Kinetic Profiling of Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of Mutations in Neo--Wildtype Metastatic Colorectal Cancer Is Transient.

PURPOSE

In metastatic colorectal cancer (mCRC), mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether mutations ever become clonally undetectable.

METHODS

CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.

RESULTS

Among the 95 patients with mutations in their archival tumor tissue, 6.3% (6/95) had undetectable mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to -wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo--WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent mutations (75%), = .046. The likelihood of synchronous metastases at cancer diagnosis (33% 63%; = .15) or liver metastases at trial baseline (50% 68.5%; = .17) was not significantly different between patients with disappearing versus persistent mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; = .52) was not significantly different between those with disappearing versus persistent mutations. The disappearance of mutations was not associated with primary tumor sidedness ( = .41), archival -mutant status ( = .16/1.00/.09), nor baseline ctDNA amplifications ( = 1.00).

CONCLUSION

We identified a 3.2%-6.3% prevalence of the neo--WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.