Survival In HER2-positive Patients Research Articles

Ki67 increase after core needle biopsy associated with worse disease outcome in HER2-negative breast cancer patients

Ki67 would change after core needle biopsy (CNB) in invasive breast cancer. However, whether Ki67 alteration (ΔKi67) influences disease outcomes remains unclear. Here we aim to evaluate the prognostic value of ΔKi67. Patients with paired CNB and open excision biopsy (OEB) samples between January 2009 and June 2016 were retrospectively analyzed. ΔKi67 was calculated as the absolute difference between Ki67 level in CNB and OEB samples, and the median value of 5% was adopted to category patients into high- and low ΔKi67 groups. Disease-free survival (DFS) and overall survival (OS) were compared between different ΔKi67 groups. Overall, 2173 invasive breast cancer patients were included. Median Ki67 was higher in OEB than CNB samples: 25.00% versus 20.00% (P < 0.001). Axillary nodal status, STI, histological grading, and molecular subtype were independently associated with ΔKi67 (P < 0.05). In the whole population, patients with low ΔKi67 showed superior 5-year DFS (89.6% vs 87.0%, P = 0.026), but similar OS (95.8% vs 94.3%, P = 0.118) compared to those with high ΔKi67. HER2 status at surgery was the only significant factor interacting with ΔKi67 on both DFS (P = 0.026) and OS (P = 0.007). For patients with HER2-negative disease, high ΔKi67 was associated with worse 5-year DFS (87.2% vs 91.2%, P = 0.004) as well as impaired 5-year OS (93.9% vs 96.8%, P = 0.010). ΔKi67 had no significant impact on survival of HER2-positive patients. Ki67 increase after CNB was significantly associated with worse disease outcomes in HER2-negative, but not in HER2-positive patients, which warrants further study.

Abstract PS6-39: A novel prognostic nomogram for 2-year survival in HER2-positive patients

Abstract Background: Targeted therapies have largely improved prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Yet, disease can still progress rapidly for some patients in the first two years after diagnosis. Our study aimed to establish a nomogram model to predict 2-year breast cancer-specific survival (BCSS) in early HER2-positive breast cancer patients. Patients and Methods: A total of 32,481 HER2-positive patients derived from Surveillance, Epidemiology, and End Results (SEER) database were included in the construction of nomogram. Concordance index (C-index) and calibration curve were used to evaluate the discrimination ability and predictive accuracy. We also tested the model in 804 patients from Shanghai Jiao Tong University Breast Cancer Data Base (SJTU-BCDB).Results: Age, estrogen receptor (ER) status, progesterone receptor (PR) status, histologic type, T stage and N stage were selected to construct the nomogram according to multivariable analysis. The 2-year BCSS rate was 95% and 60% for patients at low risk (&amp;lt;8 points) and high risk (&amp;gt;13 scores) respectively. The C-index of model derived from SEER database is 0.81 (95%CI 0.79-0.83). Sensitivity analysis was performed in patients undergoing breast surgeries with the C-index of 0.81 (95%CI 0.79-0.83). Validation in 804 patients from SJTU-BCDB showed respective C-index of 0.77 (95%CI, 0.62-0.92) in total population, 0.67 (95%CI 0.44-0.90) in patients receiving anti-HER2 therapy and 0.90 (95%CI 0.81-0.90) in those without targeted therapy.Conclusions: The novel nomogram can predict 2-year survival outcome in HER2-positive patients independent of receiving anti-HER2 therapy or not and help clinicians to adjust therapeutic strategies for those patients with higher risk. Citation Format: Li Zhu, Mengdi Chen, Jiayi Wu. A novel prognostic nomogram for 2-year survival in HER2-positive patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-39.

HER2 testing across practices-Have we come to a consensus on the ideal method of testing? A systematic literature review.

