Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma

BACKGROUND: Women with HER-2 overexpressing metastatic breast carcinoma benefit from trastuzumab-based therapy, but trastuzumab does not cross the blood-brain barrier. The authors characterized central nervous system (CNS) disease in these women. METHODS: Using pharmacy records, the authors retrospectively identified 153 women treated with trastuzumab alone or with chemotherapy for HER-2-positive metastatic breast carcinoma at Dana-Farber Partners Cancer Care from June 1998 to December 2000. A study cohort of 122 patients was identified after excluding patients without adequate clinical follow-up or who had CNS disease before trastuzumab treatment. Central nervous system disease was defined as one or more brain metastases or as leptomeningeal carcinomatosis. The median follow-up of this cohort was 23 months. RESULTS: Central nervous system metastases were identified in 34% of patients (95% confidence interval, 26-44%) at a median of 16 months after diagnosis of metastatic breast carcinoma and 6 months from the beginning of trastuzumab therapy. Ninety-three percent of patients with CNS disease presented with clinical symptoms. Five percent of patients with CNS disease had leptomeningeal involvement alone, although 14% had leptomeningeal involvement and parenchymal brain metastases. Fifty percent of patients were responding or had stable disease while receiving trastuzumab at other disease sites at the time of diagnosis of CNS metastasis. The median survival period after CNS metastases was 13 months. Fifty percent of patients died of progressive CNS disease. Patients receiving trastuzumab as first-line therapy for metastatic disease frequently developed brain metastases while responding to or stable on trastuzumab at other disease sites. CONCLUSIONS: Metastatic breast carcinoma to the CNS is common among patients receiving trastuzumab-based therapy, including patients responding to therapy outside the CNS. This may be due either to predilection for the CNS by HER-2-positive tumor cells and/or poor penetration of the CNS by trastuzumab or to improved visceral disease control leading to a longer life and onset of late tumor spread to the CNS. Efforts to characterize other risk factors for development of CNS disease, optimal screening algorithms, and new treatment strategies may be warranted.     

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.     

HER-2-positive metastatic breast cancer: optimizing trastuzumab-based therapy

Trastuzumab with a taxane as first-line therapy is now the standard of care for patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer (MBC). The search for additional and more effective trastuzumab-based therapies continues. Novel combinations of trastuzumab with chemotherapeutic agents, including vinorelbine, gemcitabine, and capecitabine, and hormonal therapy agents, such as tamoxifen and aromatase inhibitors, are currently under investigation in clinical trials. Available data suggest these combinations will provide additional treatment options that may ultimately lead to better outcomes for patients with HER-2-positive MBC. Evidence is growing for the use of trastuzumab treatment beyond disease progression and retreatment after (neo)adjuvant relapse is being explored to assist in clinical decision making. Already, the use of trastuzumab in the metastatic setting has changed HER-2-positive status from a marker of poor prognosis to one of better overall outcome, and ongoing studies should expand further the treatment options for patients with HER-2-positive MBC.     

Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.     

Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab

BackgroundCentral nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab.MethodsEligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models.ResultsA total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02–1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed.ConclusionsAdjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.     

EGFR,pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab

BackgroundIn an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of human epidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab.Patients and methodsTumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed.ResultsWe observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab.ConclusionsIn HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.     

Primary breast cancer phenotypes associated with propensity for central nervous system metastases

BACKGROUND: There is anecdotal evidence that the incidence of central nervous system (CNS) metastases in breast cancer patients is increasing. It is unclear whether specific tumor biological properties or the use of systemic therapies influence this risk. METHODS: Using a database of 10,782 patients, 2685 patients were identified who experienced recurrence distantly. Clinical and biological features were analyzed in 2 ways: (1) patients who ever had versus those who never had CNS metastases, and (2) CNS metastases as the first site of recurrence versus those who had other sites. Correlations of survival after CNS metastasis with clinical and biologic features were also analyzed. RESULTS: In the ever versus never analysis, CNS metastases were significantly associated with younger age, premenopausal status, infiltrating ductal carcinoma histology (IDC), estrogen receptor (ER) and progesterone receptor (PR) negativity, low Bcl-2, high S-phase, aneuploidy, and altered p53. Tumor size, lymph node status, and use of adjuvant systemic therapy played little role. HER-2 overexpression was not associated with an increased risk in these patients (none of whom were treated with trastuzumab) (P = .91). However, epidermal growth factor receptor (EGFR) overexpression was associated with increased risk (P = .02). A multivariate analysis revealed ER negativity (odds ratio [OR] 2.8, P < .001), IDC histology (OR 2.5, P = .02), and young age (P < .001) as independent factors for CNS metastases. The clinical and biologic profiles of primary tumors with CNS metastases at first recurrence did not differ from those with CNS metastases after recurrence to other sites, except for HER-2 status. HER-2-positive tumors were not more likely to undergo recurrence initially in the CNS (P =.04). The median survival after CNS metastases was 5.5 months and HER-2-positive patients had a shorter survival. CONCLUSIONS: Younger patients with hormone receptor-negative, highly proliferative, genomically unstable, and p53-altered tumors were at increased relative risk for CNS metastases. HER-2 expression and adjuvant systemic therapies did not increase this risk.     

Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis

BACKGROUND: Breast cancer is the second most common cause of central nervous system (CNS) metastases. Several risk factors for CNS metastases have been reported. The objective of the current study was to describe clinicopathologic characteristics and prognostic factors in breast cancer patients with CNS metastases. METHODS: The authors retrospectively evaluated clinical data from 420 patients who had been diagnosed with breast cancer and CNS metastasis between 1994 and 2004 at the University of Texas M. D. Anderson Cancer Center. RESULTS: The median age of the patients at the time of diagnosis of breast cancer was 45 years (range, 25-77 years). Premenopausal and postmenopausal patients were distributed equally. Most patients had invasive ductal histology (91.2%), grade 3 tumors (81.4%) (using the modified Black nuclear grading system), T2 tumor classification (40.1%), and N1 lymph node status (59.7%) diagnosis. Forty percent of patients had estrogen receptor (ER)-positive disease, and 34% had progesterone receptor-positive disease. HER-2/neu status was recorded for only 248 patients, and 39% of the patients in that group had HER-2/neu-positive disease. The most common sites of first metastasis were liver, bone, and lung. CNS metastasis was the site of first recurrence in 53 patients (12%). In total, 329 patients had received either neoadjuvant treatment (113 patients) or adjuvant chemotherapy (216 patients). The majority of those patients (74.4%) had received anthracycline-based regimens. Metastasis was solitary in 111 patients (26.4%), and 29 patients had only leptomeningeal metastases. The median time from breast cancer diagnosis to CNS metastasis was 30.9 months (range, from -5 months to 216.7 months). The median follow-up after a diagnosis of CNS metastasis was 6 months (range, 7-95.9 months). In all, 359 patients died, and the overall median survival was 6.8 months. Only age at diagnosis and ER status were associated significantly with overall survival in the multivariate analysis. CONCLUSIONS: The current results indicated that the prognosis remains patients with breast cancer metastatic to the CNS. More effective treatment approaches are needed for patients with CNS metastases, even for those with favorable prognostic factors, such as ER-positive tumors or younger age.     

The risk of central nervous system metastases after trastuzumab therapy in patients with breast carcinoma

BACKGROUND: Trastuzumab, which is a large monoclonal antibody that is efficacious in the treatment of patients with HER-2/neu-overexpressing, metastatic breast carcinoma, does not penetrate the blood-brain barrier and, thus, may allow the brain to become a sanctuary site for micrometastases. Few studies have compared the risk of central nervous system (CNS) metastases in patients treated with or without trastuzumab. METHODS: The authors conducted a retrospective cohort study that compared 264 patients who did not receive trastuzumab therapy with 79 patients who received trastuzumab therapy. The study was powered to detect an effect size of 0.3, which was deemed clinically significant to change future management. RESULTS: CNS metastases developed in 48.1% of patients on trastuzumab-based therapy and in 46.6% of patients on nontrastuzumab-based therapy. The association between trastuzumab therapy and subsequent CNS metastases (either brain or leptomeningeal) was not significant, with a multivariate-adjusted odds ratio of 0.91 (95% confidence interval, 0.64-1.88; P = 0.79). Similarly, there was no evidence of an association between trastuzumab and brain metastases alone (P = 0.67) or leptomeningeal metastases alone (P = 0.14). The median overall survival after the diagnosis of all CNS metastases was 26.3 months for patients who did not receive trastuzumab and 24.9 months for patients who received trastuzumab (P = 0.7). A multivariate logistic regression model found that patient age at diagnosis (P < 0.05), positive lymph node status at presentation (P < 0.01), and liver metastases (P < 0.01) were significant predictors of CNS metastases. Lung metastases showed a borderline significant P value (0.056). CONCLUSIONS: Despite the impression of many oncologists, the results of this study did not support an association between trastuzumab therapy and an increased risk of CNS metastases.     

