Abstract
Background
To date, only two studies have compared the outcomes of patients with liver-limited BRAF V600E-mutated colorectal liver metastases (CRLMs) managed with resection versus systemic therapy alone, and these have reported contradictory findings.
Methods
In this observational, international, multicentre study, patients with liver-limited BRAF V600E-mutated CRLMs treated with resection or systemic therapy alone were identified from institutional databases. Patterns of recurrence/progression and overall survival were compared using multivariable analyses of the entire cohort and a propensity score-matched cohort.
Results
Of 170 patients included, 119 underwent hepatectomy and 51 received systemic treatment. Surgically treated patients had a more favourable pattern of recurrence with most recurrences limited to a single site, whereas diffuse progression was more common among patients who received systemic treatment (19 versus 44%; P = 0.002). Surgically treated patients had longer median overall survival (35 versus 20 months; P < 0.001). Hepatectomy was independently associated with better OS than systemic treatment alone (HR 0.37, 95% c.i. 0.21 to 0.65). In the propensity score-matched cohort, surgically treated patients had longer median overall survival (28 versus 20 months; P < 0.001); hepatectomy was independently associated with better overall survival (HR 0.47, 0.25 to 0.88).
Conclusion
BRAF V600E mutation should not be considered a contraindication to surgery for patients with resectable, liver-only CRLMs.
In this international, multi-institutional study, outcomes were compared among patients with BRAF V600E, liver-limited metastatic colorectal cancer who were treated with surgery versus systemic therapy alone. Surgery was independently associated with better survival, and this was confirmed by several subanalyses that compared surgically and medically treated patients with comparable baseline disease or tumour burden. The favourable outcomes of surgery may stem from the distinct recurrence patterns of surgical patients.
Introduction
BRAF V600E is the most prevalent BRAF mutation in colorectal cancer, with a reported prevalence ranging between 8 and 15% in patients with metastatic colorectal cancer. It is less common among patients with resectable colorectal liver metastases (CRLMs) than among those undergoing systemic therapy alone (2–4 versus 5–10% respectively)1–3. This is probably because patients with BRAF-mutated (BRAFmut) metastatic colorectal cancer tend to experience widespread extrahepatic metastases, rendering them unsuitable for surgery. Conversion of initially unresectable CRLMs is achievable in up to 25% of patients, particularly among those with borderline or unresectable liver-only disease4.
The most recent meta-analysis5 of studies that analysed outcomes of patients with surgically treated BRAFmut CRLMs was published in 2021, and provided conclusive evidence that patients with BRAFmut CRLMs fare worse than those with BRAF wild-type tumours. All included studies were, however, conducted in surgical cohorts only. None compared outcomes between surgically versus systemically treated patients with BRAFmut tumours. Thus, the important question of whether or not surgery is associated with better outcomes than systemic therapy alone could be not answered. Surgery in patients with BRAFmut CRLMs has been questioned following reports of diffuse, unresectable recurrences and poor survival outcomes after surgery6,7.
Significant heterogeneity was observed in the aforementioned meta-analysis. Five studies examining outcomes of surgically treated patients reported low median overall survival (OS) times of 7–26 months, whereas two studies reported a much longer median OS time of 47–52 months1,8–13. Regarding systemically treated patients, a phase II trial14 of FOLFOXIRI (5-FU, Oxaliplatin and Irinotecan based regimen) in patients with BRAFmut metastatic colorectal cancer reported a median OS of 24.1 months. Thus, depending on which study is used as a point of reference, surgical treatment may or may not seem to have a benefit over systemic therapy alone.
Moreover, baseline disease characteristics may confound underlying treatment effects. Surgically treated patients might have a more favourable disease profile, liver-limited disease, and more limited tumour burden, which may explain the superior outcomes reported in some studies. The aim of the present study was to analyse outcomes among patients with liver-only V600E BRAFmut CRLMs treated with surgery or systemic therapy alone both in aggregate and across different risk subgroups and systemic treatments.
Methods
Selection of patients
This was a multicentre retrospective study of all patients who underwent surgical treatment for BRAFmut CRLMs at the Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, centres comprising the International Genetic Consortium for Colorectal Liver Metastasis, and seven collaborating academic institutions from Italy between 2000 and 2018 (supplementary material).
Patients older than 18 years with liver-limited metastatic disease who underwent complete resection of both the primary tumour and CRLMs, and harboured BRAF V600E mutations were eligible to participate in the study. Patients with concurrent extrahepatic disease were excluded because of the inherent challenges in matching for extent of extrahepatic disease. Specifically, patients who receive systemic treatment often have significant extrahepatic disease, whereas patients who undergo resection typically have limited or no extrahepatic involvement.
The prospectively maintained database of the nine Italian tertiary academic centres that comprise the BRAF BeCool real-world data set (supplementary material) was queried for consecutive patients with BRAFmut CRLMs who received systemic therapy alone between January 2007 and December 201815. This relatively recent time frame was selected in order to capture the effect of contemporary chemotherapy regimens and biological agents on outcomes.
Patients aged over 18 years who underwent complete resection of the primary tumour and were treated exclusively with systemic therapy for BRAFmut V600E, liver-limited metastatic colorectal cancer were considered for inclusion in the study. Of note, the BRAF BeCool database has a variable for liver-only baseline disease.
