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.     

Defining prognosis for women with breast cancer and CNS metastases by HER2 status

BackgroundThe purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and central nervous system (CNS) metastases, the effect of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive disease and to compare this with that of patients with HER2-negative disease.MethodsFive hundred and ninety-eight patients with invasive breast cancer, CNS metastases and known HER2 status were identified. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan–Meier method, and Cox models were fitted to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics.ResultsIn the multivariable model, patients with HER2-negative disease [Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15–1.95, P = 0.003] and patients with HER2-positive disease who did not receive trastuzumab (HR 2.13, 95% CI 1.51–3.00, P < 0.0001) had shorter times to CNS metastases compared with patients with HER2-positive disease who had received trastuzumab as first-line therapy for metastases. Furthermore, patients with HER2-negative disease (HR 1.66, 95% CI 1.31–2.12, P < 0.0001) and patients with HER2-positive disease who had never received trastuzumab (HR 1.34, 95% CI 0.78–2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis.ConclusionIn our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.     

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.     

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.     

Capecitabine Therapy of Central Nervous System Metastases from Breast Cancer

Central nervous system (CNS) metastases from breast cancer carry a poor prognosis. Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. Medical records of seven patients with brain metastases from breast cancer who received capecitabine treatment at Memorial Sloan-Kettering Cancer Center from 1994–2006 were reviewed. Treatment outcomes were analyzed retrospectively in those patients. Median time from breast cancer diagnosis to the development of CNS metastasis was 48 (18–165) months. Four patients had brain metastases alone, two patients had both leptomeningeal and brain metastases and one patient had leptomeningeal metastasis alone. Five out of seven patients had failed other treatment modalities before capecitabine. Three patients showed complete response (CR) and three patients had stable disease (SD) after capecitabine. The patient with leptomeningeal disease improved clinically, but refused repeat cerebrospinal fluid (CSF) studies. Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR and provide long-term control in patients with both leptomeningeal and parenchymal CNS metastases from breast cancer.     

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.     

Leptomeningeal seeding in patients with brain metastases treated by gamma knife radiosurgery

To characterize the development of leptomeningeal seeding (LMS) in patients with brain metastases after gamma knife radiosurgery (GKRS). Eight hundred and twenty-seven patients that underwent GKRS as a part of an initial treatment plan for brain metastases between January 2002 and December 2010 were included in the study. Six hundred and fifty patients were treated with GKRS alone and 177 patients received GKRS combined with upfront whole brain radiation therapy (WBRT). Actuarial curves for overall survival (OS) and the development of LMS were plotted using the Kaplan-Meier method. Median overall survival for all patients was 55?weeks (95 % CI, 47.8-62.2), and the overall incidence of LMS was 5.3 %. The actuarial rates for LMS at 6 and 12 months were 3.1 and 5.8, respectively. Uni- and multivariate analysis suggested that breast cancer and a large number of metastases (n ≥ 4) are significant risk factors of LMS (P < 0.05). Regarding treatment modalities, the addition of WBRT was found to have a significant impact on lowering the risk of LMS by multivariate analysis (P = 0.045). LMS is an important pattern of CNS failure. The risk of LMS following GKRS may be associated with multiple lesions, breast cancer, and the omission of WBRT. Additional data from large-scale, randomized controlled trials are required to identify risk factors associated with the LMS more accurately.     