Trastuzumab Retreatment after Relapse on Adjuvant Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Final Results of the Retreatment after Herceptin Adjuvant Trial

AimsTrastuzumab, in combination with chemotherapy, is the standard of care for patients with early and metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The Retreatment after HErceptin Adjuvant trial assessed the efficacy and safety of trastuzumab plus a taxane as first-line treatment for patients with metastatic breast cancer (MBC) who had relapsed after adjuvant trastuzumab for HER2-positive early breast cancer.Materials and methodsIn total, 43 patients with HER2-positive MBC who had received previous adjuvant trastuzumab for ≥10 months, with a relapse-free interval of ≥6 months after the last adjuvant trastuzumab dose, were recruited. Eligible patients (n = 41) were assigned to receive trastuzumab, either weekly or every 3 weeks, in combination with docetaxel or paclitaxel until disease progression.ResultsAt the final analysis, with a median follow-up time of 40 months, a positive response was observed in 25/41 patients (61%; 95% confidence interval: 48.7–80.4%), stable disease in 7/41 (17.1%) and progressive disease in 6/41 (14.6%). Three patients had missing response assessments (one had no measurable lesions at baseline and two had no post-baseline tumour assessments). The median progression-free survival (PFS) was 8.0 months (95% confidence interval: 6–11 months) and the median overall survival was 25.0 months (16–33 months). No correlation was found between response rate, PFS or overall survival and the duration of adjuvant trastuzumab treatment, trastuzumab-free interval, relapse-free interval, hormone receptor status or type of pre-metastatic treatment. The most common adverse events (all grades) were alopecia (32%) and diarrhoea (32%). Six patients (14.6%) developed at least one serious adverse event. No congestive heart failure or any unexpected adverse events were reported.ConclusionTrastuzumab, in combination with a taxane, is an effective and well-tolerated first-line treatment for MBC in patients who relapse after trastuzumab-based adjuvant therapy.     

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.     

Central nervous system progression among patients with metastatic breast cancer responding to trastuzumab treatment

Central nervous system (CNS) metastases from breast cancer are common and can present as the first or solitary site of disease progression. The CNS has been reported to act as a sanctuary site that denies access to many chemotherapeutic agents. We present here, a series of 10 metastatic breast cancer patients who developed CNS metastases after an initial response to trastuzumab treatment. Forty one patients with metastatic HER2-overexpressing breast cancer, without evidence of CNS involvement prior to the initiation of trastuzumab treatment, were followed during trastuzumab treatment. A neurological evaluation was performed in those patients who developed neurological signs or symptoms during the course of treatment. The clinical course and pattern of CNS involvement in these patients are discussed. Thirty two patients (78%) showed an initial response to trastuzumab treatment. Ten (31%) of the responding patients developed either isolated CNS relapse or concurrent CNS and systemic progression at a median of 43 weeks after the initiation of trastuzumab treatment. Trastuzumab as a single agent was continued following control of brain symptoms in three patients, two showed signs of systemic disease progression at 11 and 15 weeks following the diagnosis of CNS metastases, respectively. In two other patients, trastuzumab in combination with weekly chemotherapy was continued for more than 20 weeks after CNS relapse without evidence of disease progression. The incidence of CNS involvement in our group of patients was higher than expected. With more successful and prolonged systemic anti-tumour effects achieved by novel drug combinations, the risk of developing CNS metastases might be even greater. Evaluation of prophylactic cranial irradiation strategies might be studied for high-risk patients.     

Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab

We aim to investigate the incidence, patterns and timing of brain metastases in advanced breast cancer patients who have previously received trastuzumab. Eighty-seven patients who had received trastuzumab for advanced breast cancer from November 1999 to September 2003 at the Royal Marsden Hospital were assessed. With a median follow-up period of 11 months from commencing trastuzumab, 23 patients developed brain metastases (30% at 1 year; 95% CI 58-82%). Among 57 patients who had clinical benefits on trastuzumab, 12 (21%) patients developed first disease progression in brain with 75% of them had isolated CNS progression. Moreover, among patients who received trastuzumab as first line treatment, isolated brain metastases were the initial site of progression in 17% patients. Nearly all patients developed parenchymal brain disease. This study shows brain metastases are common phenomenon in HER2 positive advanced breast cancer patients receiving trastuzumab and also may implicate the brain as a sanctuary site for early relapse in this patient cohort.     

