Impact of Metastasectomy in the Multimodality Approach for BRAF V600E Metastatic Colorectal Cancer: The Mayo Clinic Experience

BRAF V600E mutations are present in 8%–10% of patients with metastatic colorectal cancer (mCRC). This study investigated the impact of metastasectomy for patients with BRAF V600E mCRC.

Abstract

Background.

BRAF V600E mutations are present in 8%–10% of patients with metastatic colorectal cancer (mCRC) and portend poor prognosis. This study investigated the impact of metastasectomy for patients with BRAF V600E mCRC.

Subjects, Materials, and Methods.

Using prospective clinical and molecular data, patients with BRAF V600E mCRC were analyzed for clinical characteristics and survival. Statistical analyses utilized the Kaplan‐Meier method, log‐rank test, and Cox proportional hazard models.

Results.

Fifty‐two patients were identified between July 1, 2008, and January 4, 2016. Patient characteristics included median age 65 years, 61% female, Eastern Cooperative Oncology Group performance status ≤1, 71% with right‐sided tumors, and 28% with liver‐limited metastasis. In the first‐line setting, 7% (4/52) received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (BEV) and 81% were treated with doublet chemotherapy consisting of fluoropyrimidine, oxaliplatin, and BEV. Median overall survival (OS) for all 52 patients was 25 months with median progression‐free survival (PFS) of 9.3 months. With median follow‐up of 18.3 months, 21 patients underwent metastasectomy with longer OS (29.1 months vs. 22.7 months, hazard ratio [HR] = 0.33; confidence interval [CI], 0.12–0.78; p = .01) and PFS (13.6 months vs. 6.2 months, HR = 0.53, CI, 0.28–0.97; p = .03) compared with the non‐metastasectomy cohort. In multivariate analysis, metastasectomy remained significant for improved survival outcomes (HR = 0.52; 95% CI, 0.07–1.02; p = .02). Median disease‐free survival after metastasectomy was 9.7 months (95% CI, 5.5–19.5). Two patients remain disease‐free at the time of last follow‐up, with one patient without relapse for greater than 2 years (28.9 months).

Conclusion.

Multimodality therapy incorporating metastasectomy for BRAF V600E mCRC should be considered and might be associated with improved overall survival in select patients.

Implications for Practice.

BRAF V600E metastatic colorectal cancer (mCRC) represents an extremely difficult molecular subset of colorectal cancer to treat. To date, this subset remains refractory to standard chemotherapies, prompting extensive clinical investigation regarding novel treatment approaches and targeted modalities. While the use of metastasectomy for expanded RAS wild‐type and RAS mutated mCRC has resulted in improved overall survival for select patients, utilization of metastasectomy in patients with BRAF V600E mCRC remains controversial. This article explores the authors' experience with BRAF V600E mCRC to ascertain whether a multidisciplinary approach incorporating metastasectomy for well‐selected patients improves overall survival.

Introduction

BRAF V600E missense mutations are present in 8%–10% of patients with metastatic colorectal cancer (mCRC) [1]. Within the BRAF kinase domain, substitution of a valine to glutamic acid at position 600 manifests as constitutive activation and oncogenic signaling along the mitogen‐activated protein kinase (MAPK) pathway [1]. BRAF mutations are implicated as an early event in the progression to colorectal cancer via the serrated pathway, responsible for the transformation of epithelia into premalignant serrated and sessile adenomas [2]. Therefore, patients with BRAF V600E mCRC reflect a distinct molecular subgroup with a characteristic clinicopathologic profile, portending a poor prognosis. BRAF V600E tends to occur in older female patients, with right‐sided advanced tumors that arise from serrated adenomas, are poorly differentiated, and have higher‐grade mucinous histology, CpG island methylator phenotype, microsatellite instability (MSI), and a distinct metastatic pattern, including a high rate of peritoneal and nodal metastases [3], [4]. Considering the aggressive clinical phenotype that clearly distinguishes BRAF V600E mCRC from wild‐type (WT) counterparts (expanded RAS WT, BRAF WT mCRC), a unique management approach for these patients is critical for improving long‐term outcomes.

