Prognostic and predictive effect of microsatellite instability (MSI) in MAGIC.

Abstract

62 Background: MSI is prognostic for survival in diverse cancers and predicts resistance to fluoropyrimidine chemotherapy in colon cancer. We examined the interaction between MSI and patient (pt) characteristics and survival for pts randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Methods: Tumor and normal control DNA was extracted from resection FFPE. MSI status was determined using the Promega MSI Analysis System (NR-21, BAT-26, BAT-25, NR-24, MONO-27). Tumors were classified as MSS when all markers were stable, MSI-L when only one marker was unstable and MSI-H with minimum of instability in two markers. MSI status was correlated with pt characteristics and survival. Results: MSI results were available for 303 pts (66% resected pts). Twenty (6.6%) and 2 (0.6%) pts were MSI-H and MSI-L. All pts with MSI-H had stomach tumors (vs.GEJ/esophagus). KRAS mutation was more common in MSI-H tumours (30% vs. 4%, p-value <0.001); rates of BRAF, PIK3CA and TP53 mutations were comparable. Median overall survival (OS) from surgery was greater for pts with MSI-H tumours treated with surgery alone (1.69y for MSS vs. not reached for MSI-H) (Table 1), whereas patients with MSI-H tumors treated with chemotherapy plus surgery had inferior outcomes compared to MSS stable pts (median OS 0.8y vs. 1.89y respectively). An interaction test for MSI-H vs. MSS status and treatment arm was positive (p=0.007). Conclusions: In MAGIC, MSI-H status is associated with a positive prognostic effect in pts treated with surgery alone, and a negative predictive effect in pts treated with chemotherapy. As pt selection biomarkers for perioperative chemotherapy are lacking, validation of this finding in an independent dataset is warranted. [Table: see text]