<i>BRAF</i>V600E Mutation in First-Line Metastatic Colorectal Cancer: An Analysis of Individual Patient Data From the ARCAD Database

Cohen, Romain; Liu, Heshan; Fiskum, Jack; Adams, Rachel; Chibaudel, Benoist; Maughan, Tim; Cutsem, Éric Van; Venook, Alan P.; Douillard, Jean-Yves; Heinemann, Volker; Punt, Cornelis J.A.; Falcone, Alfredo; Bokemeyer, Carsten; Kaplan, Richard; Lenz, Heinz‐Josef; Koopman, Miriam; Yoshino, Takayuki; Zalcberg, John; Grothey, A.; Gramont, Aimery de; Thewis, André

doi:10.1093/jnci/djab042

Cited by 28 publications

(20 citation statements)

References 37 publications

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“…It causes constitutive activation of the MAPK signaling pathway, confers high clinical aggressiveness and resistance to anti-EGFR monoclonal antibody treatment, and is associated with poor survival. 47 BRAF V600E-mutant mCRC may display the CIMP phenotype and, in 10% to 20% of cases, is also MSI-H. 48,49 BRAF V600E-mutant mCRC more often correlates with older age, female sex, proximal colon (right side location), peritoneal and hepatic metastatic spread, and mucinous or poorly differentiated histology. 50 Intriguingly, BRAF V600E-mutant CRC is not a unique disease and could display various responses to molecular target therapies.…”

Section: Mutational Landscape Of Metastatic Colorectal Cancermentioning

confidence: 99%

“…Patients with BRAF V600E-mutant mCRC have the worst prognosis, with modest efficacy of chemotherapy regimens and with a median survival of only 12 months. 45,47,49 Several selective BRAF inhibitors have been developed and evaluated in clinical trials (Table 5). 51,[136][137][138][139][140][141][142] A major therapeutic improvement was caused by the discovery that BRAF inhibition causes an escape mechanism in BRAF-mutant CRC cells, with the upregulation of EGFR-driven signaling, which allows cancer cell survival despite treatment.…”

Section: Consensus Molecular Subtype Classification Of Colorectal Cancermentioning

confidence: 99%

“…This mutation is almost mutually exclusive with KRAS and NRAS mutations. It causes constitutive activation of the MAPK signaling pathway, confers high clinical aggressiveness and resistance to anti‐EGFR monoclonal antibody treatment, and is associated with poor survival 47 . BRAF V600E‐mutant mCRC may display the CIMP phenotype and, in 10% to 20% of cases, is also MSI‐H 48,49 .…”

Section: Mutational Landscape Of Metastatic Colorectal Cancermentioning

confidence: 99%

“…Another relevant step toward a more personalized therapeutic approach has been the development of anti‐BRAF–targeted therapies. Patients with BRAF V600E‐mutant mCRC have the worst prognosis, with modest efficacy of chemotherapy regimens and with a median survival of only 12 months 45,47,49 . Several selective BRAF inhibitors have been developed and evaluated in clinical trials (Table 5).…”

Section: Integrating Molecular Target Therapies In the Continuum Of C...mentioning

confidence: 99%

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Clinical management of metastatic colorectal cancer in the era of precision medicine

Ciardiello

Martini

et al. 2022

CA A Cancer J Clinicians

296

161

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Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC.

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Section: Mutational Landscape Of Metastatic Colorectal Cancermentioning

confidence: 99%

Section: Consensus Molecular Subtype Classification Of Colorectal Cancermentioning

confidence: 99%

Section: Mutational Landscape Of Metastatic Colorectal Cancermentioning

confidence: 99%

Section: Integrating Molecular Target Therapies In the Continuum Of C...mentioning

confidence: 99%

See 2 more Smart Citations

Clinical management of metastatic colorectal cancer in the era of precision medicine

Ciardiello

Martini

et al. 2022

CA A Cancer J Clinicians

296

161

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“…BRAF mutations abnormally activate the MAPK signaling pathway, making tumors highly aggressive. Patients with BRAF V600E-mutated metastatic colorectal cancer are poorly responsive to chemotherapy and have an extremely poor prognosis with a median survival of only 12 months ( Cohen et al, 2021 ). Some selective BRAF inhibitors have been developed, such as vemurafenib and dabrafenib.…”