While there are many intricacies regarding the treatment of mCRC, two components are central for improved outcomes: the appropriate use of available biologic therapy and chemotherapy and management of oligometastatic disease due to curative potential [5]. Patients with wild‐type mCRC benefit from the ability to be exposed to multiple lines of chemotherapy over time [6]. Unfortunately, patients with BRAF V600E mCRC are inherently refractory to standard treatment, with a median progression‐free survival (PFS) of 4–6 months with first‐line therapies consisting of a chemotherapy doublet and biologic therapy and 2.5 months after second‐line chemotherapy [7], [8]. Median overall survival (OS) for BRAF V600E mCRC is 9–14 months compared with 43 months for BRAF wild‐type mCRC and up to 60.3 months for mCRC with BRAF mutations other than V600E [9]. Therefore, a lack of exposure time to subsequent lines of therapy highlights that initial treatment decisions are paramount. Regarding management of oligometastatic disease, patients with BRAF V600E mCRC undergo metastasectomy at a much lower rate, predominantly due to upfront peritoneal involvement, and for those who undergo metastasectomy, relapse‐free and overall survival is significantly shorter when compared with wild‐type mCRC cohorts [10], [11]. Therefore, effectively applying these components to the management of BRAF V600E mCRC is coupled with significant clinical challenges.

Unlike the clinical success experienced in BRAF‐mutated malignant melanoma, monotherapy with selective BRAF inhibitors as well as in combination with mitogen‐activated, extracellular signal‐regulated kinase (ERK) inhibitors in mCRC has proven to be largely ineffective [12], [13], [14]. Recently, dual inhibition of BRAF and epidermal growth factor receptor (EGFR) has regained interest with the phase II SWOG S1406 trial meeting its primary endpoint of progression‐free survival with the addition of vemurafenib to cetuximab and irinotecan compared with cetuximab and irinotecan alone (median PFS 4.4 months vs. 2.0 months; hazard ratio [HR] = 0.42; 95% confidence interval [CI], 0.26–0.66, p = .0002) for BRAF V600E mCRC in a second‐line setting, suggesting that vemurafenib sensitizes these tumors to cetuximab and irinotecan [15]. However, to date, triplet chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) and bevacizumab (BEV) represents the only available “standard of care” in the first‐line setting [16], [17]. It is important to note that the recommendation of intensified first‐line chemotherapy for BRAF V600E mCRC was initially suggested via post hoc analysis of 10 patients followed by a small prospective validation cohort of 15 patients in two corresponding phase II studies performed by the Italian GONO group, revealing improved response rates, median PFS, and OS [18], [19]. The only randomized phase III data available stems from the recently updated TRIBE study through a subgroup analysis of 28 patients with BRAF V600E mCRC, 16 of whom received FOLFOXIRI/BEV [16], [17]. Although this resulted in improved outcomes when compared with standard chemotherapy, median OS was still poor (19.0 months vs. 41.7 months) when compared with wild‐type mCRC. In view of the clear limitations of available data with questionable widespread utilization of triplet chemotherapy and metastasectomy for patients with BRAF V600E mCRC, we investigated the management approach of BRAF V600E mCRC at a large academic medical center to identify practice patterns with the most impactful clinical outcomes.

Subjects, Materials, and Methods

Patient Population

This study involved the analysis of a prospectively managed institutional database from the Mayo Clinic in Rochester, MN, USA. Fifty‐two patients with BRAF V600E mCRC were identified between July 1, 2008, and January 4, 2016. Long‐term clinical follow‐up and treatment data were available for these patients, for whom clinicopathologic characteristics, multidisciplinary management approaches, and survival outcomes were retrospectively reviewed (Table 1).

Table 1. Characteristics of 52 patients with BRAF V600E metastatic colorectal cancer.

