Risk factors for central nervous system metastasis in patients with metastatic breast cancer

Aims Patients with metastatic breast cancer (MBC) and central nervous system (CNS) involvement have an impaired survival and quality of life. In this study, we investigated the risk factors for CNS metastasis among patients with MBC. Methods The risk factors for development of CNS metastasis were analyzed in 154 patients with MBC. Expression of c-erbB-2, Ki-67, p53, and hormone receptors was examined by immunohistochemistry (IHC) in breast cancer tissue samples from the 154 patients. Kaplan-Meier and log-rank tests were used for the analysis of overall survival (OS). Chi-square test was used for univariate analysis. Results Median OS was significantly poorer for patients with CNS metastasis as compared with patients with no CNS metastasis (OS, 23 mo vs 30 mo, respectively;p = 0.03). Ki-67 and p53 overexpressions by IHC, and lung metastasis as the first site of relapse, were associated with a higher risk of developing CNS metastasis in the univariate analysis (p ≤ 0.05). The presence of lung metastasis (odds ratio [OR]= 2.82, 95% confidence interval [CI]: 1.13-7.00,p = 0.02) and p53 overexpression (OR = 2.44, 95% CI: 0.99-6.00,p = 0.05) were the two predictive factors associated with occurrence of CNS metastasis in the multivariate analysis. Conclusions In this study, the presences of lung metastasis as the first site of relapse and p53 overexpression were predictive for the occurrence of CNS metastasis in patients with MBC. Life expectancy of patients with CNS metastasis is significantly shorter than those without CNS metastasis. These results may have clinical significance in counseling MBC patients with regard to their prognosis.     

Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival.

BACKGROUND: As screening central nervous system (CNS) imaging is not routinely performed, the incidence and clinical relevance of occult CNS metastases in advanced breast cancer is unknown. PATIENTS AND METHODS: All patients screened for participation in one of four clinical trials were included; each of the trials excluded patients with known CNS involvement and required screening CNS imaging. A cohort of breast cancer patients with symptomatic CNS metastases was identified from the IU Cancer Center Tumor Registry for comparison. RESULTS: From November 1998 to August 2001, 155 screening imaging studies were performed. Twenty-three patients (14.8%) had occult CNS metastases. HER-2 overexpression (P = 0.02) and number of metastatic sites (P = 0.03) were predictive of CNS involvement by multivariate analysis. Median survival from time of metastasis (1.78 versus 2.76 years; P <0.0001) and from screening (4.67 versus 10.4 months; P = 0.0013) was shorter in patients with than without occult CNS metastasis. Survival among patients with occult CNS metastasis was similar to patients with symptomatic CNS disease. CONCLUSIONS: Patients with CNS involvement, whether occult or symptomatic, have an impaired survival. Occult CNS metastasis is relatively common, but impact on survival of treating occult CNS disease in patients with progressive systemic metastases is questionable.     

Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases

BACKGROUND: The purpose of the current study was to characterize the outcomes of patients with metastatic triple-negative breast cancers, including the risk and clinical consequences of central nervous system (CNS) recurrence. METHODS: Using pharmacy and pathology records, a study group of 116 patients who were treated for metastatic triple-negative breast cancer at Dana-Farber Cancer Institute between January 2000 and June 2006 was identified. RESULTS: The median survival from time of metastatic diagnosis was 13.3 months. Sixteen patients (14%) were diagnosed with CNS involvement at the time of initial metastatic diagnosis; overall, 46% of patients were diagnosed with CNS metastases before death. The median survival after a diagnosis of CNS metastasis was 4.9 months. The age-adjusted and race-adjusted rate of death for patients whose first presentation included a CNS metastasis was 3.4 times (95% confidence interval, 1.9-6.1 times) that of patients without a CNS lesion at the time of first metastatic presentation. Of the 53 patients who developed brain metastases, only 3 patients were judged to have stable or responsive systemic disease in the face of progressive CNS disease at the last follow-up before death. CONCLUSIONS: Triple-negative breast cancer is associated with poor survival after recurrence. CNS recurrence is common, but death as a direct consequence of CNS progression in the setting of controlled systemic disease is uncommon. Thus, it does not appear that the high rate of CNS involvement is because of a sanctuary effect, but rather is due to the lack of effective therapies in general for this aggressive subtype of breast cancer. New treatment strategies are needed.     

Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy.

PURPOSE: The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. METHODS: The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy (doxorubicin/cyclophosphamide or paclitaxel) +/- trastuzumab, and the second was a multicenter phase II trial of vinorelbine + trastuzumab. All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. RESULTS: Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. Trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. CONCLUSIONS: Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.     

