Tumour heterogeneity

Define intra-tumour and inter-tumour heterogeneity ?

Intra-tumour: variation within a tumour

Inter-tumour: variation between tumours and/or patients

Why is cancer not considered a single disease?

Tumours arise from different tissues/cells of origin and are genetically and phenotypically heterogenous; treatments may not work across all tumours or all cells in one tumour

What clinical problems can tumour heterogeneity cause?

It makes response and prognosis difficult to predict and can contribute to treatment resistance

What is precision oncology ?

Improving treatment by stratifying patients - using genetic mapping and prognostic/ predictive biomarkers - into more homogenous drug-response groups

Distinguish prognostic from predictive biomarkers

Prognostic: informs likely clinical outcome irrespective of treatment. Predictive: identifies patients likely to respond to a specific treatment

What practical requirements does the lecture give for biomarkers ?

They should be easy to measure and have consequences for therapy (e.g. whether to treat)

What four receptor-status groups are used to subdivide breast cancer ?

ER+/HER2-

ER-/HER2+

ER+/HER2

Neither (triple negative)

Receptor status influences treatment response and prognosis

What defines triple negative breast cancer

TNBC

Low or absent oestrogen, HER2 and progesterone receptor

What does hormone receptor-positive (HR+) mean ?

High oestrogen and progesterone receptor expression

How does histopathology help stratify breast cancer ?

Cell and tissue morphology, including H&E staining, can distinguish histopathological subtypes

What are the classical breast cancer grades ?

GX: cannot assess

G1: well differentiated/ low grade

G2: moderately differentiated / intermediate

G3: poorly differentiated / high

G4: undifferentiated/ high

What are the limitations of classical histology for predicting outcome

Subtype and grade provide only approximate prognosis and do not accurately predict treatment response

What sources of infra-tumour heterogeneity are listed ?

Epithelium; tumour micro environment; storms; vasculature; stem/progenitor subpopulations; clonality and maturation burden

What classical clinical/histological factors are listed as markers ?

Type/grade; nodal status; lymph/vascular invasion; tumour size; age; ethnicity; smoking; drinking and obesity; comorbidity; hormone receptor status

How is ER/HER2 receptor status assessed ?

Immuno-histopathology: receptor-specific antibody staining of tissue sections

Which therapies are associated with ER-positive and HER2-positive breast cancer

ER- directed: tamoxifen, Faslodex/fulvestrant, aromatase inhibitors.

HER2-directed: Herceptin/trastuzumab

Chemotherapy is also indicated for receptor-negative disease

What is gene expression profiling (GEP) used for ?

It measures informative gene-expression patterns to subdivide breast cancer into molecular groups, broadly mapping onto original hormone-status cohorts

What caveat about GEP subtypes is noted ?

Luminal C is commonly included within luminal B and is not regarded as a separate GEP subtype

Did original GEP panels improve prediction of treatment response or survival ?

Yes, but only for ER+/HR+ patients and only marginally

What additional benefit did GEP provide ?

It identified subtype associated genes, including known oncogenes/tumour suppressors and genes with unknown roles, creating potential prescision-therapy targets

What are the key features of MammaPrint (70 gene microarray)

Prognostic for 10 year metastasis risk, high risk DFS 87%; FDA-approved for prognostic assessment of metastasis progression

What are they key features of Oncotype DX ?

21 gene qRT-PCR panel

What are the key features of PAM50

50 gene qRT-PCR panel

What does the breast cancer index (theros) measure ?

3-gene qRT-PCR panel

What are the advantage and limitations of biomarkers panels ?

Can reduce overtreatment and guide treatment selection; MammaPrint could have altered treatment for 34 % of patients

Limitations: clinic strategies complicate standardisation/interpretation and sample collection varies

What three P objectives of molecular genetics driven personalised medicine objectives

Prevention

Prediction

Participation

What can next generation sequencing reveal ?

Detects genomic variation, single nucleotide differences, clonality and heterogeneity

Combined with transcriptomics, stratified breast cancer into 10 subtypes, improved prognostic discrimination, and identified oncogenes dirvers and passenger mutations

What additional molecular subtypes are described in recent analysis ?

Six-triple negative subtypes

Two HER2-positive subtypes

5 ER- positive subtypes

What emerging role of AI-based histopathology is mentioned ?

AI analysis of H&E stained slides is being studied to determine ER, PR and HER2 status, including multi-site validation