The study was conducted in accordance with the ethical standards of the participating institutions and was approved by all institutional review boards. A detailed ethics statement is provided in the supplementary material, along with a detailed description of how data were extracted.
The presence of the BRAF V600E mutation was identified by genetic analysis of either the primary tumour or the CRLMs using contemporary sequencing technologies at each participating institution. This was supported by data demonstrating a high concordance rate for BRAF mutational status between primary and metastatic colorectal cancer16–19.
Main outcomes of the study were OS, recurrence-free survival (RFS), and progression-free survival (PFS). To maintain consistency across both groups, all survival estimates were calculated from the date of CRLM diagnosis.
Statistical analysis
Outcomes between surgically and systemically treated patients were compared in aggregate and separately for three high-risk subgroups of surgically treated patients versus all systemically treated patients. These subgroups were formed by: selecting surgically treated patients who were matched to systemically treated patients for potential confounders; identifying a prognostic cut-off for the Clinical Risk Score (CRS) in the surgical cohort and selecting patients with scores exceeding that cut-off for comparison with the systemically treated cohort; and identifying a prognostic cut-off for the Tumour Burden Score (TBS) in the surgical cohort and selecting patients with scores exceeding that cut-off for comparison with the systemically treated cohort20,21. The TBS is a novel instrument that facilitates quantification of the disease burden in patients with CRLMs and exhibits a close correlation with outcomes. Sasaki et al. showed that a TBS of 9 or more was associated with the worst outcomes in all-comers with surgically resected CRLMs. In the fourth subanalysis, outcomes of surgically treated patients were compared with those of the subset of systemically treated patients who received intensified chemotherapy with FOLFOXIRI plus bevacizumab22. Then, the outcomes of surgically versus systemically treated patients with microsatellite-stable (MSS) tumours only were compared, as only two of seven patients in the microsatellite instability (MSI) subgroup in the systemic treatment cohort received the current standard of care, which is immunotherapy. In the final subanalysis, the aim was to identify whether or not the co-presence of specific adverse prognostic factors could identify a subset of surgical patients for whom surgery is futile owing to an exceptionally poor prognosis12.
STROBE reporting guidelines were followed (supplementary material). Continuous variables are presented as median (i.q.r.) and categorical variables as counts with percentages. Categorical variables were compared by means of the χ2 test, whereas the Mann–Whitney U test was used for analysis of continuous variables. Median follow-up was calculated using the reverse Kaplan–Meier method23. The Kaplan–Meier method and the log rank test were used for univariable survival analysis. Univariable and multivariable Cox regression analyses were performed to: assess whether a CRS of 4 or higher was prognostic of poor outcomes for patients with surgically resected BRAFmut CRLMs; identify prognostic cut-offs for CRS and TBS; and examine whether surgery (versus systemic therapy alone) is an independent predictor of OS and RFS/PFS. The number of variables included in the Cox analysis adhered to the requirement for a minimum of 10 outcome events per predictor variable. Nearest-neighbour propensity score matching for potential confounders was undertaken using the MatchIt package for R 3.5.1. Confounders were defined as variables unevenly distributed across both treatment groups (P < 0.100; primary lymph node status, disease-free interval, carcinoembryonic antigen (CEA), number of tumours exceeding 3, and bilobar disease)24. The cut-offs for the variables were selected based on recent literature24–27. Logistic regression was used to estimate the distance measure and the caliper was set to 0.01. All analyses were conducted using R 5.3.0 (https://www.r-project.org/).
Results
Baseline characteristics
Of 170 patients included, 119 underwent liver resection and 51 were treated with systemic therapy alone (Fig. S1). Baseline characteristics of surgically versus systemically treated patients are shown in Table 1. Patients who received systemic therapy alone had a higher baseline disease burden reflected by higher CEA levels, more liver metastases, and higher rate of bilobar involvement compared with surgically treated patients. No other differences were observed between groups. A detailed description of the systemic therapies and the treatment response in medically treated patients is provided in the Supplementary material.
Table 1.