乳腺癌中枢神经系统转移的预测因素和内科治疗

随着生存的改善,乳腺癌中枢神经系统转移发生几率有所增加.综合多项研究,年轻、雌激素受体阴性、HER-2过表达、已存在肺转移是可能的预测因素.新的化疗和靶向治疗药物,尤其是lapatinib,一个口服的双靶点小分子酪氨酸激酶抑制剂,为乳腺癌中枢神经系统转移患者的治疗提供了新的选择.     

Survival of breast cancer patients with synchronous or metachronous central nervous system metastases

BackgroundCentral nervous system (CNS) metastases represent a devastating complication for advanced breast cancer patients. This observational study examines the influence of patient, tumour and treatment characteristics on overall survival after synchronous or metachronous CNS metastases.MethodsInformation on 992 breast cancer patients with CNS metastases (whose primary tumour was diagnosed between 2004 and 2010) was retrieved from the Netherlands Cancer Registry (NCR). Overall survival was calculated from the date of CNS metastatic diagnosis, and the impact of prognostic factors on survival was assessed using univariate and multivariate extended Cox-regression models.ResultsWe identified 165 patients with synchronous and 827 patients with metachronous CNS metastases. The majority of patients (88%) presented with brain metastases only, 12% had leptomeningeal metastases. Overall median survival was 5.0 months. Non-triple-negative breast cancer and systemic therapy were associated with improved survival in both groups. In patients with synchronous CNS metastases, surgery for the primary tumour and the metastases also improved survival. In patients with metachronous metastases, younger age (<50 years), lower initial tumour stage (I), ductal carcinoma, a prolonged time interval until diagnosis of CNS metastasis (>1 year), and absence of extracranial metastases were associated with improved survival. Metastasectomy and radiation therapy did not provide benefit beyond the first six months.ConclusionsNo difference in survival was established between synchronous and metachronous CNS metastases. Triple-negative disease is prognostically unfavourable in both groups, while those receiving treatment have a better outcome. Metastasectomy and radiotherapy improve survival within the first six months, and additional benefit may be derived from systemic therapy.     

Central nervous system metastases in women with HER-2 positive metastatic breast cancer after treatment with trastuzumab

Background: Historically, central nervous system (CNS) metastases have been reported to occur in 10–16% of women with metastatic breast cancer (MBC) with a median survival of less than 1 year after diagnosis of CNS disease. A higher rate of CNS metastases has been described in women with metastatic breast cancer (MBC) over‐expressing HER‐2 who receive trastuzumab therapy. Aims: The aim of this study was to examine the frequency of and potential risk factors for CNS metastases in these women. Our a priori hypotheses were that in MBC patients treated with trastuzumab, CNS metastases occurred (i) more frequently than historical controls, and (ii) in women with controlled systemic disease. Methods: A retrospective cohort study of 28 consecutive patients with MBC over‐expressing HER‐2 and treated with trastuzumab and chemotherapy was performed. Results: A total of 22/25 (88%) patients who initially responded to trastuzumab had progressed within a median of 11.2 months after starting trastuzumab therapy. Central nervous system metastases occurred in 11/28 (39%) patients and the remaining 11 patients had progressed elsewhere. At diagnosis of CNS metastases, 9/11 (82%) had controlled systemic disease (CR = 2, PR = 6, SD = 1). There were trends for patients with CNS metastases to have greater than one site of metastatic disease at the commencement of trastuzumab therapy (P = 0.06), and to be hormone receptor negative at initial diagnosis (P = 0.14). The median time to diagnosis of CNS metastases after the commencement of trastuzumab therapy was 12 months (range 6–19 months). The median survival after diagnosis of CNS metastases was 12 months (range 2–22 months). Conclusions: This study demonstrates a high rate of CNS metastases (39%) in HER‐2 positive MBC patients treated with trastuzumab. At CNS metastases most patients had controlled systemic disease and the median survival after CNS relapse was 1 year. We suggest aggressive management of CNS disease in this population. Additional strategies to decrease the incidence of CNS metastases in these patients may include prophylactic whole brain irradiation and the development of novel pharmacological agents with successful CNS penetration.     

