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ESMO update in Colorectal Cancer
Update by Elizabeth Smyth
When is the optimal time for surgery following CRT for locally advanced rectal cancer? Results of the UK 6 vs 12 study
The optimal duration between completion of chemoradiotherapy and surgery for patients with resectable rectal cancer is unknown. Dr Bhoday (London) presented the results of the UK 6 vs 12 trial in which patients who were treated with preoperative chemoradiation for rectal cancer were randomised to surgery either 6 or 12 weeks following completion of chemoradiotherapy. The trial met its primary endpoint, of 237 patients randomised, a significantly higher proportion were downstaged according to MRI criteria at 12 weeks compared to 6 weeks (58% vs 43%, p=0.019), and pathological CR rates were also increased in patients operated on at 12 weeks (20% vs 9%, p<0.05). However, there was no difference in the rate of CRM positivity between the arms (68% vs 61%, p=NS).
Comment: The results of this interesting study indicate that waiting longer than the standard six weeks following completion of CRT before surgery for locally advanced rectal cancer improves both MRI downstaging and pathological complete responses in the primary tumour. However, the impact of improved pathological response on patient outcomes is less clear. In particular, the rate of CRM positivity was not significantly improved by increasing the length of time before resection, although this analysis may be underpowered. Whether improvements in tumour response in the primary tumour prior to resection can result in long term improvements in disease control for resected patients will be determined by longer follow up. The pathological complete response rate of 20% in the 12 week group is encouraging – the question of whether these patients might safely defer surgery will be answered by a recently completed clinical trial which is being conducted by the same group (NCT01047969).
MiR 31-3p as a predictor for cetuximab efficacy in the FIRE-3 trial
Dr Laurent-Puig presented the results of an analysis of MiR 31-3p as a predictor of response to chemotherapy plus cetuximab in the FIRE-3 trial. In this study, MiR 31-3p levels were assessed using a qRTPCR assay in 370 KRAS wild type tumour samples from patients who were treated with either first line FOLFIRI-bevacizumab or FOLFIRI-cetuximab in the FIRE-3 trial. Use of cetuximab was only associated with an increased odds for response in patients who were low miR31-3p expressors (OR 3.37 (1.70- 6.67), p=0.0005 vs. OR 1.25 (0.56- 2.77), p=0.56); response rates were 70% in patients with low MiR 31-3p expression who were treated with chemotherapy plus cetuximab. Low MiR 31-3p expression was also significantly predictive of early treatment response (20% reduction in tumour diameter at 6 weeks) and depth of response in the same population. MiR 31-3p was found to be differentially expressed in left and right colon cancers, right sided tumours are more likely to have high MiR 31-3p expression (61%), whereas left sided tumours are more likely to have low expression (73%) and patients with right sided tumours with high levels of MiR 31-3p expression (n=41) appeared not to benefit from of cetuximab therapy (HR 2.85 (1.19-6.85).
Comment: These data add to the growing body of evidence supporting MiR 31-3p as a predictive marker for the efficacy of anti-EGFR therapy in colorectal cancer. Data demonstrating a correlation between low MiR-31-3p levels and overall survival in FIRE-3 were presented at ASCO 2016 by the same authors.1 Lower MiR 31-3p levels were also correlated with progression free survival benefit in the PICCOLO trial in which patients were randomized to receive irinotecan or irinotecan plus panitumumab.2 In future, MiR 31-3p levels may be useful for selecting RAS wildtype patients for treatment with first line anti-EGFR therapy. Interestingly, the differential expression of MiR 31-3p may in part explain the superior results of anti-EGFR therapy in left sided colon cancers although other factors such as the prevalence of BRAF mutation and levels of EGFR ligands AREG and EREG may also play a role.
1. Laurent-Puig P, Grisoni M-L, Heinemann V, et al. MiR 31 3p as a predictive biomarker of cetuximab efficacy effect in metastatic colorectal cancer (mCRC) patients enrolled in FIRE-3 study. ASCO Meeting Abstracts. 2016;34(15_suppl):3516.
2. Laurent-Puig P, Paget-Bailly S, Vernerey D, et al. Evaluation of miR 31 3p as a biomarker of prognosis and panitumumab benefit in RAS-wt advanced colorectal cancer (aCRC): Analysis of patients (pts) from the PICCOLO trial. ASCO Meeting Abstracts. 2015;33(15_suppl):3547.