Human epidermal growth factor (HER2) is an oncogene that codes for HER2 protein. The gene is amplified, and protein is overexpressed in 20% of patients and carries a poor prognosis. HER2-positive tumors tend to be more aggressive and highly proliferative. In 2006, trastuzumab, a monoclonal antibody targeting HER2, was approved for use with chemotherapy as an adjuvant treatment for women with HER2-positive breast cancer. The drug has shown improved survival rates for women with HER2-positive breast cancer. As promised for survival in HER2-positive patients continues with new research, and as novel drug approvals emerge, HER2 assessment plays a significant role in adjuvant and in metastatic setting. HER2 assays approved by the US Food and Drug administration include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and bright field dual in situ hybridization (DISH). Accuracy of HER2 testing across laboratories has an impact on treatment as false-negative testing can deprive the patients of trastuzumab therapy. The current review will focus on the variability of HER2 testing across laboratories and the potential impact on treatment.

Abstract P1-07-24: Evaluation of the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab: A hellenic cooperative oncology group (HeCOG) study

Abstract Background-aim: Metastatic breast cancer (MBC) is an incurable disease. Trastuzumab, a recombinant humanized monoclonal antibody, was found to significantly prolongsurvival of patients with metastatic HER2 over-expressing and/or amplified breast cancer. In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Methods: Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), transcriptional profiling and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Results: Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 months and 10.4 months for HER2-positive and HER2-negative participants, respectively. Median survival was 50.4 months for HER2-positive and 38.1 months for HER2-negative patients. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR=0.43, 95% CI 0.21-0.88, Wald's p=0.022 and HR=0.43, 95% CI 0.21-0.88, p=0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR=3.53, 95% CI 1.19-10.50, p=0.023 and HR=3.37, 95% CI 1.12-10.17, p=0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR=0.43, 95% CI 0.22-0.84, p=0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR=4.81, 95% CI 1.52-15.82, p=0.008), while none of the examined factorsretained their prognostic significance for TTP or survival in the HER2-positive subgroup. Conclusions: The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP and survival in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts. Citation Format: Koutras A, Kotoula V, Koliou G-A, Kouvatseas G, Christodoulou C, Pectasides D, Batistatou A, Bobos M, Tsolaki E, Papadopoulou K, Pentheroudakis G, Papakostas P, Pervana S, Petraki K, Chrisafi S, Razis E, Psyrri A, Bafaloukos D, Kalogeras KT, Kalofonos HP, Fountzilas G. Evaluation of the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab: A hellenic cooperative oncology group (HeCOG) study [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 P1-07-24.

Improved survival in metastatic breast cancer 1985–2016

PurposeIn the last 25 years new treatment options in breast cancer have evolved. We wanted to determine whether the survival of; patients with metastatic breast cancer have improved during this period. MethodsPatients consecutively diagnosed with disseminated breast cancer 1985–2014 in the County of Kalmar, Sweden, were identified and followed to 2016. Survival was calculated for each successive 5 year interval. Separate analyses were performed for pts with ER and/or PR and HER2 positive tumours resp. ResultsMedian survival of the 784 patients increased successively from 13 to 33 months. Five year survival increased from 10 to 27%. Patients with high grade primary tumours had the shortest post recurrence survival time but their median survival increased significantly by time from 12 to 30 months, 3 year survival from 16 to 38% and 5 year from 5 to 20%. Median survival for patients with grade 2 tumours was 2 years and did not improve. Only 47 patients had grade 1 tumours and their median survival of 4 years did not change.Median survival for HER2 positive patients treated before the introduction of trastuzumab in year 2000 was 14 months and after 2000 29 months, 5 year survival improved from 2 to 31%. ConclusionsSurvival in metastatic breast cancer improved 1985–2016. For the first time a significant increase in survival time for patients with metastasis from fast-growing grade 3 tumours was seen. The most striking improvement was achieved in the HER2 positive subset.

Breast cancer with brain metastases: clinicopathologic features, survival, and paired biomarker analysis.

