Salvage stereotactic radiosurgery for breast cancer brain metastases: outcomes and prognostic factors

BACKGROUND:

Salvage stereotactic radiosurgery (SRS) is often considered in breast cancer patients previously treated for brain metastases. The goal of this study was to analyze clinical outcomes and prognostic factors for survival in the salvage setting.

METHODS:

The authors retrospectively examined 79 consecutive breast cancer patients who received salvage SRS (interval of >3 months after initial therapy), 76 of whom (96%) received prior whole‐brain radiation therapy. Overall survival (OS) and central nervous system (CNS) progression‐free survival rates were calculated from the date of SRS using the Kaplan‐Meier method. Prognostic factors were evaluated using the Cox proportional hazards model.

RESULTS:

Median age was 50.5 years. Fifty‐eight percent of this population was estrogen receptor positive, 62% was HER2 positive, and 10% was triple negative. At the time of SRS, 95% had extracranial metastases, with 81% of extracranial metastases at other visceral sites (lung/pleura/liver). Forty‐eight percent had stable extracranial disease. Median interval from initial brain metastases therapy to SRS was 8.4 months. Median CNS progression‐free survival after SRS was 5.7 months (interquartile range [IQR], 3.6‐11 months), and median OS was 9.8 months (IQR, 3.8‐18 months). Eighty‐two percent of evaluable patients received further systemic therapy after SRS. HER2 status (adjusted hazard ratio [HR], 2.4; P = .008) and extracranial disease status (adjusted HR, 2.7; P = .004) were significant prognostic factors for survival on multivariate analysis.

CONCLUSIONS:

In patients with good Karnofsky performance status, salvage SRS for breast cancer brain metastases is a reasonable treatment option, given an associated median survival in excess of 9 months. Furthermore, patients with HER2‐positive tumors at diagnosis or stable extracranial disease at the time of SRS have an improved clinical course, with median survival of >1 year. Cancer 2012. © 2011 American Cancer Society.     

Brain metastases in breast cancer

Despite therapeutic advances, the development of breast cancer brain metastases (BCBM) is still the harbinger of a dismal prognosis. Patient outcomes vary depending on factors, including tumor phenotype, extent of disease within and outside the brain, as well as patient performance status. Treatment includes surgery, radiation therapy and systemic therapy determined by patient and tumor characteristics. Despite these approaches, novel treatments are needed and there is growing interest in systemic therapies. However, the efficacy of pharmacologic agents is hampered by poor penetration of drugs across the blood–brain barrier. Therefore, there is a pressing need for a greater understanding of the natural history of BCBM to guide the development of further therapies. This review analyzes prognosis and treatment of BCBM by tumor phenotype and discusses ongoing research into new therapies.     

Brain metastases in breast cancer; natural history,prognostic factors and outcome

Summary One hundred and thirty seven breast cancer patients with CT scan documented brain metastasis (BM) were reviewed. Occurrence of brain as first site of relapse was associated with adjuvant systemic therapy of the primary tumor. Multivariate analysis showed significantly longer survival in patients without manifest systemic disease, in patients with a solitary BM, in those with neurologic symptoms present for more than 4 weeks prior to diagnosis, and in those treated with chemotherapy after diagnosis. When controlling for prognostic factors no significant difference in survival was found between surgery and radiotherapy (RT) as treatment of a solitary lesion. Tumor size, tumor necrosis and mass effect had no demonstrable influence on survival. Overall median survival was 16 weeks and 19% survived one year. Neurologic disease was the cause of death or a major contributing factor to it in 68% of the patients, indicating the need for improvement of the treatment of BM itself. These results warrant further studies on the value of surgery, RT and chemotherapy in solitary as well as multiple BM from breast carcinoma.     

Questionnaire Survey of Treatment Choice for Breast Cancer Patients with Brain Metastasis in Japan: Results of a Nationwide Survey by the Task Force of the Japanese Breast Cancer Society

