KRAS Status as a Predictor of Chemotherapy Activity in Patients With Metastatic Colorectal Cancer

Yarom, Nirit; Gresham, Gillian; Boame, Nana; Jonker, Derek J.

doi:10.1016/j.clcc.2019.05.004

Cited by 14 publications

(11 citation statements)

References 22 publications

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“…Intriguingly, patients in the HMC4 cluster demonstrated higher KRAS mutation and KRAS signaling enrichment incidences than patients in other clusters. Since growing evidence has acknowledged the association between KRAS mutation and the adverse prognostic impacts on patients with colon cancer treated with fluorouracil-based chemotherapy [ 30 , 31 ], we can conclude that the diminished benefits of chemotherapy in patients within the HMC4 cluster also resulted in the combined effects of KRAS mutation and KRAS signaling dysregulation.…”

Section: Discussionmentioning

confidence: 98%

Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer

et al. 2022

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Background Alterations in histone modifications have been reported to be related to tumorigenicity and tumor progression. However, whether histone modification can aid the classification of patients or influence clinical behavior in patients with colon cancer remains unclear. Therefore, this study aimed to evaluate histone modifier expression patterns using the unsupervised clustering of the transcriptomic expressions of 88 histone acetylation and methylation regulators. Results In this study, by consensus clustering analysis based on the transcriptome data of 88 histone modification regulators, we identified four distinct expression patterns of histone modifiers associated with different prognoses, intrinsic fluorouracil sensitivities, biological pathways, and tumor microenvironment characteristics among 1372 colon cancer samples. In these four clusters, the HMC4 cluster represented a stroma activation phenotype characterized by both the worst prognosis and lowest response rates to fluorouracil treatment. Then, we established a scoring scheme comprising 155 genes designated as “HM_score” by using the Boruta algorithm to distinguish colon cancer patients within the HMC4 cluster. Patients with a high HM_score were considered to have high stromal pathway activation, high stromal fraction, and an unfavorable prognosis. Further analyses indicated that a high HM_score also correlated with reduced therapeutic benefits from fluorouracil chemotherapy. Moreover, through CRISPR library screening, ZEB2 was found to be a critical driver gene that mediates fluorouracil resistance, which is associated with histone modifier expression patterns. Conclusions This study highlights that characterizing histone modifier expression patterns may help better understand the epigenetic mechanisms underlying tumor heterogeneity in patients with colon cancer and provide more personalized therapeutic strategies.

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Section: Discussionmentioning

confidence: 98%

Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer

et al. 2022

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“…It is not known how this fact can affect the survival. However, in previous publications, the worst survival of patients with MT-KRAS tumours has been found to be independent of the chemotherapy treatment and it has been attributed to more aggressive tumour behaviour [ 11 , 19 ]. Our data corroborate the prognostic implications associated with mutation of KRAS and its informative value as the prognostic factor in CRC patients.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of KRAS Gene Mutation on Survival of Patients with Peritoneal Metastases of Colorectal Adenocarcinoma

Díez-Alonso

Mendoza‐Moreno

Gómez-Sanz

et al. 2021

International Journal of Surgical Oncology

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Objective. The main objective of the study was to determine the effect of the presence of mutation in the KRAS gene on the survival in patients with colorectal cancer (CRC) and peritoneal metastases (PM). Materials and Methods. A retrospective cohort study was performed. Patients diagnosed with CRC with synchronous or metachronous PM between January 2006 and December 2019 were included. Data on the histopathological, clinical, and treatment factors were collected. The effect of each variable on survival was evaluated by Cox regression. Results. A total of 149 patients were included (64 women (43%) and 85 men (57%); mean age, 63 years). The long-term survival rate at 36 months was 24% (median, 21 months). KRAS mutation was detected in 75 patients (50.3%). Kaplan–Meier analysis estimated that likelihood of survival was higher in patients with wild-type KRAS tumours (35%) than in mutated-type KRAS (14%) (median: 28 vs. 15, respectively) ( P = 0.001 ). Within the categories into which the peritoneal cancer index (PCI) was classified, survival at 36 months depended on the KRAS status. Survival in wild-type KRAS tumours with PCI 1–10 was 71% and with PCI 11–20 was 26%, while in mutant-type KRAS tumours, survival was 41% and 4%, respectively ( P = 0.025 ). In the multiple regression analysis, the KRAS mutation was revealed to have an independent prognostic value (HR: 2.144; 95% CI: 1.342–3.424). Conclusion. The mutational status of the KRAS gene has demonstrated a strong association with survival and prognostic utility in patients with CRC with PM.

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“…It should be noted that in our analyzes, the mutation in the KRAS gene was significantly associated with the overall survival of patients, but the data on the presence or absence of KRAS mutations were not available for 41% of patients. KRAS mutation is an unclear prognostic factor [29] and the effect of KRAS mutations on the survival of patients with mCRC treated with chemotherapy has not been confirmed in other studies [30][31][32]. However, there are studies indicating that KRAS wild-type may be associ-ated with better prognosis in patients with mCRC receiving capecitabine-based chemotherapy [33].…”

Section: Discussionmentioning

confidence: 99%

Overweight is associated with better prognosis in metastatic colorectal cancer patients treated with bevacizumab plus FOLFOX chemotherapy

Cybulska-Stopa¹,

Ługowska²,

Wiśniowski³

et al. 2020

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Introduction: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in metastatic CRC (mCRC). Whether BMI is a prognostic or predictive factor in mCRC is unclear. We aimed to assess efficacy outcomes according to BMI in patient with metastatic colorectal cancer treated with bevacizumab plus FOLFOX chemotherapy regimen in second-line treatment. Material and methods: The analysis of 237 patients with metastatic colorectal cancer treated with bevacizumab plus FOLFOX in the second line (treated from January 2014 to August 2018) in 4 reference oncological centers in Poland. Results: The median age of the patients was 65 years (range 34-82). The median overall survival (OS) and progression-free survival (PFS) of the all 237 patient was 14.6 and 8.8 months, respectively. Comparison of obese patient (BMI > 30 kg/m 2) vs. overweight patients (BMI ≥ 25 to < 30 kg/m 2) vs. normal BMI range patients revealed a significant improvement of median OS (17.5 vs. 14.3 vs. 13.1 months, p = 0.01) and median PFS (9.4 vs. 9.1 vs. 7.3 months, p = 0.03). The Cox hazard model showed that the BMI class is an important risk factor. However, the Cox model also showed that the significance of the BMI class applies only to patients with BMI < 25 kg/m 2. This rule applies to both OS and PFS. The regression analysis also confirmed that there is a statistically significant relationship between the length of OS and PFS and the BMI value. Higher BMI was associated with a better prognosis. There were no differences in responses to treatment bevacizumab and FOLFOX chemotherapy and number adverse events according to BMI values. Conclusions: Patients with mCRC treated with chemotherapy with bevacizumab in second-line treatment with higher BMI compared with normal weight patients have better prognosis in terms of PFS and OS. In this group, we found no evidence of changes in safety profile depending on BMI. Nevertheless, further large randomized studies are needed to assess the body weight on the effectiveness of chemotherapy in combination with bevacizumab.

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KRAS Status as a Predictor of Chemotherapy Activity in Patients With Metastatic Colorectal Cancer

Cited by 14 publications

References 22 publications

Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer

Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer

Prognostic Value of KRAS Gene Mutation on Survival of Patients with Peritoneal Metastases of Colorectal Adenocarcinoma

Overweight is associated with better prognosis in metastatic colorectal cancer patients treated with bevacizumab plus FOLFOX chemotherapy

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