Brain Metastases In HER2 Research Articles

ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer.

Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation. We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model. Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3β/β-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival. We demonstrated that metastatic breast cancer cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ breast cancer.

Systemic treatment for brain metastasis in HER2- positive advanced breast cancer: what have we learned so far?

Systemic treatment for brain metastasis in HER2- positive advanced breast cancer: what have we learned so far?

Impact of Hormone Receptor Status on Development of Brain Metastases from HER2+ Breast Cancer

<h3>Purpose/Objective(s)</h3> Patients with HER2+ breast cancer (BC) are at high risk of developing and dying from brain metastases (BM) compared to patients who have HER2- disease. Some studies have suggested hormone receptor (HR) positivity can delay the development of BM possibly due to endocrine therapies controlling extracranial disease. However, the impact of HR positivity on the time to development of BM in HER2+ disease is not well understood. <h3>Materials/Methods</h3> We retrospectively reviewed data on patients with BM from BC from a single academic institution from 2005–2020, during which time trastuzumab was included in the standard of care. Patients with HER2+ BC and BM were stratified into groups based on HR status, i.e., ER+ and/or PR+. Overall survival (OS) data was analyzed using the Kaplan-Meier method with differences compared by the log-rank test. HR status and time to development of BM were compared using a two-tailed Student's t-test. <h3>Results</h3> Of 363 BC patients with BM, 67 patients (18.5%) were identified as HER2+ (median age 48; range 26–80). 63 (94%) of the 67 patients received trastuzumab. 39 (58.2%) of the 67 patients had HR+ disease (ER+ and/or PR+ disease) and 28 (41.8%) had HR- disease. 30 (76.9%) of 39 patients with HR+ disease received endocrine therapy. In HR+ patients, the median time to the diagnosis of BM was 48.4 mos (SD=57.9 mos), while in patients with HR- disease the median time to the diagnosis of BM was shorter at 29.0 mos (SD=49.1 mos) (p<0.02). The median OS after initial diagnosis of BM for patients with HR+ disease was 27.6 mos, and 9.8 mos for patients with HR- disease (p<0.46). Of the 67 patients, 20 (29.9%) patients presented with one BM, 23 (34.3%) with 2–9 BM, 17 (25.4%) patients with ≥10 BM, and 7 (10.4%) with unknown number of BM. The median number of BM in HR+ patients was 2.0 (SD=2.8), and the median number of BM in HR- patients was 1.0 (SD=3.2) (p<0.43). The median diameter of the dominant BM in HR+ patients was 2.5 cm (SD=1.4 cm; range=0.05–5.4 cm), and the median diameter of the dominant BM in HR- patients was 2.1 cm (SD=1.2 cm; range=0.2–4.4 cm) (p<0.14). Brain imaging was obtained for neurological symptoms in 45 (67.2%) patients; 5 (7.5%) were asymptomatic; and 17 (22.4%) had unknown indication for imaging. 30 patients (44.8%) had extracranial metastases at the initial time of HER2+ BC diagnosis, and their median time to the development of BM was 26.4 mos (SD=25.2 mos). In contrast, 34 patients (50.7%) had no extracranial or BM at BC diagnosis and had longer median interval time to BM development at 53.8 mos (SD=67.5 mos) (p<0.002). <h3>Conclusion</h3> The majority of patients with HER2+ BM were symptomatic at time of BM diagnosis. The most salient factors associated with a decreased time interval to development of BM included HR- status and presence of extracranial metastases at the time of initial HER2+ BC diagnosis.