Objective: A nationwide survey was performed to investigate the currentpatterns of care for brain metastasis (BM) from breast cancerin Japan. Method: A total of 351 survey questionnaires were sent to communityor academic breast oncologists who were members of the JapaneseBreast Cancer Society as of December 2005. The questionnaireconsists of 40 multiple choice questions in eight categories. Results: Of 240 institutions sent survey questionnaires, 161 (67.1%)answered; 60% of institutions answered with ‘<5’patients with BM every year; almost half (83 of 161) screenedfor BM in asymptomatic patients; surgical resection was rarelyperformed, as ~75% of institutions (118 of 160 institutions)answered ‘none or one case of surgery per year’;27% (41 of 154) preferred stereotactic radiosurgery (SRS) overwhole-brain radiotherapy (WBRT) as the initial treatment inall cases, although ~70% (100 of 154) of them answered ‘dependon cases’. The preference for SRS over WBRT mainly dependson the impressions of breast oncologists about both safety (latenormal tissue damage and dementia in WBRT) and efficacy (betterlocal control by SRS). Eighty-one percent (117 of 144) of institutionsdid not limit the number of SRS sessions as far as technicallyapplicable. Conclusion: SRS is widely used as the first choice for BM from breast cancerin Japan. Considerable numbers of Japanese breast oncologistsprefer SRS over WBRT as the initial treatment for BM. A randomizedtrial comparing SRS and WBRT is warranted.     

The regional treatment of liver metastases from breast cancer

To determine the effect of aggressive regional therapy for liver metastasis from breast cancer, we retrospectively reviewed data on 74 patients identified with liver metastases. Forty had only liver metastases. In this group of 40 patients, 18 were treated with regional therapy only, i.e., surgical resection and/or regional chemotherapy via hepatic artery or portal vein catheters whereas 22 patients had systemic chemotherapy. The two groups were comparable. The regional chemotherapy regimen was 5-FU, Adriamycin, methotrexate, and cytoxan. Median survival (27 months) for those patients treated with regional therapy (N = 18) was significantly longer than for those (N = 22) treated with systemic therapy (5 months) (P = 0.001). Only 45% of the regional treatment group failed in the liver. Our data, although retrospective and selective, suggest that certain subgroups of breast cancer patients with metastatic liver disease may benefit from aggressive regional therapy. © Wiley-Liss, Inc.     

Hypofractionated stereotactic radiotherapy for the treatment of brain metastases

BACKGROUND:

This retrospective review evaluated the efficacy and toxicity profiles of various dose fractionations using hypofractionated stereotactic radiotherapy (HSRT) in the treatment of brain metastases.

METHODS:

Between 2004 and 2007, 36 patients with 66 brain metastases were treated with HSRT. Nine of these subjects were excluded because of the absence of post‐treatment magnetic resonance imaging scans, resulting in 27 patients with a total of 52 lesions. Of these 52 lesions, 45 lesions were treated with whole‐brain radiotherapy plus a HSRT boost and 7 lesions were treated with HSRT as the primary treatment. The median prescribed dose was 25 grays (Gy) (range, 20 Gy‐36 Gy) with a median of 5 fractions (range, 4 fractions‐6 fractions) to a median 85% isodose line (range, 50%‐100%). The median follow‐up interval was 6.6 months (range, 0.9 months‐26.8 months).

RESULTS:

The median overall survival time was 10.8 months, and 66.7% of patients died of disease progression. After HSRT treatment of 52 brain lesions, 13 lesions demonstrated complete responses, 12 lesions demonstrated partial responses, 22 lesions demonstrated stable disease, and 5 lesions demonstrated progressive disease. Actuarial local tumor control rates at 6 months and 1 year were 93.9% and 68.2%, respectively. Maximum tumor dimension, concurrent chemotherapy, and a tumor volume <1 cc were found to be statistically significant factors for local tumor control. One patient had a grade 3 toxicity (according to National Cancer Institute Common Terminology Criteria for Adverse Events).

CONCLUSIONS:

HSRT provides a high level of tumor control with minimal toxicity comparable to single‐fraction stereotactic radiosurgery (SRS). The results of the current study warrant a prospective randomized study comparing single‐fraction SRS with HSRT in this patient population. Cancer 2009. © 2009 American Cancer Society.     

Central nervous system metastases in women after multimodality therapy for high risk breast cancer

