Gene Instability Predicts Relapse in Early BRAF Mutated CRC

Liam Davenport

September 23, 2021

Among early stage colorectal cancer patients with BRAF mutations, nodal stage and microsatellite instability status are significant predictors of progression, suggests a UK analysis, although treatment options remain limited.

A team from the Royal Marsden NHS Foundation Trust, London, examined data on more than 166 early stage colorectal cancer patients with BRAF mutations treated there between 2014 and 2020.

Patients with proficient mismatch repair (pMMR) were more than 4.5 times more likely to experience disease relapse over 4 years of follow-up than those with deficient mismatch repair (dMMR).

In addition, N2 stage disease was associated with a more-than threefold increased risk of relapse over N0 disease, according to the results, which were presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2021 on September 17.

"MMR status and nodal stage of disease were predictive of relapse in our real-world cohort" of early stage BRAF mutated colorectal cancer, said lead researcher Dr Justin Mencel.

'Interesting' Study

Dr Elena Elez, medical oncologist and clinical investigator, Vall d'Hebron Institute of Oncology, Barcelona, Spain, told Medscape News UK that the question asked by the study is "interesting".

"Although we know in advanced disease that the BRAF mutation constitutes a prognosis factor, it is not included the early stage guidance for colorectal cancer as a decision-making factor to prescribe chemotherapy."

She continued that it is "understandable" because of the "important" interaction between high microsatellite instability and BRAF mutation.

Dr Elez said, unfortunately, the presence of high microsatellite instability and BRAF mutation "is not enough to establish a recommendation" for prescribing chemotherapy.

She said the current findings would have additional clinical relevance if there were "a particular drug to be recommended in the adjuvant setting," aside from chemotherapy, "but that does not exist" at the moment.

Nevertheless, a "strength of the work is the number of patients is huge", she added, explaining that it is "very difficult" to find that many BRAF-mutated patients, and the researchers "tried to answer a question that has not been resolved" in the clinical setting.

Study Details

Dr Mencel and colleagues explain that BRAF mutations are relatively common in colorectal cancer, in 15% of early stage and 8% of late stage disease. However, they are seen as a "poor prognostic factor", and the patient population is heterogeneous.

To investigate the impact of BRAF genotype and other prognostic variables in early stage BRAF mutated colorectal cancer patients, the team collected data on patients treated at their hospital between March 2014 and December 2020.

They included 166 patients, of whom 55% were female. The median age was 72 years. Most tumors were located right sided, accounting for 74.1% of cases, while 25.3% had a left-sided tumor.

The majority (63.3%) of patients had stage III disease at diagnosis, while 31.9% had stage II disease. T3 stage disease was detected in 57.2% of patients, and a further 34.3% had T4 disease.

There was a fairly even spread in terms of nodal involvement, with 34.3% of patients having N0 disease, 39.7% N1, and 21.7% N2 colorectal cancer.

In terms of microsatellite instability, 51.2% of patients had dMMR, or high-frequency microsatellite instability, while 44% had pMMR. A V600E BRAF mutation was detected in 95.2% of patients.

Surgery was performed on the primary tumour in 94.6% of patients, and 52.34% had adjuvant chemotherapy.

Follow-up

Over 4 years’ follow-up, 33.1% of the patients with early stage BRAF mutated disease experienced relapse.

Univariate analysis revealed that stage at diagnosis (p=0.006), T and N stage (p=0.003 for both), the primary tumor site (p=0.02), and MMR status (p<0.001) were significantly associated with relapse.

However, relapse was not associated with patient gender or age, nor with receipt of adjuvant chemotherapy or type of BRAF mutation, although Dr Mencel concedes the latter association "is confounded by low numbers in the non-V600E mutation group".

Multivariate analysis revealed that only nodal stage and MMR status were still significantly associated with relapse.

Compared with N0 disease, patients with N1 colorectal cancer had a hazard ratio (HR) for relapse of 1.4, rising to 3.37 in those with N2 disease (p=0.01 for trend).

Patients with pMMR tumours had a HR for relapse of 4.68 (p<0.001) compared with those with dMMR tumours. This translated into a 4-year relapse-free survival in dMMR tumors of 84% versus 37% for pMMR tumours.

The study was funded by the Royal Marsden NHS Foundation Trust.

Mencel declares no relevant financial relationships.

Other authors declare relationships with Bayer; Roche; Incyte; Bayer. AstraZeneca; Clovis; Eli Lilly; 4SC; Celgene; Leap; OVIBIO; Astella; Boehinger Ingelheim; BMS; Eisai; Merck; MSD; OncXerna; Pierre Fabre; Five Prime Therapeutics; Cilag-Janssen; Servier; GSK; Amgen.

ESMO Congress 2021: Abstract 447P. Presented September 17.

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