Real-world characteristics and outcomes of patients with BRAF^V600E-mutant metastatic colorectal cancer in Australia: the COALA project

Abstract

Background

BRAF^V600E-mutated metastatic colorectal cancer (mCRC) is a biologically distinct and clinically aggressive subtype associated with poor outcomes. Real-world data on this population remains limited, particularly within the Australian health care setting.

Patients and methods

The COALA study is a national, prospective registry-based observational analysis of patients with mCRC across 21 Australian institutions. Data were extracted from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) and TRACC-Select registries and included demographics, molecular profiles, treatment patterns and overall survival (OS). Uptake and impact of encorafenib plus cetuximab (EC), since being available in Australia from May 2019, were examined.

Results

Of 2976 patients tested for BRAF, 374 (13%) harboured BRAF^V600E mutations, including 53 (24%) of the 217 ‘very-young’ subset (<40 years of age). Overall, compared with wild-type (BRAF-wt) tumours, BRAF^V600E-mutated tumours were more likely to occur in females (55% versus 39%), and right-sided primaries (60% versus 28%) occur with deficient mismatch repair (dMMR) (24% versus 3%), and/or peritoneal metastases (36% versus 20%). Only 42% of BRAF^V600E patients received second-line (2L) treatment. OS was significantly shorter in BRAF^V600E versus BRAF-wt patients [hazard ratio (HR) 1.75, 95% confidence interval 1.5-2; median 16.6 versus 32.3 months]. Among BRAF^V600E patients receiving 2L therapy, EC use versus chemotherapy was associated with a trend for improved OS (HR 0.70, median 8.6 versus 6.8 months).

Conclusions

The COALA study provides the first Australian real-world profile of BRAF^V600E-mutated mCRC. These findings underscore the importance of early and effective therapeutic strategies, and identify a novel, disproportionately affected very-young subgroup requiring targeted research and clinical focus.

Highlights

• •Twenty-four percent of mCRC patients <40 years of age had BRAF^V600E, indicating major over-representation.
• •Very-young BRAF^V600E cases had more left-sided and fewer dMMR tumours.
• •Patients with BRAF^V600E tumours had worse OS and less 2L/3L therapy access.

Introduction

Colorectal cancer (CRC) remains a leading cause of mortality worldwide with Australia and New Zealand reporting the second-highest CRC incidence rates globally.¹ Among the global phenomenon of rising incidence of early-onset CRC, Australia has the highest incidence of early-onset CRC (<50 years of age) where CRC is now the leading cause of cancer-related deaths for individuals aged 20-39 years.2, 3, 4 Most CRC-related deaths result from metastatic disease. Despite advances in prevention and adjuvant treatments, a significant proportion of patients still develop metastatic CRC (mCRC), highlighting the need for effective management strategies in advanced settings. Younger patients are more likely to present with advanced disease, often with left-sided tumours, as they are typically excluded from national screening programmes.^2,5,6

CRC is a heterogeneous disease, with differences in prognosis and treatment response influenced by primary tumour sidedness and molecular profiles. The BRAF^V600E mutation, presents in ∼8%-12% of mCRC, and is a crucial prognostic marker associated with poorer outcomes independent of clinicopathological features.^7,8 Biologically distinct from BRAF wild-type (BRAF-wt) CRC, BRAF^V600E mCRC arises via the serrated carcinogenesis pathway rather than the adenoma–carcinoma pathway.^9,10 Patients with BRAF^V600E mCRC exhibit significantly shorter overall survival (OS) and chemotherapy resistance compared with the BRAF-wt mCRC population.⁸ BRAF^V600E mCRC is molecularly distinct and is frequently associated with deficient mismatch repair (dMMR) in ∼30% of cases, compared with 5% in BRAF-wt tumours.^8,11, 12, 13, 14 The BEACON trial, the largest randomized phase III trial for BRAF^V600E-mutant mCRC, demonstrated that treatment with encorafenib and cetuximab (EC) significantly improved progression-free survival (PFS) and OS compared with FOLFIRI and cetuximab in patients who had received at least one line of systemic therapy.¹⁵ These findings led to the United States Federal Drug Administration (FDA) approval of EC in April 2020 for use after prior systemic therapy, followed by approval from the European Commission in June 2020, and approval for reimbursement in Australia via the Pharmaceutical Benefits Scheme (PBS) in January 2022. Before these approvals, EC was available in Australia through a cost-share programme beginning in May 2019. With the success of immune checkpoint inhibitor in dMMR mCRC, immunotherapy is recommended as first-line therapy (1L) for the rare population of dMMR BRAF^V600E mCRC, followed by targeted therapy (EC) in the second line.16, 17, 18 Pembrolizumab was reimbursed in Australia for dMMR mCRC in the 1L setting from August 2021. The value of integrating EC with chemotherapy as 1L therapy for proficient MMR (pMMR) BRAF^V600E mCRC has been investigated in the BREAKWATER study, with improvements in objective response rate leading to accelerated FDA approval of EC in combination with mFOLFOX6 as of 20 December 2024, with data more recently confirming benefit in PFS and OS.^15,19,20