Background: Central nervous system (CNS) relapse is increasing in breast cancer. This increase may reflect altered failure patterns from adjuvant therapy, more effective systemic therapy with improved control in non-CNS sites, or a resistant breast cancer subtype.Methods: To determine the factors associated with clinical CNS relapse, we examined response to neoadjuvant chemotherapy (chemosensitivity), time to relapse and sites of relapse in a cohort of 140 patients without evidence of metastasis at presentation.Results: At 5 years (interquartile range 3–6 years), 44 (31%) patients developed distant metastases, including 13 with CNS metastases. CNS relapse was early (median 24 months after diagnosis) and associated with relapse in bone and liver, suggesting hematogenous dissemination. Those with CNS relapse were younger at diagnosis (40 versus 49 years) and more likely to have lymphovascular invasion in the primary tumor compared with non-CNS metastases. Response to neoadjuvant chemotherapy was not different (69% versus 73% response rate) between the two groups. Extent of residual disease after chemotherapy was strongly associated with relapse outside the CNS but not CNS relapses. The CNS was an isolated or dominant site of metastasis in 8 of 13. Despite treatment, most patients with CNS involvement died of neurologic causes a median of 6 months later.Conclusion: Breast cancers that develop CNS metastases differ from those that develop metastases elsewhere. Both tumor behavior and reduced chemotherapy accessibility to the CNS may contribute to increased CNS involvement in breast cancer patients treated with multimodality therapy.     

Chemotherapy and pattern of metastases in breast cancer patients

A retrospective analysis of all breast cancer patients who died of their disease at Harper Grace Hospital during 1962 to 1976, was conducted to determine the pattern of metastases and its relation to chemotherapy. The autopsy incidence of distant metastases, to all organ sites, was noted to be higher among patients who previously received cytotoxic therapy, compared with those who did not. Such incidence was unrelated to differences in patients' age, menopausal status, and disease-free interval. It is postulated that chemotherapy contributes to the wider metastases, especially to the central nervous system and meninges, in a breast cancer patient. This is possibly due to a longer survival of patients treated.     

Isolated limb perfusion with melphalan for femoral metastases of breast cancer: case report

BACKGROUND AND OBJECTIVES: Complications of bone destruction occur in 10-29% of breast cancer patients with skeletal metastases. Palliative treatment consists of systemic chemotherapy, hormonal treatment, radiotherapy, and/or surgery in the case of (impending) fracture. A case is presented where isolated limb perfusion was applied for this indication. METHODS: A 43-year-old woman with extensive femoral metastases of breast cancer with impending fracture was treated with isolated limb perfusion (ILP) with melphalan. Radiotherapy had resulted only in pain reduction, and intramedullary fixation was opted against because stable fixation was considered not feasible due to the location of the metastases. ILP with high-dose melphalan (10-20 times the amount that can be administered systemically) under normothermic (37-38 degrees C) conditions, resulted in partial remission and reossification. RESULTS: One year after ILP, until her death 2 years later, due to progressive metastases at other sites, the patient was able to bear weight again on her left leg. CONCLUSIONS: In selected patients with symptomatic large bone metastases from breast cancer, and no other treatment options, ILP with melphalan may be used for successful palliation.     

39例乳腺癌并肝转移诊治体会

目的：总结乳腺癌并肝转移的临床诊断及治疗特点。方法：回顾性分析2008年1月到2013年8月期间西安交通大学医学院第二附属医院收治的39例乳腺癌并肝转移患者的临床详细资料。结果：本文对39例乳腺癌并肝转移患者进行分析,随访3年余,生存27例,死亡12例,均死于肿瘤进展,中位疾病进展时间（PFS）为25个月,中位随访时间（MSR）为17个月,诊治过程中肿瘤反反复复,呈难治、多药耐药倾向。结论：乳腺癌并肝转移预后差,治疗棘手,关键在于早期发现、早期诊治。对于HER-2阳性患者,赫塞汀靶向治疗是一个有效的治疗选择;对于疗效较好的患者,维持治疗是非常必要的。通过积极综合治疗,可以延长生存期,提高生活质量。     

Brain metastases free survival differs between breast cancer subtypes

Background:

Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010.

Methods:

Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test.

Results:

Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34–16.66) compared with 18 months (95% CI: 14.46–21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71–44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014).

Conclusion:

Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.     

Impact of systemic targeted agents on the clinical outcomes of patients with brain metastases

Background

To determine the clinical benefits of systemic targeted agents across multiple histologies after stereotactic radiosurgery (SRS) for brain metastases.

Methods

Between 2000 and 2013, 737 patients underwent upfront SRS for brain metastases. Patients were stratified by whether or not they received targeted agents with SRS. 167 (23%) received targeted agents compared to 570 (77%) that received other available treatment options. Time to event data were summarized using Kaplan-Meier plots, and the log rank test was used to determine statistical differences between groups.