Baseline characteristics of entire cohort of surgically versus systemically treated patients with BRAF V600E-mutated liver-limited colorectal liver metastases
| Surgically treated (n = 119) | Systemically treated (n = 51) | P‡ | |
|---|---|---|---|
| Age (years), median (i.q.r.) | 64.0 (56.7–71.0) | 65.3 (59.4–69.8) | 0.458§ |
| Sex | 0.421 | ||
| Male | 64 (53.8) | 24 (47) | |
| Female | 55 (46.2) | 27 (53) | |
| Primary tumour side | 0.377 | ||
| Right | 70 (72.2) | 31 (79) | |
| Left | 27 (27.8) | 8 (21) | |
| T category of primary tumour | 0.368 | ||
| T1 | 3 (2.5) | 0 (0) | |
| T2 | 11 (9.4) | 2 (4) | |
| T3 | 67 (57.3) | 29 (58) | |
| T4 | 36 (30.8) | 19 (38) | |
| Primary lymph node involvement | 0.093 | ||
| No metastases | 33 (28.2) | 8 (16) | |
| Metastases | 84 (71.8) | 42 (84) | |
| Primary tumour grade | 0.540 | ||
| 0 | 5 (5.3) | 1 (2) | |
| 1 | 44 (46.8) | 20 (39) | |
| 2 | 43 (45.7) | 29 (57) | |
| 3 | 2 (2.1) | 1 (2) | |
| CEA (μg/l), median (i.q.r.) | 7.7 (3.2–19.4) | 22.0 (4.3–93.2) | 0.008§ |
| Disease-free interval (months) | 0.068 | ||
| < 12 | 94 (81) | 47 (92) | |
| ≥ 12 | 22 (19) | 4 (8) | |
| Prehepatectomy chemotherapy | |||
| No | 66 (55.5) | ||
| Yes* | 53 (44.5) | ||
| Oxaliplatin | 41 | ||
| Irinotecan | 21 | ||
| Capecitabine | 5 | ||
| Anti-VEGF | 15 | ||
| Anti-EGFR | 12 | ||
| Resectability status | |||
| Initially resectable | 91 (80.5) | ||
| Converted | 22 (19.5) | ||
| Diameter of largest CRLM (cm), median (i.q.r.) | 2.3 (1.6–4.5) | 2.5 (1.6–5.3) | 0.404§ |
| No. of CRLMs, median (i.q.r.) | 2.0 (1.0–4.0) | 6.0 (4.0–11.0) | < 0.001§ |
| Bilobar distribution | < 0.001 | ||
| No | 77 (64.7) | 14 (27) | |
| Yes | 42 (35.3) | 37 (73) | |
| Surgical margin status | |||
| R0 | 104 (87.4) | – | |
| R1 | 15 (12.6) | – | |
| Ablation associated with hepatectomy | |||
| No | 99 (89.2) | ||
| Yes | 12 (10.8) | ||
| KRAS mutated | 0.057 | ||
| No | 110 (93.2) | 51 (100) | |
| Yes | 8 (6.8) | 0 (0) | |
| MSI status | 0.644 | ||
| MSS | 72 (79.1) | 21 (75) | |
| MSI | 19 (20.9) | 7 (25) | |
| MSI unknown | 28 | 23 | |
| Mucinous histology | 0.219 | ||
| No | 83 (74.1) | 33 (65) | |
| Yes | 29 (25.9) | 18 (35) | |
| Posthepatectomy chemotherapy† | |||
| No | 29 (24.4) | ||
| Yes* | 90 (75.6) | ||
| Oxaliplatin | 47 | ||
| Irinotecan | 23 | ||
| Capecitabine | 3 | ||
| Anti-VEGF | 29 | ||
| Anti-EGFR | 1 | ||
| 5-FU | 5 | ||
| Salvage surgery (n = 11) | |||
| Hepatectomy | 8 (72.7) | ||
| Pulmonary resection | 1 (9.1) | ||
| Abdominal wall surgery | 2 (18.2) |
Values are n (%) unless otherwise indicated. *Some patients received more than one regimen, so percentages for type of systemic therapy are not reported. †Regimen unknown for 22 patients. CEA, carcinoembryonic antigen; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; CRLM, colorectal liver metastasis; MSI, microsatellite instability; MSS, microsatellite stable; 5-FU, 5-fluorouracil. ‡χ2 test, except §Mann–Whitney U test.
Overall survival
Median follow-up was 63 and 49 months for surgically and systemically treated patients respectively. One patient died within 90 days of surgery. Median OS in the entire cohort was 27 (i.q.r. 23–34) months. Patients treated with surgery had longer median OS (35 (28–46) versus 20 (14–22) months; P < 0.001) (Fig. 1a). Liver resection was independently associated with better OS in multivariable analysis (Table 2).
Fig. 1.
Overall survival for surgically versus systemically treated patients
a Whole cohort and b after propensity score matching. *Excluding six patients who had unknown overall survival; †excluding one patient with unknown date of diagnosis of colorectal liver metastases (CRLMs). a,b P < 0.001 (log rank test).
Table 2.
Univariable and multivariable overall survival analysis for entire cohort
| Univariable analysis | Multivariable analysis | |||
|---|---|---|---|---|
| HR | P | HR | P | |
| Age > 60 years | 0.94 (0.64, 1.37) | 0.739 | ||
| Female sex | 0.91 (0.63, 1.31) | 0.611 | ||
| T category | ||||
| T1–T2 | 1.00 (reference) | |||
| T3–T4 | 1.06 (0.55, 2.03) | 0.859 | ||
| Lymph node metastases | 2.34 (1.42, 3.84) | < 0.001 | 1.86 (0.96, 3.62) | 0.065 |
| Disease-free interval < 12 months | 1.60 (0.90, 2.85) | 0.112 | ||
| Tumour size > 3 cm | 1.17 (0.80, 1.69) | 0.418 | ||
| CEA (μg/l)* | 1.00 (0.99, 1.00) | 0.456 | ||
| > 3 tumours | 1.69 (1.17, 2.44) | < 0.001 | 1.35 (0.67, 2.72) | 0.396 |
| Bilobar disease | 1.53 (1.06, 2.22) | 0.024 | 0.89 (0.45, 1.75) | 0.742 |
| Left-sided primary tumour | 0.70 (0.43, 1.14) | 0.154 | ||
| KRAS mutated | 0.60 (0.24, 1.47) | 0.263 | ||
| MSI | 0.43 (0.23, 0.82) | 0.010 | 0.52 (0.26, 1.04) | 0.064 |
| Treatment type | ||||
| Systemic therapy alone | 1.00 (reference) | |||
| Surgery | 0.38 (0.26, 0.57) | < 0.001 | 0.37 (0.21, 0.65) | <0.001 |
| Grade | ||||
| 0–1 | 1.00 (reference) | |||
| 2–3 | 1.36 (0.90, 2.04) | 0.145 | ||
| Mucinous histology | 1.22 (0.82, 1.82) | 0.331 | ||
Values in parentheses are 95% confidence intervals. Prognostic factors that were only applicable to one cohort could not be included in the analysis (for example adjuvant chemotherapy was administered only to patients with surgically treated colorectal liver metastases). *HR values are shown per unit increase. CEA, carcinoembryonic antigen; MSI, microsatellite instability.
