A sequencing-based index settles clonality between paired GI tumours

Design

Retrospective diagnostic accuracy study with validation cohort

Population

120 paired GI, HPB and peritoneal tumours from 60 patients

Primary outcome

Discrimination of clonal from non-clonal pairs

Effect

AUROC 0.986 (0.962 to 1.0); sensitivity 96.2%, specificity 100% vs 71.2% and 62.5% for morphology

This study tested a clonal-relatedness index (CRI) — shared alterations divided by the average total alterations — on next-generation sequencing data from 120 paired gastrointestinal, hepatopancreaticobiliary and peritoneal tumours in 60 patients, 52 pairs known clonal and 8 non-clonal.

Median CRI was 0.85 in clonal and 0.24 in non-clonal pairs. It discriminated with AUROC 0.986 (95% CI 0.962 to 1.0), with an optimal cut-off of 0.53. CRI had sensitivity 96.2%, specificity 100% and positive predictive value 100%, against 71.2%, 62.5% and 92.5% for morphology and immunohistochemistry. In hypermutated tumours morphology fell to 42.9% sensitivity, while CRI held 85.7% sensitivity and 100% specificity. Performance held in a validation cohort.

The question — metastasis or second primary — directly changes staging and treatment. Many patients already have panel sequencing on both tumours, so the index can often be calculated from existing reports. The non-clonal group was small (8 pairs), so specificity is less certain than it looks.

• When both tumours have been sequenced, calculate shared over average total alterations; a value above about 0.5 favours clonal relatedness.
• Use sequencing rather than morphology alone when the tumours are hypermutated or mismatch-repair deficient.
• Report the basis for any metastasis-versus-second-primary opinion so oncologists can weigh it.
• Treat the 0.53 cut-off as provisional; only eight non-clonal pairs informed it.

Why it matters

Morphology misjudged clonality most often in exactly the hypermutated tumours where it matters.

Don't overread it

Only eight non-clonal pairs; the 100% specificity rests on few cases.

The statistics, in plain English

An AUROC of 0.986 means the index almost always ranked a clonal pair above a non-clonal one. Perfect specificity from eight non-clonal pairs could easily be lower in a larger series.

Read the rest in the app

You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.

Get Daily Doctor — free

Scan to keep reading on your phone. No account needed to start.