The aim of this study was to describe clinicopathologic features of patients with breast cancer brain metastasis (BCBM); to evaluate survival after diagnosis of BCBM; and to compare estrogen receptor (ER), progesterone receptor (PR), and HER2 expression in the paired primary and brain tumors. We identified 140 consecutive patients who underwent craniotomy for BCBM (either for diagnostic purpose or with therapeutic intent) at the University of Texas MD Anderson Cancer Center between 2002 and 2009. Most patients had invasive ductal histology (91%), grade 3 tumors (67%), and positive axillary lymph node (64%). Of the tumors, 56% were ER-negative, 62% were PR-negative, 44% were HER2-positive, and 28% were triple negative (TN). Brain metastasis (BM) was solitary in 51% of patients. Median interval from breast cancer diagnosis to BM was 46 months; median survival after BM was 14.1 months. In the univariate analysis, younger age, solitary brain metastasis, and ER or PR positivity in the breast tumors were associated with longer survival. There was a statistical trend toward increased survival in HER2-positive patients compared with HER2-negative patients (18 vs. 11 months). In the multivariate analysis, predictors for longer survival included younger age, solitary brain lesion, and HER2 positivity in the breast cancer. Biomarkers were evaluated in paired primary and brain tumors in 35 patients for ER status, 34 for PR status, and 36 for HER2 status. Discordant rates were 28% for ER, 20% for PR, and 3% for HER2. Compared with unselected breast cancer patients at the same institution, patients with breast cancer who had brain metastases had a higher proportion of hormone receptor-negative, HER2-positive, and TN tumors. Younger age, solitary brain lesion, and HER2 expression were independent predictors of better survival in patients with BCBM. HER2 status was highly concordant between the paired primary and brain tumors, whereas changes of ER and PR status occurred in a substantial proportion of the patients. These findings are important for making effective treatment decisions for patients with BCBM.

Multicenter large-scale study of prognostic impact of HER2 expression in patients with resectable gastric cancer.

Although some small-scale studies have suggested that human epidermal growth factor receptor 2 (HER2)-positive status in gastric cancer is associated with poor outcomes, the prognostic value of HER2 is still controversial. Since intratumoral HER2 heterogeneity is also an important issue, a multicenter large-scale study was conducted to evaluate the prognostic impacts of HER2 expression and intratumoral heterogeneity in gastric cancer. This study included 1,148 gastric cancer patients who underwent gastrectomy in 11 institutions. HER2 expression was centrally evaluated with immunohistochemistry and fluorescence in situ hybridization, and intratumoral HER2 heterogeneity was evaluated for HER2-positive tumors. Overall survival was compared between HER2-positive and HER2-negative patients and between the homogeneous and heterogeneous groups. The HER2-positive rate was 15.7 %, and HER2 expression was significantly associated with histological type. HER2 expression scores obtained by immunohistochemistry showed a distinct influence on survival, and HER2-positive patients showed much poorer survival than HER2-negative patients [hazard ratio (HR) 1.59, 95 % confidence interval (CI) 1.24-2.02; P < 0.001). The subgroup analysis by pathological tumor stage showed a similar trend of poor survival in HER2-positive patients. Both intestinal type and diffuse type showed significant poor survival in HER2-positive patients. Cox multivariate analysis revealed that HER2 expression was an independent prognostic factor (HR 1.96, 95 % CI 1.51-2.55; P < 0.001). HER2 heterogeneity was observed in 75.4 % of HER2-positive cases, but the prognosis in the heterogeneous group was similar to that in the homogeneous group. Our study demonstrated that HER2 overexpression is an independent prognostic factor in patients with any stage of resectable gastric cancer. Intratumoral HER2 heterogeneity did not affect prognosis.

P85 protein expression is associated with poor survival in HER2-positive patients with advanced breast cancer treated with trastuzumab.