Real-world evidence (RWE) is crucial to assess the uptake and impact of these treatments in routine clinical practice, particularly given the aggressive nature of BRAF^V600E mCRC, which excluded many from clinical trials. The primary objective of the COALA registry-based study was to utilise real-world prospective data to describe baseline characteristics of patients with BRAF^V600E-mutant mCRC in Australia with key secondary objectives describing the treatment patterns, clinical uptake, and outcomes for patients treated with EC, providing insights into the real-world effectiveness of this treatment regimen.

Methods

Data source

The COALA study is a multicentre, registry-based observational study conducted across Australia, focusing on adults with BRAF^V600E-mutant mCRC. Data were obtained from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) and TRACC-Select registries.²¹ Established in 2009, TRACC prospectively collects comprehensive mCRC patient data from multiple Australian hospitals. TRACC-Select, launched in June 2022, focuses on real-world treatment outcomes in molecularly defined and young-onset CRC, including cases with dMMR, BRAF^V600E, KRAS^G12C, HER2, POLE, and FGFR2 mutations, NTRK fusions, or diagnosis at age ≤40 years. Data from both registries, the largest for CRC across Australia, encompassing 21 sites (6 private and 15 public) were collated for the COALA study. The study was approved by Melbourne Health ethics committee (HREC/18/MH/28).

Study population

Eligible patients were 18 years of age or older and had confirmed mCRC with BRAF mutation testing via locally approved next-generation sequencing or polymerase chain reaction. Registry data from July 2009 (inception of TRACC) to January 2025 were analysed for baseline characteristics. Time-to-event analyses included patients who progressed on 1L therapy.

Two primary cohorts were analysed: BRAF^V600E-mutant and BRAF-wt patients. Patient characteristics [e.g. sex, age, Eastern Cooperative Oncology Group performance status], clinicopathological features [e.g. de novo metastatic disease, number and sites of metastases, primary tumour location, dMMR, and RAS status], treatment patterns (e.g. lines of systemic therapy), and survival outcomes (PFS and OS) were compared between the cohorts. Primary tumour locations were categorised as: right-sided (caecum, ascending colon, hepatic flexure, or transverse colon), left-sided (beyond the splenic flexure), and rectal (lower border within 12 cm of the anal verge). MMR status was determined by immunohistochemistry staining of the MMR genes (MLH1, PMS2, MSH2 and MSH6) at local institutions. Patients with BRAF^V600E -mutant tumours accessing EC via cost-share programme and PBS were included but those accessing EC via a clinical trial were excluded. Given the rising incidence of young-onset CRC, we analysed the density distribution for age at diagnosis of BRAF^V600E mutant mCRC. We then analysed the incidence of BRAF^V600E mutation by age group, categorised as very young (<40 years), young (40-59 years) and older (60+ years).

Outcomes

The primary objective was to describe baseline clinicopathological features of patients with BRAF^V600E mCRC in the real world. Secondary objectives were to describe temporal BRAF mutation testing rate and prevalence, treatment patterns in patients with BRAF^V600E mCRC, OS in BRAF^V600E mutant and wild-type mCRC patients receiving treatment of metastatic disease (overall and by treatment regimen), as well as 2L PFS in BRAF^V600E mutant mCRC patients by treatment regimen. PFS was defined as the time between the start of treatment to disease progression or death, and OS as the time from metastatic disease diagnosis or a particular treatment regimen to death. Patients without progression or death at the time of analysis were censored at the last follow-up visit. Patients who discounted treatment without progression were also censored for PFS analyses. Due to the lack of RECIST assessment in real-world data, objective response rate could not be accurately evaluated.

