Editing Breast cancer (section)

== '''Pathophysiological features''' ==

=== Molecular markers ===

** ER background
*** Positive in about 80% of breast cancers
*** Ligand-dependent transcription factor, member of the steroid hormone receptor superfamily. When oestrogen binds, promoter regions of DNA are triggered. Has two subunits - ER-alpha and ER-beta
**** See 'reproductive physiology' under 'O+G' for background on oestrogens
*** Clinical ER assays measure ER-alpha, and quantitate using immunohistochemistry, and level of expression predicts response to endocrine therapy - 70% of ER+/PR+ cancers respond
*** Graded on intensity of scoring (0 to 3+) and proportion of staining (percentage)
**** >1% staining is considered positive
**** 1-10% is low positive
**** Allred Score out of 8 combines intensity and positivity
*****[[File:Allred-score-guidelines-for-ER-and-PR-evaluation.png|none|Allred score for ER and PR evaluation|thumb|441x441px]]
*** 65% of ER+ cancers are also PR+
*** Some ER-/PR+ cancers also respond to endocrine therapy, but this is a rare combination
** HER2
*** Tyrosine kinase receptor which functions as a protooncogene when amplified
**** Based on ERBB2 gene, chromosome 17
**** External to internal signalling, influencing growth and differentiation via PI3K, MAPK, JAK/STAT pathways
**** Doesn't bind to ligands, but is activated when it dimerizes with itself or other EGFR family members
*** Associated with high-grade cancers with axillary involvement, and decreased ER/PR expression. HER2 overexpression is also a poor prognostic factor on its own.
*** Amplified '''(rather than mutated)''' in about 13% of breast cancers
*** Scored on a scale of 0 to 3+
**** 0 or 1+ is considered negative
**** 2+ is equivocal - send for ISH
**** 3+ is positive (>30% of cells)
*** Inhibiting the function of the HER-2 receptor slows the growth of HER-2 positive tumours

=== Molecular profiling - breast cancers can be broken down into four different groups depending on the 'molecular portrait' ===

** Note that the molecular profile is independent of histological subtype (e.g. ductal vs lobular)

** Oestrogen receptor (ER)
*** '''Luminal A''' (40%)
**** ER+, PR+, HER2-; Ki67 <14%
**** Low-grade and good prognosis
**** 'Luminal' refers to the similar molecular profile to luminal epithelium of normal breast tissue
**** This type has best response rate to endocrine therapy
**** PR positivity predicts response to endocrine therapy regardless of ER positivity
**** Doesn't typically respond well to chemotherapy
*** '''Luminal B''' (20%)
**** ER+, PR+/-, HER2+/-; Ki67 >14%
**** Worse prognosis than luminal A
**** Has a lower response to endocrine therapy than luminal A but higher response to chemotherapy
** '''HER-2 enriched''' (10%)
*** ER-, PR-, HER2+
*** Characterised by high expression of HER2 and proliferation gene clusters and low expression of luminal clusters
*** Some are ER+ but not that common
*** Often node-positive
*** P53 mutations
** '''Basal-like''' (15%)
*** ER-, PR-, HER2-
*** Gene cluster profile similar to basal epithelial cells, characterised by low expression of the luminal and HER2 gene clusters - typically triple negative, but about 20% are not.
*** Not the same as triple-negative, although there is a lot of overlap between the two categories
*** Most aggressive breast cancer, accounts for about 10-20% of cases.
*** More frequently affects younger patients <40 years.
*** Tumours tend to be larger, palpable, higher grade
*** Distant mets often occur at visceral sites and are seen within the first 3 years after diagnosis
*** 20% of triple negative cancers are BRCA1 positive, and 10% of basal-like tumours overall are BRCA1 positive

=== Genetic expression profile analysis ===

** Oncotype DX is the most well-validated score: 21 genes analysed and used to produce a Recurrence Score (RS) between 0 and 100 for '''ER+, HER2-, node negative''' cancers
*** 0-17 low risk: hormone therapy alone is likely sufficient
*** 18-30 intermediate risk - consider offering chemotherapy in addition to endocrine therapy, especially in younger patients
*** >30 high risk: chemotherapy followed by endocrine therapy

=== Prognostic factors ===

** Grade (Elston-Ellis system a.k.a. Nottingham Histologic System, which is a modification of the Scarff-Bloom-Richardson grading system)
*** Determined by percentage of tubule formation/cell differentiation, nuclear pleomorphism and mitotic activity - 'TNM' (tubules, nuclear, mitoses)
*** Each scored out of 3, then a total score out of 9
*** Well-differentiated (grade 1)
*** Moderately-differentiated (grade 2)
*** Poorly-differentiated (grade 3)
** LVI - independent risk factor
** Ki-67 - independent
** Hormone receptors
*** ER/PR+ is associated with improved outcomes
*** HER2 is unfavourable

* Metastases

** Can metastasise by both lymphatic and haematogenous routes
** Can affect any organ, but liver, lungs and bone are the commonest
** Luminal A tends to be bone-only, while HER2+ or triple negative tends to be visceral
** Lobular can go anywhere, but especially peritoneal or pleural

=== Synoptic report ===

** Macroscopic
*** Number of specimens
*** Intra-op consultation
*** Method of localisation
*** Type and laterality
*** Orientation
*** Size - medial-lateral, anterior-posterior, superior-inferior
*** Weight
*** Multiple macroscopically visible tumours?
*** Nature of tumour
*** Tumour size
*** Macroscopic margins
*** Skin
*** Muscle
** Microscopic
*** Multiple tumours?
*** Maximum invasive tumour size
*** Histologic grade
**** Tubules
**** Nuclear grade
**** Mitotic rate
*** Invasive carcinoma subtype
*** LVI
*** Skin involvement
*** Treatment effect
*** DCIS
*** Microcalcification
*** Paget disease
*** Margin involvement by invasive cancer or DCIS?
*** Distance from closest margin
*** Lobular neoplasm
*** Associated breast changes
** Sentinel nodes
*** Total number
*** Macro-metastases
*** Micrometastases
*** Isolated tumour cells
*** Extra-nodal spread
*** Treatment effect
** Ancillary tests
*** HR
*** PR
*** HER2