THE ROLE FOR MASTECTOMY

Finally, our review would not be completely without mention of the management of oligometastatic disease. Distinct from other cancer types, CRC is one of the rare solid tumors where cure is feasible in the presence of limited metastatic disease.59 However, careful selection for metastasectomy is widely acknowledged as a predictor for the benefit of surgical intervention. Relevant to this discussion is whether the detection of BRAFV600E mutation should deter providers from pursuing metastectomy.

In a single-center retrospective study of 92 patients, the presence of BRAFV600E was associated with less frequent presentations of liver-limited disease (41 vs 63%; P<0.01) and, not surprisingly, fewer patients with a BRAFV600E mutation were candidates for metastectomy (41 vs 26%; P<0.01).20 Among those patients with BRAFV600E tumors who underwent metastectomy, a trend toward shorter recurrence-free survival after metastectomy (7 vs 11 months, P=0.084) and a significantly shorter OS (2-year OS 61 vs 86%; P=0.003) were reported. Additionally, of the 20 patients with BRAFV600E mutations who underwent resection with curative intent (15 for liver metastases, four for lung metastases, and one for ovarian metastasis), 18 (90%) patients developed recurrence.

Given the high risk of recurrence after metastectomy in this population, along with the potential morbidity of surgery, we recommend metastectomy only in very carefully selected patients who have truly liver-limited disease and have previously achieved durable disease control in response to systemic therapy.

FUTURE DIRECTIONS

Reflecting the rapid evolution of efforts for this small subset of CRC patients, the first-ever Phase III study is now underway evaluating the combination of BRAF, EGFR, and MEK inhibition (Figure 2).46 The Phase III BEACON CRC study is currently enrolling patients with BRAFV600E metastatic CRC to evaluate the combination of encorafenib, cetuximab, and the MEK inhibitor binimetinib.60 In the initial safety lead-in, 30 patients received triplet therapy with good tolerability and a confirmed overall response rate of 41%.61 Additionally, there is suggestion of a possibly more durable response than has previously been seen with BRAF inhibition, with 76% of patients remaining on study at a median of 5.6 months of treatment. The Phase III component is currently enrolling to the three arms of encorafenib plus cetuximab vs encorafenib, cetuximab and binimetinib vs FOLFIRI, or irinotecan plus cetuximab (at the discretion of the investigator) (NCT02928224). BEACON will potentially serve as a licensing trial for BRAF-inhibitor-based combination therapy for metastatic CRC but is not projected to reach its accrual goal until 2019.

(To view a larger version of Figure 2, click here.)

Further efforts to elucidate other mechanisms of resistance to BRAF inhibition are an area of active investigation. As an example, researchers have identified increased Wnt pathway signaling as potentially cooperating with signaling through the MAPK pathway to sustain BRAFV600E tumor growth. We are currently awaiting results of NCT02278133, which has completed the enrollment of patients with both BRAFV600E and Wnt pathway mutations who were treated with the Wnt inhibitor WNT974 in combination with encorafenib and cetuximab.62

Finally, clinical trials combining therapies targeting the MAPK pathway with immunotherapy are in development.

SUMMARY OF RECOMMENDATIONS FOR CLINICAL PRACTICE

Acknowledging that most data guiding the management of patients with metastatic BRAFV600E CRC are based upon small sample sizes and that the management of this condition is dynamic, the following clinical recommendations represent a compilation from the currently available data, existing clinical practice guidelines, as well as our own clinical experiences.

Current NCCN guidelines recommend genomic testing to specifically include BRAF testing at the time of diagnosis of metastatic CRC.31 The testing can be done either on the primary tumor or on tissue from a metastatic site, as the results for this gene have been shown to be highly concordant.63 With improved recognition of poor prognosis and distinct clinical features of this population, earlier identification of a BRAFV600E mutation may expand therapeutic and/or clinical trial options before a patient faces clinical deterioration.

For fit patients with a de novo presentation of metastatic CRC with BRAFV600E mutation for whom a clinical trial is not immediately available, we recommend considering FOLFOXIRI plus bevacizumab as first-line therapy in effort to obtain disease control.

The likelihood of response from anti-EGFR monotherapies is low, and we recommend against the use of anti-EGFR therapy in patients with a known BRAFV600E tumor31 outside of the context of a clinical trial, particularly for those with right-sided primary tumors.

For MSI-high tumors harboring a BRAFV600E mutation, we recommend treatment with a checkpoint inhibitor treatment prior to considering BRAF-targeted therapy due to the higher potential for durable disease control; however, we acknowledge that checkpoint inhibitors and targeted therapies have not been studied in a head-to-head comparison.

For MSS tumors harboring a BRAFV600E mutation or for patients with MSI-high BRAFV600E-mutated tumors who have previously progressed on a checkpoint inhibitor, we recommend enrollment on a clinical trial when feasible. However, we acknowledge that access to a tertiary medical center is not available to all patients.

Pending results of the ongoing Phase III BEACON trial, the sum of data to date support the hypothesis that while targeted agents appear to be inactive as monotherapies in BRAFV600E-mutant CRC, combinations of BRAF, MEK, and other pathway inhibitors may have at least temporary efficacy. Access to these medications is currently not FDA approved for the treatment of metastatic BRAFV600E CRC; however, off-label use of these combinations merits consideration and is substantiated by a growing body of literature. In view of this, January 2018 updates to the NCCN Colorectal Guidelines included new recommendations regarding the treatment of these patients and off-label usage is likely to be more readily available. Currently, our preferred combinations include dabrafenib, trametinib, and panitumumab,41 or vemurafenib, cetuximab, and irinotecan,47 with selection based upon toxicity profiles.

In highly selected patients with very limited liver-only metastasis(es), curative intent metastectomy can be considered. However, patients should be counseled extensively on the high risk of recurrence following any surgical intervention.