Among the 44 surgical patients who were alive at last follow-up, 11 were actual 5-year survivors. Of these, two were still alive 10 years after surgery and can be considered cured. In contrast, among the 11 systemically treated patients who were alive at last follow-up, there were no actual 5-year survivors.
Recurrence- and progression-free survival, and patterns of recurrence/progression
Median RFS for surgically treated patients was longer than median PFS for systemically treated patients (13 (12–18) versus 9 (6–10) months; P < 0.001) (Fig. 2a). Surgery was independently associated with improved RFS in multivariable analysis (Table S1). Of six surgical patients with 5-year follow-up, five remained recurrence-free at 5 years. In contrast, there were no systemically treated patients without disease progression at 5-year follow-up. Notably, the patient with the longest ongoing complete response (after follow-up of 29 months) had a tumour showing MSI and was treated with immunotherapy.
Fig. 2.
Recurrence/progression-free survival for surgically versus systemically treated patients
a Whole cohort and b after propensity score matching. *Excluding one patient with unknown date of diagnosis of colorectal liver metastases (CRLMs) and one with unknown recurrence status. a P < 0.001, b P = 0.030 (log rank test).
Of the 95 surgically treated (79.8%) and 47 systemically treated (92%) patients who experienced recurrence and progression, the specific sites of recurrence and progression were documented for 93 and 43 patients respectively (Table 3). The rate of diffuse (intrahepatic and extrahepatic) progression was higher in systemically treated patients (44 versus 19%; P = 0.002).
Table 3.
Patterns of recurrence/progression among patients treated surgically versus systemically in the entire cohort
| Surgically treated (n = 119) | Systemically treated (n = 51) | P* | |
|---|---|---|---|
| Recurrence/progression | 0.071 | ||
| No | 24 (20.2) | 4 (8) | |
| Yes | 95 (79.8) | 47 (92) | |
| Recurrence/progression site | 0.002 | ||
| Liver only | 46 (49.5) | 20 (47) | |
| Extrahepatic only | 29 (31.2) | 4 (9) | |
| Both | 18 (19.3) | 19 (44) |
Values are n (%) unless otherwise indicated. *χ2 test.
Outcomes after disease recurrence/progression
Among surgically treated patients, those who underwent salvage surgery had the most favourable median OS (46 months), but even surgical patients who experienced recurrence but did not undergo salvage surgery had better median OS after recurrence than systemically treated patients who experienced progressive disease (14 (10–19) versus 7 (6–10) months; P < 0.001) (Fig. S2). Among 26 surgical patients who experienced recurrent disease and were alive at last follow-up, there were 3 actual 5-year survivors. In contrast, none of the systemically treated patients survived for more than 2.5 years after disease progression.
Subanalyses
Propensity score-matched cohorts
Baseline characteristics of surgically versus systemically treated patients after propensity score matching are summarized in Table S2. Matched surgical patients had better OS than systemically treated patients (28 (25–47) versus 20 (14–22) months; P < 0.001) (Fig. 1b). Surgery was independently associated with better OS in multivariable analysis (Table S3). Median RFS was longer for matched surgically treated patients (13 versus 9 months; P = 0.030) (Fig. 2b). Consistent with the main analysis, the rate of diffuse (intrahepatic and extrahepatic) recurrence in systemically treated patients was higher than that in matched surgical patients (39% versus 13%; P = 0.009).
Surgically treated patients with high Clinical Risk Scores versus systemically treated patients
As only eight patients had a CRS of 4 or higher in the study cohort12, a CRS of at least 3 was investigated as potential prognostic factor. Fifty-eight patients in the surgical cohort had a CRS of 3 or more. This CRS cut-off was independently associated with shorter OS (HR 2.16, 95% c.i. 1.04 to 4.47). Despite faring worse than the unselected surgical cohort, surgical patients with a CRS of at least 3 had longer OS than systemically treated patients (median 28 versus 20 months; P = 0.004).
Surgically treated patients with advanced Tumour Burden Scores versus systemically treated patients
Only 14 patients had a TBS of 8 or higher in the study cohort. Therefore, a TBS of at least 7 (23 patients) was employed as a prognostic cut-off, and was found to be independently associated with shorter OS in multivariable analysis (HR 2.30; 95% c.i. 1.11 to 4.46). Despite faring worse than the unselected surgical cohort, surgical patients with a TBS of 7 or more had longer median OS compared than systemically treated patients (24 versus 20 months; P = 0.050).