^aMicrosatellite stability status available for 29 patients (55%).

Data Collection

The selected patient cohort was analyzed for specific pathologic and clinical characteristics, including age, sex, performance status, tumor sidedness, prior receipt of adjuvant therapy, sites of metastatic disease, metastasectomy, administration of first‐line chemotherapy, response rates, BRAF mutation status, MSI, and survival. Primary sites were categorized into right‐sided and left‐sided tumors (generally defined as right‐sided involving tumors arising from the cecum to the transverse colon and left‐sided tumors arising from the splenic flexure to the anorectal junction). At Mayo Clinic, microscopic examination was first performed by a pathologist to identify areas of tumor for enrichment by macrodissection. BRAF mutation testing was then performed in conjunction with extended RAS testing via targeted next‐generation sequencing evaluating for somatic mutations within the BRAF (exons 11 and 15), HRAS (exons 2 and 3), NRAS (exons 2, 3, and 4), and KRAS (exons 2, 3, and 4) genes. This included the testing of somatic mutations in KRAS codons 12, 13, 61, 117, and 146; NRAS codons 12, 13, 61, and 146; HRAS codons 12, 13, and 61; and BRAF codons 594, 596, and 600. MSI status was predominantly identified by immunohistochemistry (defined as loss of MSH2, MLH1, MSH6, or PMS2) or DNA testing of microsatellite markers (defined as MSI‐high with the presence of two or more foci showing instability).

Reported metastatic sites are reflective of metastases that developed in our patient cohort over the course of their disease and include liver, peritoneal, lung, retroperitoneal and mesenteric lymph nodes, ovarian, skeletal, and genitourinary. All patients included in this analysis were treated at Mayo Clinic Rochester and data were confirmed by review of medical records, operative notes, chemotherapy orders, and/or imaging. Research was conducted under appropriate institutional review board protocols and waivers.

Statistical Analysis

Associations between BRAF mutant tumors and clinical characteristics (sex, primary site, MSI status, metastasectomy, use of anti‐EGFR therapy, resection of primary) and sites of metastatic disease were analyzed using Fisher's exact test. Survival rates were estimated with the Kaplan‐Meier method and compared by log‐rank test. All patients were included in the univariate survival analysis. Multivariate survival analysis included all significant variables in the univariate analysis; however, due to the limited number of events (24 deaths), only three variables were evaluated at a time, with the use of Cox proportional hazard models to adjust for potential confounding factors. All reported p values are two‐sided, and p values less than .05 are considered statistically significant. The software program SAS/JMP 10 (SAS Institute, Cary, NC, www.sas.com) was used for univariate analysis and multivariate analysis.

Results

BRAF V600E mCRC

We identified 52 patients with known BRAF V600E mCRC treated primarily at Mayo Clinic Rochester between July 1, 2008, and January 4, 2016, with complete follow‐up and survival data available (Table 1). The median age of patients was 65 years. Sixty‐one percent of patients were female (n = 32). Patients had an Eastern Cooperative Oncology Group performance status of 0 (63%) or 1 (37%). Thirty‐five percent of patients had previously received adjuvant therapy prior to the diagnosis of metastatic disease. Within our cohort, 28% of patients presented with liver‐limited metastasis. Other sites of distant metastatic disease included peritoneal, lung, distant lymph nodes (retroperitoneal and mesenteric), skeletal, vaginal, and bladder (supplemental online Table 1). Forty percent of patients underwent metastasectomy.

Utilization of FOLFOXIRI/BEV for BRAF V600E mCRC

Seven percent (4/52) of patients received FOLFOXIRI/BEV as first‐line treatment with an average of eight cycles. Of the remaining 48 patients, 39 (81%) were treated primarily with fluoropyrimidine and oxaliplatin‐based chemotherapy along with biologic therapy, of which BEV was most commonly used. Response rates revealed 2 patients with complete response, 10 patients with partial response, 16 patients with stable disease, and 15 patients with progressive disease, per version 1.1 of the response evaluation criteria (RECIST 1.1) in solid tumors. FOLFIRI‐based regimens were used in the second line. The most common reasons documented by providers for not utilizing FOLFOXIRI/BEV are listed in supplemental online Table 2.

