Breast Cancers With Brain Metastases are More Likely to be Estrogen Receptor Negative, Express the Basal Cytokeratin CK5/6, and Overexpress HER2 or EGFR

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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, MD
• American Journal of Surgical Pathology
• Volume 30, Number 9, September 2006
• Intern ???

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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 gt5 of tumor nuclei immunoreactive
• HER2, CK5/6?23 , EGFR?13
• X2 analysis (Plt0.05)

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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 (T1lt2, T225, T3gt5 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 ? 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

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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 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.

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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
  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

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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 pts ?detection of occult meta earlier
  ?amenable to treatment.
• Development of prophylactic treatment regimens
  and novel targeted therapeutic strategies.

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