Medline ® Abstracts for References 2,6,8-19

The characteristics of brain metastases (BM) that develop after breast-conserving therapy (BCT) for early-stage breast cancer (BC) remain incompletely defined. We examined 1,434 consecutive patients with stage I/II invasive BC who received BCT from 1997 to 2006, 91 % of whom received adjuvant systemic therapy, according to BC subtype. Median follow-up was 85 months. Overall 5-year cumulative incidence of BM was 1.7 %; 0.1 % for luminal A, 3.3 % for luminal B, 3.2 % for luminal-HER2, 3.7 % for HER2, and 7.4 % for triple negative (TN). Women who developed BM were more likely at BC diagnosis to be younger (P < .0001) and have node-positive (P < .0001), grade 3 (P < .0001), hormone receptor-negative (P = .006), and HER2-positive (P = .01) tumors. Median time from BC diagnosis to BM was 51.4 months (range, 7.6-108 months), which was longer among luminal versus non-luminal subtypes (P = .0002; median, 61.4 vs. 34.5 months). Thirty-four percent of patients who developed distant metastases (DM) eventually developed BM. Median time from DM to BM was 12.8 months but varied by subtype, including 7.4 monthsfor TN, 9.6 months for luminal B, and 27.1 months for HER2. Eighty-one percent of all BM patients presented with neurologic symptoms. Median number of BM at diagnosis was two, and median BM size was 15 mm, with TN (27 mm) and luminal B (16 mm) exhibiting the largest median sizes. In conclusion, the risk of BM after BCT varies significantly by subtype. Given the large size and symptomatic presentation among luminal B and TN subtypes, earlier BM detection might improve quality of life or increase eligibility for non-invasive treatments including stereotactic radiosurgery. Women with DM from these two BC subtypes have a high incidence of BM with a short latency, suggesting an ideal target population for trials evaluating the utility of MRI screening.

Adjuvant systemic treatment for breast cancer has evolved resulting in improved outcomes. A relevant question is whether these advances have changed the pattern of distant relapse. Women diagnosed with stage I-III breast cancer were divided into three time cohorts according to changes in adjuvant therapy; A: 1989-1991-CMF chemotherapy in premenopausal and tamoxifen for postmenopausal women; B: 1992-1997-anthracycline chemotherapy and tamoxifen for pre/postmenopausal women; C: 1998-2001-broader use of anthracyclines. The primary endpoint was 5-year cumulative incidence of bone metastasis (BM) as first site of metastasis (FSOM) versus non-bone metastasis (NBM). The ratios NBM/BM in each period were calculated. The eligibility criteria were met by 21,415 cases; Cohorts A: 1989-1991 (n = 3,915), B: 1992-1997 (n = 9,229) and C: 1998-2001 (n = 8,271). Between 1989 and 2001, the percentage of patients receiving adjuvant chemotherapy increased from 23.1 to 34.4%. A decline in cumulative 5-year incidence rates for BM and NBM as FSOM was seen comparing cohort A to C, P<0.0001. The ratio NBM/BM was significantly increased from 1.53 in the early cohort to 2.00 in the later one, P = 0.0083. The most prominent increase (84%) was in the ER-negative group, chemotherapy treated, P = 0.0272. A significant decline in 5-year cumulative incidence of metastases and an increase in the proportion of NBM as first site of metastasis were observed between earlier and later cohorts. This may reflect the need for more successful adjuvant treatment options for aggressive breast cancer subtypes which are more likely to present with early spread to visceral organs. Understanding patterns of relapse may help design new adjuvant strategies.

In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranialdisease and treatment with lapatinib were independent prognostic factors for TTD from BM.

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.

BACKGROUND: A higher incidence of central nervous system (CNS) metastases in HER-2-positive metastatic breast cancer (MBC) has recently been reported.

MATERIALS AND METHODS: Aims of this observational study were to evaluate the incidence of CNS metastases in HER-2-positive MBC patients, to define the outcome of patients with CNS metastases, and to identify the risk factors for CNS relapse.

RESULTS: Between April 1999 and June 2005 we treated 122 consecutive HER-2-positive MBC patients with chemotherapy and trastuzumab. At a median follow-up of 28 months from the occurrence of metastatic disease, 43 patients (35.2%) developed CNS metastases. The median time to death from the diagnosis of CNS metastases was 23.46 months. At multivariate analysis we found that only premenopausal status at diagnosis of breast cancer and visceral metastases as the dominant site at relapse were significantly associated with a higher risk for CNS metastases.

