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

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.

• 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.

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.

• 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)

Results

• Less than 50 years old.

• ER negative.• ER(+) cells for the BM

group was lower.

• High-grade tumors (Bloom Richardson)• Axillary lymph node metastases

• Larger tumors (T1<2, T2:2~5, T3>5 cm)

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

• Examples of 3+ staining

• Express EGFR• Express CK5/6• Her2 over expression

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+

• 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.

• 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.

• 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

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.

Thanks for your attention !