Central nervous system metastases in patients with high-risk breast carcinoma after multimodality treatment

BACKGROUND: The current study was performed to determine the incidence of central nervous system (CNS) metastases and to examine associated disease characteristics in a group of patients with locally advanced breast carcinoma (LABC) or inflammatory breast carcinoma (IBC) treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX). METHODS: Seven hundred sixty-eight patients treated with multimodality therapy between 1982 and 2000 in any of 6 neoadjuvant trials were eligible for the current study. Five hundred ninety-two patients (77%) had LABC, and 176 (23%) had IBC. CNS disease was defined as the presence of brain metastases or leptomeningeal disease. Time to detection of CNS disease and overall survival were estimated using the Kaplan-Meier product-limit method, and differences were evaluated using log-rank tests. RESULTS: The median patient age was 48 years. Most tumors were classified as T4 lesions (58%) and exhibited lymph node involvement (78%). Fifty-one percent of all tumors had positive hormone receptor status. At a median follow-up duration of 9.5 years, 61 patients (8%) had developed CNS metastases, with the CNS representing the first site of recurrence for 38 of these 61 (63%). Characteristics associated with the development of CNS metastases over time included negative hormone receptor status (P = 0.03), Grade 3 disease (P = 0.01), and larger tumor size (P = 0.02). The median time to detection of CNS metastases was 2.3 years. Ten patients (16%) remained alive after treatment for CNS metastases. The median survival from the time of diagnosis of CNS metastases was 8 months. CONCLUSIONS: CNS metastases from breast carcinoma were relatively uncommon and were strongly associated with more aggressive clinical presentation. Survival from the time of diagnosis of such metastases generally was short.     

Improved palliation of cerebral metastases in epithelial ovarian cancer using a combined modality approach including radiation therapy, chemotherapy, and surgery.

PURPOSE: Recent reports suggest an increasing incidence of CNS metastases in patients with ovarian cancer. We reviewed our experience in the management of brain metastases from ovarian carcinoma and merged our results with those of several other series reported in the literature to determine prognostic factors and the role of chemotherapy, radiation therapy, and surgery. PATIENTS AND METHODS: From 1977 to 1990, 15 of 795 patients who were treated for epithelial ovarian cancer at Duke University developed brain metastases. Fourteen of the patients were treated for their brain metastases; this included radiation therapy (RT; four), surgery and RT (one), RT and systemic chemotherapy (six), and all three treatment modalities (three). A meta-analysis was performed that combined the data from the current series with those of several recent clinical series that reviewed patients with brain metastases from ovarian carcinoma (67 patients total) to elucidate the impact of treatment and extent of disease on survival. RESULTS: In the current series, median survival (MS) after the diagnosis of brain metastases was 9 months. For the combined series, MS was 5 months. Thirteen patients who were treated with whole-brain RT and systemic chemotherapy (MS, 7 months), 10 patients who were treated with RT and surgery (MS, 10 months), and nine patients who were treated with all three modalities (MS, 16.5 months) had significantly longer survival than 19 patients who were treated with RT alone (MS, 3 months) (P = .05, P = .01, and P < .001, respectively). In a multivariate analysis, the only variable that provided prognostic information was treatment, namely the addition of systemic chemotherapy or surgery to RT for the treatment of brain metastases. CONCLUSION: Multimodal treatment of patients with brain metastases from ovarian cancer can result in significant palliation.     

Prognostic Factors and Survival According to Tumor Subtype in Women With Breast Cancer Brain Metastases

