Clinical Impact of PI3K/BRAF Mutations in RAS Wild Metastatic Colorectal Cancer: Meta-analysis Results

Mohamed, Amr; Twardy, Brandon; Abdallah, Nadine; Akhras, Alaa; Ismail, Hibah; Zordok, Magdi; Schrapp, Kelly; Attumi, Taraq; Tesfaye, Anteneh; El‐Rayes, Bassel F.

doi:10.1007/s12029-018-0062-y

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…In the present study, our results suggested that BRAF mutation was associated with shorter OS in both MSS CRC patients and MSI CRC patients overall and in all subgroups stratified by cancer type, tumor stage, and treatment, which were similar with the prognostic value of BRAF mutation in entire CRC and mCRC. 79 – 84 Similar to the previous results, we also found the poor prognostic effects of BRAF mutation in both MSS and MSI CRC treated with surgery and adjuvant therapy, and MSI did not change the poor effect of BRAF mutation. 85 Our results also revealed that MSI was not associated with OS in BRAF wt patents with CRC overall or in stage I–III CRC, similar to the study by Gkekas et al 78 performed in stage II CC regardless of BRAF mutation.…”

Section: Discussionsupporting

confidence: 89%

“…Multiple meta-analyses were performed in mCRC to explore the associations of BRAF mutation with prognosis and achieved consistent results that BRAF mutation was significantly associated with shorter PFS and OS. 80 – 84 In stage II–III CRC treated with surgery and adjuvant therapy, BRAF mutation was also found to be associated with shorter OS and DFS. 85 However, there was no meta-analysis study summarizing the prognosis of the CRC patients with different subtypes defined by MSI and BRAF mutation, ie, MSS/ BRAF wt, MSS/ BRAF mut, MSI/ BRAF wt, and MSI/ BRAF mut.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic value of the combination of microsatellite instability and <em>BRAF</em> mutation in colorectal cancer

Yang¹,

Wang²,

Jin³

et al. 2018

CMAR

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PurposeThe aim of this study was to investigate the prognostic value of the combination of microsatellite instability (MSI) and BRAF V600E mutation in colorectal cancer (CRC).Materials and methodsWe compare the prognosis difference among CRC patients with four subtypes according to MSI and BRAF mutation, ie, microsatellite stable/BRAF wild type (MSS/BRAFwt), MSS/BRAF mutation (MSS/BRAFmut), MSI/BRAFwt, and MSI/BRAFmut, by pooling the previous related reports and public available data sets till December 2017 for the first time.ResultsTwenty-seven independent studies comprising 24,067 CRC patients were included. Meta-analysis suggested that, compared with MSS/BRAFwt subtype, MSS/BRAFmut was associated with shorter overall survival (OS) (N=25, HR = 2.018, 95% CI = 1.706–2.388, P=2.220E-16), while there was a trend of association of MSI/BRAFmut with OS (N=13, HR = 1.324, 95% CI = 0.938–1.868, P=1.096E-01) and no association of MSI/BRAFwt with OS (N=17, HR = 0.996, 95% CI = 0.801–1.240, P=9.761E-01). Compared with MSI/ BRAFwt subtype, MSI/BRAFmut was a poor factor for OS (N=22, HR = 1.470, 95% CI = 1.243–1.740, P=7.122E-06). Compared with MSS/BRAFmut subtype, both MSI/BRAFwt (N=11, HR = 0.560, 95% CI = 0.433–0.725, P=1.034E-05) and MSI/BRAFmut (N=16, HR = 0.741, 95% CI = 0.567–0.968, P=2.781E-02) were favorable for OS. Subgroup analysis revealed similar results in all subgroups except the subgroup of stage IV cancer, in which MSI showed poor effects on OS in BRAF wild-type patients (N=6, HR = 1.493, 95% CI = 1.187–1.879, P=6.262E-04) but not in BRAF-mutated patients (N=5, HR = 1.143, 95% CI = 0.789–1.655, P=4.839E-01). Meta-analysis regression and test of interaction revealed no interaction of MSI with BRAF mutation when evaluating the associations of MSI/BRAF mutation subtypes with OS in CRC.ConclusionAmong the four subtypes according to MSI and BRAF mutation, MSS/BRAFmut was a poor prognostic factor, while MSS/BRAFwt and MSI/BRAFwt were comparable and favorable and MSI/BRAFmut was moderate in CRC. The combination of MSI/BRAF mutations could facilitate the planning of individualized treatment strategies and prognosis improvement in CRC.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Prognostic value of the combination of microsatellite instability and <em>BRAF</em> mutation in colorectal cancer

