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.     

乳腺癌脑转移全脑放疗预后及预后指数分析

目的 探讨乳腺癌脑转移患者全脑放疗(WBRT)预后以及不同预后指数差别。
方法 对2006-2010年间接受WBRT的99例乳腺癌脑转移患者进行Logrank法单因素与Cox法多因素预后分析,计算并比较RPA、GPA、BSBM、Rades、Carsten预后指数评分的敏感性和特异性。
结果 全组患者中位随访时间49个月,中位生存期为10个月。单因素分析显示年龄、脑转移时卡氏评分、是否伴有颅外转移、原发肿瘤控制情况、脑转移数目和WBRT后全身治疗与总生存相关(χ²=0.00~55.51,P=0.013~0.000),多因素分析证实卡氏评分<70和WBRT后全身治疗与总生存相关(χ²=35.26、7.21,P=0.000、0.007)。RPA、GPA、BSBM、Rades、Carsten预后指数评分对预测生存期≤3个月乳腺癌脑转移患者的敏感性和特异性分别为100%和85%、95%和62%、95%和86%、95%和84%、95%和85%。
结论 乳腺癌脑转移患者WBRT后全身治疗可改善患者总生存。对预测生存期≤3个月患者敏感性最好的为RPA指数,特异性最好的为BSBM指数。     

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.     

Treatment outcomes and unfavorable prognostic factors in patients with occult breast cancer

Aims

The purpose of this study was to evaluate the treatment outcomes and prognostic factors in patients with occult breast cancer (OBC).

Methods

We retrospectively analyzed 95 patients with OBC who were treated at our facility between January 1998 and June 2010. Of the 95 patients, 64 underwent mastectomy plus axillary lymph node dissection (ALND) with or without post-mastectomy radiation (Mast + ALND group), 13 underwent ALND followed by ipsilateral breast radiotherapy (BR + ALND group) and the remaining 18 were treated with ALND (ALND group).

Results

Patients who underwent Mast + ALND or BR + ALND had significantly improved rates of locoregional recurrence-free survival (LRFS) and recurrence/metastasis-free survival (RFS) than patients who only underwent ALND (p < 0.05). There were no significant differences in the LRFS (p = 0.718), RFS (p = 0.935) and breast cancer-specific survival (BCSS) (p = 0.991) rates between the patients who underwent Mast + ALND compared with those who received BR + ALND. Multivariate analysis revealed that patients with four or more involved lymph nodes had significantly worse outcomes (p = 0.042, HR = 4.63, 95% CI = 1.66–32.47 for BCSS and p = 0.038, HR = 3.62, 95% CI = 1.08–20.77 for RFS).

Conclusions

Patients with OBC who received ALND and subsequent breast radiotherapy had similar outcomes to patients who underwent mastectomy. The presence of four or more involved lymph nodes may independently predict poor outcomes of OBC.     

Diagnosis and management of spinal metastases from breast cancer

Conclusions Metastases to the spine is a common manifestation of breast cancer leading to considerable reduction in the patient's quality of life due to troublesome back pain and neurologic morbidity. It is not uncommon for spinal metastases to be an early and predominant manifestation of the patients systemic disease process. Although the breast cancer must be considered to be advanced, these patients will frequently have a reasonable functional status at the time of diagnosis of the spinal metastases. Accordingly, an aggressive approach of management should be considered in such patients so as to potentially achieve the most effective palliation. In the setting of breast cancer metastatic to the spine, radiation/systemic steroidal therapy remains the first line of management. The principle exception favoring primary surgical management is roentgenographic evidence of spinal instability related to the vertebral involvement by the metastatic process. The surgical team must also remain ready to intervene early with surgical decompression and spinal stabilization when any neurologic deterioration occurs during radiation therapy. When surgery is indicated, the anterior transthoracic approach to spinal metastases is an effective means of palliating these breast cancer patients.A team approach involving the spinal surgeon, thoracic surgeon and anesthesiologist optimizes the care of the patient requiring thoracic spinal decompression of metastatic disease. Involvement of the thoracic surgeon in these patients care can result in expeditious thoracic exposure of the pathologic area of concern and valuable contribution to the post-operative care of these unfortunate patients.     

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

Background  Recently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab. Methods  We retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months. Results  Among the patients who received a trastuzumabcontaining regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2–14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0–45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (≤50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases. Conclusion  Patients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (≤50 years) who had recurrent breast cancer with liver metastases.     

Possible factors in remote metastases in female breast cancer

The association of metastases (M) with age of patient, stage of disease, the gross and microscopic characteristics of the primary tumor, its physical location, the postradiational status of the breast, the extent and level of histological nodal involvement, the type of surgery practiced, and the host's biological environment are analysed. The authors conclude that the critical factor in systemic dissemination in female breast cancer is the extent and level of metastatic nodal involvement. Though the association between stage of disease, character of tumor (T), and histology are significant, the crucial factor seems to be the nodal involvement. Systemic metastases are significantly higher in inner quadrant tumors. Possible methods of circumventing this dissemination are discussed.     