Estrogen receptor profile of patients with breast cancer metastatic to bone marrow

The estrogen receptor (ER) profile of patients with breast cancer metastatic to bone marrow (BM) has not been widely reported. The charts of all patients having a diagnosis of breast cancer and undergoing bone marrow aspiration or biopsy at the Cleveland Clinic during the period of January 1980 through September 1982 were reviewed. Thirty-nine patients were so identified; of these 39 patients, 28 had estrogen receptor determination performed on a primary or a metastatic tumor specimen. Of the 28 patients with known ER, ten (36%) had ER less than 5 fmoles/mg cytosol protein, three (11%) had ER or 5 to 10 fmoles/mg, and 15 (54%) had ER greater than 10 fmoles/mg. Of the 39 patients with BM involvement, 36 (92%) had cortical bone involvement documented on x-ray or isotopic bone scan. Liver involvement was documented in 6/34 (18%) patients, pulmonary involvement in 14/37 (38%) patients, CNS relapses in 3/39 (8%), and locoregional recurrences in 19/39 (49%). The most significant hematologic finding was a hemoglobin of less than 12 gm% in 21/37 (57%). The most frequent biochemical abnormality was an elevation of the alkaline phosphatase in 30/39 (77%). The majority of breast cancer patients have a positive ER and ER-positive breast cancer has a tendency to metastasize to cortical bone. Bone marrow involvement by breast cancer is closely associated with cortical bone involvement; accordingly, bone marrow metastases are often associated with a positive ER.     

Estrogen receptor status as a prognostic indicator for stage I breast cancer patients

Summary The prognostic value of estrogen receptor determination was studied for 510 stage I (axillary node negative) breast cancer patients treated by mastectomy alone.Results at 60 months after mastectomy indicate that stage I patients whose tumors lack estrogen receptors fall into a significantly poorer prognostic group for both recurrence and survival than those whose tumors contain estrogen receptors.Within the postmenopausal group, estrogen receptor negative (ER –) patients are recurring more rapidly than estrogen receptor positive (ER +) patients. Within the premenopausal group, ER + patients have a recurrence rate identical to ER– patients, which is apparent only after prolonged follow-up.In contrast to postmenopausal ER + patients, premenopausal ER + patients appear to have no prognostic advantage over the ER – patients, and thus constitute a high risk group for which adjuvant endocrine therapy might prove beneficial.Participating Investigators: Frank M. Barry, M.D., A.M. Cooperman, M.D., Ludwig Deppisch, M.D., Robert L. Druet, M.D., Caldwell Esselstyn, M.D., Y.S. Fu, M.D., Vernon D. Hacker, M.D., Harold B. Houser, M.D., Ezra Steiger, M.D. and Elden C. Weckesser, M.D.     

Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study

BACKGROUND:

A series of retrospective studies have reported that patients with human epidermal growth factor receptor 2(HER2)‐positive breast cancer are at a greater risk of central nervous system (CNS) metastases. Trastuzumab, which does not cross the blood‐brain barrier, has been associated with this increased risk.

METHODS:

The authors evaluated incidence, survival, and risk factors for CNS metastases in the incident breast cancer population systematically collected by the Parma Province Cancer Registry over the 4‐year period between 2004 and 2007.

RESULTS:

A total of 1458 patients with a diagnosis of stage I to III invasive breast cancer were analyzed for study purposes. At a median follow‐up of 4.1 years, CNS events were observed in 1.3% and 5% of HER2‐negative patients and HER2‐positive patients, respectively (P < .0001). The administration of trastuzumab either as adjuvant therapy or for metastatic disease was associated with a significantly increased risk of CNS involvement at first disease recurrence and after first extracranial recurrence, respectively. According to multivariate analysis, HER2‐positive status and trastuzumab treatment, high Ki‐67 index, and hormone receptor negativity remained independent risk factors for the development of CNS metastasis.

CONCLUSIONS:

To the authors' knowledge, this is the first population‐based cancer registry study analyzing factors associated with CNS recurrence in a general population of newly diagnosed breast cancer patients with known HER2 status. The data from the current study provide evidence that patients with HER2‐positive breast cancer have a significantly higher incidence of CNS metastasis after treatment with trastuzumab. Improvements in systemic control and overall survival associated with trastuzumab‐based therapy may lead to an “unmasking” of CNS disease recurrence that would otherwise remain clinically silent before a patient's death. Cancer 2011. © 2010 American Cancer Society.     

原发性中枢神经系统淋巴瘤患者预后的影响因素分析

目的 探讨原发性中枢神经系统淋巴瘤(PCNSL)患者预后的影响因素.方法 收集82例PCNSL患者的临床资料,包括性别、年龄、病灶数量、病灶部位、病灶直径、治疗方法、意识状态、体力状况(PS)评分等一般资料,以及脑脊液(CSF)常规检测指标(CSF蛋白质、CSF氯化物)和生化检测指标[血清乳酸脱氢酶(LDH)、β2微球...     