Statistical analysis

Analyses were descriptive, continuous variables were presented as medians and percentages. Probability density histograms were used to explore age variation across the cohort. Statistical differences between BRAF^V600E -mutant and BRAF-wt groups were assessed using chi-square test for categorical variables. Survival outcomes were analysed using the Kaplan–Meier method with the log-rank test. Data were analysed using SAS Enterprise Guide, version 8.1.

Results

BRAF mutation testing rate, prevalence, and baseline characteristics

A total of 4850 patients with mCRC were identified (Figure 1). The proportion of mCRC patients tested for BRAF mutation increased over time (24% in 2009 to 2013, 72% in 2014 to 2018, 80% in 2019 to 2024, P ≤ 0.0001). Of the 2976 patients tested for BRAF mutations between 2009 and 2024, 13% (n = 374) and 87% (n = 2577) were BRAF^V600E mutant and wild-type, respectively; 25 patients had non-V600E BRAF mutations. Baseline clinicopathological characteristics for patients with BRAF^V600E-mutated and wild-type mCRC are outlined in Table 1. Compared with the BRAF wild-type cohort, patients with BRAF^V600E mutated tumours were more likely to be female (55% versus 39%), have right-sided tumours (60% versus 28%), be dMMR (24% versus 3%), have a higher number of metastatic sites at diagnosis (3+ metastatic sites, 27% versus 18%) and have peritoneal metastasis (36% versus 20%). Liver and lung metastases were less common in BRAF^V600E-mutated tumours than wild-type tumours. As expected, RAS alterations were rare in the BRAF^V600E cohort (n = 8, 2.2%).

Figure 1.

CONSORT diagram of patients included in COALA study. 1L, first-line; 2L, second-line; 3L+, third-line (and beyond); mCRC, metastatic colorectal cancer; wt, wild-type.

Table 1.

Baseline characteristics of metastatic colorectal cancer patients in the COALA study

	Total patients N = 2951	BRAFV600En = 374	BRAF-wt n = 2577	P value
Median age in years (range)	63 (19-93)	63 (23-92)	63 (19-93)
Sex (%)				<0.001
female	1223 (41)	207 (55)	1016 (39)
male	1728 (59)	167 (45)	1561 (61)
ECOG (%)				0.14
0-1	2626 (89)	323 (86)	2303 (89)
2+	291 (10)	44 (12)	247 (10)
unknown	34 (1)	7 (2)	27 (1)
Primary site (%)				<0.001
right	951 (32)	224 (60)	727 (28)
left	1026 (35)	86 (23)	940 (36)
rectum	861 (29)	38 (10)	823 (32)
multiple/unknown	113 (4)	26 (7)	87 (3)
De novo metastatic (%)				0.06
no	1161 (39)	131 (35)	1030 (40)
yes	1790 (61)	243 (65)	1547 (60)
MMR status (%)				<0.001
dMMR	181 (6)	92 (24)	89 (3)
pMMR	2292 (78)	246 (66)	2046 (79)
unknown	478 (16)	36 (10)	442 (17)
Number of met. sites (%)				<0.001
1	1426 (48)	138 (37)	1288 (50)
2	945 (32)	134 (36)	811 (32)
3+	580 (20)	102 (27)	478 (18)
Liver (%)				<0.001
no	1111 (38)	184 (49)	927 (36)
yes	1840 (62)	190 (51)	1650 (64)
Lung (%)				0.0004
no	2036 (69)	288 (77)	1748 (68)
yes	915 (31)	86 (23)	829 (32)
Peritoneum (%)				<0.001
no	2299 (78)	239 (64)	2060 (80)
yes	652 (22)	135 (36)	517 (20)

dMMR, deficient mismatch repair; ECOG, Eastern Cooperative Oncology Group; Met., metastases; MMR, mismatch repair; pMMR, proficient mismatch repair.

We observed a bimodal distribution of BRAF^V600E occurrence with peaks in the <40 and 60-70 year age groups (Figure 2A). The very-young group had a significantly higher incidence of BRAF^V600E mutation than the young and older patients (24.4% versus 9.8% versus 12.8%; Figure 2B). We also observed some statistically significant differences in the clinicopathological characteristics of BRAF^V600E tumours between the age groups with the very young more likely to have left-sided primaries (very young 42%, young 27%, older 17%), a higher number of metastatic sites at diagnosis (3+ metastatic sites: very young 42%, young 32%, older 21%) and less likely to be associated with dMMR (very young 6%, young 9%, older 35%) (Table 2). There were no differences in clinicopathological factors between patients treated at regional and metropolitan centres.

