Trastuzumab-based Adjuvant Therapy Research Articles

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

ABSTRACTIntroduction: Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development.Areas covered: This review article focuses on neratinib in the treatment of HER2-positive breast cancer – early and metastatic stage – and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug.Expert opinion: The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

Abstract S5-02: Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET)

Abstract Background: Neratinib (Puma Biotechnology Inc), an irreversible pan-HER tyrosine kinase inhibitor, was evaluated in a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET) to assess for improved invasive DFS (iDFS) in women with early-stage HER2+ breast cancer (BC) after trastuzumab-based therapy (clinicaltrials.gov NCT00878709). Primary efficacy analysis at 2-yrs demonstrated iDFS of 93.9% and 91.6% neratinib and placebo, respectively (HR 0.67, 95% CI 0.50–0.91; P=0.009). Greater benefit was observed in hormone-receptor (HR)-positive and centrally- confirmed HER2 subsets – HR 0.51, p=0.001 and HR 0.51 p=0.002, respectively [Chan et al. ASCO 2015]. We report an exploratory analysis of efficacy after 3-yrs of follow-up. Methods: Women with HER2+ BC were randomly assigned to oral neratinib 240 mg/day or matching placebo for 1 year, stratified by nodal status, HR-status and prior trastuzumab regimen. The study was initiated in April 2009 with recruitment ceased in October 2011, limiting follow-up to 2 years. In January 2014, follow-up was restored to 5 years. During year 1, physical examinations were performed at 3-monthly intervals, at 4-monthly intervals in year 2 and then 6-monthly to 5-years; with mammography performed annually. Patients were asked to re-consent following ethics approval of the January 2014 protocol amendment. During years 3 to 5, disease-free survival (DFS) and survival events were identified from medical records. A descriptive analysis of iDFS, to investigate the durability of neratinib effect was performed after 3-yrs of follow-up. Data for overall survival remains blinded until 248 events have occurred. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using stratified Cox proportional-hazards models. Results: The intention-to-treat population included 2840 patients (neratinib, N 1420; placebo, P=1420). Central HER2 testing has now been performed in 2041 pts (72%) - HER2-positive 1709 (84%) and HER2-negative 332 (16%). Pts were randomized within 12-months of completion of prior adjuvant trastuzumab in 2297 (81%) pts. Three-yr iDFS for ITT population demonstrated HR 0.74, [95% CI 0.56-0.96]. In the ITT pts who were randomized within 1-yr of trastuzumab completion, iDFS HR 0.72 [0.54-0.95]. For pts who had centrally-confirmed (cc) HER2-positive disease , iDFS HR 0.70 [0.50-0.98]. Pts with HR-positive disease had 3-yr iDFS HR 0.57 [0.39-0.82] and HR-negative pts HR 0.96 [0.67-1.45]. Overall survival data are not yet mature. Conclusions: Exploratory analysis at 3-years supports the significant benefit seen in the primary analysis of 12-months of neratinib following adjuvant trastuzumab-based therapy. Patients who consistently derived the greatest benefit were 1) patients who received neratinib within 12 months of completing adjuvant trastuzumab; 2) centrally confirmed HER2 positive patients and 3) HR positive patients. Citation Format: Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harker G, Masuda N, Neskovic Konstantinovic ZB, Petrakova K, Guerrero Zotano AL, Iannotti N, Rodriguez GI, Tassone P, von Minckwitz G, Ejlertsen B, Chia SKL, Mansi J, Barrios CH, Buyse M, Wong A, Bryce R, Ye Y, Martin M. Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-02.

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. Wyeth, Pfizer, Puma Biotechnology.

Invasive disease-free survival benefit following neratinib as extended adjuvant therapy in centrally-confirmed HER2+ early-stage breast cancer: The ExteNET phase III randomized placebo-controlled trial.