Management of patients with brain metastases receiving trastuzumab treatment for metastatic breast cancer

Background: With the more effective control of visceral metastases in patients with metastatic breast cancer (MBC), an increasing number of patients face brain metastases (BM). The aim of this retrospective analysis was to investigate the incidence and factors affecting the prognosis of patients with BM under trastuzumab treatment for MBC. Patients and Methods: A total of 75 HER2positive patients treated with trastuzumab for MBC were included. Results are discussed in the context of the current literature. Results: Patients who developed BM (n = 29) had longer median progression-free survival (PFS) during first-line chemotherapy and longer overall survival (OS) after diagnosis of MBC than 46 patients without BM (PFS: 27 vs. 14 months, p = 0.039; OS: 46 vs. 18 months, p = 0.067). Median survival of patients with continuation of trastuzumab after diagnosis of BM was longer than survival of patients with discontinuation of trastuzumab treatment after BM (18 vs. 3 months, p = 0.006). Survival of patients who were treated with surgery and radiotherapy for BM was better compared with radiotherapy alone (9 vs. 5 months, p = not significant) or best supportive care (9 vs. 2 months, p = 0.049). Conclusions: Continuation of trastuzumab treatment as well as resection of BM seem to give further benefit in the treatment of patients with HER2-overexpressing MBC.     

Cardiac toxicity of trastuzumab in metastatic breast cancer patients previously treated with high-dose chemotherapy: a retrospective study

HER-2 overexpression is associated to a poor prognosis in high-risk and metastatic breast cancer (MBC) patients treated with high-dose chemotherapy (HDC). HER-2 status is also a predictive factor and when trastuzumab is administered in combination with or sequentially to chemotherapy, a significant disease-free and/or overall survival improvement has been observed in HER-2+ early and MBC. Unfortunately, in both settings, trastuzumab is associated with an increased risk of cardiac dysfunction (CD). We have reviewed the clinical charts of HER-2-overexpressing MBC patients treated with trastuzumab after HDC. Age, baseline left ventricular ejection fraction (LVEF), radiation therapy on cardiac area, exposure to anthracycline, single or multiple transplant, high-dose agents, trastuzumab treatment duration were recorded as potential risk factors. In total, 53 patients have been included in the analysis. Median LVEF at baseline was 60.5%; at the end of trastuzumab (data available for 28 patients only), it was 55% (P = 0.01). Five out of the 28 (17.9%) patients experienced CD. Two out of 53 (3.8%) patients developed a congestive heart failure. Age > or = 50 years and multiple transplant procedure were potential risk factors for CD. The overall incidence of CD observed in this population of HER-2+ MBC patients treated with trastuzumab after HDC is not superior to that reported with concomitant trastuzumab and anthracyclines. However, patients with age > or = 50 years or receiving multiple course of HDC should be considered at risk for CD.     

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.     

不同分子亚型乳腺癌脑转移患者的临床特征和预后分析

目的探讨不同分子亚型乳腺癌脑转移(BCBM)患者的临床特点和预后。方法收集201例BCBM患者的临床资料,根据原发肿瘤激素受体及表皮生长因子受体2(HER-2)表达状态,将患者分为3个不同分子亚型,并分析不同亚型BCBM患者的临床特征及生存情况。结果 201例患者中,Luminal型68例(33.8%),HER-2型87例(43.3%),三阴型46例(22.9%)。全组患者初始转移部位依次为肺68例(33.8%)、骨63例(31.3%)、肝52例(25.9%)和脑27例(13.4%)。不同亚型患者初始转移部位不同(P<0.05),Luminal型患者骨转移的发生率最高(41.2%),HER-2型肝转移的发生率为35.6%,三阴型患者脑转移的发生率为30.4%。不同亚型患者首次复发至出现脑转移时间(TTBM)不同Luminal型为18.1个月,HER-2型为16.8个月,三阴型患者为8.3个月,差异有统计学意义(P=0.005);Luminal型患者总生存时间为95.7个月,HER-2型总生存时间为72.2个月,三阴型患者总生存时间为41.6个月,差异有统计学意义(P=0.002)。HER-2型患者脑转移前采用抗HER-2治疗的TTBM为21.9个月,较未行抗HER-2治疗的TTBM(7.2个月)明显延长(P=0.002)。结论肺、骨、肝和脑是乳腺癌最常见的远处转移部位。三阴型乳腺癌患者容易发生脑转移且预后最差,三阴型和HER-2型未行抗HER-2治疗患者容易早期出现脑转移,抗HER-2治疗可以延缓脑转移的发生。     

Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer

We report the first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for human epidermal growth factor receptor (HER)-2-positive locally recurrent (LR) or metastatic breast cancer (MBC). Patients were aged ≥18 years with confirmed breast adenocarcinoma, measurable LR/MBC and documented HER-2-positive disease. Patients received bevacizumab (15 mg/kg on day 1) plus trastuzumab (8 mg/kg on day 1 of cycle 1, 6 mg/kg on day 1 of each subsequent cycle) plus capecitabine (1,000 mg/m2 twice daily, days 1-14) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Eighty-eight patients were enrolled; 40 (46%) are still on study treatment. The median follow-up was 8.8 months (range, 0.9-17.1 months). The overall response rate, the primary endpoint, was 73% (95% confidence interval [CI], 62%-82%), comprising 7% complete and 66% partial responses. The median progression-free survival interval was 14.4 months (95% CI, 10.4 months to not reached [NR]), with 35 events. The median time to progression was 14.5 months (95% CI, 10.5 months to NR), with 33 events. Treatment was well tolerated; main side effects were grade 3 hand-foot syndrome (22%), grade ≥3 diarrhea (9%), and grade ≥3 hypertension (7%). Overall, 44% of patients experienced grade ≥3 treatment-related adverse events and 13 patients discontinued capecitabine because of toxicity, but continued with bevacizumab and trastuzumab. Heart failure was seen in two patients. The combination of bevacizumab, trastuzumab, and capecitabine was clinically active as first-line therapy for patients with HER-2-positive MBC, with an acceptable safety profile and no unexpected toxicities.     

Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: a multi-institutional phase II trial.

PURPOSE: To determine the efficacy and safety of weekly docetaxel and trastuzumab as first- or second-line therapy in women with HER-2-overexpressing metastatic breast cancer and to correlate the efficacy of trastuzumab with HER-2 status as determined by immunohistochemistry assay and fluorescent in situ hybridization (FISH). PATIENTS AND METHODS: Twenty-six women with HER-2-positive (HercepTest [Dako Corp, Carpenteria, CA]2 to 3+) metastatic breast cancer were enrolled onto this study of trastuzumab (4 mg/kg load; 2 mg/kg/wk administered intravenously) and docetaxel (35 mg/m2/wk for 6 weeks). RESULTS: Using an intent-to-treat analysis, the overall response rate was 50% (13 of 26 patients). Eight patients (31%) had a period of stable disease posttherapy. Among HER-2 3+ patients, the overall response rate was 63% (12 of 19 patients) compared with a 14% response rate (one of seven patients) for HER-2 2+ patients (P=.07). Patients with FISH-positive tumors experienced an overall response rate of 64%. Median time to progression was 12.4 months for the entire cohort (HER-2 3+ tumors, 12.3 months; HER-2 2+ lesions, 9.5 months) and median survival was 22.1 months. All HER-2 3+ patients were FISH-positive; the only HER-2 2+ patient responding to treatment was also FISH-positive. Grade 4 toxicities occurred in four patients; most toxicities were mild. CONCLUSION: Trastuzumab plus docetaxel is an active and well-tolerated regimen in women with HER-2 3+ overexpressing or FISH-positive metastatic breast cancer.     

Complete response of severe symptomatic bone marrow metastases from heavily pretreated breast cancer with a 3-weekly trastuzumab schedule. A clinical case

Overexpression of HER-2/neu in breast cancer has been associated with more aggressive disease and poor overall survival. Trastuzumab, a recombinant humanized monoclonal antibody with high affinity for the HER-2 protein, inhibits the growth of breast cancer cells overexpressing HER-2. Trastuzumab showed, as second-line treatment, 15% of objective response in metastatic breast cancer. Bone marrow metastases are detectable in 23% of the patients with advanced breast cancer at first relapse and this rate increases in patients with metastatic disease. We report a case of a complete response of bone marrow metastases from breast cancer using a 3-weekly trastuzumab schedule, in a heavily pretreated patient with severe symptomatic pancytopenia.