Abstract P1-17-05: Prognostic impact of initial treatment modality for brain metastasis in metastatic breast cancer

Abstract Background: The routine screening of brain metastasis (BM) is not recommended in patients with metastatic breast cancer (MBC) by guidelines. Due to survival improvement and increased use of magnetic resonance imaging (MRI) contribute the increasing of MBC BM incidence. The incidence of BM and survival from BM were various by molecular subtypes. The prognostic role of early detection of oligo BM and subsequent local treatment by subtypes is not clear. We aimed to compare BM free survival (BMFS) and BM overall survival (BMOS) by both treatment modalities and subtypes. Methods: In the Yonsei Breast Cancer MBC Database, we identified 1252 MBC patients who were diagnosed from 2006 to 2016. Data of 358 MBC patients (127 HR+/HER2-, 80 HR+/HER2+, 64 HR-/HER2+, 87 HR-/HER2-) with BM were available for the analysis. BMFS was defined as the time from the diagnosis of MBC to the diagnosis of BM. MBC patients with initial BM were excluded from analysis of BMFS. BMOS was defined as the time from the diagnosis of BM to any cause of death. Treatment modalities were analyzed as three categories; whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and neurosurgery. Results: Among the 1252 MBC patients, 47.7%, 14.7%, 13.1%, 17.6%, and 6.9% had HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-, and unknown subtypes, respectively. The incidence of initial BM were highest among patients with HR-/HER2- (14.5%) and were lowest with HR+/HER2- (5.2%) Incidence of initial metastasisInitial metastatic sitesHR+/HER2-, n(%)HR+/HER2+, n(%)HR-/HER2+, n(%)HR-/HER2-, n(%)Unknown, n(%)PBrain31 (5.2)16 (8.7)12 (7.3)32 (14.5)6 (6.9)&amp;lt;0.001Lung197 (33)72 (39.1)62 (37.8)99 (45)33 (37.9)0.036Liver137 (22.9)46 (25)52 (31.7)56 (25.5)16 (18.4)0.122Bone403 (67.5)109 (59.2)66 (40.2)90 (40.9)48 (55.2)&amp;lt;0.001Distant LN176 (29.5)74 (40.2)60 (36.6)93 (42.3)22 (25.3)0.011Pleura116 (19.4)19 (10.3)23 (14)40 (18.2)13 (14.9)0.045 . The median BMFS was 17.3 months (95% confidence interval (CI); 14.32-20.28) among the all patients with BM. The median BMFS was significantly shorter in the ER-/HER- subtypes (12 months, 95% CI; 20.73-31.67), and followed by ER-/HER2+ (14.8 months, 95% CI; 11.50-18.10), ER+/HER2+ (20.9 months, 95% CI; 16.88-24.92), and ER+/HER2- (26.2 months, 95% CI; 20.73-31.67). The median BMOS was significantly better in the SRS (16.8 months; 95% CI; 13.53-20.07) and surgery group (13.4 months, 95% CI; 7.19-19.61) compared with WBRT (6.9 months, 95% CI; 5.04-8.76) and no treatment (1.2 months, 95% CI; 0.32-2.08). Conclusions: Incidence of initial BM and BMFS were significantly different by subtypes. Patients who were treated with SRS or neurosurgery showed better survival compared to WBRT. This findings support to consideration of screening of BM in HER2+ or triple negative subtypes for the early detection of oligo BM. Citation Format: Kim GM, Cho YU, Kim SI, Park S, Park HS, Kim JY, Chun YJ, Sohn J. Prognostic impact of initial treatment modality for brain metastasis in metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-17-05.

Role of HER2 in brain metastasis of breast cancer: a systematic review and meta-analysis.

Breast cancer is one of the most common cancers among women worldwide and the HER2 receptor plays an important role in its development and progression. This systematic review aimed to summarize the role of HER2 in brain metastasis in patients with breast cancer. We conducted a literature search by advanced search in title field using the Scopus, Pubmed, and Google scholar databases until the end of June 2014. With metastasis, metastatic, HER2, brain, and breast cancer, as terms of search we selected 31 articles, which were reviewed by two independent and blinded expert reviewers. The studies were first selected according to their titles and abstracts. Quality of the studies were then assessed using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) protocol for observational studies and CONSORT(Consolidation of Standards for Reporting Trials) protocol for clinical trials. For statistical analyses, we used STATA, version 11.0 software. Forest and funnel diagrams were drawn and for heterogeneity, index was also considered. Also we used meta regression analysis. Finally, we reviewed 10 studies. The prevalence of brain metastasis in HER2- positive breast cancer patients was 24.9%. There was publication bias in the reviewed studies. Meta regression analysis showed that follow up time had no significant effect (p=0.396) on the prevalence of brain metastasis. The results showed a high prevalence of brain metastasis in HER2 positive breast cancer patients.