117 Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab pre-treated HER2-positive (HER2+) metastatic breast cancer (BC). ExteNET is an ongoing multicenter randomized placebo-controlled phase III trial evaluating the efficacy and safety of a 1-year course of neratinib in patients with early-stage HER2+ BC after trastuzumab-based adjuvant therapy (clinicaltrials.gov: NCT00878709). Methods: Women with locally-confirmed early-stage HER2+ BC were randomly assigned to oral neratinib 240mg/day or matching placebo for 1 year. Archived diagnostic tumor samples were submitted for HER2 gene amplification testing at a central laboratory. Primary endpoint: invasive disease-free survival (iDFS). Secondary endpoints: DFS including ductal carcinoma in situ (DFS+DCIS); distant disease-free survival (DDFS); time to distant recurrence (TDR). Stratified Cox proportional-hazards models were used to estimate hazard ratios (HR) for the ITT and amended ITT (aITT) populations; unstratified models were used for the centrally confirmed HER2 population. Treatment groups were compared using 2-sided log-rank tests. Results: The ITT population included 2840 patients (neratinib, N=1420; placebo, N=1420). The higher-risk aITT population (i.e. node-positive disease and randomized ≤1 year of completing prior trastuzumab) included 1873 patients (neratinib, N=938; placebo, N=935). Of the tumor samples analyzed, 1463 (86%) were centrally confirmed (neratinib, N=741; placebo, N=722). Conclusions: Neratinib significantly improves iDFS in trastuzumab-treated early-stage HER2+ BC patients. An enhanced treatment effect is observed with neratinib in women with centrally confirmed HER2+ tumors. Clinical trial information: NCT00878709. [Table: see text]

Demographic, tumor and clinical features of clinical trials versus clinical practice patients with HER2-positive early breast cancer: results of a prospective study.

Several randomized clinical trials (RCTs) have demonstrated the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancer (BC). However, RCT patients may not invariably be representative of patients routinely seen in clinical practice (CP). To address this issue, we compared the clinical and tumor features of RCT and CP patients with HER2-positive BC. From January to December 2012, 650 consecutive patients with HER2-positive early BC, treated in 36 different types of Italian healthcare facilities, were enrolled in this study. Age, treatment, tumor size (T), nodes (N), grade (G), estrogen receptor (ER) and progesterone receptor (PgR) status were prospectively collected in these CP patients. The same data were extracted from the main adjuvant trastuzumab RCTs and pooled using the random-effects model of DerSimonian and Laird. RCT and CP patients were compared by using the Cochran Q statistics. Versus RCT patients, CP patients were more likely to be older than 50 years (65 vs. 49 %; p < 0.0001) and to have HR (ER and/or PgR)-positive (72 vs. 54 %; p < 0.0001) BC and less likely to have tumor >2 cm (T ≥ 2 cm 39 vs. 59 %; p < 0.0001), positive N (47 vs. 89 %; p < 0.0001) and a high G (61 vs. 67 %; p = 0.0241). CP patients more frequently received adjuvant endocrine therapy (70 vs. 57 %; p < 0.0003) and less frequently adjuvant chemotherapy (97 vs. 99.7 %; p < 0.0001). Most tumor and clinical features differed significantly between CP and RCT patients. These data raise concerns about the applicability of RCT results to CP patients.

Survher: A retrospective multicenter study comparing demographic and tumor characteristics of clinical trials versus clinical practice patients with HER2-positive breast cancer.

640 Background: Several clinical trials (CT) have shown remarkable efficacy of trastuzumab-based adjuvant therapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancers (BC). Ho...

Outcomes of her2-positive Early-Stage Breast Cancer in the Trastuzumab Era: A Population-Based Study of Canadian Patients

Breast cancer is heterogenous, with variable expression of the estrogen receptor (er), progesterone receptor (pr), and human epidermal growth factor receptor 2 (her2). Overexpression of her2 is generally considered a negative prognostic feature, but whether outcomes for her2-positive early breast cancer remain different from those for other subtypes in the era of trastuzumab-based adjuvant therapy is unknown. Using a retrospective chart review, we compared overall survival (os) and relapse-free survival (rfs) in 3 groups of patients with early-stage breast cancer: er-positive or pr-positive (or both) and her2-negative ["hormone receptor-positive" (hr+)]; her2-positive (her2+); and er-negative, pr-negative, and her2-negative ["triple-negative" (tn)]. In the 503 charts analyzed (332 hr+, 94 her2+, 77 tn), the 5-year os and rfs were, respectively, 94.2% and 87.2% for hr+ patients, 88.6% and 74.9% for her2+ patients, and 85.4% and 76.2% for tn patients. On multivariate analysis, the os for the her2+ subtype was similar to that for the hr+ subtype (hazard ratio:1.07; 95% confidence interval: 0.31 to 3.67 with hr+ as reference), but os was significantly worse for tn patients than for hr+ patients (hazard ratio: 4.37; 95% confidence interval: 1.56 to 12.24). In her2+ patients, the 5-year os and rfs trended better for patients with er+ or pr+ disease than for patients with er-negative and pr-negative disease (5-year os: 92.1% vs. 86.9%; 5-year rfs: 79.8% vs. 71.4%). Of her2+ patients, just 80.9% received trastuzumab, including 33.3% of her2+ patients with sub-centimetre tumours. In the trastuzumab era, patients with her2+ and hr+ early breast cancer have similar outcomes, while tn patients experience a significantly worse os than either of the foregoing groups. Outcomes for her2+ patients may differ by er and pr status. Trastuzumab was underutilized in this cohort.

