Data on patients with BRAF V600E-mutant CRC and liver-only metastases are scarce. This was the largest dedicated cohort (n = 105, regardless of treatments received) study to date, bringing an additional support that their resection is beneficial.
The profit of liver resection is in line with findings in two recent retrospective studies. Johnson et al. showed that among 52 patients with BRAF V600E metastatic CRC, the median OS was significantly prolonged when liver resection with curative intent was performed: 29.1 versus 22.7 months, HR 0.33, 95% CI: 0.12–0.78, P = 0.01. In the second study, 43 out of 282 patients underwent surgery, with a median OS of 47.4 months versus 19.5 months for those who had no metastasectomy (HR 0.469, 95% CI: 0.288–0.765; P = 0.0024). In addition, a recent case-matched study demonstrated that BRAF mutations did not increase the risk of relapse after CRLM surgery compared to BRAF wild-type disease (HR 1.16, 95% CI 0.72–1.85; P = 0.547). The high proportion of patients undergoing resection in our cohort should reflect the fact that the assessment of mutational status was probably not performed in patients with poor prognosis.
To allow comparison with unresected patients, we defined OS as the time from CRLM diagnosis, whereas previous studies have reported OS from the date of liver surgery. Nonetheless, the median post-operative OS starting from the date of surgery in our cohort (28 months) was in line with those in previous studies: from 22.6 months reported by Schirripa et al. (n = 12) to 47.4 months reported by De la Fouchardière et al. (n = 35)[17–20]. OS results remain lower than the previous publication from Bachet et al. with a median OS of 52.7 months (n = 66). The exclusion of non-V600E BRAF mutated-patients in our study may explain this difference. Relapse free survival and progression free survival were not included in our study as the definitions would differ for resected and unresected groups.
The positive results of primary tumor resection in the unresected CRLM group were surprising and should be interpreted with caution due to the small number of patients involved (30 versus 26). Indeed, a recent study showed that primary tumor resection followed by chemotherapy was not superior to chemotherapy alone (HR 1.10 [0.76–1.59], one-sided P = 0.69). The trial was terminated early for futility reason.
In our cohort, a small proportion of patients received an upfront triplet regimen with or without bevacizumab (12/79, 15%), with a median OS of 16.6 months (6.7–not reached). Of note, the majority of the cohort presented a good performance status (84% in the group treated exclusively with chemotherapy). An intensive regimen has been assumed beneficial in BRAF-mutant patients with unresectable liver-limited disease to date, based on a pooled analysis of a small number of patients (n = 20). However, a recent meta-analysis of five randomized trials comparing FOLFOXIRI plus bevacizumab with doublet plus bevacizumab in 105 BRAF V600E-mutant patients showed no increased benefit in the intensive therapeutic arm.
Among the patients treated with chemotherapy only, 63% received second-line treatment; this rate is superior to those reported in the COIN trial (33%) (23) and in a matched case-control study (51%). Beyond the second line, candidates for treatment decreased dramatically to 35%, and it is important to pinpoint that only 50% of patients received the three major cytotoxic drugs: 5-FU/leucovorin, oxaliplatin, and irinotecan. Our study showed that even if BRAF-mutant metastatic disease is confined to one organ, the prognosis remains poor when the patient is treated with chemotherapy only.
Our study population mostly received standard chemotherapies, not new practice-changing therapies. Recently, mitogen-activated protein kinase pathway-targeted therapies have demonstrated better efficacy. In the BEACON trial, the combination of encorafenib, a BRAF inhibitor, and cetuximab (anti-EGFR) with or without binimetinib, a MEK inhibitor, was associated with a significantly longer OS than standard chemotherapy after at least one prior line in a large cohort of patients with BRAF V600E mutations. The same regimen as a first-line is currently under investigation in a phase II trial (ANCHOR-CRC).
ICIs represent another therapeutic option, especially for MSI-H mCRC. The phase III KEYNOTE-177 study demonstrated that first-line pembrolizumab was associated with significant progression-free survival improvement over chemotherapy in MSI-H mCRC (median progression-free survival of 16.5 versus 8.2 months, HR = 0.60; 95% CI 0.45–0.80, P = 0.0002). The benefit of pembrolizumab was consistent in the BRAF V600E-mutant subgroup. In our cohort, very few patients received ICI after chemotherapy failure (n = 3), explained by the period of inclusion. MSI-H status was not reliable for any conclusions due to insufficient data. In a recent study, MSI-H status was associated with significantly longer OS in a BRAF-mutant mCRC population (n = 194) treated with standard chemotherapies.
The major weakness of our study is related to the differences between the resected and unresected CRLM groups with the bias of less aggressive disease in the resected group. However, this should be counterbalanced by increased liver surgery ability and moreover, the initial resectability or unresectability status might have been subject to variability between the centers. The reasons for non-resectability were not specified, and patients could be considered unresectable solely based on the presence of BRAF mutations.
The missing data in our cohort represent an important limitation, and some known prognostic factors, such as MSI status, were not included in the statistical analysis. Therefore, a case-matched study (resected and unresected CRLM) was not feasible. A prospective study with current therapeutic strategies (ICI for MSI-H and anti-BRAF plus anti-MEK for non-MSI-H) should be considered.
With all the limitations of a retrospective study, this was conducted in the largest cohort of BRAF V600E mutant patients with CRLM reported to date. A subgroup difficult to look at given its rarity, also prospective studies would be difficult to realize.