A study of the anatomic distribution of brain metastases in HER2+ breast cancer: Implications for hippocampal avoidance PCI.

e11578 Background: While only 20% of all breast cancer is HER2+, it represents a disproportionate majority of breast cancer brain metastases, and up to half of these patients will die of CNS diseas...

Correlation Between Quantitative HER-2 Protein Expression and Risk for Brain Metastases in HER-2+ Advanced Breast Cancer Patients Receiving Trastuzumab-Containing Therapy

Correlation Between Quantitative HER-2 Protein Expression and Risk for Brain Metastases in HER-2+ Advanced Breast Cancer Patients Receiving Trastuzumab-Containing Therapy

Correlation Between Quantitative HER-2 Protein Expression and Risk for Brain Metastases in HER-2+ Advanced Breast Cancer Patients Receiving Trastuzumab-Containing Therapy

Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group.

P2-12-05: Correlation between Quantitative HER2 Protein Expression and Risk of Brain Metastases in HER2−Positive Advanced Breast Cancer Patients Receiving Trastuzumab-Containing Therapy.

Abstract Background. Patients with HER2−positive breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Within HER2−positive breast cancer tumors, it is possible to resolve a ∼1.5-log range of HER2 protein expression using a novel quantitative HER2 assay (HERmark®). We investigated the correlation between quantitative HER2 protein expression in primary breast cancers and the time to brain metastases (TTBM) in HER2−positive advanced breast cancer patients treated with trastuzumab. Methods. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER2−positive metastatic breast cancer, defined as 3+ categorical staining by immunohistochemistry (IHC). HER-2/neu gene copy number was subsequently quantified as HER2/CEP17 ratio by central laboratory fluorescence in situ hybridization (FISH). HER2 protein was quantified as total HER2 protein expression (H2T) by the HERmark assay in formalin-fixed, paraffin-embedded primary tumor samples. HER2 variables were correlated with clinical features and TTBM measured from the initiation of trastuzumab-containing therapy. Results. H2T level (continuous variable) was correlated with shorter TTBM (HR=2.3; p=0.013), whereas HER2 gene amplification by FISH (p=0.28) and continuous HER2/CEP17 ratio (p=0.25) had no significant prognostic impact. The correlation between continuous H2T level and TTBM was confirmed in a multivariate analysis (HR=3.2; p=0.021). Controlling for the competing risk of death from causes other than brain metastases, continuous H2T remained a strong correlate of TTBM (HR=2.7; p=0.0009). In the subset of patients that was centrally-determined HER2 positive by FISH (117 patients), above-median H2T level was significantly associated with shorter TTBM (HR=2.4; p=0.005), whereas this was not true for median FISH/CEP17 ratio (p=0.4). In a multivariate analysis of this subset, continuous H2T (p=0.021) and a time dependent covariate capturing time to non-brain metastases (p=0.0044) were prognostic for TTBM, whereas FISH/CEP17, ER, PgR and grade were not. Conclusions. These data reveal a strong relationship between quantitative HER2 protein expression levels and the risk of brain relapse in HER2−positive advanced breast cancer patients. Consequently, quantitative assessment of HER2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-05.

P1-10-02: Burden of Brain Metastases in HER2−Positive Breast Cancer: Healthcare Use and Costs from a French Observational Retrospective Multicenter Study.