Assessment of prognostic scores in brain metastases from breast cancer

Background

Breast cancer (BC) is the second most common cause of brain metastases (BM). Optimal management of BM from BC is still debated. In an attempt to provide appropriate treatment and to assist with optimal patient selection, several specific prognostic classifications for BM from BC have been established. We evaluated the prognostic value and validity of the 6 proposed scoring systems in an independent population of BC patients with BM.

Methods

We retrospectively reviewed all consecutive BC patients referred to our institution for newly diagnosed BM between October 1995 and July 2011 (n = 149). Each of the 6 scores proposed for BM from BC (Sperduto, Niwinska, Park, Nieder, Le Scodan, and Claude) was applied to this population. The discriminative ability of each score was assessed using the Brier score and the C-index. Individual prognostic values of clinical and histological factors were analyzed using uni- and multivariate analyses.

Results

Median overall survival was 15.1 months (95% CI,11.5–18.7). Sperduto-GPA (P < .001), Nieder (P < .001), Park (P < .001), Claude (P < .001), Niwinska (P < .001), and Le Scodan (P = .034) scores all showed significant prognostic value. The Nieder score showed the best discriminative ability (C-index, 0.672; Brier score error reduction, 16.1%).

Conclusion

The majority of prognostic scores were relevant for patients with BM from BC in our independent population, and the Nieder score seems to present the best predictive value but showed a relatively low positive predictive value. Thus, these results remain insufficient and challenge the routine use of these scoring systems.     

Brain metastases from breast cancer: usefulness and limits of prognostic scores

Approximately 10 to 30% of patients with metastatic breast cancer will develop brain metastases (BM) during the disease course. Whole-brain radiation therapy (WBRT) is considered the standard treatment for most patients, particularly those with extensive intracranial disease, providing symptom relief and increasing median and overall survival. Despite WBRT, the prognosis for the general population of patients with BM remains poor, with a median survival time of approximately five months. Several studies have examined the relative contributions of patient characteristics to survival and have attempted to identify subgroups of patients with substantially different outcomes in order to tailor therapy and to influence the design, stratification and interpretation of future clinical trials. This review examines prognostic scores and their validation in patients with BM from breast carcinoma. We also discuss the prognostic value of specific parameters for breast carcinoma, such as tumor HR status, HER2 over-expression or specific treatment parameters, and the value and limits of these prognostic scores in clinical practice.     

Brain metastases in breast cancer: prognostic factors and management

In this retrospective study, 162 breast cancer patients were analysed in whom brain metastases had been diagnosed clinically between 1969 and 1995 at a single institution. 145 patients were treated with megavoltage irradiation (60 cobalt or 6 MV) of the whole brain using opposed fields. The most common applied schedule consisted of 30 Gy in 15 daily fractions over 3 weeks. 10 patients underwent surgery and 17 patients received symptomatic treatment only. The median age was 50 years (range 30–78 years). 81 of 162 patients (50%) were premenopausal. Women younger than 40 years of age had a shorter survival (median 12 weeks) than those of all other groups (median 29 weeks). Median survival was 82 weeks for the 10 surgical patients, 26 weeks for the 145 patients treated with radiotherapy and 5 weeks for the patients who received symptomatic (corticosteroid) therapy only. Patients with solitary metastases treated with radiation alone (45 patients) had a survival of 44 weeks versus 23 weeks in patients with multiple brain metastases. Multivariate stepwise regression analyses revealed Karnofsky Index, dose of radiation (P<0.001), solitary metastases (P<0.04) and primary tumour size (P<0.04) as significant prognostic factors for survival.     

74例乳腺癌骨转移的临床预后因素分析

目的:探讨乳腺癌骨转移的临床特征并分析其预后因素。方法:回顾74例乳腺癌骨转移好发部位、病灶特点、发生时间、激素受体分布情况等并用COX比例风险模型进行乳腺癌骨转移预后因素分析。结果:乳腺癌骨转移好发部位在胸部与脊柱,尤其是肋骨和腰椎,几乎均为溶骨性病灶。骨转移平均发生时间为术后33.4个月。骨转移患者中激素受体阳性率比例较高。COX比例风险模型分析显示雌激素受体状况、病理类型和初发单/多发骨转移情况是影响乳腺癌骨转移预后的独立因素。结论:雌激素受体状况、病理类型和初发单/多发骨转移情况是影响乳腺癌骨转移预后的独立因素。对乳腺癌骨转移规律的认识有助于临床诊断和治疗。     

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.     