Surgically treated patients versus patients treated with FOLFOXIRI plus bevacizumab
Surgical patients had better OS than systemically treated patients who received FOLFOXIRI plus bevacizumab (35 versus 21 months; P < 0.001) (Fig. S3). This benefit was sustained in surgical patients with a CRS of 3 or higher (28 versus 21 months; P = 0.002) or a TBS of at least 7 (24 versus 21 months; P = 0.015).
Surgically versus systemically treated patients with microsatellite-stable tumours
Surgically treated patients with MSS tumours had better OS than their systemically treated counterparts (median 28 versus 15 months; P < 0.001) (Fig. S4). This survival benefit persisted in surgically treated patients with a CRS of 3 or more (24 versus 15 months; P < 0.001).
Surgically versus systemically treated patients with unfavourable characteristics
Surgically treated patients with unfavourable characteristics had better survival than systemically treated patients (median 26 versus 15 months; P < 0.001) (Fig. S5).
Discussion
The findings of this study contradict the notion that surgery may be futile because of early, diffuse recurrences. Specifically, although most surgical patients had recurrent disease, only a minority experienced simultaneous intrahepatic and extrahepatic recurrence, unlike systemically treated patients who developed progression, with nearly half showing progression at multiple sites. It is possible that the early surgical reduction of tumour burden drove the favourable pattern of recurrence. This finding was consistent in the propensity-matched cohort. This may explain why survival after recurrence for surgical patients was more favourable than survival after progression for systemically treated patients; in fact, a small percentage of surgically treated patients survived for 5 years or more after recurrence, whereas all systemically treated patients died from disease within 2.5 years of the first documented progression. The impact of recurrence pattern on survival is further supported by the fact that surgical patients who did not undergo salvage surgery for recurrence still fared better than systemically treated patients who had progressive disease. In all analyses, surgical treatment was associated with improved OS.
Although a few studies have evaluated the role of metastasectomy in BRAFmut metastatic colorectal cancer, most reported on outcomes of liver-only disease in aggregate with other sites of metastatic colorectal cancer28,29. This is problematic given the prognostic significance of concurrent extrahepatic disease. In fact, a previous study showed that the presence of both a BRAF V600E mutation and extrahepatic disease was associated with a median OS of only 6.5 months and an 18-month OS rate of zero.3 By comparison, another study26 reported a median OS time of 34 months and a 5-year survival rate of 28% in patients with unknown mutational status and concurrent extrahepatic disease. Thus, for patients with concurrent extrahepatic disease, it appears that surgery is futile for those with BRAF V600E-mutated CRLMs and indicated for those with BRAF V600E wild-type CRLMs.
To date, only two studies22,30 (both published in the past 3 years) have compared the outcomes of patients with BRAFmut liver-only CRLM who were treated with surgery versus systemic treatment alone. Of note, these two studies reported contradictory findings. The authors of the multicentre study22 from Japan concluded that even technically resectable BRAFmut liver-only CRLMs should be considered oncologically unresectable. Their cohort, however, included only five patients with resected BRAF V600E-mutated CRLMs, which precluded a matched analysis. In contrast, a multicentre study from France included 49 patients who underwent resection of BRAF V600E-mutated, liver-limited CRLMs. Surgery was associated with longer OS compared with systemic therapy alone. The authors of this study did not perform a matched analysis either.
The present study had some limitations. It was not possible to fully match patient characteristics in the context of a retrospective study. In addition, the outcomes for patients with MSI tumours treated with surgery versus chemotherapy and immunotherapy were not compared, as only two of seven systemically treated patients received immunotherapy31. Of note, the systemic cohort also did not receive BRAF inhibitors, which is not reflective of contemporary clinical practice. Future studies should independently assess the outcomes of patients with upfront resectable disease and those with initially unresectable disease that converts to resectable and compare both with appropriately matched systemically treated patients. The present study did not pursue this analysis owing to the small sample size, particularly in the conversion surgery group.
Although the development of new prognostic biomarkers and analytical approaches may eventually help identify patients whose tumours are not ‘biologically resectable’, this study suggests that the mere presence of a BRAF V600E mutation should not be a contraindication to surgery for patients with resectable liver-limited CRLMs, particularly those with MSS tumours.
Supplementary Material
Acknowledgements
G.A.M. and J.J.W. contributed equally to this work. The authors thank Dr N. Bampatsikou for excellent technical support.
Contributor Information
Georgios Antonios Margonis, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Jaeyun Jane Wang, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Thomas Boerner, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Roberto Moretto, Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa, Italy.
Stefan Buettner, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nikolaos Andreatos, Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Johan Gagnière, Department of Digestive and Hepatobiliary Surgery—Liver Transplantation U1071 Inserm/Clermont-Auvergne University Hospital of Clermont-Ferrand, Clermont-Ferrand, France.
Doris Wagner, Department of General Surgery, Medical University of Graz, Graz, Austria.
Inger Marie Løes, Department of Clinical Science, University of Bergen, Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Francesca Bergamo, Unit of Medical Oncology 1, Department of Oncology, Veneto Institute of Oncology, IRCCS, Padua, Italy.
Filippo Pietrantonio, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Mario Scartozzi, Medical Oncology, University Hospital of Cagliari, Cagliari, Italy.
Andrea Spallanzani, Department of Oncology and Haematology, Division of Oncology, University Hospital of Modena, Modena, Italy.