Survival Analysis

Median follow‐up of all patients (n = 52) in our cohort was 18.3 months with 24 deaths. Table 2 summarizes the results of the univariate survival analysis. In our cohort of patients with BRAF V600E mCRC (n = 52), median OS for all patients treated at Mayo Clinic was 25 months (Fig. 1A) with median PFS of 9.3 months (Fig. 1B), reflecting worse survival when compared with BRAF wild‐type control patients treated at Mayo Clinic (249 patients, median OS: 43 months). Patients that underwent metastasectomy at any point throughout their treatment course had a significantly longer OS (29.1 months vs. 22.7 months, HR = 0.33; CI, 0.12–0.78; p = .01; Fig. 2A) and PFS (13.6 months vs. 6.2 months, HR = 0.53, CI, 0.28–0.97; p = .03; Fig. 2B) when compared with those who did not undergo metastasectomy. In multivariate analysis, adjusting for other covariates potentially associated with OS (age, sidedness, gender, synchronous vs. metachronous metastasis, adjuvant therapy), metastasectomy remained statistically significant for improved survival outcomes (HR 0.52; 95% CI, 0.07–1.02; p = .02).

Table 2. Univariate survival analysis for 52 patients with BRAF V600E metastatic colorectal cancer.

^aOther‐only metastasis: ovarian (4 patients), retroperitoneal and mesenteric lymph node (11 patients), skeletal (3 patients), vaginal (1 patient), and bladder (1 patient) metastasis.

Abbreviations: EGFR, epidermal growth factor receptor; mOS, median overall survival; MSI, microsatellite instable; MSS, microsatellite stable.

Figure 1.

Median overall survival and progression‐free survival for BRAF V600E metastatic colorectal cancer. n = 52. Median follow‐up: 18.3 months. (A): Median overall survival: 25 months. (B): Median progression‐free survival: 9.3 months.

Abbreviation: PFS, progression‐free survival.

Figure 2.

Median overall survival and progression‐free survival for metastasectomy versus no metastasectomy in BRAF V600E metastatic colorectal cancer. n = 52. Median follow‐up: 18.3 months for survivors. Twenty‐one patients underwent resection; 7 deaths. (A): Median overall survival favored metastasectomy (29.1 months; blue) over no metastasectomy (22.7 months; red); hazard ratio (HR) = 0.33, confidence interval [CI], 0.12–0.78; p = .01. (B): Median progression‐free survival for metastasectomy versus no metastasectomy favored metastasectomy (13.6 months; blue) over no metastasectomy (6.2 months; red); HR = 0.53, CI, 0.28–0.97; p = .03.

Complete resection of metastases was performed in 21 patients (40%). Complete resection was defined as resection of all identifiable metastatic disease with curative intent and included partial hepatectomy, optimal debulking surgery, and pulmonary wedge resection. Seven of 21 patients who underwent metastasectomy died during the follow‐up period. Follow‐up data are available for 14 patients who were alive at the time of last follow‐up. Twelve of these 14 patients have developed recurrent metastatic disease (supplemental online Table 3). The median disease‐free survival after undergoing metastasectomy was 9.7 months (95% CI, 5.5–19.5 months). Two patients remain disease‐free at the time of last follow‐up. Of these, one patient who underwent resection of a solitary liver metastasis in segment VII has been without recurrent disease for more than 2 years (28.9 months; supplemental online Table 3).

