Refinement of Breast Cancer Classification by Molecular Characterization of Histological Special Typ

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Refinement of Breast Cancer Classification by
Molecular Characterization of Histological
Special Types

• Angel A. Rodriguez, MD
• Baylor College of Medicine
• Journal Club, 11/4/08

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Outline

• Background on different special types of invasive
  breast cancer
• Materials and Methods
• Results
• Future Directions

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Acute myeloid leukemias

• FAB Classification
• M0 minimally differentiated
• M1 myeloblastic leukemia without maturation
• M2 myeloblastic leukemia with maturation
• M3 hypergranular promyelocytic leukemia
• M4 myelomonocytic leukemia
• M4Eo variant, increase in marrow eosinophils
• M5 monocytic leukemia
• M6 erythroleukemia (DiGuglielmo's disease)
• M7 megakaryoblastic leukemia

• WHO Classification
• AML with recurrent cytogenetic translocations
• AML with t(821)(q22q22)
• AML1/CBFalpha/ETO
• Acute promyelocytic leukemiaAML with
  t(1517)(q22q12) and variants PML/RARalpha
• AML with abnormal bone marrow eosinophils
  inv(16)(p13q22) vagy t(1616)(p13q22)
  CBFbeta/MYH1
• AML with 11q23 MLL abnormalities
• AML with multilineage dysplasia
• With prior MDS
• Without prior MDS
• AML with myelodysplastic syndrome, therapy
  related
• Alkylating agent related
• Epipodophyllotoxin related
• Other types
• AML not otherwise categorized

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Special Type
Non-Special Type
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Infiltrating Lobular Carcinoma

• 5-15 of all BCs
• 70-90 ER, HER2-
• HRT
• Less microcalcifications on mammography
• Palpable mass
• Single file linear cords
• E-cadherin negative
• Pleomorphic HER2 , worse prognosis

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Tubular Carcinoma

• lt2 of all BCs, older
• ER, HER2-
• Small size, no LN involvement
• Detectable on mammogram, spiculated
• Open tubules with single layer of epithelial
  cells
• Very good prognosis

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Mucinous A and B

• 2 of all BCs, older
• Palpable lump
• ER
• Small uniform round cells floating in mucus
• A Hypocellular,
• B Hypercellular
• Favorable prognosis

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Diab, S. G. et al. J Clin Oncol 171442 1999
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Diab, S. G. et al. J Clin Oncol 171442 1999
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Medullary Carcinoma

• 1-7 of all BCs, younger
• Well circumscribed on mammogram, soft on
  palpation,
• Triple negative
• Sheets of poorly differentiated cells,
• Scant stroma, no glandular structures
• Prominent lymphocytic infiltrate, pushing margins
• Better prognosis than IDC
• Large overlap withBRCA1

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Neuroendocrine

• 2-5
• Form alveolar structures or solid sheets of cells
  producing peripheral palisading
• Chromogranin A and B, synaptophysin, NSE, TTF-1,
• Grade determines prognosis

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Micropapillary

• lt2
• Hollow aggregates of malignant cells
• Appear like tubules with obliterated lumens
• Vascular invasion and LN positivity
• Unknown prognosis

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IDC with Osteoclastic Giant Cells

• ER-, PR-
• Associated with all other histologic types
• Osteoclastic giant cells, histiocytic
• 5 yr OS 70

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Apocrine

• 0.3 4
• Presence of apocrine cells in gt90 of tumor cells
• GCDFP-15
• Prognosis same as IDC

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Metaplastic

• lt1
• Admixture of adenocarcinoma with dominant areas
  of spindle cell, squamous, mesenchymal
  differentiation
• Chemoresistant

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Adenoid Cystic

• 1/1000 BCs
• Similar to salivary, lung, and cervix
• Low grade malignant tumor
• Typically cured by mastectomy,
• Hematogenous spread

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Materials and Methods

• 113 specimens
• 45 additional IDC NOS
• 11 different special type
• Frozen tissue bank of NKI/AVL
• H E
• Tumor cellularity ranged from 60 to 95
• RNA Isolation
• Independent review by three pathologist

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Tissue Microarrays

• 600 µm tissue cores from paraffin-embedded,
  deparaffinixed in xylene, hydrated in alcohol,
  then stained and scored
• Kruskal-Wallis test, testing equality of
  population medians among groups

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RNA Isolation and microarray expression profiling

• RNA quality assessed, OD 260/280 ratio gt1.95 were
  included
• Oligo microarrays 34,580 probe sets representing
  24,650 genes.
• Agilent DNA microarray scanner

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Oncotype Recurrence Score
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Results
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Results
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Unsupervised hierarchical clustering

• Selection of genes that were significantly
  regulated (plt0.01) in at least 14 of the 113
  samples with missing data in lt 4 samples,
  resulting in a set of 8,513 genes.
• Cluster 3.0 software was used for clustering,
  centred Pearson correlation as the similarity
  metric and complete linkage clustering

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Classification

• Molecular subtype classification
• Intrinsic/UNC gene list, 1098/1300 unique genes
  identified
• 70-gene prognosis profile
• 60 genes identified
• Good vs Poor
• 21-gene recurrence score
• Low, Intermediate, High

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Molecular Subtypes of Special Types
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Adenoid cysticDownregulation of migration,
proliferation, and immune response
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Antigen Presenting Pathway
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Mucinous B
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Neuroendocrine
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Clinical Scenarios

• 54 year old woman with Rt Br Ca, Tubular, ER,
  PR, HER2-, 1.5 cm, Gr 1, Ki67lt10, 1/10
  LN(1mm), Luminal A, RS is High and/or poor risk
  by 70-gene Prognosis Profile.
• 63 year old woman with Lt Br Ca, Metaplastic,
  ER-, PR-, HER2-, 0.7 cm, LN- Basal-like, 70-gene
  PP is Good Risk.

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Clinical Scenarios

• 57 year old woman with Lt Br Ca, Metaplastic,
  ER-, PR-, HER2-, 1.4 cm, Gr 3, Ki67 50, LN-,
  Basal-like, 70-gene PP is Good Risk.
• 63 year old woman with Lt Br Ca, Adenoid cystic,
  ER-, PR-, HER2-, 0.7 cm, LN- Basal-like, 70-gene
  PP is Poor Risk.

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MINDACT
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Conclusion

• ILC and IDC are heterogeneous tumors
• Special types are less heterogeneous
• Some special types are are specific entities
• Micropapillary
• Is molecular apocrine a better clinical
  classification?
• Sensitive to AR inhibition
• Histological subtypes do not constitute distinct
  entities ???
• neuroendocrine differentiation, mucinous A,
  mucinous B are all luminal.
• Basal-like tumors are a heterogeneous group of
  tumors
• Adenoid cystic, medullary, metaplastic
• Can modern molecular tests be used to guide to
  treatment of special types of breast cancer?
• No information regarding special (pure
  tubular, lobular, mucinous, papillary)

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Future Directions

• It is critical to develop new approaches to
  identify subgroups of patients with basal-like
  breast cancer that have a good prognosis or a
  high likelihood of response to chemotherapy.
• Deeper insight into the molecular heterogeneity
  of basal-like cancers may contribute to the
  identification of novel therapeutic agents for
  this molecular tumor type.

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Future Direction

• Should the WHO criteria be reduced to a smaller
  set based on their molecular profiles?