Figure 2.

Age density distribution with prevalence of BRAF^V600E across age groups. (A) Age density histogram for BRAF^V600E cohort and (B) Prevalence of BRAF^V600E according to age categories.

Table 2.

Characteristics of BRAF^V600E cohort according to age categories

	Age category			P value
	18-39 ‘Very young’ n = 53 (%)	40-59 ‘Young’ n = 94 (%)	60+ ‘Older’ n = 227 (%)
Sex				0.16
female	31 (58)	42 (46)	127 (58)
male	22 (42)	50 (54)	92 (42)
ECOG				0.016
0-1	49 (92)	89 (95)	185 (82)
2+	4 (8)	4 (4)	36 (15)
unknown	0	1 (1)	6 (3)
Primary site				<0.001
right	25 (47)	52 (55)	147 (65)
left	22 (42)	25 (27)	39 (17)
rectum	6 (11)	14 (14)	18 (7)
multiple/unknown	0	3 (3)	23 (10)
MMR status				<0.001
dMMR	3 (6)	8 (9)	81 (35)
pMMR	49 (92)	75 (79)	122 (54)
unknown	1 (2)	11 (12)	24 (11)
Number of met. sites				0.033
1	13 (24)	33 (36)	92 (41)
2	18 (34)	31 (33)	85 (37)
3+	22 (42)	30 (31)	50 (22)
Liver				0.006
yes	35 (66)	54 (58)	101 (45)
Lung				0.88
yes	11 (21)	21 (22)	54 (24)
Peritoneum				0.06
yes	26 (49)	36 (38)	73 (32)

dMMR, deficient mismatch repair; ECOG, Eastern Cooperative Oncology Group; Met., metastases; MMR, mismatch repair; pMMR, proficient mismatch repair.

Treatment patterns in BRAF^V600E-mutant and wild-type mCRC

For 2976 mCRC patients tested for BRAF^V600E, we assessed the proportion of patients with BRAF^V600E-mutant and BRAF-wt mCRC receiving 1L to third-line and beyond (3L+) of treatment. First-line therapy was received by 85% (n = 317/374) of patients with BRAF^V600E-mutant and 85% (n = 2183/2577) with BRAF-wt mCRC. Of these 1L regimes, 212 received a triplet chemotherapy, 19% (n = 59) in the BRAF^V600E-mutant group and 7% (n = 153) in the BRAF-wt mCRC patients (Supplementary Table S1, available at https://doi.org/10.1016/j.esmorw.2025.100178). Second-line (2L) therapy was administered to 42% (n = 157) of BRAF^V600E patients and 46% (n = 1197) of BRAF-wt patients, whereas 3L+ therapy was received by 15% (n = 56) and 25% (n = 635), respectively (Figure 3). A small proportion of patients received either surgery or radiotherapy without systemic therapy or no therapy at all. Among the BRAF^V600E mCRC patients receiving 2L+ therapy (n = 157), EC was administered in 39% (n = 62) overall, of which 82% (n = 51) was given in 2L therapy, and 18% (n = 11) in 3L+ therapy. No patients received binimetinib. Overall 13% (n = 8) accessed EC via the cost-share programme and 87% (n = 54) via PBS.

Figure 3.

Proportion of patients who received first-line, second-line, and third-line (and beyond) systemic therapy. 1L, first-line; 2L, second-line; 3L+, third-line (and beyond); wt, wild-type.

In the dMMR BRAF^V600E-mutant mCRC subgroup (n = 92), after pembrolizumab’s approval in Australia in August 2021, 97% (n = 38/39) of patients received immunotherapy in the 1L setting. Of these, 11 patients progressed on 1L pembrolizumab after January 2022, to receive 2L therapy, with 82% (n = 9) receiving EC as their 2L treatment.