Abstract Background HER2+ status is associated with poor prognosis and a high incidence of brain metastases (BM) in breast cancer (BC). Addition of HER2−targeted therapies to conventional chemotherapy has significantly improved survival in HER2+ patients (pts). Management of BM implies a multidisciplinary therapeutic approach involving medical oncology, radiation oncology and neurosurgery teams. Nevertheless available data evaluating health resources use and associated costs are limited. Our objective was to describe treatment patterns and healthcare costs associated with HER2+ BMBC patients. Patients and methods An observational retrospective study was conducted on 207 HER2+ BC pts, newly diagnosed with BM as first site of relapse or as secondary metastases between January 2006 and December 2008. Pts were recruited in 10 hospitals, all funded by a prospective payment system based on Diagnosis Related Groups (DRG). Individual data concerning initial diagnosis, distant and BM relapses, treatments, complications and hospitalization stays were collected during a 2 year — follow-up. DRGs 2007 official tariffs (per-case payment basis) and 2007 expensive innovative drugs tariffs (drugs paid to hospitals by Health Insurance in addition to per-case payments) were used to estimate direct medical costs from the Health Insurance perspective. Survival was estimated using Kaplan Meier method. In the presence of cost-censored data, a partitioned estimator was used to adjust censoring costs (Bang and Tsiatis, Biometrics, 2002). Results 91.8% (190/207) of BMBC pts received radiation therapy, 84.5% (175/207) received chemotherapy including HER2 targeted treatments and 12.6% (26/207) were treated by neurosurgery. 72.5% (150/207) of pts were hospitalized at least once during the follow-up period. Pts had on average 2.90 hospital stays (range 1–8). The median duration of stay was 9 days (1-221). Complications leading to re-hospitalization were recorded in 45.9% (95/207) of pts. The median overall survival from the diagnosis of BM was 13 m. Hospital healthcare costs were concentrated on the 6 first months following BM diagnosis. Mean cost of BMBC management was 18,480€/patient within the 6 first months and decreased to 16,306€ from 7–12 months, 15,844€ from 13–18 months, and 15,225€ from 19–24 months. The proportion of costs attributed to inpatient hospitalizations stay (treatments and complications) was similar to the one attributed to drugs whatever the period of follow-up. Pts with BM as first site of relapse consumed more healthcare resources compared to pts with secondary BM (38,813€/pt vs 32,253€/pt after one year of follow-up, respectively). Conclusions Healthcare resources spending is mainly concentrated at the beginning of metastatic disease management, especially for patients with BM as first site of relapse. These results illustrate the use of expensive treatments in the first months following BM diagnosis. Individual data derived from this observational study allowed us to gather more specifically treatment patterns for HER2+ BMBC in order to estimate the costs more accurately. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-10-02.

The risk for brain metastases in HER2 3+ BC five years after primary BC diagnosis.

e11091 Background: More than 30% of HER2 3+ BC develops brain metastases (BM) eventually, usually in the first 2-3 years after BC diagnosis. Risk for distant metastases in HER2 3+ BC remains for ma...

LANDSCAPE: An FNCLCC phase II study with lapatinib (L) and capecitabine (C) in patients with brain metastases (BM) from HER2-positive (+) metastatic breast cancer (MBC) before whole-brain radiotherapy (WBR).

