Genotype, phenotype and outcomes in colorectal cancer

• Main Author: Southward, Katie Hannah
• Published: University of Leeds 2016
• Subjects: 616.99
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713695

Stage II/III CRCs are currently treated by surgery, then stage III and stage II patients exhibiting high-risk pathological features undergo a course of 5-FUbased adjuvant chemotherapy, often with oxaliplatin added. Improved characterisation of stage 11/111 tumours is required in order to improve their treatment and to ensure that drugs are only given to patients where there is evidence of a likely response. This will reduce the unnecessary and costly overtreatment of these patients, as well as the associated unpleasant side effects. Pyrosequencing, immunohistochemistry, FISH, and next-generation sequencing were used in order to assess a number of molecular markers of high-risk stage 11 CRCs in two cohorts. Of the markers tested, only mutation in KRAS was prognostic in stage 11/11I CRC (HR = 1.4). Mutation of BRAF, NRAS, PIK3CA and overexpression/amplification of HER-2 were not prognostic or predictive of response to 5-FU chemotherapy in the QUASAR-1 trial. TOP2A was coamplified with HER-2 in 28% cases. Copy number profiles produced from this cohort showed the differences between dMMR and pMMR, and the effect of high stromal content on CNV. Cases from the QUASAR-1 fit into one of three groups regarding CNV which need further characterisation and their relationship to prognosis needs to be established. KRAS mutation is a prognostic marker in stage 11/11I disease and could be tested for routinely. Importantly none of the other markers tested predicted a worse outcome with 5-FU-based chemotherapy. TOP2A is frequently coamplified with HER-2 suggesting that a subset of these cases may respond to anthracycline therapy.