Treatment efficacy

PFS in the 1L setting for BRAF^V600E-mutant and wild-type subgroups was shorter for the BRAF^V600E group [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.24-1.61; median 7.5 versus 11.5 months], regardless of therapy received. In the 2L setting, PFS was assessed for the BRAF^V600E group in patients receiving EC versus other therapies, with a PFS of 4.2 months and 3.1 months, respectively (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmorw.2025.100178). In 2L+ therapy, the median duration of treatment was 3.7 months for EC and 2.8 months for other treatments. Durable response on EC treatment (≥6 months) was seen in 18% (n = 11) of patients versus non-durable response (<6 months) in 60% (n = 37); 22% (n = 14) of patients remained on therapy or were lost to follow-up for response assessment at the time of analysis.

Overall survival

We compared the OS between the BRAF^V600E and BRAF-wt cohorts overall (Figure 4A). After a median follow-up of 50.5 months, OS was shorter in the BRAF^V600E group (HR 1.75, 95% CI 1.5-2; median 16.6 versus 32.3 months). OS was further evaluated from the commencement of 2L therapy in the BRAF^V600E-mutant cohort, comparing patients who received EC versus other therapies. Median OS was longer in those who received EC (HR 0.701, 95% CI 0.48-1.1; median 8.6 months versus 6.8 months) (Figure 4B). OS by age group was also analysed to identify any variation based on age; however, no statistically significant difference was demonstrated (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmorw.2025.100178).

Figure 4.

Kaplan–Meier curves for overall survival. (A) Overall survival (OS) for all metastatic colorectal cancer (mCRC) in COALA study. (B) Overall survival (OS) in BRAF^V600E-mutant metastatic colorectal cancer cohort receiving second-line (2L) therapy.CI, confidence interval; EC, encorafenib plus cetuximab; HR, hazard ratio.

Discussion

The COALA study provides nationally representative RWE on BRAF^V600E-mutant CRC in Australia, affirming its aggressive clinical behaviour and poor prognosis. Consistent with previous literature, patients with BRAF^V600E mutations were more likely to be female, have right-sided primaries, peritoneal metastases, and a higher burden of metastatic disease.^7,22 In keeping with previously published literature we demonstrated the significantly poorer OS of those with BRAF^V600E-mutant mCRC compared with BRAF-wt (median OS 16 months versus 32.3 months), despite comparable access to 1L therapies (85% versus 85%). Median OS for EC-treated patients is consistent with the landmark BEACON study.

The COALA study sheds light on the molecular landscape of BRAF^V600E-mutated mCRC. Overall a similar prevalence to previously reported literature of concurrent dMMR status was observed (24%).²³ Although the small cohort size precluded definitive conclusions on outcomes for dMMR/BRAF^V600E patients, prior literature has consistently shown poorer OS in this population compared with dMMR wild-type patients.²⁴ Variability in RAS co-mutation rates was also noted, with COALA’s rates aligning with some international cohorts but differing from others, which report RAS co-mutation rates between 0% and 10%.25, 26, 27

Consistent with prior data, BRAF^V600E-mutations were associated with worse PFS and OS outcomes.²⁸ Previous small-scale RWE studies have demonstrated associations between metastatic sites and prognosis, with lymph node-only metastases linked to improved OS and peritoneal disease linked to worse OS.²⁹ Other studies have demonstrated prognostic scoring in BRAF^V600E mCRC based not only on sites of disease but also CA19.9, lactate dehydrogenase, neutrophil/lymphocytic ratio, and circulating tumour DNA (ctDNA) BRAF variant allele frequency (VAF).^30,31 Specifically, exploratory ctDNA analysis from the BEACON trial showed that baseline ctDNA VAF levels of BRAF^V600E were associated with differential outcomes where higher baseline VAF correlated with shorter OS in all treatment arms.³² Although COALA’s findings align with the poorer OS, the size of the cohort limited analysis for survival according to sites of disease or these other potential prognostic factors.

A bimodal age distribution was identified, with a unique peak in the very-young subgroup (<40 years of age). A novel and striking observation in COALA was the over-representation of BRAF^V600E in patients <40 years of age, accounting for 24% of cases in this group. Unlike the broader BRAF^V600E population, these very-young patients more frequently had left-sided/rectal tumours and were less likely to be dMMR. This distinct phenotype suggests a potentially biologically unique subgroup that warrants further molecular characterisation and dedicated therapeutic strategies. In line with previously published literature the older BRAF^V600E group in COALA had a higher prevalence of dMMR at 35%.³³

The rising incidence of CRC in younger populations has been well documented,³ with the highest increases observed in individuals aged 20-29 years.^34,35 However, this study is the first to emphasise the disproportionate impact of BRAF^V600E mutations on very-young patients. Although prior research on early-onset CRC (<50 years of age) has shown no statistically significant difference in BRAF^V600E prevalence compared with BRAF-wt populations,^2,25,36 the COALA study demonstrates a distinct subgroup within the very-young population with a greater prevalence of BRAF^V600E mutations.