To investigate the immunohistochemical expression of p85 in a cohort of trastuzumab-treated HER2-positive and HER2-negative metastatic breast cancer patients. The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients. Samples were evaluated by immunohistochemistry for p85, estrogen receptors (ER), progesterone receptors (PgR), HER2, Ki67, PTEN and phosphorylated Akt (S473 and T308). HER2 status was studied by fluorescence in situ hybridization, as well. PIK3CA mutational status was also evaluated. Median follow-up for all patients was 72 months. Central re-evaluation for HER2 revealed only 111 HER2-positive cases, with the remaining 72 patients being HER2-negative. Median survival was longer in HER2-positive patients (50.7 months) compared to HER2-negative patients (36.6 months) both treated with trastuzumab, but this difference has not reached significance (p = 0.068). In total, 62% of the patients were found positive for p85, however the p85 protein was not found to be differentially expressed in HER2-positive versus HER2-negative cases. There were no significant associations between protein expression of p85 and any of the markers under study, or with time to progression. Positive p85 protein expression was however associated with poor survival in trastuzumab-treated HER2-positive patients. In our cohort of trastuzumab-treated HER2-positive breast cancer patients, positive p85 protein expression appears to be a prognostic factor of poor survival and, if validated, might have important implications in the treatment of such patients.

HER-3 expression in HER-2-amplified breast carcinoma

Aim of the studyTo determine whether the expression of HER-3 influences the survival of HER-2 positive patients with breast cancer (BC).Material and methodsIn the present work, the expression of HER-3 in a group of 35 HER-2 positive patients with BC was studied by performing immunohistochemistry (IHC) in formalin-fixed paraffin embedded tissues.ResultsHigher HER-3 status if estimated by IHC correlated significantly with older age of the patients. HER-3 expression did not correlate with estrogen or progesterone receptor status, pT or pN. There was also no significant difference in disease-free or overall survival (DFS and OS) between groups with different HER-3 expression, although some tendencies were seen as HER-3 expression in over 50% of cells was a factor of worse 5- and 10-year survival.ConclusionsFurther studies should be performed on a larger group of patients to confirm the prognostic role of HER-3 status determined by IHC in BC.

Abstract P1-14-01: Adding capecitabine and trastuzumab to neoadjuvant breast cancer chemotherapy - first survival analysis of the GBG/AGO intergroup-study GeparQuattro.

Abstract Background: Previous results of the GeparQuattro study demonstrated that adding capecitabine either simultaneously or sequentially to EC-Docetaxel (D) neoadjuvant chemotherapy could not increase pathological complete response rates (pCR) (von Minckwitz G, JCO 2010). However, patients with HER2-positive disease treated simultaneously with trastuzumab showed a significant higher pCR rate than patients with HER2-negative disease treated with chemotherapy alone (Untch M, JCO 2010). We here report survival after a median follow up of 58 months including 279 relapses and 191 deaths. Patients and methods: Patients with either large operable (cT3) and locally advanced (cT4) tumors, or hormone-receptor (HR)-negative receptor status, or HR-positive tumors but clinically node-positive disease were recruited to receive 4 cycles of EC (90mg/m2/600mg/m2) and randomized to either 4 cycles of D (100mg/m2) or 4 cycles of DX (75mg/m2/1800mg/m2) or 4 cycles of D (75mg/m2) followed by 4 cycles of X (1800mg/m2) (D→X). Patients with HER-2 positive tumors received 1 year of trastuzumab, the first part concurrent to all chemotherapy cycles. All patients with HR+ tumors received endocrine therapy according to current standard. The intent-to-treat survival analysis included 1421 patients for the chemotherapy question and 1495 patients for the trastuzumab question. Analyses were adjusted by age, stage, size, nodal status, histologic type, grade, hormone-receptor (HR) and HER2-status at baseline (if applicable). Results: No difference in DFS and OS was seen for patients receiving D, DX or D-X overall (hazard ratio 0.978, p = 0.984 and hazard ratio 0.986, p = 0.684, respectively) as well as by phenotype defined according to St. Gallen (all P&amp;gt;0.354). Patients with HER2-positive disease treated additionally with trastuzumab showed significantly better OS (p = 0.015) compared to patients with HER2-negative disease treated with chemotherapy alone. DFS was significantly better for trastuzumab-treated patients with HR-negative tumors (p = 0.046), but not with HR-positive tumors (p = 0.790). OS after first relapse was significantly better in trastuzumab-retreated patients with HER2-positive tumors (p = 0.032) compared to relapsed patients with HER2-negative tumors. Patients with an early response after 4 cycles, with a clinical response at surgery and with a pCR showed a significantly better DFS and OS compared to patients without pCR (p = 0.022, P &amp;lt; 0.0001, P &amp;lt; 0.0001). This benefit was most prominent in patients with triple-negative tumors. Conclusions: Survival analysis of the GeparQuattro study confirmed the results of the primary endpoint analysis on pCR. Capecitabine could not improve outcome when added to anthracycline-taxane-based chemotherapy. As suggested by a recent integrated multi-level meta-analysis (von Minckwitz, BCRT 2011) effect of capecitabine could not be properly assessed in this study as planned docetaxel doses in arms DX and D®X were lower than in arm D. Survival of HER-2 positive patients surmounts that of HER2-negative patients if trastuzumab is used in the neoadjuvant as well as in the metastatic setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-01.