509 Background: With an incidence of 30%-40%, BM are common complications of HER2+ MBC. Their therapeutic management remains a challenge. As responses on central nervous system (CNS) localization have been reported with L+C combination after WBR, we sought to evaluate the clinical interest of this combination as 1st line treatment for BM in HER2+ MBC patients (pts) with the aim to avoid or to delay WBR. Methods: Eligible pts had HER2+ MBC with BM not previously treated with WBR, C or L. Pts received L1250 mg/day and C2000 mg/m2/day, days 1-14, every 21 days. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% volumetric reduction of CNS lesions in the absence of increasing steroid use, progressive neurologic symptoms, or progressive extra-CNS disease. Using a Simon’s optimal two-stage design with a minimum interesting CNS-OR rate of 20%, 41 evaluable patients were needed. Secondary endpoints included: time to progression (TTP) for both CNS and extra CNS disease; time to WBR; prognostic and predictive value of circulating tumor cells (CTC) and toxicity. Results: From 04 /2009 to 08/2010, 45 pts were enrolled. Median age was 56 (range 35 to 79), 37 pts had multiple metastatic sites, PS was 0 (17 pts), 1 (25 pts) or 2 (2 pts); 36 pts had two or more BM and 42 had previously received trastuzumab. 41 pts received at least 2 cycles of study treatment. 43 pts were evaluable for efficacy endpoints, with a median follow-up of 10 months (range 2.9-16.5). The CNS-OR rate was 67% (95%CI 51-81), with a median time from inclusion to response of 1.8 month. Median TTP was 5.5 months (95% CI 3.9-5.9) and median time to WBR was 8.3 months (95% CI 5.1-11.7). At baseline, 21/42 pts had ≥ 1CTC, vs 7/39 at day 21, p<0.01 (correlation study ongoing). 20 patients (44%) experienced grade 3 or 4 treatment related toxicity, treatment was discontinued due to toxicity in 3 pts. At the time of analysis, 21 pts had received WBR and 10 pts had died. Conclusions: With a high response rate, L + C is an active treatment option and a viable alternative to immediate WBR for HER2+ MBC pts with newly diagnosed BM.

490 Long term survival and incidence of brain metastasis in HER2- positive (HER2+) metastatic breast cancer patients (MBC) treated with trastuzumab (T): an institutional based review

490 Long term survival and incidence of brain metastasis in HER2- positive (HER2+) metastatic breast cancer patients (MBC) treated with trastuzumab (T): an institutional based review

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

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. 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. 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). 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.

Prognostic value of HER-2/neu overexpression for the development of brain metastasis after treatment of early breast cancer

21044 Background: Several studies have addressed the incidence of brain metastasis in HER-2/neu-overexpressing metastatic breast cancer. However, the relevance of HER-2/neu overexpression as a risk factor for brain metastases in breast cancer has not yet been clearly defined. The aim of this study is to analyze the risk of brain metastasis in HER-2/neu-positive early breast cancer patients in comparison with HER-2/neu-negative patients. Methods: We used tissue microarray to examine HER- 2/neu overexpression by immunohistochemistry (IHC) in 773 consecutive patients diagnosed with breast carcinoma who underwent surgery between January 1993 and December 1998. Patients were considered HER-2/neu-positive if they were 3+ on IHC testing. A total of 194 (25.1%) patients with HER-2/neu-overexpressing newly diagnosed breast cancer were identified in our study. The medical records and pathologic data of all 773 patients were reviewed retrospectively. Results: During a median follow-up period of 8.1 years, brain metastasis were identified in 7.2% (14 patients) with 194 HER-2/neu-overexpressing breast cancer compared with 2.6% (15 patients) in 597 HER-2/neu-negative patients (hazard ratio 2.924 [1.385–6.175], P=0.005). More HER-2/neu-overexpressing patients developed distant metastasis (33.5% vs. 18.8%, P=0.0001). The 8-year overall survival was 76.1% for HER-2/neu-negative patients versus 56.4% for HER-2/neu-positive patients (P&lt;0.00001). By multivariate analysis, HER-2/neu overexpression, tumor size larger than 2 cm, at least one positive node, and progesterone receptor (PR)-negativity were independent risk factors for the development of brain metastases. Conclusions: Our data show that HER-2/neu overexpressing early breast cancer patients are at significantly increased risk for brain metastases. Also, our results demonstrate that HER-2/neu overexpression is an important independent prognostic factor of early breast cancer, and suggest that more aggressive adjuvant chemotherapy and radiologic screening to detect brain metastases should be considered in this population. No significant financial relationships to disclose.