Section: Discussionmentioning

confidence: 99%

Survival for patients with metastatic colon cancer underwent cytoreductive colectomy in the era of rapid development of anticancer drugs: A real-world analysis based on updated population dataset of 2004–2018

2022

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Objective: Metastatic colon cancer (mCC) poses a great threat to the survival of patients suffering from it. In the past decade, many clinical trials have been carried out to improve the prognosis of patients with mCC. Numerous treatments have emerged, and satisfactory efficacy has been demonstrated in randomized phase III trials in highly selective patients with mCC. Our present study aims to investigate whether these therapeutic advances can be reflected to the broader mCC patients who performed cytoreductive colectomy.Method: General and prognostic data for patients diagnosed with mCC who underwent cytoreductive colectomy between 2004–2018 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model. The hazard ratio (HR) and its 95% confidence interval (CI) were used to evaluate the influence of risk factors on prognosis.Results: A total of 26,301 patients diagnosed with mCC treated with cytoreductive colectomy were included in this study. The median overall survival was 19 months (range, 17–23). The good prognosis was associated with patients diagnosed at the most recent year, younger age, non-black race, female, married, without previous history of malignancy, no second malignancy onset, descending/sigmoid/splenic flexure colon tumor, normal CEA levels at diagnosis, low primary tumor burden, T1/T2 stage, N0 stage, single organ metastasis, underwent surgical resection of synchronous distant metastatic lymph nodes or organs, a high number of lymph-node examinations, low positive lymph-node ratio and received adjuvant chemotherapy. The proportion of patients surviving for ≥24 months increased from 37% in 2004 to 44.2% in 2016 (p < 0.001), especially in ≤49 years patients [46.8% in 2004 to 57.8% in 2016 (p < 0.001)]. The percentage of patients who died within 3 months decreased between 2004 and 2018 (from 19.6% to 15.7%; p < 0.001).Conclusion: Over a span of 15 years, the long-term survival has improved in real-world mCC patients who were treated with cytoreductive colectomy, especially among younger patients. However, the median overall survival remains not substantial.

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HAMLET effect on cell death and mitochondrial respiration in colorectal cancer cell lines with KRAS/BRAF mutations

Žilinskas

Stukas

Jasukaitiene

et al. 2023

J Cancer Res Clin Oncol

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Purpose Treatment of advanced colorectal cancer (CRC) depends on the correct selection of personalized strategies. HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a natural proteolipid milk compound that might serve as a novel cancer prevention and therapy candidate. Our purpose was to investigate HAMLET effect on viability, death pathway and mitochondrial bioenergetics of CRC cells with different KRAS/BRAF mutational status in vitro. Methods We treated three cell lines (Caco-2, LoVo, WiDr) with HAMLET to evaluate cell metabolic activity and viability, flow cytometry of apoptotic and necrotic cells, pro- and anti-apoptotic genes, and protein expressions. Mitochondrial respiration (oxygen consumption) rate was recorded by high-resolution respirometry system Oxygraph-2 k. Results The HAMLET complex was cytotoxic to all investigated CRC cell lines and this effect is irreversible. Flow cytometry revealed that HAMLET induces necrotic cell death with a slight increase in an apoptotic cell population. WiDr cell metabolism, clonogenicity, necrosis/apoptosis level, and mitochondrial respiration were affected significantly less than other cells. Conclusion HAMLET exhibits irreversible cytotoxicity on human CRC cells in a dose-dependent manner, leading to necrotic cell death and inhibiting the extrinsic apoptosis pathway. BRAF-mutant cell line is more resistant than other type lines. HAMLET decreased mitochondrial respiration and ATP synthesis in CaCo-2 and LoVo cell lines but did not affect WiDr cells’ respiration. Pretreatment of cancer cells with HAMLET has no impact on mitochondrial outer and inner membrane permeability.

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BRAFV600E Mutation in First-Line Metastatic Colorectal Cancer: An Analysis of Individual Patient Data From the ARCAD Database

Cited by 28 publications

References 37 publications

Clinical management of metastatic colorectal cancer in the era of precision medicine

Clinical management of metastatic colorectal cancer in the era of precision medicine

Survival for patients with metastatic colon cancer underwent cytoreductive colectomy in the era of rapid development of anticancer drugs: A real-world analysis based on updated population dataset of 2004–2018

HAMLET effect on cell death and mitochondrial respiration in colorectal cancer cell lines with KRAS/BRAF mutations

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