Survival of patients with HER2-positive gastric cancer with introduction of trastuzumab.

128 Background: ToGA study showed that trastuzumab given in combination with first-line chemotherapy (fluoropyrimidine plus cisplatin) improved the overall survival of HER2-positive patients with advanced gastric cancer (AGC). Meanwhile, the prognostic value of HER2 or the efficacy of trastuzumab in second- or further-line chemotherapy remains controversial. Methods: We retrospectively analyzed 567 patients with AGC who initiated systemic chemotherapy before March 2011. Among them, 287 were evaluated for their HER2 status. HER2 positivity was defined as IHC 3+ or IHC 2+ with amplification by FISH. Treatment outcomes were compared between patients with HER2-positive and HER2-negative AGC. To evaluate the impact of exposure to trastuzumab in any line of chemotherapy, we applied time-varying covariates (TVC) analysis to avoid possible lead-time bias. Results: The median survival time (MST) of HER2-evaluated patients (n=287) tended to be better than that of HER2-non-evaluated patients (n=280, 14.5 vs. 13.2 months; P=0.03). Among the HER2-evaluated patients, 47 (16.3%) were HER2-positive and had longer survival than HER2-negative patients (24.1 vs. 13.4 months; P=0.05). Among the HER2-positive patients, 35 received trastuzumab; 15 patients received it as first-line therapy and 20 received it as second- or further-line therapy. The MST of HER2-positive patients with trastuzumab treatment was significantly longer than that of HER2-positive patients without trastuzumab (26.6 vs. 13.5 months; P=0.015). HER2-negative patients and HER2-positive patients without trastuzumab had similar survival durations. According to multivariate analysis with TVCs, exposure to trastuzumab was independently associated with better prognosis (HR 0.54, P=0.04). Conclusions: Although the retrospective nature and small sample size are major limitations of this study, recent HER2-positive AGC patients showed a better prognosis than HER2-negative patients, especially with the introduction of trastuzumab.

A case for more intensive systemic therapy for patients with locally advanced rectal cancer: even in the face of a pathologic complete response.

Using the standard slide-based techniques of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), it has been firmly established that human epidermal growth factor receptor 2 (HER2) is overexpressed in adenocarcinoma of the upper gastrointestinal tract. In the ToGA trial, the addition of the monoclonal antibody trastuzumab to a standard regimen of cisplatin and fluoropyrimidine resulted in a clinically and statistically significant benefit in terms of response rate, median progression-free survival, and median overall survival in HER2-positive patients. Major differences exist, however, between HER2 testing in gastric/gastroesophageal junction (GEJ) cancer versus breast cancer, and the ToGA trial employed a significant modification of the breast cancer scoring criteria. As trastuzumab approaches regulatory approval in the United States for gastric/GEJ cancer, it is critical that pathologists and diagnostic laboratories learn and apply the unique criteria for assessing gastric/GEJ tumors for their HER2 status defined by the ToGA investigators, as they ready themselves for the approximately 50,000 new specimens that will be tested for HER2 status by both IHC and FISH each year.

