1. Breast Cancers With Brain Metastases are More Likely to be Estrogen Receptor Negative, Express the Basal Cytokeratin CK5/6, and Overexpress HER2 or EGFR David G. Hicks, MD American Journal of Surgical Pathology Volume 30, Number 9, September 2006 Intern 楊兆傑

2. Introduction Breast cancer metastasis to the lungs, CNS, liver, skeletal system are significant. The metastatic cascade is complex. In 1889, Stephen Paget : “Seed and Soil Hypothesis“. Breast cancer metastatic to brain is associated with significant morbidity and poor survival.

3. Breast cancer present at a young age, ER negative, prior pulmonary metastases, seem to be at increased risk. Over expression of the HER2 with more aggressive clinical course seems to be associated with a higher incidence of BM. Diagnosis of breast cancer → High risk of CNS metastases ? Cohort study for clinical-pathologic features and predictive markers that might help to identify this high-risk subgroup.

4. Materials and methods 55 breast cancer patients who had received radiation therapy for CNS metastasis at the Cleveland Clinic Foundation. 254 patients who remained free of metastases for an average of 67 months and 40 patients who developed a mixture of visceral and bone metastatic disease without CNS metastasis.

5. Antibodies used for immunohistochemistry. Peroxidase-conjugated secondary antibody/3,3V-diaminobenzidine chromogen step. ER+ >5% of tumor nuclei immunoreactive HER2, CK5/6→2~3+, EGFR→1~3+ X 2 analysis (P<0.05)

6. Results

7. Less than 50 years old. ER negative. ER(+) cells for the BM group was lower.

8. High-grade tumors (Bloom Richardson) Axillary lymph node metastases Larger tumors (T 1 5 cm)

9. Photomicrographs examples of CK5/6(A), EGFR(B), HER2(C) in tumor samples from patient who developed CNS recurrence. Examples of 3+ staining

10. Express EGFR Express CK5/6 Her2 over expression

11. Discussion Risk for developing CNS recurrence → express the CK5/6, overexpress HER2 or EGFR. Younger, high-graded, ER negative 4 major classes –HER 2 + –HER 2 - HR+ –Basal-like HER2- HR- CK5/6+ EGFR+

12. Basal-like subtype breast cancer: lack of ER expression, low expression of HER 2, and strong expression of the basal cytokeratins (CK5, CK6, CK17) Aggressive, poor prognosis Nielsen et al, EGFR expression in 54% of basal CK+ and associated with poor survival independent of nodal status and tumor size. More likely to demonstrate CNS meta. EGFR expression←→basal like phenotype.

13. BRCA1 breast CA, basal-like phenotype. 67% of BRCA1 mutation developed BM, 0% of BRCA2, 10% of noncarriers. Tumors with basal-like phenotype → risk for BM. BRCA1 might benefit from screening to detect occult metastastic disease.

14. HER2, a member of the EGFR superfamily HER2+ → proliferation, survival, apoptosis resistance, invasion, migration Trastuzumab, a monolclonal Ab to HER2 Bendell et al, 34% of 122 pts BM, 23m Clayton et al, 25% of 93 pts BM, 10.8m Miller et al, MRI screened 155 pts with met →15% occult BM (HER2+) 1. HER-2 over expression → meta aggressiveness 2. patient survival↑ → BM develop 3. Transtuzumab poor penetrate BBB

15. Conclusions HER 2-positive, basal-like classes have ↑risk for CNS metastases. It seems likely: screening programs for such high-risk p’ts →detection of occult meta earlier →amenable to treatment. Development of prophylactic treatment regimens and novel targeted therapeutic strategies.

16. Thanks for your attention !