Companion Diagnostics
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Direct answer
A companion diagnostic is a laboratory test whose result is required before a specific drug can be prescribed — trastuzumab only after proven HER2 positivity, crizotinib or alectinib only after a demonstrated ALK rearrangement — in contrast to complementary diagnostics, which inform without mandating. The pathologist therefore sits at the gateway of targeted therapy: immunohistochemistry scores HER2 as 0, 1+, 2+ or 3+, reflexing equivocal results to in-situ hybridisation; ALK testing proceeds by fluorescence in-situ hybridisation, immunohistochemistry or sequencing; and mismatch-repair immunohistochemistry opens the door to programmed death-1 immunotherapy in microsatellite-instability-high tumours regardless of organ. The list of drug-test pairs — HER2-trastuzumab, EGFR-gefitinib or osimertinib, ALK-alectinib, ROS1, BRAF V600E-vemurafenib, KRAS G12C-sotorasib — is the highest-yield table in modern surgical-pathology examination.
What you must remember
- Definition discipline: companion (test mandatory for the drug) versus complementary (test guides, drug usable without it) — the distinction examiners probe first.
- Breast pair: HER2 by immunohistochemistry with 2+ reflexed to in-situ hybridisation; 3+ or amplified opens trastuzumab, pertuzumab and trastuzumab emtansine — the same rule applies in advanced gastric and gastro-oesophageal junction cancer.
- Lung pairs: EGFR sensitising mutations (exon 19 deletion, L858R) for gefitinib, erlotinib and osimertinib; ALK rearrangements for alectinib and crizotinib; ROS1 rearrangements for entrectinib and crizotinib.
- Melanoma and hairy-cell pair: BRAF V600E for vemurafenib and dabrafenib-trametinib in melanoma; the same mutation is present in the great majority of classic hairy cell leukaemia.
- Tumour-agnostic approval: microsatellite-instability-high or mismatch-repair-deficient tumours qualify for pembrolizumab whatever the organ — the paradigm-shifting approval.
- KRAS arc: long the negative predictor (anti-EGFR antibodies in colorectal cancer only for extended RAS wild-type), now a positive target with sotorasib and adagrasib for G12C mutants.
- Regulatory frame: companion diagnostics are approved devices linked to drug labels — in India, CDSCO-regulated kits aligned to the prescribing information of the paired drug.
Sequencing a lung adenocarcinoma workup
A 58-year-old never-smoker has a lung adenocarcinoma biopsy. The pathologist first conserves tissue, spending it on a minimal diagnostic panel of immunohistochemistry and molecular studies, because every millimetre counts. Broad-panel sequencing reports an EGFR exon 19 deletion; the oncologist starts osimertinib without any need for ALK or ROS1 testing, since these drivers are mutually exclusive in practice. Had the panel been negative, ALK fluorescence in-situ hybridisation or immunohistochemistry would follow, then ROS1, then PD-L1 tumour proportion scoring for immunotherapy planning. The choreography exists because each drug-test gate is absolute: giving trastuzumab to a HER2-negative breast cancer or alectinib to an ALK-negative lung cancer is both futile and a regulatory breach. Pathology, in this workflow, is no longer downstream of oncology — it is the prescription's trigger.
Where candidates slip
The KRAS story trips most: candidates memorise "KRAS mutation predicts no benefit from cetuximab or panitumumab in colorectal cancer" (correct, extended RAS testing now standard) and then wrongly assume KRAS has no targeted therapy — G12C inhibitors ended that era. The second slip is HER2 2+ read as positive; only 3+ immunohistochemistry or in-situ hybridisation amplification justifies anti-HER2 therapy, and pre-analytical fixation (six to 72 hours in formalin) is part of the validity chain. Third, PD-L1 is called a companion diagnostic universally; in many settings it is complementary, scoring informs rather than mandates, unlike HER2 or ALK. Finally, mismatch-repair immunohistochemistry (MLH1, MSH2, MSH6, PMS2) serves double duty — Lynch screening and immunotherapy qualification — and losing either end of that duality costs marks.
Frequently asked questions
What defines a companion diagnostic?
A test whose result is prerequisite for prescribing its paired drug — for example, HER2 amplification for trastuzumab — unlike a complementary diagnostic, which guides without mandating.
What follows a HER2 immunohistochemistry score of 2+?
Reflex in-situ hybridisation for amplification; only amplification (or a 3+ score) qualifies the patient for anti-HER2 therapy.
Which tumour-agnostic approval changed targeted therapy?
Pembrolizumab for microsatellite-instability-high or mismatch-repair-deficient solid tumours, the first approval based on a biomarker rather than an organ of origin.
Why is extended RAS testing done in colorectal carcinoma?
RAS-mutant tumours derive no benefit from cetuximab or panitumumab, so extended KRAS and NRAS testing protects patients from futile antibody therapy.
Which method detects an ALK rearrangement?
Break-apart fluorescence in-situ hybridisation is the reference standard, with validated ALK immunohistochemistry an accepted screening or confirmatory approach.
Which mutation links melanoma therapy and hairy cell leukaemia?
BRAF V600E — targetable with vemurafenib or dabrafenib in melanoma and present in the great majority of classic hairy cell leukaemia.