Predictive factors of response to first-line chemotherapy in 1426 women with metastatic breast cancer

Since response to chemotherapy is a major determinant of survival in metastatic breast cancer, the purpose of our study was to analyse the predictive factors of response. 1426 patients enrolled into eight consecutive randomised trials of anthracycline-based first-line chemotherapy in metastatic breast cancer, between 1977 and 1992, were analysed. A forward stepwise logistic regression analysis was used. The objective response rate (ORR) to chemotherapy in the total population was 63.6% (95% confidence interval (CI): 61.5–67.7). The complete response rate was 17.5%. Multivariate analysis defined adjuvant chemotherapy, lactate dehydrogenase (LDH), Karnofsky index (KI), and pleural and lung metastases to be the five main variables correlated with ORR. A predictive score was calculated using the coefficient of these five variables. The score was established as follows: −1.32+0.54 (if prior adjuvant chemotherapy)+0.80 (low KI)+0.75 (raised LDH)+0.49 (lung metastases)+0.51 (pleural metastases). A low score (less than −0.78) was associated with an ORR greater than 70.0%, representing 41.2% of our population. An intermediate score (between −0.78 and 0) was associated with an ORR of 50 to 70%, representing 37.5% of our population and a positive score was associated with an ORR of less than 50%, representing 21.3% of our population. This score can be used to predict objective response rates to first-line anthracycline-based chemotherapy. This method now needs to be evaluated prospectively in phase II trials. Identification of various risk groups may also be useful for interpretation and design of clinical trials.     

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.     

Evaluation of 2 whole-brain radiotherapy schedules and prognostic factors for brain metastases in breast cancer patients

BACKGROUND: The majority of breast cancer patients with brain metastases receive whole-brain radiotherapy (WBRT) and have a survival of only a few months. A short WBRT regimen would be preferable if it provides survival that is similar to that achieved with longer programs. This retrospective study compared survival and local control within the brain resulting from short-course WBRT with longer programs in 207 breast cancer patients. METHODS: Sixty-nine patients treated with 5 fractions of 4 grays (Gy) each given within 5 days were compared with 138 patients treated with 10 fractions of 3 Gy each given over 2 weeks or 20 fractions of 2 Gy each given over 4 weeks. Six additional potential prognostic factors were investigated: age, Karnofsky performance score (KPS), number of brain metastases, the presence of extracranial metastases, interval from tumor diagnosis to WBRT, and recursive partitioning analysis (RPA) class. RESULTS: On univariate analysis, the WBRT regimen was not found to be associated with survival (P=.254) or local control (P=.397). Improved survival was associated with a KPS>70 (P<.001), single brain metastasis (P=.023), the absence of extracranial metastases (P<.001), and lower RPA class (P<.001). On multivariate analysis, which was performed without RPA class because this is a confounding variable, KPS (relative risk [RR] of 4.00; P<.001) and the presence of extracranial metastases (RR of 1.54; P=.024) maintained statistical significance. On univariate analysis, local control was associated with KPS (P<.001) and RPA class (P<.001). On multivariate analysis, local control was found to be associated with a KPS>70 (RR of 5.75; P<.001). CONCLUSIONS: Short-course WBRT with 5 fractions of 4 Gy each resulted in survival and local control that were similar to longer programs in breast cancer patients with brain metastases. The dose of 5 fractions of 4 Gy each appears preferable for the majority of these patients because it is less time consuming and more convenient.     

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.     

Prognostic factors for node-negative breast cancers: Results of a study program by the Japanese breast cancer society

Background  Prognostic factors for predicting the recurrence of node-negative breast cancers have been controversial. The present study was performed to elucidate practically useful prognostic factors using formalin-fixed paraffin sections. Methods  This was a case-controlled multi-institutional study that composed 40 patients with recurrent node-negative breast cancer and 80 patients with node-negative breast cancer but without recurrence after radical surgery. Tumors were smaller than 3 cm in diameter and were treated surgically between January 1, 1985 and December 31, 1990. The recurrent and non-recurrent cases were matched with regard to their age, adjuvant chemotherapy and the year in which surgery was performed. Fourteen immunohistochemical factors and 8 histological factors of the primary tumor were studied on formalin-fixed, paraffin-embedded sections by immunohistochemical and histochemical analyses. Results  According to univariate analysis, factors such as progesterone receptor (PgR), MIB-1, CD44_v6, CD44_v9 and platelet-derived endothelial cell growth factor (PDECGF) were significantly different between the recurrent and non-recurrent groups (p>0.1; Wilcoxon-Mann-Whitney analysis). Chisquared test showed significant differences in MIB-1, cdc2 and stromal plasminogen activator receptor (suPAR). Histologically, mitotic count was also significantly different between the two groups (p>0.005). Multivariate analysis revealed that positivity for cdc2 (p=0.01), high mitotic count (p=0.04) and negativity for CD44_v9 (p=0.02) were independent prognostic factors among variables selected by univariate analysis, and that positivity for MIB-1 (p=0.03) and cdc2 (p=0.01), and negativity for CD44_v9 (p=0.03) were independent prognostic factors among the immunohistochemical markers examined. Conclusion  Our results indicated that positivity for MIB-1 and cdc2, high mitotic count and negativity for CD44_v9 could serve as independent factors for predicting the recurrence of node-negative breast cancer.     

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