CONCLUSION: The CNS metastasis incidence is very high in HER-2-positive MBC, but the survival after CNS relapse in these patients is longer than in patients unselected for HER-2 status, because of the better control of extracranial disease obtained by trastuzumab. The identified risk factors for CNS relapse could allow us to select a subgroup of HER-2-positive MBC patients as candidates for active surveillance for CNS progression (by computed tomography or magnetic resonance imaging) and/or as candidates for accrual in trials of prevention of CNS relapse.

Amplification or over-expression of the HER2/neu receptor is present in 20-30% of invasive breast cancers and in 60% of intraductal breast carcinomas. Patients with HER2/neu gene aberrations have more aggressive disease, frequent disease recurrence and a shorter survival. Trastuzumab (herceptin) is a monoclonal antibody selectively directed against the HER2/neu receptor. The addition of trastuzumab to chemotherapy in HER2/neu-positive advanced breast cancer patients has increased complete and partial response rates, and prolonged time to progression and overall survival. However, a relatively common failure site in patients administered trastuzumab is the central nervous system (CNS). CNS metastases in these patients seem to develop despite responses achieved in extracerebral sites. This pattern of failure has mainly been attributed to the lack of trastuzumab penetration to the CNS owing to the high molecular weight (145 kDa) of this molecule. Additionally, increased risk of CNS relapse may be associated with improved systemic control of extracerebral metastases and prolonged survival without brain protection (a sanctuary site). Finally, it was postulated that HER2/neu over-expression and/or amplification might predispose to brain metastases. The aim of this article is to discuss the pathophysiology of this phenomenon and its clinical implications.

Between 100,000 and 170,000 patients with cancer develop central nervous system (CNS) metastases each year in the U.S., of which approximately 20% carry a primary diagnosis of breast cancer. As a consequence of improvements in systemic therapy, which have allowed patients to live longer with advanced cancer, CNS metastases are emerging as an important sanctuary site, and the incidence may be increasing in patients with particular tumor subtypes. Unless there are improvements in the treatment of CNS disease, a growing proportion of patients may be at risk of experiencing both morbidity and mortality as a result of uncontrolled CNS progression, often at a time when their extra-CNS disease is apparently under control. This article reviews changes in the epidemiology and natural history of women with brain metastases from HER2-positive breast cancer over the last decade and presents the therapeutic challenges and opportunities that have arisen in this setting. First, the apparent increase in CNS disease among women with HER2-positive breast cancer, relative to historical controls, is discussed, followed by consideration of potential causes of this observation. Next, the implications of CNS disease, in terms of prognosis and the potential development of preventive strategies are considered. Finally, new developments in systemic approaches to the treatment of CNS disease, including cytotoxic chemotherapy and targeted therapy, are explored.

PURPOSE: registHER is a prospective, observational study of 1,023 newly diagnosed HER2-positive metastatic breast cancer (MBC) patients.

EXPERIMENTAL DESIGN: Baseline characteristics of patients with and without central nervous system (CNS) metastases were compared; incidence, time to development, treatment, and survival after CNS metastases were assessed. Associations between treatment after CNS metastases and survival were evaluated.

RESULTS: Of the 1,012 patients who had confirmed HER2-positive tumors, 377 (37.3%) had CNS metastases. Compared with patients with no CNS metastases, those with CNS metastases were younger and more likely to have hormone receptor-negative disease and higher disease burden. Median time to CNS progression among patients without CNS disease at initial MBC diagnosis (n = 302) was 13.3 months. Treatment with trastuzumab, chemotherapy, or surgery after CNS diagnosis was each associated with a statistically significant improvement in median overall survival (OS) following diagnosis of CNS disease (unadjusted analysis: trastuzumab vs. no trastuzumab, 17.5 vs. 3.8 months; chemotherapy vs. no chemotherapy, 16.4 vs. 3.7 months; and surgery vs. no surgery, 20.3 vs. 11.3 months). Although treatment with radiotherapy seemed to prolong median OS (13.9 vs. 8.4 months), the difference was not significant (P = 0.134). Results of multivariable proportional hazards analyses confirmed the independent significant effects of trastuzumab and chemotherapy (HR = 0.33, P<0.001; HR = 0.64, P = 0.002, respectively). The effects of surgery and radiotherapy did not reach statistical significance (P = 0.062 and P = 0.898, respectively).

CONCLUSIONS: For patients with HER2-positive MBC evaluated in registHER, the use of trastuzumab, chemotherapy, and surgery following CNS metastases were each associated with longer survival.

