1. 2-6-20151 Analysis of risk factors predicting time to development of brain metastases presented at the 44 th Annual ASCO Meeting, June 2 2008, McCormick Place Chicago, Abstract #1076 Michael Knauer 1, Andrea Rottenfusser 2, Rupert Bartsch 3, Karin Dieckmann 2, Catharina Wenzel 3, Sabine Fromm 2, Helmut Eiter 4, Guenther G Steger 3, Christoph C Zielinski 3, and Alexander de Vries 4 1 Department of Surgery, Academic Teaching Hospital Feldkirch, 2 Department of Radiotherapy, Medical University of Vienna, 3 First Department of Medicine and Cancer Centre, Clinical Division of Oncology, Medical University of Vienna, 4 Department of Radiotherapy, Academic Teaching Hospital Feldkirch, Austria

2. 2-6-20152 Abstract Background: Different groups reported an increased incidence of brain metastases (BM) in patients (pts) with Her2-positive breast cancer (BC). Usually, this is attributed to prolonged survival due to trastuzumab (T), in association with the inability of antibodies to pass the blood-brain-barrier. Furthermore, based on preclinical data, it was suggested that Her2- positive BC had an increased affinity to brain tissue. We investigated factors potentially associated with shorter time to development of BM. Patients and Methods: 194 pts with BM from BC were identified at two Austrian centres. All received whole brain radiotherapy (WBRT) of 30 Gy. Data concerning epidemiology, histology, and outcome, is available. A multivariate analysis (Cox regression) was performed to identify factors significantly associated with early development of BM. Results: Median age was 55 years, and time to development of BM was 29 months (m), range 2 – 254 m, 95% CI 22.97- 35.03. Overall survival following WBRT was 7 m. The following factors predicted shorter time to development of BM: negative endocrine receptor status (p=0.026), Her2-positive disease (p=0.003), stage IV disease at first presentation (p<0.001), and lung metastases (p=0.043). Discussion: Risk factors associated with increased incidence of BM have already been described. Our data show that Her2– positive BC is significantly associated with early development of BM, while no influence of T was observed. These results underline preclinical data suggesting a higher affinity of Her2-positive BC to the brain. T, on the other hand, had no prophylactic effect. Therefore, trials evaluating the combination of T with substances able to penetrate into the brain are warranted.

3. 2-6-20153 Background Since the introduction of trastuzumab in the nineties, different centres reported an increase incidence of brain metastases (BM) in patients with Her2-positive breast cancer (BC)1,2 While risk factors associated with development of brain metastases are well defined, little is known about patients at high risk for early development of brain disease

4. 2-6-20154 Her2 and brain metastasis The increased incidence of brain metastases in Her2 positive tumours is usually attributed to trastuzumab, as the introduction of this compound lead to prolonged survival, in association with the inability of antibodies to pass an intact blood-brain-barrier As Her2 may also cause increased tumour angiogenesis via induction of HIF1α, it was recently suggested that the Her2-positive BC phenotype had a higher affinity to brain tissue

5. 2-6-20155 Patients and Methods A total number of 194 patients treated for BM from breast cancer were identified at two Austrian centres All had received whole brain radiotherapy (WBRT) of 30 Gy with or without boost irradiation or surgical resection A multivariate analysis (Cox regression model) was performed to identify factors associated with shorter time to development of brain metastases The following variables were included: age at primary diagnosis of BC (≤ 35 years vs. > 35 years), grading (grade 1, 2 vs. grade 3), ER/PgR-status (positive vs. negative), Her2-status, tumour stage at diagnosis (localized vs. stage IV), lung metastases, liver metastases, trastuzumab (T) before diagnosis of BM

6. 2-6-20156 Patient characteristics CentresMedical University of Vienna General Hospital Feldkirch Number194 patients from 2004 until 2007 Age at diagnosis of BMmedian 55 years range 28 - 81 years Pts ≤ 35 years at diagnosis13 pts Histological subtypeductal 114 pts lobular 80 pts Grading G1/2 70 pts G3 98 pts ER/PgR positive 58 pts / 38 pts Her2-positive53 pts Primary metastatic disease33 pts Lung / Liver metastases72 pts / 72 pts

7. 2-6-20157 Results Median age at WBRT was 55 years, range 28 – 81 years 81 pts received further local therapy (boost irradiation or neurosurgical resection) Time to development of BM was 29 months, range 2 – 254 months, 95% CI 22.97-35.03 Overall survival following WBRT was 7 months, range 1 – 83 months, 95% CI 5.08-8.92

8. 2-6-20158 Survival after development of BM

9. 2-6-20159 Multivariate analysis Age at primary diagnosis of BCn.s. Grading n.s. ER/PgR-status p=0.026 Her2-status p=0.003 Tumour stage at diagnosis p<0.001 Lung metastasesp=0.043 Liver metastases n.s. Trastuzmab before diagnosis of BMn.s.

10. 2-6-201510 Discussion and Summary Her2–positive BC is significantly associated with shorter time to development of BM No influence of trastuzumab was observed Therefore, trials evaluating the combination of trastuzumab with substances able to penetrate into the brain are warranted

11. 2-6-201511 References (1) Bendell JC, Domchek SM, Burstein HJ et al (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97(12):2972–2977 (2) Clayton AJ, Danson S, Jolly S et al (2004) Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 91(4):639–643