原发性中枢神经系统淋巴瘤35例临床及预后分析

目的：探讨原发中枢神经系统淋巴瘤（PCNSL）临床特点、诊治方案及临床疗效。方法：总结2001年1月-2008年1月收治的35例PCNSL患者,均经病理证实为B细胞来源非霍奇金淋巴瘤并接受放疗,其中25例放疗后接受化疗。结合文献对原发性中枢神经系统淋巴瘤患者的临床特点、病理学检查、影像学表现、治疗及预后进行回顾性分析。结果：本病以中老年人多见,发病急,病程短,病情进展快。临床表现复杂,颅内高压为主要表现之一。CT、MRI增强扫描病灶多呈均匀明显强化,可单发或多发。35例患者中位生存时间23月,1年生存率74．3％,3年生存率25．7％,5年生存率5．71％。肿瘤全切及局部切除者,生存率未见明显统计学差异（P=0．053）,加化疗疗效优于不加化疗（P=0．012）。结论：PCNSL临床表现多样,影像学缺乏特异性,极易误诊,确诊需要依靠病理学检查,最佳治疗方案是手术加放疗、化疗的联合治疗。PCNSL侵袭性强,生存期短,其预后主要与发病年龄、多灶性、一般状态有关。     

Prognostic factors and long-term survival in 585 patients with metastatic breast cancer treated with epirubicin-based chemotherapy

Background:Analysis of prognostic factors in patients withmetastatic breast cancer treated with epirubicin-based chemotherapy. Patients and methods:Data from 469 patients treated withepirubicin-based chemotherapy for metastatic breast cancer were used.Prognostic factors were identified (Cox multivariate analysis). A prognosticindex was compiled and risk groups were established accordingly. Theapplicability of the index was investigated in a series of 116 patients. Results:The prognostic factors identified were: liver, pleural,soft tissue, lung and bone metastases, performance status >2, advancingage, abnormal elevation of serum lactate dehydrogenase and negative/unknownoestrogen receptor status. Four risk groups were established: good,intermediate I, intermediate II and poor. The median and five-year survivalsin percentage were: good: 34 months (26%); intermediate I: 19 months(6%); intermediate II: 12 months (0%); poor: 7 months(1%). The corresponding values in the applicability group were: 32months (23%); 28 months (22%); 18 months (5%); and 6months (0%). Conclusions:It is more the number and impact on the organsinvolved, that predict the patients survival. The construction of aprognostic index could be helpful in assessing the outlook for patients,especially the quite dramatic difference in long-term survival between thegood and poor risk patients.     

原发性中枢神经系统淋巴瘤35例临床及预后分析

目的:探讨原发中枢神经系统淋巴瘤(PCNSL)临床特点、诊治方案及临床疗效。方法:总结2001年1月-2008年1月收治的35例PCNSL患者,均经病理证实为B细胞来源非霍奇金淋巴瘤并接受放疗,其中25例放疗后接受化疗。结合文献对原发性中枢神经系统淋巴瘤患者的临床特点、病理学检查、影像学表现、治疗及预后进行回顾性分析。结果:本病以中老年人多见,发病急,病程短,病情进展快。临床表现复杂,颅内高压为主要表现之一。CT、MRI增强扫描病灶多呈均匀明显强化,可单发或多发。35例患者中位生存时间23月,1年生存率74.3%,3年生存率25.7%,5年生存率5.71%。肿瘤全切及局部切除者,生存率未见明显统计学差异(P=0.053),加化疗疗效优于不加化疗(P=0.012)。结论:PCNSL临床表现多样,影像学缺乏特异性,极易误诊,确诊需要依靠病理学检查,最佳治疗方案是手术加放疗、化疗的联合治疗。PCNSL侵袭性强,生存期短,其预后主要与发病年龄、多灶性、一般状态有关。     

乳腺癌的预后因素研究进展

乳腺癌的预后指标是一个传统的研究课题。随着新的检测方法及预后指标不断涌现。我们对乳腺癌的临床病程及生物学行为有了更充分的了解,从而指导合理的临床治疗。当前许多分子生物学的预后指标还在进一步的研究之中,其中一部分具有很广阔的研究前景,但目前它们还未列入常规的检测项目。本文就目前已确立的乳腺癌的预后指标以及一部分未来可能有实用价值的预后因素作一综述。     

Risk factors for brain relapse in patients with metastatic breast cancer.