Breast cancer (BC) is the second most cause of central nervous system (CNS) metastases. Studies report that almost one third of patients (pts) with triple-negative, one-third with human epidermal growth factor receptor 2 (HER2)-positive and 15% of those with hormone receptor-positive, HER2-negative metastatic breast cancer will develop brain metastases. It is known that the development of symptomatic brain metastases in women with advanced breast cancer is associated with poor prognosis, irrespective of local and systemic treatments. In the present study, we aim to determine the association between BC subtypes and CNS metastases occurrence and prognosis. Retrospective analysis of 309 BC patients with CNS metastases, confirmed by pathological and/or radiological methods, treated in a Cancer Center between 2003 and 2021, was obtained to identify clinicopathologic factors associated with early onset of brain metastases and survival outcomes. For analysis purposes, 3 BC subtypes were considered according to hormone receptor status and HER-2 expression: ER and/or PR positive, HER-2 positive and triple negative. The median time between diagnosis of BC and detection of CNS metastases was 43 months, and it was significantly shorter in triple negative group (8 months). Twenty-one patients (6,8%) had CNS metastases at BC diagnosis, with CNS being the first site of recurrence in 35,3%, mainly in HER2 positive. Most of the patients had parenchymal metastases (n = 245) and 37 (12%) had leptomeningeal (LM) disease, with predominance in ER and/or PR positive subtype (70,3%). In patients submitted to CNS surgery, the concordance between primary tumor and metastases subtype was higher in triple negative (76,9%) compared to 63,2% in HER-2 positive and 38,9% in ER and/or PR positive group (P < 0.05). After CNS involvement, 25,4% (n = 34) of patients with triple negative disease did not receive any systemic therapy, compared to 30,6% (n = 41) in HER-2 positive and 44% (n = 59) in ER and/or PR positive groups (P = 0.05). Median survival after CNS metastases was 9 months, but significantly longer in HER-2 positive group (16 months) and in patients submitted to surgical resection of CNS metastases, irrespectively of subtype (22 months vs 5 months in other treatment modalities). In multivariate Cox regression analysis, having HER-2 positive tumor was an independent prognostic factor for increasing survival after CNS metastases (HR 0.60, 95% CI: 0.41-0.87, P = 0.007), regardless the therapeutic strategy. Clinical behavior and prognosis of CNS metastases varies according to BC subtype. The association between LM disease and ER and/or PR positive tumors should be explored in upcoming studies. Also, these patients’ prognosis depends on the availability of specific treatment options, therefore, innovative and effective therapeutic approaches are needed, in order to improve survival and quality of life of these patients.     

Tissue polypeptide antigen activity in cerebrospinal fluid: a marker of central nervous system metastases of breast cancer

Tissue polypeptide antigen (TPpA) in the cerebrospinal fluid (CSF) was measured in 59 consecutive breast cancer patients with suspected central nervous system (CNS) metastases. Subsequently, we determined that 13 patients had parenchymal brain metastases, 10 had leptomeningeal carcinomatosis, and 36 had no CNS involvement. The concentration of TPpA, which is a nonspecific marker for cell proliferation, was significantly higher in patients with CNS metastases than in those without it (P less than .0001; Mann-Whitney test). A tentative cutoff value for CNS metastases was set at 95 U/L TPpA; the upper limit of values indicating absence of CNS metastases was 89 U/L. Given these cutoff points, the sensitivity of TPpA as a marker for CNS metastases was 74% and the specificity was 100%; the predictive values of positive and negative tests were 100% and 86%, respectively. In 16 patients with CNS metastases, no correlation was found between TPpA activity in corresponding CSF and blood samples (correlation coefficient, Spearman's rho = .4; P greater than .1). In three patients treated for leptomeningeal carcinomatosis, the measurements of CSF TPpA showed correlation between the presence of tumor cells in the CSF and neurological clinical function. TPpA concentrations decreased in parallel with the clinical response and increased prior to CNS disease progression. As a marker for CNS metastases, the level of TPpA in the CSF in breast cancer patients appears to be superior to the level of protein, lactate dehydrogenase, or glucose, which showed very low sensitivity (41%, 47%, and 8%, respectively). For quantitative evaluation of treatment for leptomeningeal carcinomatosis, the TPpA level appears to be valuable and superior to CSF cytology, because tumor cells are not always present in CSF samples from patients with this condition.     