Bruno Vincenzi, Department of Medical Oncology, Campus Bio-Medico, Università di Roma, Rome, Italy.
Efstathios Antoniou, Third Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, ‘Attikon’ University General Hospital, Athens, Greece.
Emmanouil Pikoulis, Third Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, ‘Attikon’ University General Hospital, Athens, Greece.
Andrea Sartore-Bianchi, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Division of Clinical Research and Innovation, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Georgios Stasinos, Technical Chamber of Greece, Athens, Greece.
Kazunari Sasaki, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
Timothy M Pawlik, Department of Surgery, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Armando Orlandi, Comprehensive Cancer Centre, Medical Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Rome, Italy.
Nicoletta Pella, Department of Oncology, ASUFC University Hospital of Udine, Udine, Italy.
Fabian Fitschek, Department of General Surgery, Medical University of Vienna, Vienna, Austria.
Klaus Kaczirek, Department of General Surgery, Medical University of Vienna, Vienna, Austria.
Aurélien Dupré, Department of Surgery, Léon Bérard Cancer Centre Lyon, Lyon, France.
Ioannis Pozios, Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany.
Katharina Beyer, Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany.
Peter Kornprat, Department of General Surgery, Medical University of Graz, Graz, Austria.
Federico N Aucejo, Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Richard Burkhart, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Matthew J Weiss, Northwell Health Cancer Institute, Zucker School of Medicine at Hofstra, New York, New York, USA.
Per Eystein Lønning, Department of Clinical Science, University of Bergen, Department of Oncology, Haukeland University Hospital, Bergen, Norway.
George Poultsides, Technical Chamber of Greece, Athens, Greece.
Chiara Cremolini, Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa, Italy.
Martin E Kreis, Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany.
Michael D’Angelica, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Funding
This work was funded by National Cancer Institute award P30-CA008748 and partially by Italian Ministry of Health Finalized Grant, project number GR-2019–12368903. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Author contributions
Georgios Antonios Margonis (Conceptualization, Formal analysis, Resources, Supervision, Writing—original draft, Writing—review & editing), Jane Wang (Investigation, Resources, Writing—original draft, Writing—review & editing), Thomas Boerner (Investigation, Resources, Writing—review & editing), Roberto Moretto (Investigation, Resources, Writing—review & editing), Stefan Buettner (Formal analysis, Resources, Writing—review & editing), Nikolaos Andreatos (Investigation, Writing—review & editing), Johan Gagnière (Investigation, Resources, Writing—review & editing), Doris Wagner (Investigation, Resources, Writing—review & editing), Inger Marie Loes (Investigation, Resources, Writing—review & editing), Francesca Bergamo (Investigation, Resources, Writing—review & editing), Filippo Pietrantonio (Investigation, Resources, Writing—review & editing), Mario Scartozzi (Investigation, Resources, Writing—review & editing), Andrea Spallanzani (Investigation, Resources, Writing—review & editing), Bruno Vincenzi (Investigation, Resources, Writing—review & editing), Efstathios Antoniou (Investigation, Writing—review & editing), Emmanouil Pikoulis (Writing—review & editing), Andrea Sartorebianchi (Investigation, Resources, Writing—review & editing), Georgios Stasinos (Formal analysis, Writing—review & editing), Kazunari Sasaki (Investigation, Resources, Writing—review & editing), Timothy Pawlik (Investigation, Writing—review & editing), Armando Orlandi (Investigation, Resources, Writing—review & editing), Nicoletta Pella (Investigation, Resources, Writing—review & editing), Fabian Fitschek (Investigation, Resources, Writing—review & editing), Klaus Kaczirek (Investigation, Resources, Writing—review & editing), Aurélien Dupré (Investigation, Resources, Writing—review & editing), Ioannis Pozios (Investigation, Resources, Writing—review & editing), Katharina Beyer (Investigation, Resources, Writing—review & editing), Peter Kornprat (Investigation, Resources, Writing—review & editing), Federico N. Aucejo (Investigation, Resources, Writing—review & editing), Richard Burkhart (Investigation, Resources, Writing—review & editing), Matthew Weiss (Resources, Writing—review & editing), Per Eystein Lönning (Investigation, Resources, Writing—review & editing), George Poultsides (Investigation, Resources, Writing—review & editing), Chiara Cremolini (Investigation, Resources, Supervision, Writing—review & editing), Martin Kreis (Conceptualization, Resources, Supervision, Writing—review & editing), and Michael D’Angelica (Conceptualization, Resources, Supervision, Writing—original draft, Writing—review & editing)
Disclosure
F.P. declares honoraria from Merck-Serono, Amgen, Bayer, Servier, Takeda, Pierre-Fabre, MSD, BMS, and Astellas; and research grants for no-profit studies from AstraZeneca, BMS, Agenus, and Amgen. C.C. declares honoraria from Amgen, Bayer, Merck, Roche, and Servier; a consulting or advisory role with Amgen, Bayer, MSD, and Roche; speakers’ bureau with Servier; research funding from Bayer, Merck, and Servier; and travel, accommodation, and expenses from Roche and Servier. M.S. declares advisory board and speakers’ bureau with Amgen, GSK, Merck, Servier, MSD, and BMS. B.V. declares consulting fees from Eisai, Lilly, Bayer, Deciphera, PharmaMar, Blueprint, Pfizer, GSK, Accord, and Abbott; and research support from PharmaMar, Novartis, and Lilly. A.S.-B. declares advisory boards and personal fees from Amgen, Bayer, BMS, Novartis, and Servier. The authors declare no other conflict of interest.