Of note, clinical factors associated with poorer survival, although not statistically significant, included BRAF V600E mCRC MSI tumors compared with BRAF V600E mCRC microsatellite‐stable (MSS) tumors (19.6 months vs. 23.8 months, HR = 2.15; CI, 0.44–8.84; p = .28; Fig. 3) and the use of anti‐EGFR therapy in addition to chemotherapy compared with chemotherapy alone (24.4 months vs. 27.6 months, p = .59) for BRAF V600E mCRC (Fig. 4). Type of metastatic spread was also suggestive of clinical implications for overall survival. Patients with BRAF V600E mCRC with peritoneal‐only metastatic disease had worse overall survival compared with patients who presented with multiple metastasis or liver‐limited metastasic disease (supplemental online Fig. 1).

Figure 3.

Median overall survival (OS) for BRAF V600E metastatic colorectal cancer (mCRC) microsatellite‐instable (MSI) tumors compared with BRAF V600E mCRC microsatellite‐stable (MSS) tumors. n = 29. BRAF V600E mCRC MSI tumors (n = 6; median OS, 19.6 months; blue) have worse overall survival compared with BRAF V600E mCRC MSS tumors (n = 23; median OS, 23.8 months; red); hazard ratio = 2.15, confidence interval, 0.44–8.84; p = .28.

Figure 4.

Median overall survival (OS) based on the use of anti‐epidermal growth factor receptor (anti‐EGFR) therapy in addition to chemotherapy (FOLFOX/FOLFIRI) versus chemotherapy alone in BRAF V600E metastatic colorectal cancer. n = 52. Use of anti‐EGFR therapy in combination with chemotherapy (n = 9; median OS, 24.4 months; red) was numerically suggestive of poorer OS compared with chemotherapy alone (n = 43; median OS, 27.6 months; blue); p = .59.

Discussion

Molecular characterization has proven to augment the clinical management of mCRC, as identifying mutational status (expanded RAS, BRAF) provides both meaningful prognostic and predictive therapeutic implications. Although BRAF V600E mCRC represents only 8%–10% of all mCRC cases, an ongoing research focus identifying novel treatment modalities is desperately needed. Shifting BRAF V600E status from merely a marker of poor prognosis to a key molecular target of therapy has resulted in intriguing clinical trial design with much‐awaited future promise [15], [20], [21]. Nonetheless, there remains a clear paucity of data to guide current oncology practice. In our series, we sought to identify multidisciplinary treatment approaches that resulted in meaningful clinical outcomes for BRAF V600E mCRC.

As of 2017, intensified chemotherapy with FOLFOXIRI/BEV has emerged as the recommended first‐line therapy for BRAF V600E mCRC. Due to the lack of phase III data on this therapy as well as the relatively low incidence of BRAF V600E mCRC, this recommendation stems primarily from phase II studies as well as a small subgroup analysis of the phase III TRIBE study [16], [17], [18], [19]. The use of intensified chemotherapy resulted in both OS and PFS benefits, as well as improved response rates for patients with BRAF V600E, when compared with standard FOLFIRI/BEV‐based therapy [16], [17]. Based on these findings, FOLFOXIRI/BEV has been recommended by the European Society for Medical Oncology as a first‐line therapy for fit patients with BRAF V600E mCRC (level II, B [22]).

In the current series, we found that 7% (4/52) of patients received FOLFOXIRI/BEV as first‐line treatment for BRAF V600E mCRC. This observation predominantly reflects the facts that the initial report of intensified therapy from the TRIBE study was published in October 2014 and that a proportion of patients in our cohort were treated prior to the availability of the data. However, residual peripheral neuropathy, pending BRAF status, age, and prior progression on oxaliplatin‐based chemotherapy were identified as factors precluding the use of an intensified chemotherapy regimen among providers at our institution who were aware of the data, potentially highlighting practical limitations of the use of this treatment for all patients with BRAF V600E mCRC. A rational next step for clinical trial design would be to compare FOLFOXIRI/BEV with the recently reported successful combination of vemurafenib, cetuximab, and irinotecan to identify the most efficacious and tolerable first‐line therapy for patients with BRAF V600E mCRC [15].

