cells which could not be killed by prior chemotherapy due to blood brain barrier or whether brain was the first site of disseminated metastatic disease with remaining sites having only microscopic tumor deposits is unclear. Few studies to date have been able to shed a light on this issue. After reviewing the literature, we found only one single institutional, retrospective analysis of 128 breast cancer patients with brain metastases as the first and isolated site of recurrence. This analysis revealed that 42.1 % of these patients (N = 54) had only one metastatic brain lesion. Of those patients, 28% were HR positive and HER2 negative, while 37% and 35% were TNBC and HER2 positive respectively . In this study factors that impacted poorer patient survival were Karnofsky performance status of < 70, more than 1 metastatic brain lesion, presence of leptomeningeal disease and non-receipt of systemic therapy after diagnosis of metastatic disease. Indeed, patients who did not receive systemic therapy had considerably poorer survival of only 4 months compared to survival of 15 months for patients treated with systemic therapy (p < 0.001). This finding suggests that perhaps patients with radiographic evidence of isolated brain metastases could have more widely disseminated microscopic disease that is undetectable on staging scans. Management of breast cancer patients with brain only metastases is very challenging as very few studies have been conducted to provide evidence for efficacy and safety of systemic treatments for this clinical scenario. In fact, the overwhelming majority of therapeutic clinical trials excluded patients with progressive CNS metastases due to poor prognosis and this resulted in paucity of data supporting or refuting use of many otherwise effective therapeutic options for breast cancer. Complicating the problem is the fact that most cytotoxic agents are unable to cross the blood brain barrier and therefore are expected to have limited activity in controlling brain metastases. Yet, there are a few studies performed in women with breast cancer and CNS metastases suggesting that drugs with smaller molecular weight (such as capecitabine, cyclophosphamide or liposomal doxorubicin as well as small molecule tyrosine inhibitors) can produce limited responses in the CNS and therefore are likely to penetrate the brain parenchyma at least to some extent [19,20,21]. Furthermore, intrathecal therapy can be beneficial although its limited activity has to be carefully weighed against its multiple toxicities and risks . In melanoma, a few studies have demonstrated benefit of combining brain radiation and immune checkpoint inhibitors, although studies in patients with breast cancer have not been performed . No prospective randomized trials have been conducted to evaluate the role of systemic therapy (whether endocrine, targeted or cytotoxic agents) following resection and/or stereotactic radiation therapy of solitary brain metastasis. Whether use of systemic therapy in this setting would decrease the probability of disease progression and improve survival is an important yet unanswered question. Single institution retrospective study has suggested a beneficial role of systemic chemotherapy following local therapy for brain metastases in patients with breast cancer and no evidence of disease outside of the CNS.  Prospective studies to sort this out and establish most effective treatment approaches to patients with isolated CNS metastases will be challenging due to a small incidence of solitary brain metastases in breast cancer patients.
Taken together, we strongly feel that eligibility criteria of clinical trials that have been studying novel and promising agents for breast cancer need to become more permissive to allow enrollment patients with progressive CNS disease as this clinical setting is one of the most challenging problems for oncologists to treat and therefore represents a highly unmet need.