Evaluation of the Predictive Value of IGF-IRa, IGF-IRb, UPA, and PAI-1 in Patients with Advanced Breast Cancer (ABC) Treated with Trastuzumab.

Abstract Background: It has been shown that the HER2 and uPA/PAI-1 pathways independently affect the aggressive behavior of breast tumors. While HER2 positive patients have been shown to respond to trastuzumab, the role of uPA and PAI-1 in patients with advanced breast cancer (ABC) treated with trastuzumab is unclear, while the IGF-IR pathway appears to mediate resistance to trastuzumab.Material and Methods: Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 138 patients with ABC treated with trastuzumab in the first-line. Clinical information was retrieved from medical records. The median age of the patients was 55 years, with 31% being premenopausal. HER2, IGF-IRa, IGF-IRb, uPA, PAI-1, Ki-67, ER, and PgR were assessed centrally by immunohistochemistry (IHC), while HER2 was also assessed centrally by FISH. All stains were examined by 2 independent pathologists, using the Allred 8-unit system for IGF-IRa and IGF-IRb, a combination of a proportion score from 0 to 5 and an intensity score on a scale of 0 to 3 (none, weak, moderate, strong). uPA protein expression was considered positive if &amp;gt;75% of the cells showed intense staining, with PAI-1 deemed positive when &amp;gt;6% of the cells showed mild staining. PFS and survival from the initiation of trastuzumab were estimated by the Kaplan-Meier method and compared using the log-rank test.Results: Trastuzumab alone or in combination with chemotherapy and/or hormonal therapy was given as first-line treatment in all patients. HER2 gene amplification was confirmed in 89 cases, while in 49 patients HER2 was found to be non-amplified (HER2 negative patients). As expected, survival of HER2 positive patients was found to be significantly longer (50.7 months vs. 30.5 months, p&amp;lt;0.0001), with no significant differences found in PFS (14.0 months vs. 9.2 months, p=0.124). IGF-IRa, IGF-IRb, uPA, or PAI-1 positive patients were not found to have significantly different PFS or survival in either HER2 positive or negative patients.Discussion: Protein expression of IGF-IRa, IGF-IRb, uPA, or PAI-1 assessed by IHC was not found to be associated with significantly different survival in patients with advanced breast cancer treated with trastuzumab in the current analysis. Studies are ongoing to include patients receiving second-line treatment with trastuzumab and evaluation of PI3K mutations. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2036.

Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Central Nervous System Metastases

To determine the incidence, outcomes, and current strategies for management of brain metastases in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A literature review was performed to obtain data on central nervous system metastases in patients with breast cancer. HER2 amplification/overexpression is a prognostic and predictive factor for the development of CNS metastases. Autopsy data show that the incidence rate for CNS metastases in patients with breast cancer is approximately 30%; this may be higher (ie, 30% to 50%) in patients with HER2-positive disease. Treatment with trastuzumab is not associated with an increased incidence of CNS metastases. Data from three phase III adjuvant trials showed the incidence was similar between patients who received trastuzumab and those who did not. Furthermore, trastuzumab can significantly improve overall survival in HER2-positive patients who already have CNS metastases compared with patients who do not receive trastuzumab or those who have HER2-negative brain metastases. This survival advantage is conferred via systemic control of the disease. The current standard of care for patients with CNS metastases is whole-brain radiotherapy (WBRT), with or without surgery, or stereotactic radiosurgery. In the future, novel therapies or combinations of therapies may additionally improve survival in these patients. The incidence of CNS metastases in trastuzumab-treated patients is similar to that in all patients with HER2-positive disease. Trastuzumab can improve survival in patients with HER2-positive disease with CNS metastases.