Supplementary material
Supplementary material is available at BJS online.
Data availability
The data sets used in the present study are not publicly available but may be available from the corresponding author on reasonable request depending on the policy and procedures of the institutions that participated in the consortia.
References
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- 14. Loupakis F, Cremolini C, Salvatore L, Masi G, Sensi E, Schirripa M et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer 2014;50:57–63 [DOI] [PubMed] [Google Scholar]
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- 17. Brannon AR, Vakiani E, Sylvester BE, Scott SN, McDermott G, Shah RH et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol 2014;15:454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Fujiyoshi K, Yamamoto G, Takahashi A, Arai Y, Yamada M, Kakuta M et al. High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases. Oncol Rep 2017;37:785–792 [DOI] [PubMed] [Google Scholar]
- 19. Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30:2956–2962 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–318; discussion 318–321 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Sasaki K, Morioka D, Conci S, Margonis GA, Sawada Y, Ruzzenente A et al. The tumor burden score: a new ‘Metro-ticket’ prognostic tool for colorectal liver metastases based on tumor size and number of tumors. Ann Surg 2018;267:132–141 [DOI] [PubMed] [Google Scholar]
- 22. Kobayashi S, Takahashi S, Nomura S, Kojima M, Kudo M, Sugimoto M et al. BRAF v600e potentially determines ‘oncological resectability’ for ‘technically resectable’ colorectal liver metastases. Cancer Med 2021;10:6998–7011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Clark TG, Bradburn MJ, Love SB, Altman DG. Survival analysis part I: basic concepts and first analyses. Br J Cancer 2003;89:232–238 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Kamphues C, Andreatos N, Kruppa J, Buettner S, Wang J, Sasaki K et al. The optimal cut-off values for tumor size, number of lesions, and CEA levels in patients with surgically treated colorectal cancer liver metastases: an international, multi-institutional study. J Surg Oncol 2021;123:939–948 [DOI] [PubMed] [Google Scholar]
- 25. Lillemoe HA, Passot G, Kawaguchi Y, DeBellis M, Glehen O, Chun YS et al. RAS/TP53 co-mutation is associated with worse survival after concurrent resection of colorectal liver metastases and extrahepatic disease. Ann Surg 2022;276:357–362 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Leung U, Gonen M, Allen PJ, Kingham TP, DeMatteo RP, Jarnagin WR et al. Colorectal cancer liver metastases and concurrent extrahepatic disease treated with resection. Ann Surg 2017;265:158–165 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004;240:644–657; discussion 657–658 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Johnson B, Truty JZ, Smoot MJ, Nagorney RL, Kendrick DM, Kendrick ML et al. Impact of metastasectomy in the multimodality approach for BRAF V600E metastatic colorectal cancer: the Mayo Clinic experience. Oncologist 2018;23:128–134 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Prasanna T, Wong R, Price T, Shapiro J, Tie J, Wong HL et al. Metastasectomy and BRAF mutation; an analysis of survival outcome in metastatic colorectal cancer. Curr Probl Cancer 2021;45:100637. [DOI] [PubMed] [Google Scholar]
- 30. Javed S, Benoist S, Devos P, Truant S, Guimbaud R, Lievre A et al. Prognostic factors of BRAF V600E colorectal cancer with liver metastases: a retrospective multicentric study. World J Surg Oncol 2022;20:131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt Cet al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:2207–2218 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data sets used in the present study are not publicly available but may be available from the corresponding author on reasonable request depending on the policy and procedures of the institutions that participated in the consortia.
References
- 1. Karagkounis G, Torbenson MS, Daniel HD, Azad NS, Diaz LA Jr, Donehower RC et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer 2013;119:4137–4144 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Margonis GA, Boerner T, Bachet JB, Buettner S, Moretto R, Andreatos N et al. Demystifying BRAF mutation status in colorectal liver metastases: a multi-institutional, collaborative approach to 6 open clinical questions. Ann Surg 2023;278:e540–e548 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Uutela A, Nordin A, Osterlund E, Halonen P, Kallio R, Soveri LM et al. Resectability and resection rates of colorectal liver metastases according to RAS and BRAF mutational status: prospective study. Br J Surg 2023;110:931–935 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Gau L, Ribeiro M, Pereira B, Poirot K, Dupre A, Pezet D et al. Impact of BRAF mutations on clinical outcomes following liver surgery for colorectal liver metastases: an updated meta-analysis. Eur J Surg Oncol 2021;47:2722–2733 [DOI] [PubMed] [Google Scholar]
- 6. Frankel TL, Vakiani E, Nathan H, DeMatteo RP, Kingham TP, Allen PJ et al. Mutation location on the RAS oncogene affects pathologic features and survival after resection of colorectal liver metastases. Cancer 2017;123:568–575 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Kobayashi S, Takahashi S, Takahashi N, Masuishi T, Shoji H, Shinozaki E et al. Survival outcomes of resected BRAF V600E mutant colorectal liver metastases: a multicenter retrospective cohort study in Japan. Ann Surg Oncol 2020;27:3307–3315 [DOI] [PubMed] [Google Scholar]
