Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group

Modest, Dominik Paul; Ricard, Ingrid; Heinemann, Volker; Hegewisch-Becker, S.; Schmiegel, Wolff; Porschen, Rainer; Stintzing, Sebastian; Graeven, Ullrich; Arnold, Dirk; Weikersthal, Ludwig Fischer von; Gießen-Jung, Clemens; Stahler, Arndt; Schmoll, Hans‐Joachim; Jung, Andreas; Kirchner, Thomas; Tannapfel, Andrea; Reinacher‐Schick, Anke

doi:10.1093/annonc/mdw261

Cited by 251 publications

(207 citation statements)

References 31 publications

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“…The frequency of KRAS mutations (33.3%) and BRAF mutations (2.3%) in the present study were in accordance with a previous retrospective observational study that also involved Chinese patients with mCRC (34.8 and 3.4%, respectively) (20). However, the KRAS and BRAF mutation rate was slightly higher in the Western population (37.3 and 6%) (10). Since the morbidity and mortality of CRC in China were different from that in Western countries, the KRAS and BRAF mutation rates in different regions required further exploration (21).…”

Section: Discussionsupporting

confidence: 91%

“…This result was consistent with the evidence from in vitro studies, in which codon 12 mutations may increase aggressiveness due to increased transforming capacity and decreased levels of apoptosis (16,30). Previously, meta-analysis also revealed the predictive value that codon 12 mutations possessed by pooling the data from five randomized trials researching patients with mCRC in Western countries (10). In that meta-analysis, G12C was associated with inferior OS compared with KRAS wild-type; however, the results of the present study demonstrated that G12D and G12V were associated with decreased OS times.…”

Section: Discussionsupporting

confidence: 88%

“…KRAS codon 12 mutations, especially G12D and G12V were revealed to exhibit predictive value for poor overall survival. To the best of our knowledge, studies concerning KRAS mutations have primarily been conducted only in the Western population (10,11). The impact of KRAS mutation, especially its different mutational sites, on the survival of Chinese population was uncertain and controversial.…”

Section: Discussionmentioning

confidence: 99%

“…However, whether KRAS mutations are correlated with decreased survival in patients with mCRC remains controversial. Previous studies have indicated that KRAS mutations present statistically significant reductions in overall survival (OS) and disease-free survival (DFS) (10)(11)(12). Nevertheless, evidence of the association between KRAS mutations and poor OS in patients with mCRC is obtained primarily in Western countries and certain Asian countries; few data about prognostic significance of KRAS mutations in mCRC are available in Chinese patients (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

et al. 2017

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Abstract. KRAS mutations serve a function in tumorigenesis of colorectal cancer (CRC) and guide the use of targeted drugs. However, the prognostic value of KRAS mutations and their subtypes remain controversial. The present study aimed to investigate the correlations between KRAS mutations and clinicopathological characteristics, and their prognostic significance in Chinese patients with metastatic CRC (mCRC). A total of 135 patients with mCRC were analyzed for KRAS mutations. Mutations in codon 12 and 13 were identified in 45 (33.3%) patients. Only 3 patients harbored a mutation of V600E. Compared with male patients, KRAS codon 12 mutations were more common in female patients (P<0.05). KRAS codon 13 mutations tended to arise in right-sided compared with left-sided colon cancer (P<0.05). Survival analysis was performed in 101 patients receiving primary tumor resection. Compared with KRAS codon 12 wild-type, codon 12 mutations were markedly correlated with a poorer survival (log-rank P= 0.002). No prognostic significance was revealed in codon 13 mutations. In univariate analysis, mortality risk was significantly increased by subtypes of G12D and G12V [hazard ratio (HR) =2.313, 95% confidence interval (CI) =1. P=0.03; HR=2.621, P=0.04, respectively]. The results of the present study suggested that codon 12 mutations, in particular G12D and G12V, predicted a negative prognosis in Chinese patients with mCRC. These findings require further confirmation via prospective studies with larger samples.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

et al. 2017

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“…KRAS mutations were found in 50.87% of our patients, which is higher than in previous reports from other countries [49,50] . In the current study, KRAS mutations showed no significant difference between males and females, although some studies reported increased frequency among males [50] , and other reports demonstrated different patterns of KRAS mutations in men and women [49,50] . Our findings not only supported the well-established role of KRAS mutation in predicting resistance to the EGFR-blocking antibody cetuximab, but also highlighted the role of KRAS mutation as a predictive marker of poor prognosis and inferior patient survival.…”

