Mutation burden and other molecular markers of prognosis in the QUASAR2 clinical trial of colorectal cancer treated with curative intent
Session type: Proffered paper sessions
Theme: Diagnosis and therapy
The decision to give adjuvant chemotherapy after resection of stage II/III colorectal cancer (CRC) is based mainly on pathological factors such as tumour and nodal stage, with microsatellite instability (MSI) the only molecular marker routinely used. However, patient outcomes remain variable and stratification needs to be improved. While several relatively large studies have assessed molecular indicators of colorectal cancer (CRC) prognosis, most analyses have been restricted to a handful of markers.
In 511 stage II/III CRCs from the QUASAR2 clinical trial, we assessed a panel of 82 cancer genes for mutations and additionally derived a measure of overall mutation burden.
We initially refined the molecular pathways of CRC carcinogenesis. Pathogenic mutations in the genes NF1 and NRAS from the mitogen-activated protein kinase pathway co-occurred, as did SMAD4 and BRAF mutations, whilst there was a negative association between mutations in DNA damage response genes TP53 and ATM. Using relapse-free survival as an endpoint, TP53, KRAS, BRAF and GNAS mutations were independently associated with poor prognosis. In contrast, mutation burden was associated with good prognosis, even after excluding MSI+ and POLE-mutant ultramutator tumours. We successfully validated these associations in an additional Australian set of 296 stage II/III CRCs. In an extended analysis of 1,732 QUASAR2 and Australian CRCs for which KRAS, BRAF and MSI status was available, KRAS and BRAF mutations were specifically associated with poor prognosis in MSI- cancers, but not in MSI+.
In summary, a multi-gene panel has identified new prognostic associations in CRC with both TP53 mutation and mutation burden, and confirmed associations with KRAS and BRAF. We conclude that even a modest-sized gene panel can provide important information for use in clinical practice, and may allow existing and novel therapies to be targeted to poor prognostic sub-groups while sparing patients with good outcomes unnecessary and toxic treatment.