BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

Nakayama, Izuma; Hirota, Toru; Shinozaki, Eiji

doi:10.3390/cancers12113236

Cited by 26 publications

(31 citation statements)

References 200 publications

(368 reference statements)

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“…Differently from recent publications on this topic [ 11 , 18 , 76 ], in this review we focused on ongoing clinical trials with the aim to define future developments of treatment for this subset of patients [ 11 , 18 , 76 ] ( Figure 3 ). Our search led to identification of six different treatment strategies directed against BRAF V600E mutant mCRC.…”

Section: Discussionmentioning

confidence: 99%

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Mauri

Bonazzina

Amatu

et al. 2021

Cancers

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The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

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Section: Discussionmentioning

confidence: 99%

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Mauri

Bonazzina

Amatu

et al. 2021

Cancers

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“…In addition, a recent study proved that the addition of bevacizumab to NAC shows good efficacy and safety in the clinical treatment of ovarian cancer, and this method also has a good research prospect in other tumors [ 22 ]. BRAF mutation has been proven to predict the efficacy of targeted drugs in the treatment of colorectal cancer and is an independent negative factor affecting the clinical efficacy of bevacizumab added to chemotherapy [ 23 , 24 ]. Hence, this study included LARC patients with BRAF mutation.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant Chemotherapy plus Bevacizumab Combined with Total Mesorectal Excision in Treating Locally Advanced Rectal Cancer Patients with BRAF Mutation: Clinical Benefit and Safety

Song

Wang

et al. 2021

Computational and Mathematical Methods in Medicine

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Objective. To investigate clinical benefit and safety of neoadjuvant chemotherapy (NAC) plus bevacizumab combined with total mesorectal excision (TME) in treating patients with BRAF-mutated locally advanced rectal cancer (LARC). Methods. This study included LARC patients with BRAF mutation admitted to the Oncology Department of Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, between June 2013 and December 2018. Patients in the control group received a standard treatment regimen of TME combined with NAC ( n = 45 ), and patients in the observation group received NAC plus bevacizumab combined with TME ( n = 55 ). The short-term clinical efficacy of the two groups after NAC treatment was observed and compared, including differences in the pathological downstaging rate. The incidence of perioperative complications and adverse reactions during neoadjuvant therapy was compared to evaluate the safety of the treatment. Besides, the relapse-free survival (RFS) and overall survival (OS) of patients were analyzed to evaluate the long-term clinical benefit of the treatment. Results. Compared with the control group, the ypT staging rate ( p = 0.014 ) in the observation group was markedly lower. In addition, patients in the observation group had a prominently lower overall incidence of complications ( p < 0.001 ) during the perioperative period and a remarkably lower incidence of leukopenia ( p = 0.037 ) during neoadjuvant therapy. In terms of long-term clinical benefit, the RFS of patients in the observation group was evidently longer ( p = 0.037 ) than that in the control group. Conclusion. Compared with TME plus NAC treatment, the short-term and long-term clinical benefits are higher and safety is more favorable of NAC plus bevacizumab combined with TME in treating LARC patients.

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“…The BRAF V600E mutation is the more common BRAF mutation in CRC and is responsible for a poor prognosis, resulting in nearly a two-fold increase in mortality relative to wild-type BRAF in the metastatic setting [ 71 ]. Usually, BRAF V600E mutations are associated with a right-sided primary tumor, advanced age, female sex, high tumor grade, and precursor sessile serrated adenomas [ 72 ]. BRAF V600E CRC is also associated with the CpG island methylator phenotype (CIMP status), which may result in the epigenetic inactivation of MLH1 , inducing a mismatch repair deficiency (dMMR) and, consequently, a MSI phenotype [ 73 ].…”

Section: Braf Inhibitors In Mcrcmentioning

confidence: 99%

“…Among BRAF V600E mCRC patients, approximately 20% exhibit deficient dMMR [ 72 ]. More than 200 BRAF uncommon ( non-V600E ) mutations have been identified, with a combined incidence ranging from 1.6% to 5.1%.…”

Section: Braf Inhibitors In Mcrcmentioning

confidence: 99%

Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

Giordano

Parcesepe

Bruno

et al. 2021

IJMS

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Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

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BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

Cited by 26 publications

References 200 publications

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Neoadjuvant Chemotherapy plus Bevacizumab Combined with Total Mesorectal Excision in Treating Locally Advanced Rectal Cancer Patients with BRAF Mutation: Clinical Benefit and Safety

Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

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