- 8. Deshwar A, Margonis GA, Andreatos N, Barbon C, Wang J, Buettner S et al. Double KRAS and BRAF mutations in surgically treated colorectal cancer liver metastases: an international, multi-institutional case series. Anticancer Res 2018;38:2891–2895 [DOI] [PubMed] [Google Scholar]
- 9. Loes IM, Immervoll H, Sorbye H, Angelsen JH, Horn A, Knappskog S et al. Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases. Int J Cancer 2016;139:647–656 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Schirripa M, Bergamo F, Cremolini C, Casagrande M, Lonardi S, Aprile G et al. BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection. Br J Cancer 2015;112:1921–1928 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Margonis GA, Buettner S, Andreatos N, Kim Y, Wagner D, Sasaki K et al. Association of BRAF mutations with survival and recurrence in surgically treated patients with metastatic colorectal liver cancer. JAMA Surg 2018;153:e180996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Gagniere J, Dupre A, Gholami SS, Pezet D, Boerner T, Gonen M et al. Is hepatectomy justified for BRAF mutant colorectal liver metastases?: a multi-institutional analysis of 1497 patients. Ann Surg 2020;271:147–154 [DOI] [PubMed] [Google Scholar]
- 13. Bachet JB, Moreno-Lopez N, Vigano L, Marchese U, Gelli M, Raoux L et al. BRAF mutation is not associated with an increased risk of recurrence in patients undergoing resection of colorectal liver metastases. Br J Surg 2019;106:1237–1247 [DOI] [PubMed] [Google Scholar]
- 14. Loupakis F, Cremolini C, Salvatore L, Masi G, Sensi E, Schirripa M et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer 2014;50:57–63 [DOI] [PubMed] [Google Scholar]
- 15. Loupakis F, Intini R, Cremolini C, Orlandi A, Sartore-Bianchi A, Pietrantonio F et al. A validated prognostic classifier for (V600E)BRAF-mutated metastatic colorectal cancer: the ‘BRAF BeCool’ study. Eur J Cancer 2019;118:121–130 [DOI] [PubMed] [Google Scholar]
- 16. Bhullar DS, Barriuso J, Mullamitha S, Saunders MP, O’Dwyer ST, Aziz O. Biomarker concordance between primary colorectal cancer and its metastases. EBioMedicine 2019;40:363–374 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Brannon AR, Vakiani E, Sylvester BE, Scott SN, McDermott G, Shah RH et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol 2014;15:454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Fujiyoshi K, Yamamoto G, Takahashi A, Arai Y, Yamada M, Kakuta M et al. High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases. Oncol Rep 2017;37:785–792 [DOI] [PubMed] [Google Scholar]
- 19. Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30:2956–2962 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–318; discussion 318–321 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Sasaki K, Morioka D, Conci S, Margonis GA, Sawada Y, Ruzzenente A et al. The tumor burden score: a new ‘Metro-ticket’ prognostic tool for colorectal liver metastases based on tumor size and number of tumors. Ann Surg 2018;267:132–141 [DOI] [PubMed] [Google Scholar]
- 22. Kobayashi S, Takahashi S, Nomura S, Kojima M, Kudo M, Sugimoto M et al. BRAF v600e potentially determines ‘oncological resectability’ for ‘technically resectable’ colorectal liver metastases. Cancer Med 2021;10:6998–7011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Clark TG, Bradburn MJ, Love SB, Altman DG. Survival analysis part I: basic concepts and first analyses. Br J Cancer 2003;89:232–238 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Kamphues C, Andreatos N, Kruppa J, Buettner S, Wang J, Sasaki K et al. The optimal cut-off values for tumor size, number of lesions, and CEA levels in patients with surgically treated colorectal cancer liver metastases: an international, multi-institutional study. J Surg Oncol 2021;123:939–948 [DOI] [PubMed] [Google Scholar]
- 25. Lillemoe HA, Passot G, Kawaguchi Y, DeBellis M, Glehen O, Chun YS et al. RAS/TP53 co-mutation is associated with worse survival after concurrent resection of colorectal liver metastases and extrahepatic disease. Ann Surg 2022;276:357–362 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Leung U, Gonen M, Allen PJ, Kingham TP, DeMatteo RP, Jarnagin WR et al. Colorectal cancer liver metastases and concurrent extrahepatic disease treated with resection. Ann Surg 2017;265:158–165 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004;240:644–657; discussion 657–658 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Johnson B, Truty JZ, Smoot MJ, Nagorney RL, Kendrick DM, Kendrick ML et al. Impact of metastasectomy in the multimodality approach for BRAF V600E metastatic colorectal cancer: the Mayo Clinic experience. Oncologist 2018;23:128–134 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Prasanna T, Wong R, Price T, Shapiro J, Tie J, Wong HL et al. Metastasectomy and BRAF mutation; an analysis of survival outcome in metastatic colorectal cancer. Curr Probl Cancer 2021;45:100637. [DOI] [PubMed] [Google Scholar]
- 30. Javed S, Benoist S, Devos P, Truant S, Guimbaud R, Lievre A et al. Prognostic factors of BRAF V600E colorectal cancer with liver metastases: a retrospective multicentric study. World J Surg Oncol 2022;20:131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt Cet al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:2207–2218 [DOI] [PubMed] [Google Scholar]