CNS Metastases in Breast Cancer

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1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer CNS Metastases in Breast Cancer

2 CNS Metastases in Breast Cancer Version 2006: Maass / Junkermann Version : Bischoff / Diel / Lück Version 2010: Nitz / Jonat

3 CNS Metastases in Breast Cancer Incidence Breast cancer is the 2 nd most common cause of CNS metastases Increasing incidence, (under)estimated to be up to 40% At Autopsy: Parenchymal CNS metastases ~30 40% Leptomeningeal CNS metastases ~5 16% Increasing incidence due to More effective (combined modality- trastuzumab) treatment of extracerebral sites with improved prognosis Increasing use of MRI in diagnostic evaluation

4 CNS Metastases in Breast Cancer Risk Factors Young age (<50 y vs 50 y ) Negative estrogen receptor status G3 HER1 and HER2 overexpression Basal-like cell type / triple negative Prior trastuzumab therapy Breast Cancers With Brain Metastases are More Likely to be Estrogen Receptor Negative, Express the Basal Cytokeratin CK5/6, and Overexpress HER2 or EGFR

5 CNS Metastases Prognostic Factors Brain metastases = unfavourable prognostic factor (1 st year: ~12 %, 2 nd year: ~4-8 %, 5 th year: ~2% survivors) LoE 2a Favourable prognostic factors in the presence of brain metastases: Extent of CNS metastases: - Solitary (1 2) vs. multiple ( 3): HR : 1.33 LoE 2a Extent of extracerebral metastases: - None vs. little vs. extensive: HR : 1 vs vs LoE 2a Age: - <60 vs vs. >70 y.: HR : 1 vs vs. 1.40; not significant LoE 2a Performance status (ECOG): - 0 vs. 1 vs. 2 vs. 3: HR: 1 vs vs LoE 2a Interval between primary diagnosis and CNS metastases: - <2 y vs. >2 ys. HR 1 vs LoE 2a Response to treatment: - RT vs. Op +/- RT: HR 0.38 vs LoE 2a Positive endocrine receptor status (rare) LoE 2a LDH: - High vs low LoE 2b HR = Hazard ratio

6 Classification of Brain Metastasis by Recursive Partitioning Analysis (RPA) Med. Survival (mo) RPA I: KPS > 70 11,6 < 65 yrs. no extracerebral mets controlled primary tumor RPA II: all other patients 6,0 RPA III: KPS < 70 3,0

7 Independent Prognostic Factors in BM Multivariate analyses of significant factors associated with survival by Cox regression VARIABLE P HR (95%-confidence interval) SURGICAL RES < SINGLE METASTASES KPS >= BS-BM RPA < CONTR PRIM TU NO EXCRANIAL MET < Viani GA et al. BMC Cancer 2007, 7:53

8 Single Brain Metastases Multimodality Therapy Oxford / AGO LOE / GR Neurosurgery +/- whole brain radiotherapy (WBRT)*: Improved local control rate and survival 2b B ++ Neurosurgery 2a B + SRS (lesions < 3 cm ø) +/- WBRT * 2b B ++ advantage: single shot technique Stereotactic radiosurgery (SRS) <3 cm ø 2a B + * Poor prognosis: additional WBRT not recommended

9 Brain Metastases (1 4 lesions) Radiotherapy Oxford / AGO LoE / GR WBRT + StRadSurg boost (vs. WBRT) 2a B ++ Improved local control rate and survival WBRT 2b B + SRS (lesions < 3 cm ø) +/- WBRT* 2b B ++ advantage: single shot technique Stereotactic fractionated RT (SFRT) 3b B +/- * Poor prognosis: additional WBRT not recommended

10 Multiple Brain Metastases Oxford / AGO LoE / GR WBRT (add corticosteroids*) 1a A ++ Prolonged RT 3b B x 3 Gy 2b B + Radiochemotherapy 3b C +/- Chemotherapy alone 3a D - Corticosteroids alone 3a B +/- In case of radioresistance: Chemotherapy alone 3a D +/- Lapatinib +/- Capecitabine (HER2 pos. disease) 2b B +/- *Symptom adjusted therapy

11 Treatment Approach for Brain Metastases in Breast Cancer Progression Progression New bulky lesions

12 Leptomeningeal Carcinomatosis Local Therapy Intrathecal or ventricular therapy Oxford / AGO LoE / GR MTX mg 2 3x/ week (+/- folinic acid rescue) 2b B ++ Liposomal cytarabine 50 mg, q 2w 3b C ++ Thiothepa 3b C + Steroids 4 D +/- Trastuzumab 4 C - Radiotherapy Focal (bulky disease) 4 D + WBRT 4 D + Neuraxis (disseminated spinal lesions ) 4 D -

13 Randomized Controlled Trial- Depocyt vs MTX I.T. In Pts With Neoplastic Menigitis Investigational drug: sustained release formulation of cytarabine (DepoCyt ) maintenance in lumbar and ventricular fluid for > 14 days (regardless of the site of drug administration) Schedule: DepoCyt 50 mg, q 2w MTX 10 mg biweekly (induction phase of 1 month, followed by 3months of consolidation therapy). Glantz et al., Clin. Cancer Res. `99

14 DepoCyt vs. MTX: Intent-to-treat-analysis End point DepoCyt (n=31) Breast cancer: n=11 MTX (n=30) Breast cancer: n=11 p-value ORR 26% 20% 0.76 OS (days) Survivors (6 months) Survivors (12 months) % 17% % 7% 0.43 Glantz et al., Clin. Cancer Res. `99