Approximately 30% of patients with colorectal cancer develop liver metastasis, accounting for two‐thirds of patient deaths [5], [23]. Metastasectomy of liver‐limited disease provides the best chance of cure for select patients with mCRC [5]. Therefore, a multidisciplinary approach evaluating patients with mCRC for the appropriate utilization of metastasectomy is a critical component for enhancing outcomes. Unfortunately, due to the aggressive clinicopathologic features of BRAF V600E mCRC, many patients present with extensive peritoneal and/or distant lymph node involvement rather than liver‐limited metastatic disease, precluding surgical candidacy at a much higher rate than patients with wild‐type mCRC [4], [10], [11]. In our series, patients with peritoneal involvement had markedly worse overall survival (18.9 months) than patients with multiple other metastatic sites (29 months) and liver‐limited metastatic disease (27.6 months).

Three studies have previously identified BRAF V600E mutation status as a strong negative prognostic factor for worse relapse‐free and overall survival after metastasectomy when compared with RAS/BRAF wild‐type counterparts [10], [11], [24]. Although these data have solidified the known aggressive clinical phenotype of BRAF V600E mCRC, to conclude that pursuing metastasectomy in all patients with BRAF V600E mCRC is a futile endeavor may not be accurate. There remains no question that BRAF V600E mCRC is a far more aggressive molecular subtype of mCRC than extended RAS wild‐type or BRAF wild‐type mCRC. We propose that the following question may be more pertinent: Within BRAF V600E mCRC, are there distinct subgroups that will benefit from aggressive multidisciplinary management of disease? In the current study, we demonstrate within our cohort of BRAF V600E mCRC that management of oligometastatic disease does in fact result in enhanced clinical outcomes.

The results of the current series reveal that among our cohort of patients with BRAF V600E mCRC, longer median OS and PFS were noted in patients who underwent metastasectomy compared with the non‐metastasectomy cohort. This survival benefit is intriguing, especially in the context of only 7% of patients receiving FOLFOXIRI/BEV in our series, suggesting that for a well‐selected patient population, utilization of metastasectomy can produce meaningful survival benefit within this aggressive subtype of mCRC. Although our data confirm prior reports that risk of relapse after metastasectomy remains high for BRAF V600E mCRC, we demonstrate long‐term disease‐free intervals with potential for cure can still be achieved for select patients.

While we acknowledge that a potential bias of the current study is a possible enrichment for patients with liver‐limited metastatic disease, our findings suggest there remains a “better‐risk,” biologically responsive group of patients that can enjoy durable control of disease after resection of oligometastasis. Considering the aggressive clinicopathologic nature of BRAF V600E mCRC, further investigation regarding extensive preoperative evaluation prior to metastasectomy is warranted, potentially including PET/CT or diagnostic laparoscopy to confirm the presence of surgically amenable disease. However, withholding appropriate treatment modalities from patients with BRAF V600E mCRC primarily based on mutational status would be a disservice to patients and likely result in worse survival outcomes.

Finally, two interesting trends were noted in our series. First, in regard to prognosis, MSI‐high (MSI‐H) status is known to result in improved survival in early‐stage colorectal cancer (CRC), with a lack of benefit of 5‐FU‐based adjuvant chemotherapy in stage II as opposed to stage III disease [25], [26], [27]. The overall prognostic effect of MSI‐H status in advanced CRC remains less clear. Previous work has revealed that in mCRC, poorer survival was noted in MSI‐H patients when compared with MSS patients; however, this difference was not significant in BRAF V600E mCRC [4]. A secondary analysis of two randomized adjuvant colorectal clinical trials including 1,395 patients revealed on multivariable analysis that patients with tumors with deficient mismatch repair proteins (dMMR) had significantly better survival after recurrence (SAR) than patients with tumors with proficient mismatch repair proteins (pMMR) [28]. However, considering the strong association of dMMR and BRAF V600E, further subgroup analysis of dMMR and BRAF V600E as a combined variable in relation to SAR reported that patients had similarly poor adjusted median SAR times if tumors were dMMR plus mutant BRAF V600E or pMMR plus mutant BRAF V600E, although both groups had shorter SAR when compared with pMMR and BRAF wild‐type, highlighting the poor prognostic effect of BRAF V600E [28]. In the current study, patients with MSI‐H BRAF V600E mCRC had a numerical trend towards a worse overall survival when compared with patients with MSS BRAF V600E mCRC tumors. Interestingly, both patients who remain without evidence of disease after metastasectomy in our cohort were MSS. As targeting BRAF V600E and the MAPK pathway has transformed the treatment paradigm for this disease, a similar approach of targeting MSI‐H/dMMR mCRC with immunotherapy may revitalize treatment options for BRAF V600E mCRC (Clinical trial information: KEYNOTE 177 [NCT02563002]; CheckMate 142 [NCT02060188]).