Results

Patients who received SRS with targeted agents vs those that did not had improved overall survival (65% vs. 30% at 12 months, p < 0.0001), improved freedom from local failure (94% vs 90% at 12 months, p = 0.06), improved distant failure-free survival (32% vs. 18% at 12 months, p = 0.0001) and improved freedom from whole brain radiation (88% vs. 77% at 12 months, p = 0.03). Improvement in freedom from local failure was driven by improvements seen in breast cancer (100% vs 92% at 12 months, p < 0.01), and renal cell cancer (100% vs 88%, p = 0.04). Multivariate analysis revealed that use of targeted agents improved all cause mortality (HR = 0.6, p < 0.0001).

Conclusions

Targeted agent use with SRS appears to improve survival and intracranial outcomes.     

Pathogenesis and vascular integrity of breast cancer brain metastasis

Dogma dictates that brain metastasis originate from the proliferation of extravasated tumor cells and that the blood-brain barrier (BBB) prevents the delivery of chemotherapeutic drugs to the tumors. The purpose of this study was to clarify the relationship between tumor localization and progression and the involvement of BBB function in a murine model of breast cancer brain metastasis. Green fluorescent protein expressing MDA-MB435 breast cancer cells were injected into the left ventricle of nude mice. At various time points, the entire vasculature was labeled with rhodamine-conjugated albumin. The tumors and vasculature were then imaged by laser-scanning confocal and stereo fluorescence microscopy. About 75% of the cells that reached the brain extravasated and grew perivascularly. Twenty five percent of the cells, however, proliferated within the vasculature and ultimately led to thrombosis-like infarction of the brain parenchyma. The tumorigenic "embolus" served as a sustained release source of tumor cells to downstream sites. Continuing intravascular tumor expansion led to disruption of the BBB and to overflow of cells that progressed along the vessels perivascularly to distant sites that regained protection of the BBB. Breast cancer brain metastases involve both extravascular and intravascular growth of tumor cells. These distinct pathways contribute to different pathological phenotypes that generate a heterogeneous BBB that facilitates or inhibits the delivery of chemotherapeutic drugs to the tumor.     

Phase II trial of patupilone in patients with brain metastases from breast cancer

Background

For patients with progressive breast cancer brain metastasis (BCBM) after whole brain radiotherapy (WBRT), few options exist. Patupilone is an epothilone that crosses the blood–brain barrier. We hypothesized that patupilone would produce a 35% 3-month CNS progression-free survival in women with BCBM after WBRT.

Methods

This multicenter phase II trial included 2 cohorts. Group A included women with progressive BCBM after WBRT. Group B was an exploratory cohort of patients with either leptomeningeal metastases or untreated brain metastases. The primary goal was to observe a 35% 3-month CNS progression-free survival in Group A. The sample size was 45 for Group A and 10 for Group B. Patients received patupilone 10 mg/m² once every 3 weeks until progression. Responses were scored according to the Macdonald criteria.

Results

Fifty-five patients (45 in Group A, 10 in Group B) enrolled. In Group A, the 3-month CNS progression-free survival was 27%, the median overall survival was 12.7 months, and the overall response rate was 9%. In Group B, which enrolled 5 patients with leptomeningeal disease and 5 with no prior WBRT, no responses occurred and 8 patients had CNS progression before 3 months. Systemic responses occurred in 15% of patients, including a complete response in liver metastases. Diarrhea occurred in 87% of patients; 25% had grade 3 and 4 adverse events.

Conclusions

Patupilone in patients with BCBM did not meet the efficacy criteria and had significant gastrointestinal toxicity. Further study of brain-penetrant agents is warranted for patients with CNS metastases from breast cancer.     

多西紫杉醇联合卡培他滨治疗乳腺癌肝转移的临床观察

目的：观察多西紫杉醇联合卡培他滨（TX）序贯卡培他滨单药维持治疗乳腺癌肝转移（breast cancerliver metastases,BCLM）的疗效和安全性。方法：回顾性分析TX方案治疗蒽环/和紫杉类药治疗的乳腺癌肝转移患者39例。全组共化疗230周期,中位周期数6周期（4-8周期）。有效者TX方案化疗6-8周期后序贯卡培他滨单药维持直至不能耐受或病情进展。结果：全组39例患者,4周期化疗后CR0例,PR20例（51.3%）,SD14例（35.9%）,PD 5例（12.8%）,有效率51.3%,临床获益率87.2%。TTP 2.8-36.5月,中位TTP5月。结论：应用TX方案序贯卡培他滨维持治疗蒽环/和紫杉类治疗后乳腺癌肝转移疗效确切,毒副反应能耐受,值得临床推广。     