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

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

Effect of adjuvant trastuzumab treatment in conventional clinical setting: an observational retrospective multicenter Italian study

Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23 %) patients completed 1-year trastuzumab treatment. In 128 patients (12.77 %), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician’s decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32 months, 107 breast cancer relapses were recorded (overall frequency, 10.67 %), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (<18 months from the start of treatment) compared to recurrences in bone after the end of treatment and wash-out of the drug (>18 months from the start of treatment) (35.89 vs. 14.28 %, p = 0.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases.

Role of renal function on the development of cardiotoxicity associated with trastuzumab-based adjuvant chemotherapy for early breast cancer

Anthracyclines, taxanes and trastuzumab are used for therapy in early breast cancer (EBC) overexpressing Human Epidermal Growth Factor 2 (HER2+). These drugs, considered alone, do not present potential nephrotoxicity. However, renal dysfunction (RD) may increase the myocardial sensibility to the insult of these chemotherapies used in combination. The aim of the study is to assess the role of RD on the development of cardiotoxicity associated with trastuzumab-based adjuvant therapy (aTrastC) for EBC. Clinical and echocardiographic data of 499 women with ERB2+ EBC were analyzed. At 12-month evaluation, any symptoms of heart failure or decrease in left ventricular ejection fraction (LVEF) were recorded. Patients who had cardiotoxicity (n = 130, 26 %) were older (57 ± 11 vs. 55 ± 11 years; p = 0.03), had lower glomerular filtration rate (GFR) (76 ± 15 vs. 83 ± 19 ml/min/1.73 m(2); p = 0.003), higher LVEF (69 ± 6 vs. 63 ± 5 %; p < 0.001) and received more frequent doses of doxorubicin (18 vs. 9 %; p = 0.01) than those who did not. In patients with GFR 60-90 and <60 ml/min/1.73 m(2), the 1-year event rate of cardiotoxicity was 25 and 38 %, respectively. ROC analysis showed that the best cut-off point of GFR for predicting cardiotoxicity was 78 ml/min/1.73 m(2) (AUC = 0.66, [95 % CI 0.57-0.74]). Multiple logistic regression revealed that GRF <78 ml/min/1.73 m(2) was the strongest predictor of cardiotoxicity (OR 3.32 [CI = 1.30-8.65]), independent of doxorubicin treatment and left ventricular ejection fraction. A reduced renal function represents a condition of higher risk of developing cardiotoxicity at 12-month follow-up in patients with HER2 + EBC treated with aTrastC.

Clinical Updates on EGFR/HER Targeted Agents in Early-Stage Breast Cancer

Recent updated reports from the large adjuvant trials in HER2-positive breast cancer indicate that the remarkable benefits of adding trastuzumab to chemotherapy appear, so far, to be sustained rather than transient. Other studies show that even small, node-negative, HER2-positive tumors carry some risk of recurrence and might benefit from trastuzumab-based adjuvant therapy. Evaluations of HER2 test results have examined the benefit of trastuzumab in cancers that exhibit focally positive gene amplification and also have raised the question of whether the criteria that correlate HER2 positivity with trastuzumab benefit in the adjuvant setting may be different from the criteria that apply in the treatment of metastatic disease. New results from trials combining targeted agents in the treatment of metastatic breast cancer provide strong rationale for the current adjuvant trials. In addition, neoadjuvant studies lend further support for combining targeted agents and may also provide an optimal setting to identify biomarkers that correlate with patient outcome. A new generation of therapies, including novel targeted agents and vaccines, is moving forward in clinical development and will be incorporated into adjuvant regimens in the future.

