BRAF-Mutant Advanced CRC Patients Have Poorer Outcomes

Advanced colorectal cancer (CRC) patients with BRAF mutations have markedly worse prognosis than non-mutant patients, according to a large analysis. Post-progression survival in particular is worse among BRAF-mutant advanced CRC.

Previous reports have shown poor outcomes in BRAF-mutated advanced CRC. “The mechanism for the poor prognosis is poorly understood, and it is unclear at what point in the advanced CRC treatment pathway that BRAF-mutant outcomes diverge from wild-types,” wrote study authors led by Gary Middleton, MD, of the University of Birmingham in the United Kingdom. The new analysis aimed to provide more clarity to the disease course and how these patients respond to therapy.

The study included 2,530 patients from three randomized trials. Of those, 231 patients (9.1%) had BRAF-mutant advanced CRC, which is consistent with previously published proportions; they were compared to non-mutant patients with regard to progression-free survival, response rate, and other outcomes. The results were published online ahead of print in Annals of Oncology.

Two of the three trials were first-line therapy trials (COIN and FOCUS); in those combined, the median overall survival was 10.8 months in BRAF-mutant patients and 16.4 months in wild-type patients, for a hazard ratio (HR) of 1.49 (95% CI, 1.23–1.80; P < .001). The third trial (PICCOLO), which examined second-line irinotecan, showed shorter overall survival with BRAF-mutated advanced CRC, but it did not reach significance, at 6.7 months vs 10.2 months and an HR of 1.21 (95% CI, 0.84–1.76; P = .31).

BRAF status did not have the same marked effect on progression-free survival and disease control rate. In the first-line trials, the disease control rate was 59.2% in mutant patients and 72% in wild-type patients, for an odds ratio of 0.76 (95% CI, 0.49–1.20; P = .24). Median progression-free survival was 5.7 months vs 6.3 months, for an HR of 1.14 (95% CI, 0.91–1.42; P = .26).

After progression occurred, though, mutation status appeared to have a large impact. In the first-line trials, post-progression survival was 3.2 months in BRAF-mutant patients and 8.1 months in wild-type patients, for an HR of 1.65 (95% CI, 1.03–2.67; P = .038). This was independent of which first-line therapy was used.

Notably, in one trial the BRAF-mutant patients were less likely to receive second-line therapy after progression (33% vs 51%; P = .0002). In the other, 30.7% of wild-type patients received salvage therapy, compared with only 10.3% of BRAF-mutant patients (P = .020).

“Our analyses suggest … that the point at which outcomes markedly diverge between BRAF-mutant and wild-types is following progression on or after benefit from first-line chemotherapy,” the authors wrote. This is likely related to rapid progression through first-line therapy and subsequent rapid deterioration leaving patients unfit for subsequent therapy, and a higher likelihood of rapid progression following a good initial response to therapy. “Vigilance is required to ensure the appropriate delivery of treatment after first-line progression.”