Prognostic Significance of Human Epidermal Growth Factor Receptor Positivity for the Development of Brain Metastasis After Newly Diagnosed Breast Cancer

As survival in breast cancer patients is improving, brain metastases are becoming increasingly prevalent. The risk of brain metastases in newly diagnosed human epidermal growth factor receptor 2 (HER-2) -overexpressing breast cancer patients is not yet fully defined. We aimed to analyze the risk of brain metastasis in newly diagnosed HER-2-positive breast cancer patients in comparison with HER-2-negative patients. To determine the incidence of brain metastases in HER-2-overexpressing patients, we analyzed a cohort of newly diagnosed 301 HER-2-positive and 363 HER-2-negative patients identified between January 1998 and December 2003. The association between histologic features and the occurrence of brain metastases was evaluated with univariate and multivariate Cox regression analysis. Median follow-up was 3.9 years. Brain metastases were identified in 9% (27 patients) with HER-2-overexpressing breast cancer compared with only 1.9% (7 patients) in the HER-2 negative patients (hazard ratio 4.23 [1.84-9.74], P = .0007). HER-2 overexpression, tumor size larger than 2 cm, at least one positive node, and grade 2/3 disease were predictors of brain metastases in univariate analysis. In multivariate analysis, HER-2 overexpression, tumor size larger than 2 cm, and hormone-receptor negativity were independent prognostic factors for the development of brain metastases, whereas hormone-receptor expression was protective. Our study shows that newly diagnosed HER-2-overexpressing breast cancer patients are at increased risk for brain metastases. Because most brain metastases occur after the development of systemic disease, these findings prompt consideration of brain prophylaxis strategies with HER-2-inhibiting small molecules able to cross the blood-brain barrier and/or radiologic screening to detect asymptomatic brain metastases.

Prognostic significance of HER-2/neu over-expression on the incidence of brain metastasis in newly diagnosed breast cancer

649 Background: As systemic therapy improves, brain metastases (BM) from breast cancer are becoming increasingly evident. An increased risk of BM in HER-2/neu over-expressing metastatic breast cancer patients has been suggested. However, the relationship between HER-2/neu over-expression and the risk of BM in newly diagnosed breast cancer patients is unknown. Methods: To determine incidence of BM in HER-2/neu over-expressing breast cancer patients, a cohort of patients between 01/1998 and 12/2003 with uniform HER-2/neu testing were identified from a cancer registry. A total of 460 patients with HER-2/neu over-expression and 500 patients with HER-2/neu negative disease were reviewed. Patients were excluded if there was breast cancer diagnosed before 01/1998 or others cancer. A total of 301 HER-2/neu over-expressing and 363 HER-2/neu negative patients were included for this analysis. The association between histological features and the occurrence of BM were evaluated with univariate and multivariate analyses. Results: BM were identified in 8% (24 patients) of HER-2/neu over-expressing breast cancer patients compared to only 1.7% (6 patients) in the HER-2/neu negative patients (hazard ratio 5.15 [2.079–12.78], p=0.0001). In patients with recurrent disease, the proportion of BM for HER-2/neu over-expressing patients was 24% compared to 10% in HER-2/neu negative patients. HER-2/neu over-expression, tumor size &gt;2cm, ≥ 4 nodes positive and grade 2/3 were predictors of BM in univariate analysis. In multivariate analysis, HER-2/neu over-expression and tumor size&gt;2cm were an independent prognostic factors for the development of BM, while hormone receptors expressions was protective (p=0.02). Conclusions: Our population based study show that newly diagnosed HER-2/neu over-expressing breast cancer patients are at significantly increased risk for BM. As most BM occur in HER-2/neu over-expressing patients with systemic metastatic disease, these findings could prompt consideration of brain prophylaxis strategies and/or serial radiologic screening to detect asymptomatic BM. No significant financial relationships to disclose.