Brain metastases from epithelial ovarian cancer. The Hellenic Cooperative Oncology Group (HeCOG) experience and review of the literature

BACKGROUND: Brain metastases from epithelial ovarian cancer (EOC) are rare. A retrospective study of all patients diagnosed with brain metastases from EOC over the last 20 years, according to the Hellenic Cooperative Oncology Group (HeCOG) tumor registry, was conducted. PATIENTS AND METHODS: A total of 1450 patients with EOC were treated within various HeCOG protocols from 1983 to 2004. Seventeen (1.17%) of them developed brain metastases. RESULTS: The median age at diagnosis of brain metastases was 58 years (range, 24 to 77). At initial diagnosis, 2 patients had stage II, 12 had stage III and 3 had stage IV disease. Serous papillary adenocarcinoma was the most common histological subtype [12 patients (71%)]. All patients had received initial cisplatin-based chemotherapy. The median time from initial diagnosis to central nervous system (CNS) relapse was 15.9 months (range, 1.4 to 70.8). The CNS was the only site of disease in 13 (76.5%) patients, whereas 4 (23.5%) patients had additional extracranial disease. Two (12%) patients with isolated single brain lesions underwent surgical excision of the metastases, followed by whole brain radiation therapy (WBRT) and chemotherapy. Four (24%) patients were treated with WBRT alone, 6 (35%) patients with WBRT plus chemotherapy and 2 (12%) had only supportive care, while 3 (18%) patients decided not to have any further treatment after the diagnosis of brain metastases. The median survival time from diagnosis of CNS relapse was 5.7 months (range, 0.2 to 22.6) and the median survival time from diagnosis of EOC was 27.4 months (range, 3.0 to 71.4). In patients with CNS recurrence as the only site of disease, the median survival time from diagnosis of CNS relapse was 5.3 months (range, 0.6 to 22.6) and in those with both CNS and extracranial disease, the median survival time was 3.9 months (range, 0.2 to 11.9) (p=0.5597). There was a statistically significant difference in survival for those treated with WBRT plus chemotherapy (10.0 months) versus those treated with WBRT alone (1.5 months) and those who had only supportive care (0.2 months) (p=0.0003). CONCLUSION: The incidence of cerebral metastases in our patients with EOC was 1.17%, which is consistent with the mean value of all series reported in the literature. The prognosis of patients with brain metastases from EOC is poor. Patients who had WBRT and chemotherapy fared better than those who received WBRT alone.     

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.     

Trastuzumab treatment in patients with breast cancer and metastatic CNS disease

Background: Patients with metastatic central nervous system (mCNS) disease progression from breast cancer have a poor prognosis and often develop associated neurological complications. Human epidermal growth factor receptor 2 (HER2)-positivity status increases the risk of developing mCNS disease. Trastuzumab is an mAb that targets HER2 and is known to extend survival across all stages of HER2-positive breast cancer.Design: This review considers evidence from preclinical and clinical studies examining the value of continuing trastuzumab treatment in patients who develop mCNS disease. A wealth of data from clinical studies showed that trastuzumab prolonged survival in patients with mCNS disease, compared with no trastuzumab treatment, by effectively controlling their non-CNS disease. Trastuzumab has also been shown to penetrate an impaired blood–brain barrier to a limited degree, such as during radiotherapy, and intrathecal delivery of trastuzumab to the central nervous system (CNS) has shown promise. Research efforts are focussing on improving the delivery of trastuzumab to the CNS.Conclusion: Evidence indicates that patients with mCNS disease from HER2-positive breast cancer should continue to receive trastuzumab to control HER2-positive metastases outside the CNS and receive established therapies to control the mCNS disease.     

Conversion of epidermal growth factor receptor 2 and hormone receptor expression in breast cancer metastases to the brain

ABSTRACT: INTRODUCTION: We investigated the status of estrogen receptor alpha (ERalpha), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) in primary tumor and in the corresponding brain metastases in a consecutive series of breast cancer patients. Additionally, we studied factors potentially influencing conversion and evaluated its association with survival. METHODS: The study group included 120 breast cancer patients. ERalpha, PR and HER2 status in primary tumors and in matched brain metastases was determined centrally by immunohistochemistry and/or fluorescence in situ hybridization. RESULTS: Using the Allred score of >3 as a threshold, conversion of ERalpha and PR in brain metastases occurred in 29% cases for both receptors, mostly from positive to negative. Conversion of HER2 occurred in 14% of patients and was more balanced either way. Time to brain relapse and the use of chemotherapy or trastuzumab did not influence conversion, whereas endocrine therapy induced conversion of ERalpha (P=0.021) and PR (P=0.001), mainly towards their loss. Receptor conversion had no significant impact on survival. CONCLUSIONS: Receptor conversion, particularly loss of hormone receptors, is a common event in brain metastases from breast cancer, and endocrine therapy may increase its incidence. Receptor conversion does not significantly impact survival.     

Trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer

Background: Brain metastases are frequently encountered in Her2 positive advanced breast cancer. It is still not clear, if trastuzumab treatment should be continued following their diagnosis. In this analysis we evaluated if trastuzumab was able to influence time to in-brain progression (TTP) and overall survival (OS). For this reason, we compared patients who continued on trastuzumab with a historical control group. Patients and Methods: Seventeen Her2 positive patients receiving whole brain radiotherapy for brain metastases and continuing on trastuzumab were identified. As historical control group, thirty-six patients treated before 2002 were identified from a breast cancer database. We performed a multivariate analysis (Cox regression) to explore which factors were potentially able to significantly influence TTP and OS. Results: Median TTP was 6 months, range 1–33+ months. Median OS was 7 months, range 1–38 months. Seventeen patients received trastuzumab after WBRT. Factors associated with prolonged TTP were KPS (p = 0.001), and intensified local treatment (p = 0.004). A trend towards longer TTP was observed in patients treated with trastuzumab (p = 0.068). OS was significantly influenced by KPS (p < 0.001), and continued antibody therapy (p = 0.001). Conclusion: Two parameters were significantly associated with prolonged OS: KPS and trastuzumab. While there was a trend towards prolonged TTP in patients with trastuzumab treatment after WBRT, this did not reach statistical significance. It appears therefore reasonable to suggest continuation of antibody therapy in patients with good performance status despite disease spreading to the brain. Concerning activity of trastuzumab in brain metastases themselves, no final conclusion is possible.     

Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab,trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA

BackgroundResults from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA.Patients and methodsPatients received pertuzumab/placebo: 840 mg in cycle 1, then 420 mg; trastuzumab: 8 mg/kg in cycle 1, then 6 mg/kg; docetaxel: initiated at 75 mg/m². Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan–Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival.ResultsThe incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39–0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39–1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449).ConclusionsWhile the incidence of CNS metastases was similar between arms, our results suggest that pertuzumab, trastuzumab, and docetaxel delays the onset of CNS disease compared with placebo, trastuzumab, and docetaxel.ClinicalTrials.govNCT00567190.     

Central nervous system metastases in a cohort of metastatic breast cancer patients treated with trastuzumab

Background  Several analyses suggest an increase of brain metastases in HER2 over-expressing breast cancers treated with trastuzumab as compared to historical series of unselected patients. Patients and methods  We analyzed the incidence of central nervous system (CNS) metastases in 78 patients with HER2 over-expressing breast cancer treated with trastuzumab between July 2000 and June 2006 at the Oncology Department of University Federico II in Naples. We also characterized and compared patients with and without CNS involvement. Results  The median follow-up was 35.3 months (95%CI 26.3–44); median overall survival was 56 months (95%CIs 46-nr); 5 patients showed CNS involvement before trastuzumab therapy while 31 developed CNS metastases during trastuzumab treatment. The median overall survival after CNS metastases was 25.4 months (95%CIs 15.2-nr); patients with CNS lesions showed worse overall survival than patients without CNS lesions (39.1 vs. 75 months, p = 0.005). Conclusion  CNS metastases are common events in patients with metastatic HER2 over-expressing breast cancer treated with trastuzumab; the impact on survival is detrimental even if survival after CNS metastases is longer than historical reports. Appropriate investigation of the role of CNS imaging screening and the prophylactic treatment strategies for CNS represents a priority research in this setting. E. Montagna and G. Cancello have contributed equally to this work.