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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, MDAmerican Journal of Surgical Pathology Volume 30, Number 9, September 2006
Intern 楊兆傑
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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.
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• 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.
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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.
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• 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+
• X2 analysis (P<0.05)
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Results
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• Less than 50 years old.
• ER negative.• ER(+) cells for the BM
group was lower.
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• High-grade tumors (Bloom Richardson)• Axillary lymph node metastases
• Larger tumors (T1<2, T2:2~5, T3>5 cm)
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• Photomicrographs examples of CK5/6(A), EGFR(B), HER2(C) in tumor samples from patient who developed CNS recurrence.
• Examples of 3+ staining
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• Express EGFR• Express CK5/6• Her2 over expression
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Discussion• Risk for developing CNS recurrence → exp
ress the CK5/6, overexpress HER2 or EGFR.• Younger, high-graded, ER negative• 4 major classes
– HER 2 +– HER 2 - HR+– HER 2 - HR+– Basal-like HER2- HR- CK5/6+ EGFR+
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• 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 b
asal CK+ and associated with poor survival independent of nodal status and tumor size.
• More likely to demonstrate CNS meta.• EGFR expression←→basal like phenotype.
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• 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.
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• HER2, a member of the EGFR superfamily• HER2+ → proliferation, survival, apoptosis resist
ance, 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
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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.
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Thanks for your attention !