Multicentric observational study to assess clinical characteristics of HER2-positive breast cancer patients treated with adjuvant anti-HER2 therapy.

e11093 Background: The standard treatment for HER2-positive breast cancer patients is trastuzumab, which improves disease-free survival when used in the adjuvant setting, in combination or following chemotherapy. Our purpose was to assess clinical characteristics of HER2-positive primary breast cancer (PBC) patients treated with anti-HER2 therapy. Methods: A multicentric, observational, transversal study was performed. All patients with HER2-positive PBC treated with adjuvant anti-HER2 therapy were eligible. Results: A total of 230 women treated with adjuvant trastuzumab were evaluated. Median age: 53.2 years (45-78); PS 0: 200 (87%), PS 1: 28 (12.2%); Postmenopausic: 121 (52.6%). Stage IIA: 68 (30%). Infiltrating ductal carcinoma: 209 (91%). Tumor histologic grade III was present in 54%. Overexpression of HER2 was assessed by immunohistochemistry in 99.6% of patients, of whom 88.3% were HER2-postive (3+). Positive Progesterone receptors (PR): 105 (46.3%); Positive Estrogen receptors (ER): 122 (53.7%); PR (+)/ER (+): 91 (40.1%). Fifty percent underwent radical mastectomy. 64% had positive axillary nodes and 36% were node-negative. 24% received neoadjuvant chemoteraphy and 74% adjuvant chemotherapy. Adjuvant radiotherapy: 173 (75.2%); adjuvant hormonal therapy: 140 (60.9%). Antracicline and taxanes based combination was the most frequent chemotherapy in the neo-adjuvant (77%) and adjuvant setting (65%), especially in node-positive patients. Platinum-based chemotherapy was only used in 10% and 5% of patients with neoadjuvant and adjuvant therapy respectively. Trastuzumab was administered following chemotherapy in 65.4%, showing a higher percentage of node-negative patients (75%) than those node-positive (60%) (p < 0.05). Adjuvant trastuzumab was administered every 3 weeks in 87% whereas 13% received a weekly administration, without significant differences between node-positive or negative patients. Conclusions: The characterization of HER2-positive PBC patients that receive adjuvant trastuzumab and their treatment patterns may guide oncologists about patient's eligibility for trastuzumab-based adjuvant therapy. No significant financial relationships to disclose.

Multifactorial CNS relapse susceptibility in HER2-positive breast cancer patients: First results from a population-based registry study

1117 Background: A series of retrospective studies have reported a higher incidence of central nervous system (CNS) metastases in HER-2-positive (HER-2+) metastatic breast cancer. Trastuzumab, which does not cross the blood-brain barrier, has been associated with this increased risk. Methods: The aim of this study was to evaluate incidence, survival, and risk factors of CNS metastases in the incident breast cancer population systematically collected by the Tumor Registry of Parma Province over the 4-year period, 2004–2007. Study endpoints were: any distant metastasis as first event; CNS metastasis as first event; CNS metastasis at any time. Associations between CNS metastases and HER-2 status in the entire population and between trastuzumab and CNS metastases in HER-2+ patients (pts) were estimated. A multivariate analysis was performed to test the effect of covariates. Results: We evaluated the total resident population (n = 1500) of breast cancer pts diagnosed during the period 2004–2007 in Parma Province. Two-hundred and twenty-five pts (15%) were HER-2+ (IHC 3+/FISH amplified). Of these, 100 pts were treated with adjuvant trastuzumab-based therapy. At a median follow-up of 36 months from the diagnosis, the incidence of CNS relapse was 3% (1.3% as first recurrence). The median time to death from the diagnosis of CNS metastases was 25 months. Among the HER-2+ pts, there was a significant association between trastuzumab and subsequent CNS metastases (p = 0.02). However, in multivariate analysis, HER-2 status regardless of trastuzumab therapy was found to be the only independent predictive factor for CNS metastases (either as first or as subsequent recurrences; p &lt; 0.01). Conclusions: This is the first population-based registry study analyzing CNS metastases in breast cancer in relation to tumor biological features, systemic treatment, and clinical outcome. Based on our results, HER-2 status independently distinguishes pts with a higher risk of CNS metastases. It is however presumable that, in some cases, improvements in systemic control and overall survival associated with trastuzumab-based therapy lead to an “unmasking” of CNS relapse that would otherwise have remained clinically silent prior to a patient's death. No significant financial relationships to disclose.