Module 18: Personalised Cancer Medicine – Targeting Oncogenes

What is the core principle of Stratified (Personalised) Cancer Medicine?

Moving away from a 'one-size-fits-all' approach to one where treatment is tailored to the molecular profile of a patient's specific tumour.

How is Breast Cancer stratified based on receptor status?

ER+/PR+: Amenable to hormone therapies; HER-2+: Amenable to Herceptin; Triple Negative: Requires standard chemotherapy or experimental trials.

What is HER-2 (ErbB2) and why is it a target?

A tyrosine kinase receptor oncogene that, when overexpressed, causes excessive growth signalling and aggressive tumour behaviour.

How does Herceptin (Trastuzumab) exert its anti-tumour effect?

Binds to HER-2 to prevent dimerisation (blocking the growth signal).

Flags the cell for Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) by Natural Killer (NK) cells.

What are the two 'Companion Diagnostics' for HER-2 testing?

Immunohistochemistry (IHC): Measures protein expression on the cell surface (Score 0-3+).

FISH (Fluorescence In Situ Hybridisation): Detects the number of gene copies (Gold standard for "equivocal" IHC 2+ cases).

What is meant by the term 'Oncogene Addiction'?

The phenomenon is where a tumour depends on a single mutated pathway for survival, making it vulnerable to targeted therapy.

Why must you test for K-Ras mutations before using Cetuximab?

If K-Ras is mutated, the growth signal is 'stuck on', making EGFR blockade ineffective.

Which cancers are commonly treated with Cetuximab/Panitumumab?

Colorectal and Head & Neck cancers in patients with K-Ras wild-type tumours.

What is the BRAF V600E mutation, and where is it found?

A specific point mutation found in ~50% of Melanomas that drives the MAP-Kinase pathway.

What is Vemurafenib and how does it illustrate personalised medicine?

A targeted kinase inhibitor that specifically fits the mutated BRAF V600E protein.

What is the primary clinical challenge with targeted BRAF inhibitors?

Acquired Resistance, where tumours evolve bypass mutations leading to relapse.

How are oncogenic mutations detected using a 'PCR-panel' approach?

Panels test hundreds of potential mutations at predictable hotspots in a single assay.

What is the role of TaqMan qPCR in stratified medicine?

It allows for allele-specific detection of mutations among normal DNA strands.

Define a 'Dominant-Negative' mutation in the context of cancer medicine.

A mutation where a single mutated protein disrupts the function of a complex of normal proteins.

Why is 'triple-negative' breast cancer so difficult to treat?

it lacks the estrogen, progesterone, and HER2 receptors that standard targeted therapies. meaning doctors cannot use hormone-blocking drugs or HER2 inhibitors; as a result, treatment must rely on more aggressive chemotherapy or newer immunotherapies to combat its high rate of growth and early metastasis

What is the 'Pathway Integrity' rule in targeted therapy?

Targeted therapy only works if the entire signalling pathway downstream of the target is intact (wild-type). If a "downstream mediator" is mutated, the "upstream blocker" will fail to function.