In this study, 42%-46% of patients with mCRC received 2L therapy, aligning with findings from other RWE studies.²² Among patients with BRAF^V600E mutations, there is a trend for improvement in OS for EC-treated patients but this did not reach statistical significance likely due to the small sample size.¹⁵ Fewer BRAF^V600E patients accessed 3L therapies and the OS for those with a BRAF^V600E-mutated tumour remained inferior to those with wild-type tumours. This underscores the need for early access to effective treatments in BRAF^V600E-mutated mCRC, as many patients may not reach later lines of therapy.

Although 1L treatments were not extensively examined in this study, a higher proportion with BRAF^V600E-mutated tumours received triplet chemotherapy compared with the wild-type population (19% versus 7%). Despite real-world practices, individual patient met-analyses have not demonstrated benefit of the escalated triplet regimes in BRAF-mutant tumours.³⁷ The TRIBE study demonstrated a median OS of 13.2 months in the BRAF^V600E group compared with 29.8 months in the entire CRC cohort,^15,38 again providing evidence of this group having a poorer OS despite intensified 1L therapy.

Therapy sequencing remains crucial in mCRC management. The recent BREAKWATER trial showed further improved outcomes when EC was combined with chemotherapy in the 1L setting for patients with BRAF^V600E-mutant pMMR tumours, suggesting this will become the new standard of care.¹⁹ In the KEYNOTE 177 and the Checkmate 8HW studies, 1L pembrolizumab and ipilimumab and nivolumab were superior to chemotherapy in dMMR mCRC, including 25% of patients had BRAF^V600E-mutant tumours.^23,39,40 Subgroup analysis from these studies showed that BRAF^V600E dMMR tumours derived similar benefit from immunotherapy to BRAF-wt tumours. In Australia, only pembrolizumab is funded for 1L use. Following the regulatory approval of pembrolizumab, most patients in the COALA study with dMMR BRAF^V600E-mutated mCRC received 1L immunotherapy (97%), followed by EC as 2L therapy (86%). RWE suggests current preferred practice for dMMR BRAF^V600E mCRC patients is 1L immunotherapy followed by EC. The results of the SEAMARK trial (NCT05217446), which aims to assess if first-line combination of pembrolizumab and EC is more efficacious than pembrolizumab alone in dMMR BRAF^V600E-mutant tumours, are eagerly anticipated.⁴¹

The strengths of this study are its use of a large, prospectively maintained, multicentre registry capturing real-world treatment patterns and outcomes across both public and private health systems in Australia. The integration of molecular, clinical, and temporal data allowed comprehensive analyses, including identification of a novel ‘very-young’ BRAF^V600E-mutant cohort with distinct clinicopathological features that should be further investigated.

This study has several limitations. As with many RWE studies, incomplete molecular profiling, censoring, and unmeasured confounding may affect the generalisability of the findings and limits our ability to explore the prognostic impact of additional genomic alterations. Adverse events and response rates were not consistently reported, and the absence of quality-of-life data limited insights into treatment tolerability. The lack of centralised pathology review precluded analysis of histological subtypes and consensus molecular subtypes. In addition, small sample sizes hindered definitive conclusions for specific subgroups, such as dMMR/BRAF^V600E-mutated tumours and those with concurrent RAS/BRAF alterations. Importantly, this study was hypothesis-generating rather than hypothesis-testing, and its findings should be interpreted in that context.

Conclusion

In conclusion, the COALA study underscores the aggressive nature of BRAF^V600E-mutated mCRC, the poorer outcomes associated with this mutation, and the need for early use of effective therapies such as EC. The identification of a disproportionate prevalence of BRAF^V600E mutations in the very-young subgroup (<40 years of age) with a distinct phenotype (higher left-sided/rectal disease and lower dMMR) is a novel finding, suggesting that this population may require dedicated research focus and tailored therapeutic strategies.