激素受体阳性乳腺癌脑转移药物治疗研究进展

目的 乳腺癌是仅次于肺癌最易发生脑转移的原发肿瘤.激素受体阳性乳腺癌是转移性乳腺癌的主体,脑转移是该类患者的主要死亡原因,但目前对于激素受体阳性乳腺癌脑转移(breast cancer brain metastases,BCBM)的有效治疗报道较少.本研究旨探讨激素受体阳性BCBM药物治疗的相关研究进展.方法 应用PubMed及CNKI期刊全文数据库检索系统,以"乳腺癌、脑转移和激素受体阳性乳腺癌"等为,检索2005-01-2016-06相关文献,共检测到中文文献128条,英文文献55条.纳入标准:1)BCBM的危险因素及其预后;2)BCBM的当前治疗选择;3)激素受体阳性BCBM药物治疗.根据纳入标准,符合分析的文献25篇.结果限制BCBM药物治疗进展的主要原因是血脑屏障的存在.激素在BCBM治疗中的疗效尚不明确,但有大量个案报道他莫昔芬等内分泌药物对BCBM治疗有效.非对照试验表明某些细胞毒类药物,如卡培他滨、替莫唑胺(temozolomide,TMZ)和卡莫司汀晶片植入剂,对激素受体阳性BCBM有效,但没有足够证据支持具体的治疗方案.免疫抑制剂abemaciclib在激素受体阳性BCBM患者中的应用正处于Ⅱ期临床试验阶段.虽然高分子药物难以通过完整的血脑屏障,但研究证实部分单克隆抗体,如曲妥珠单抗和贝伐单抗,对BCBM治疗有效.纳米药物传递系统能提高中枢神经系统药物转移,有较好发展前景.由纳米颗粒包裹的多柔比星和etirinotecanpegol对治疗激素受体阳性BCBM有一定的疗效.结论尽管目前没有专门批准用于激素受体阳性BCBM系统治疗的药物,但有大量的临床试验正在进行中,将为临床治疗带来启示.     

Treatment and outcome of brain metastasis as first site of distant metastasis from breast cancer

Twenty-eight consecutive patients with breast cancer were analyzedwho presented with a single brain metastasis asfirst site of distant metastasis. The response tosurgery with postoperative radiation therapy (RT) (9 patients)and to non-surgical therapy as first-line treatment was100% and 89% respectively with a significant differencein median recurrence-free intervals of 23 months andof 5 months respectively (p=0.033). Retreatmentof a local relapse by surgery (± RT,± chemotherapy) or by non-surgical treatment resulted ina response in 6 of the 7 operatedpatients and in 5 of the 6 non-operatedpatients with a median duration of response of7 months (range 2–20 months) and of 3months (range 2–4 months) respectively. The overall mediansurvival of the 28 patients with a singlebrain metastasis was 16 months (range 2–39 months).The median survival in the primarily operated patientswas 23 months, in the primarily not-operated group10 months, and in the never-operated group 9months. In comparison, the response to non-surgical treatmentin 20 consecutive patients who presented with multiplebrain metastases as first site of distant metastasiswas 55% with a median recurrence free intervalof 4 months. The median survival in thisgroup was 4 months, which was significantly shorterthan survival of patients with single brain metastasis(p=0.0036). These results suggest that breastcancer patients with a single brain metastasis asfirst presentation of relapse constitute a specific subgroupwith a favorable response to treatment and along survival especially if they can be treatedby surgery with postoperative RT.     

Brain metastases from ovarian cancer

Brain metastasis from ovarian carcinoma is a relatively rare phenomenon. At NYU Medical Center five patients were treated for this entity from 1982 to 1985. The stage at presentation ranged from stage I to stage III, and all patients had received or were receiving chemotherapy. Two patients had active disease elsewhere at diagnosis of brain metastasis, but three patients were otherwise NED. Three patients had solitary cerebellar disease, and two patients had multiple lesions. All patients were treated with whole brain radiotherapy to 3 000 cGy, with neurological improvement in three of the five patients.The central nervous system may need special consideration for prophylactic treatment in those patients with ovarian cancer who receive adjuvant chemotherapy.     

Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases

BackgroundSixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival.MethodsWe determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues.ResultsWe demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified cold-inducible RNA-binding protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain.ConclusionsThese data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying postoperative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected BrM.