Section: Discussioncontrasting

confidence: 74%

Clinicopathological Features and Predictive Factors for Colorectal Cancer Outcome in the Kingdom of Saudi Arabia

et al. 2016

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Background/Aims: Colorectal cancer (CRC) is the most frequent cancer and a leading cause of cancer death in the Kingdom of Saudi Arabia (KSA). To date, no nationwide screening programs have been adopted. This prospective, longitudinal study investigated factors influencing the outcome of CRC in Saudi patients. Methods: Patients completed a CRC awareness questionnaire. Colonoscopy, CT/MRI, histopathology of tumor biopsies, and KRAS and BRAF testing were performed. Patients were treated according to their stage. All patients were followed until the end of the study and 3- and 5-year survival was assessed. Results: Sixty percent of study patients with sporadic CRC presented with significantly advanced disease (stages III and IV) with or without metastases at entry. Patients showed low levels of awareness of the risk factors and signs of CRC. Patients presented at a median age of 50 years. Family history of CRC and ulcerative colitis were positive in 11 and 6% of patients, respectively. Stage III/IV tumors with distant metastases at enrollment, right-sided tumors, mucinous tumors, lymphovascular invasion, and KRAS (51%) or BRAF (28%) mutations predicted poor prognosis and survival. Conclusion: CRC in KSA is usually diagnosed at advanced stages with metastases and KRAS/BRAF, and is associated with poor prognosis and short survival. Nationwide awareness campaigns and screening programs for CRC are critical for prevention, early detection and adequate management of CRC.

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Diagnosis and Treatment of Metastatic Colorectal Cancer

Biller

Schrag

2021

JAMA

1,458

851

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ImportanceColorectal cancer (CRC) is the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850 000 deaths annually. Of new colorectal cancer diagnoses, 20% of patients have metastatic disease at presentation and another 25% who present with localized disease will later develop metastases.ObservationsColorectal cancer is the third most common cause of cancer mortality for men and women in the United States, with 53 200 deaths projected in 2020. Among people diagnosed with metastatic colorectal cancer, approximately 70% to 75% of patients survive beyond 1 year, 30% to 35% beyond 3 years, and fewer than 20% beyond 5 years from diagnosis. The primary treatment for unresectable metastatic CRC is systemic therapy (cytotoxic chemotherapy, biologic therapy such as antibodies to cellular growth factors, immunotherapy, and their combinations.) Clinical trials completed in the past 5 years have demonstrated that tailoring treatment to the molecular and pathologic features of the tumor improves overall survival. Genomic profiling to detect somatic variants is important because it identifies the treatments that may be effective. For the 50% of patients with metastatic CRC with KRAS/NRAS/BRAF wild-type tumors, cetuximab and panitumumab (monoclonal antibodies to the epithelial growth factor receptor [EGFR]), in combination with chemotherapy, can extend median survival by 2 to 4 months compared with chemotherapy alone. However, for the 35% to 40% of patients with KRAS or NRAS sequence variations (formerly termed mutations), effective targeted therapies are not yet available. For the 5% to 10% with BRAF V600E sequence variations, targeted combination therapy with BRAF and EGFR inhibitors extended overall survival to 9.3 months, compared to 5.9 months for those receiving standard chemotherapy. For the 5% with microsatellite instability (the presence of numerous insertions or deletions at repetitive DNA units) or mismatch repair deficiency, immunotherapy may be used in the first or subsequent line and has improved treatment outcomes with a median overall survival of 31.4 months in previously treated patients.Conclusions and RelevanceAdvances in molecular profiling of metastatic CRC facilitate the ability to direct treatments to the biologic features of the tumor for specific patient subsets. Although cures remain uncommon, more patients can anticipate extended survival. Genomic profiling allows treatment selection so that more patients derive benefit and fewer are exposed to toxicity from ineffective therapies.

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Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group

Cited by 251 publications

References 31 publications

Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

Mutations in KRAS codon 12 predict poor survival in Chinese patients with metastatic colorectal cancer

Clinicopathological Features and Predictive Factors for Colorectal Cancer Outcome in the Kingdom of Saudi Arabia

Diagnosis and Treatment of Metastatic Colorectal Cancer

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