Secondly, in regard to treatment, constitutive BRAF activity evades upstream EGFR inhibition; therefore, monotherapy with EGFR inhibition was suspected to have limited clinical response in BRAF V600E mCRC. Retrospective reviews of clinical trials as well as a large meta‐analysis have revealed that the use of EGFR inhibition as monotherapy or in addition to chemotherapy did not significantly improve PFS, OS, or overall response rates in patients with BRAF V600E mCRC compared with control regimens [29], [30], [31]. Preclinical models have elegantly shown that isolated BRAF inhibition results in feedback reactivation of the EGFR protein as the underlying mechanism of resistance [32]. This trend was consistent within our series of BRAF V600E mCRC, as use of anti‐EGFR therapy in combination with chemotherapy was numerically suggestive of poorer OS when compared with treatment with chemotherapy alone.

We acknowledge that the current study has several limitations. First, patients evaluated at a large academic center tend to have an excellent performance status as compared with all patients with advanced colorectal cancer, reflecting a potential selection and referral bias. Also, the non‐randomized, retrospective, and single‐institutional experience of the study presents additional limitations to the data. Finally, we report an enhanced survival outcome among patients with BRAF V600E mCRC who underwent metastasectomy at our institution but recognize that within our cohort selection, bias due to an enrichment of surgically resectable liver‐limited metastatic disease is possible considering the clinical predominance and poor survival outcomes of unresectable peritoneal disease in patients with BRAF V600E mCRC.

Conclusion

In our study, patients with BRAF V600E mCRC who underwent metastasectomy for management of oligometastatic disease had longer median OS and PFS when compared with the non‐metastasectomy cohort. Long‐term disease‐free interval with a potential for cure is possible for a select group of patients with BRAF V600E mCRC. Clinical investigation incorporating the use of immunotherapy for MSI‐H BRAF V600E mCRC may potentially shift the treatment paradigm for this aggressive disease. Our results suggest that a multimodality approach incorporating the utilization of metastasectomy for select patients with BRAF V600E mCRC can be offered and may reflect a critical component for enhanced survival outcomes.

See http://www.TheOncologist.com for supplemental material available online.

Author Contributions

Conception/design: Benny Johnson, Zhaohui Jin, Benjamin R. Kipp, Axel Grothey

Financial support: none

Administrative support: none

Provision of study material or patients: Benny Johnson, Zhaohui Jin, Mark J. Truty, Rory L. Smoot, David M. Nagorney, Michael L. Kendrick, Axel Grothey

Collection and/or assembly of data: Benny Johnson, Zhaohui Jin

Data analysis and interpretation: Benny Johnson, Zhaohui Jin, Mark J. Truty, Rory L. Smoot, David M. Nagorney, Michael L. Kendrick, Benjamin R. Kipp, Axel Grothey

Manuscript writing: Benny Johnson, Zhaohui Jin, Axel Grothey

Final approval of manuscript: Benny Johnson, Zhaohui Jin, Mark J. Truty, Rory L. Smoot, David M. Nagorney, Michael L. Kendrick, Benjamin R. Kipp, Axel Grothey

Disclosures

Benjamin R. Kipp: Abbott Molecular Inc. (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board