Transcript Breast Cancers With Brain Metastases are More Likely to be

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
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 → express 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
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.
• 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
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
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 !