BACKGROUND: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer. PATIENTS AND METHODS: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting. RESULTS: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.9-9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7-11, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases. CONCLUSION: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.     

Prognostic factors for patients with hepatic metastases from breast cancer

Median survival from liver metastases secondary to breast cancer is only a few months, with very rare 5-year survival. This study reviewed 145 patients with liver metastases from breast cancer to determine factors that may influence survival. Data were analysed using Kaplan-Meier survival curves, univariate and multivariate analysis. Median survival was 4.23 months (range 0.16-51), with a 27.6% 1-year survival. Factors that significantly predicted a poor prognosis on univariate analysis included symptomatic liver disease, deranged liver function tests, the presence of ascites, histological grade 3 disease at primary presentation, advanced age, oestrogen receptor (ER) negative tumours, carcinoembryonic antigen of over 1000 ng ml(-1) and multiple vs single liver metastases. Response to treatment was also a significant predictor of survival with patients responding to chemo- or endocrine therapy surviving for a median of 13 and 13.9 months, respectively. Multivariate analysis of pretreatment variables identified a low albumin, advanced age and ER negativity as independent predictors of poor survival. The time interval between primary and metastatic disease, metastases at extrahepatic sites, histological subtype and nodal stage at primary presentation did not predict prognosis. Awareness of the prognostic implications of the above factors may assist in selecting the most appropriate treatment for these patients.British Journal of Cancer (2003) 89, 284-290. doi:10.1038/sj.bjc.6601038 www.bjcancer.com     

Prognostic factors for patients with liver metastases from breast cancer

Summary Background The prognosis of patients with liver metastases from breast cancer is commonly poor. After initial diagnosis of hepatic metastases, a median survival time of 1–20 months can be expected. The definition of prognostic factors for such patients may influence therapeutic decisions. In particular, the characterization of patients who can expect long-term survival could assist in optimizing treatment. Methods We retrospectively studied n=350 patients with liver metastases from breast cancer. All patients were stratified following their survival after occurrence of liver metastases. Kaplan–Meier studies were performed, as well as univariate and multivariate analyses of several clinical, histopathological and therapeutic factors. Results Median survival time was 14 months. N=66 (18.9%) patients survived longer than 36 months after the primary diagnosis. Multivariate analysis showed prognostic relevance for the time interval between the primary diagnosis of breast cancer and the initial diagnosis of hepatic metastases (p<0.05). Furthermore, prognostic relevance was found for the pattern of metastasization (p<0.05) and for signs of hepatic dysfunction (ascites, jaundice, p<0.005). Univariate analysis showed a prognostic benefit for patients with an expression of Ki-67<20%, p53<50% and a positive hormonal receptor status. Patients who received a regional therapy survived on average longer than patients who were only treated systemically (33 versus 11 months, p<0.001). Conclusions Consideration of prognostic implications of the described parameters may help to find the most appropriate treatment for patients with liver metastases from breast cancer. The possibility of local therapeutic interventions should be considered in a defined subgroup.     

中晚期乳腺癌脑转移患者的危险因素分析

目的:探讨中晚期乳腺癌患者发生脑转移的危险因素。方法:回顾性分析2004年8月-2014年8月期间来我院治疗的中晚期乳腺癌患者的临床资料。根据是否发生脑转移将患者分为实验组和对照组,实验组由发生脑转移的80例患者组成,对照组由未发生脑转移的100例患者组成。采用Logistic逐步回归分析,分析中晚期乳腺癌患者发生脑转移的危险因素。结果:两组患者PR状况、绝经状况以及临床分期等差异不具有统计学意义（P>0.05）。两组患者的年龄、KPS评分、ER状况、HER-2状况、肿瘤直径大小以及组织学分级等临床资料差异较大,具有统计学意义（P<0.05）。经Logistic回归逐步分析可知,组织学分级(Ⅲ级)的优势比最高（Wald=11.486）,是影响患者发生脑转移的最危险因素,其次是肿瘤直径大小（≥5cm）（Wald=10.654）、ER状况（阴性）（Wald=9.123）,年龄（＜55岁）影响最小（Wald=6.085）。结论:中晚期乳腺癌患者发生脑转移的因素较多,如年龄、KPS评分、ER状况、HER-2状况、肿瘤直径大小以及组织学分级等,治疗过程中,应加以重视,以降低患者转移率。