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 ofpatients.

With improvements in diagnostic and therapeutic options and a corresponding improvement in survival, central nervous system (CNS) metastasis is becoming a more frequent diagnosis in breast cancer patients. It can be assumed that up to 30% of metastatic breast cancer (MBC) patients may experience CNS metastasis during the course of their disease. Moreover, it has been reported that patients with human epidermal growth factor receptor (HER)-2-overexpressing MBC are at a higher risk for CNS involvement. Whereas locoregional treatment modalities such as surgery, radiosurgery, and whole-brain radiotherapy still must be considered as the treatment of first choice, the armamentarium of systemic treatment modalities has been expanded by the introduction of small molecules such as the tyrosine kinase inhibitors. Rather than analyzing the risk factors for the development of CNS metastasis and reviewing the standard diagnostic and therapeutic approaches in patients with CNS involvement, this review focuses specifically on systemic treatment modalities in patients suffering from CNS metastasis from HER-2-overexpressing MBC.

PURPOSE: Prognostic and predictive factors are well established in early-stage breast cancer, but less is known about which metastatic sites will be affected.

METHODS: Patients with early-stage breast cancer diagnosed between 1986 and 1992 with archival tissue were included. Subtypes were defined as luminal A, luminal B, luminal/human epidermal growth factor receptor 2 (HER2), HER2 enriched, basal-like, and triple negative (TN) nonbasal. Distant sites were classified as brain, liver, lung, bone, distant nodal, pleural/peritoneal, and other. Cumulative incidence curves were estimated for each site according to competing risks methods. Association between the site of relapse and subtype was assessed in multivariate models using logistic regression.

RESULTS: Median follow-up time among 3,726 eligible patients was 14.8 years. Median durations of survival with distant metastasis were 2.2 (luminal A), 1.6 (luminal B), 1.3 (luminal/HER2), 0.7 (HER2 enriched), and 0.5 years (basal-like; P<.001). Bone was the most common metastatic site in all subtypes except basal-like tumors. In multivariate analysis, compared with luminal A tumors, luminal/HER2 and HER2-enriched tumors were associated with a significantly higher rate of brain, liver, and lung metastases. Basal-like tumors had a higher rate of brain, lung, and distant nodal metastases but a significantly lower rate of liver and bone metastases. TN nonbasal tumors demonstrated a similar pattern but were not associated with fewer liver metastases.

CONCLUSION: Breast cancer subtypes are associated with distinct patterns of metastatic spread with notable differences in survival after relapse.

BACKGROUND: This retrospective study sought to define the incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer (TNBC).

METHODS: A total of 2448 patients with stage I through III TNBC who were diagnosed between 1990 and 2010 were identified. We computed the cumulative incidence of developing brain metastases as a first site of recurrence at 2 and 5 years. Cox proportional hazards models were fitted to determine factors that could predict for the development of brain metastases as a first site of recurrence. The Kaplan-Meier product limit method was used to compute survival following a diagnosis of brain metastases.

RESULTS: At a median follow-up of 39 months, 115 (4.7%) patients had developed brain metastases as a first site of recurrence. The cumulative incidence at 2 and 5 years was 3.7% (95% confidence interval [CI]= 2.9%-4.5%) and 5.4% (95% CI = 4.4%-6.5%), respectively. Among patients with stage I, II, and III disease, the 2-year cumulative incidence of brain metastases was 0.8%, 3.1%, and 8%, respectively (P<.0001). The 5-year cumulative incidence was 2.8%, 4.6%, and 9.6% among patients with stage I, II, and III disease, respectively (P<.0001). In the multivariable model, patients with stage III disease had a significant increase in the risk of developing brain metastases as a first site of recurrence (hazards ratio = 3.51; 95% CI = 1.85-6.67; P = .0001) compared to patients with stage I disease. Those with stage II disease had a nonsignificant increased risk of developing brain metastases as a first site of recurrence (hazards ratio = 1.61; 95% CI = 0.92-2.81; P = .10) compared with patients with stage I disease. Median survival following a diagnosis of brain metastases was 7.2 months (range, 5.7-9.4 months).

CONCLUSIONS: Patients with nonmetastatic TNBC have a high early incidence of developing brain metastases as a first site of recurrence, which is associated with subsequent poor survival. Patients with stage III TNBC in particular would be an ideal cohort in which to research preventive strategies. Cancer 2012.©2012 American Cancer Society.

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.