Yang¹,

Wang²,

Jin³

et al. 2018

CMAR

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“…Smeby et al concluded that the role of genetic alterations may depend on molecular backgrounds; it may therefore be concluded that the association of PIK3CA mutations with clinicopathologic characteristics depends on distinct molecular contexts [62]. Since numerous studies have demonstrated the prognostic and predictive value of PIK3CA mutations in KRAS-wild CRC, the association between PIK3CA mutations and clinicopathologic features in wild-type KRAS may differ from unselected patients [6,59,63].…”

Section: Discussionmentioning

confidence: 99%

PIK3CA mutation and clinicopathological features of colorectal cancer: a systematic review and Meta-Analysis

et al. 2019

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Background: There is conflicting evidence regarding the association between PIK3CA mutations and clinicopathological features of colorectal cancer (CRC). We performed a comprehensive meta-analysis investigating the association between PIK3CA mutations and clinicopathological features in CRC, including subgroup analysis of mutations in exons 9 and 20, to elucidate the role of PIK3CA mutations in CRC. Materials and Methods: A detailed literature search was performed within the PubMed, Web of Science, and Embase databases, examining the associations between PIK3CA mutations and demographic characteristics, clinicopathologic parameters, and molecular features in patients with CRC. The odds ratios with 95% confidence intervals were used to estimate the effect of PIK3CA mutations on outcome parameters. Results: Forty-four studies enrolling 17621 patients were eligible for inclusion. PIK3CA mutations were associated with proximal tumor location, mucinous differentiation, KRAS mutations, and microsatellite instability (MSI). Subgroup analysis demonstrated that PIK3CA exon 9 mutations were positively associated with proximal tumor location and KRAS mutations, and negatively associated with BRAF mutations and MSI; exon 20 mutations were associated with proximal tumor location, KRAS mutations, BRAF mutations and MSI. Conclusions: Our findings suggest that overall or exon-specific PIK3CA mutations showed null associations with key clinicopathological parameters, including disease stage and tumor differentiation, indicating that PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC. As PIK3CA mutations were found to be closely associated with KRAS mutations, their relationship warrants further investigation. Since PIK3CA exon 9 and 20 mutations showed different tendencies with regard to BRAF mutation and MSI status, they may have distinct molecular impacts on CRC.

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“…The prevalence of PTEN loss and mutation was 19%-58% and 7%-9%, respectively, in patients with wildtype KRAS mCRC [19,[24][25][26][27] . For those patients with wild-type KRAS exon 2 mCRC, PIK3CA mutation and PTEN alterations were associated with poorer objective response rate and OS for anti-EGFR therapy in two metanalyses [28,29] . However, there might be different predictive effects between different PIK3CA mutations and different techniques detecting PTEN alterations.…”

Section: Other Biomarkersmentioning

confidence: 95%

Molecular biomarkers in current management of metastatic colorectal cancer

Tanasanvimon¹

2018

JCMT

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Over the past two decades, the treatment outcomes in metastatic colorectal cancer (mCRC) have been remarkably improved, largely from the evolution of systemic therapy. Also, the molecular biomarkers have played a major role in this improvement by their predictive value in current treatment paradigm in mCRC. Currently, extended RAS mutation analysis is required for consideration of anti-epidermal growth factor receptor therapy in patients with mCRC. Several uncommon gene alterations have emerged as the potential targets for their matched molecular targeted therapy. Although, most patients with mCRC do not derive benefit from immunotherapy. By using microsatellite instability or mismatch repair test, we are now able to identify a small subgroup of patients with mCRC who have a very good response to immune checkpoint inhibitors. With the increasing number of required biomarkers in mCRC management, multiplex gene panel testing is now replacing single gene testing strategy. In patients accessible to matched molecular targeted therapy, especially for clinical trials, the comprehensive genomic profiling might be the preferred testing method. Although, it is potentially benefit in mCRC treatment, the liquid biopsy is not yet clinically applicable. The optimal utilization of molecular biomarker testing is required for best treatment outcomes in individual patients.

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Clinical Impact of PI3K/BRAF Mutations in RAS Wild Metastatic Colorectal Cancer: Meta-analysis Results

Cited by 7 publications

References 21 publications

Prognostic value of the combination of microsatellite instability and <em>BRAF</em> mutation in colorectal cancer

Prognostic value of the combination of microsatellite instability and <em>BRAF</em> mutation in colorectal cancer

PIK3CA mutation and clinicopathological features of colorectal cancer: a systematic review and Meta-Analysis

Molecular biomarkers in current management of metastatic colorectal cancer

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