KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Garcia-Carbonero, Nuria; Martínez‐Useros, Javier; Li, Weiyao; Orta, Alberto; Pérez, Núria Teixidó; Caramés, Cristina; Hernández, Tatiana; Moreno, Irene; Serrano, Gloria; Garcı́a-Foncillas, Jesús

doi:10.3390/cells9010219

Cited by 57 publications

(51 citation statements)

References 78 publications

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“…These observations further support the maintenance of the main driver gene alterations in CRCs undergoing metastatic spreading [ 45 ]. The detection of KRAS mutations in metastatic CRC is important because implies a negative prognosis and a poor response to standard chemotherapy [ 68 ].…”

Section: Effect Of Therapy On Mutational Landscape Of Metastatic Cmentioning

confidence: 99%

Genetic Alterations of Metastatic Colorectal Cancer

Testa

Castelli

2020

Biomedicines

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Genome sequencing studies have characterized the genetic alterations of different tumor types, highlighting the diversity of the molecular processes driving tumor development. Comprehensive sequencing studies have defined molecular subtypes of colorectal cancers (CRCs) through the identification of genetic events associated with microsatellite stability (MSS), microsatellite-instability-high (MSI-H), and hypermutation. Most of these studies characterized primary tumors. Only recent studies have addressed the characterization of the genetic and clinical heterogeneity of metastatic CRC. Metastatic CRC genomes were found to be not fundamentally different from primary CRCs in terms of the mutational landscape or of genes that drive tumorigenesis, and a genomic heterogeneity associated with tumor location of primary tumors helps to define different clinical behaviors of metastatic CRCs. Although CRC metastatic spreading was traditionally seen as a late-occurring event, growing evidence suggests that this process can begin early during tumor development and the clonal architecture of these tumors is consistently influenced by cancer treatment. Although the survival rate of patients with metastatic CRC patients improved in the last years, the response to current treatments and prognosis of many of these patients remain still poor, indicating the need to discover new improvements for therapeutic vulnerabilities and to formulate a rational prospective of personalized therapies.

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Section: Effect Of Therapy On Mutational Landscape Of Metastatic Cmentioning

confidence: 99%

Genetic Alterations of Metastatic Colorectal Cancer

Testa

Castelli

2020

Biomedicines

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“…Currently, only a few molecular markers have been implemented for the management of CRC although these have mainly been for therapy stratification such as testing for activating KRAS , NRAS and BRAF gene mutations as exclusion criteria for the use of EGFR-targeted therapies in metastatic CRC (mCRC) [ 2 ]. Although RAS and BRAF mutations are considered to be poor prognostic factors [ 7 ], outside of targeted therapies, they are not used for outcome predictions in routine CRC diagnostics. Recently, tumor microsatellite instability (MSI) traditionally used to identify Lynch syndrome patients [ 8 ], was rediscovered as a biomarker for immunotherapy in CRC [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Immuno-Interface Score to Predict Outcome in Colorectal Cancer Independent of Microsatellite Instability Status

Nestarenkaite

Fadhil

Rasmusson

et al. 2020

Cancers

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Tumor-associated immune cells have been shown to predict patient outcome in colorectal (CRC) and other cancers. Spatial digital image analysis-based cell quantification increases the informative power delivered by tumor microenvironment features and leads to new prognostic scoring systems. In this study we evaluated the intratumoral density of immunohistochemically stained CD8, CD20 and CD68 cells in 87 cases of CRC (48 were microsatellite stable, MSS, and 39 had microsatellite instability, MSI) in both the intratumoral tumor tissue and within the tumor-stroma interface zone (IZ) which was extracted by a previously developed unbiased hexagonal grid analytics method. Indicators of immune-cell gradients across the extracted IZ were computed and explored along with absolute cell densities, clinicopathological and molecular data, including gene mutation (BRAF, KRAS, PIK3CA) and MSI status. Multiple regression modeling identified (p < 0.0001) three independent prognostic factors: CD8+ and CD20+ Immunogradient indicators, that reflect cell migration towards the tumor, were associated with improved patient survival, while the infiltrative tumor growth pattern was linked to worse patient outcome. These features were combined into CD8-CD20 Immunogradient and immuno-interface scores which outperformed both tumor-node-metastasis (TNM) staging and molecular characteristics, and importantly, revealed high prognostic value both in MSS and MSI CRCs.

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“…The role of RAS and BRAF mutations as prognostic factors has been evaluated by many researchers. RAS mutations are considered a negative prognostic factor in multiple trials, but some data contradicts this result [42][43][44]. BRAF mutations are associated with a shorter OS (10-16 months) in mCRC patients.…”

Section: Discussionmentioning

confidence: 99%

The Coexistence of RAS and BRAF Mutations in Metastatic Colorectal Cancer: A Case Report and Systematic Literature Review

Afrăsânie

Gafton

Marinca

et al. 2020

JGLD

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Background and Aims: The coexistence of RAS and BRAF mutations is extremely rare, occurring in approximately 0.05% of patients with metastatic colorectal cancer (mCRC). Starting from a case presentation, this review aims to examine the prevalence, clinical, histopathological and molecular features of tumors with concomitant mutations. Methods: Case report and systematic review. We performed a systematic literature search in PubMed and EMBASE using the following MeSH terms: “coexistence” OR “concomitant” AND “RAS” AND “BRAF” AND “colorectal cancer” from the inception of the databases onwards. Results: We present the case of a 53-year-old man diagnosed with metastatic rectal adenocarcinoma with both a KRAS and a BRAF mutation. The review included eleven papers reporting on a total of 30 mCRC cases with concomitant RAS and BRAF mutations. The male/female ratio was 11/5. The average age was 58.5 years. The tumor was located in nine cases on the right colon and in two cases in the left colon. 43.3% of subjects had liver metastases, and 6.6% had lung metastases. Next-generation sequencing (NGS) was used in 36.6% of cases and polymerase chain reaction (PCR) in 16.6% of cases. KRAS mutations were present in 83.3% of patients and NRAS mutations in 16.6% of patients. Survival could be assessed in 10 patients and the median was 21.1 months (about 30% lower than the survival in the general mCRC population). Conclusion: The results of this systematic review suggest the need to design a cohort study (either prospective or retrospective) to better characterize the patients with concomitant RAS and BRAF mutations and to establish the optimal treatment for this rare situation.

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KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Cited by 57 publications

References 78 publications

Genetic Alterations of Metastatic Colorectal Cancer

Genetic Alterations of Metastatic Colorectal Cancer

Immuno-Interface Score to Predict Outcome in Colorectal Cancer Independent of Microsatellite Instability Status

The Coexistence of RAS and BRAF Mutations in Metastatic Colorectal Cancer: A Case Report and Systematic Literature Review

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