PharmacologyTier 1Medical Sciences concept

Predictive biomarkers for targeted cancer therapy response (KRAS, BRAF, MSI)

Core concept

Prognostic = outcome regardless of treatment. Predictive = predicts benefit from a specific drug
- BRAF V600E in mCRC is both - poor prognosis and predicts anti-EGFR failure
Two mechanisms of prediction
- Target present - the drug needs its target (HER2, ER, EGFR fusion, PD-L1)
- Pathway bypass - a downstream activating mutation makes upstream blockade futile
EGFR -> RAS -> RAF -> MEK -> ERK
- Mutation downstream of the antibody = constitutive signalling = no benefit

Biomarker	Setting	Implication
RAS wild-type (KRAS + NRAS exons 2/3/4)	mCRC	Required for cetuximab/panitumumab benefit
RAS mutant (~45%)	mCRC	No anti-EGFR benefit at all, any tumour side
BRAF V600E (8-10%)	mCRC	Poor prognosis; encorafenib + cetuximab (+FOLFIRI)
MSI-high / dMMR (4-5% metastatic, ~15% early)	Any solid tumour	Pembrolizumab; predicts poor benefit from adjuvant 5-FU in stage II
HER2 amplified	Breast, gastric, CRC	Trastuzumab, pertuzumab, T-DXd
ER/PR	Breast	Endocrine therapy
PIK3CA mutant	ER+ breast	Alpelisib
EGFR / ALK / ROS1 / KRAS G12C	NSCLC	Osimertinib / alectinib / crizotinib / sotorasib
BRCA1/2, HRD	Ovarian, breast, prostate, pancreas	PARP inhibitors
NTRK fusion	Tumour-agnostic	Larotrectinib, entrectinib

Tumour sidedness is a modifier, not a substitute - left-sided RAS-wild-type gains most from anti-EGFR; right-sided wild-type gains substantially less
ER+/HER2- metastatic breast progressing on CDK4/6i -> everolimus + endocrine, or alpelisib if PIK3CA-mutant
MSI arises by MMR loss (MLH1, MSH2, MSH6, PMS2) - sporadic MLH1 promoter hypermethylation vs germline Lynch
- BRAF V600E or MLH1 methylation favours sporadic over Lynch

Test RAS, BRAF and MMR/MSI on every metastatic colorectal cancer before systemic therapy - the result changes the first-line regimen
Giving cetuximab to a RAS-mutant tumour is pure toxicity - acneiform rash, dec Mg, no benefit
dMMR immunohistochemistry doubles as Lynch syndrome screening -> germline testing, cascade family screening, colonoscopic surveillance
Liquid biopsy (ctDNA) detects acquired RAS mutations driving anti-EGFR resistance and supports rechallenge decisions
HER2 IHC 0 vs 1+/2+ now matters - HER2-low tumours respond to trastuzumab deruxtecan

Immunohistochemical markers in cancer pathology - Ki-67, HER2, hormone receptors
Monoclonal antibody target identification; antibody-drug conjugates
Immune checkpoint inhibitor mechanism - MSI-high as the predictive marker
Lynch syndrome and mismatch repair; hereditary cancer syndromes
Chemotherapy drug mechanisms by class

3 more sections, plus exam facts

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