Prognostic Value of Autophagy, Microsatellite Instability, and KRAS Mutations in Colorectal Cancer

132 Background: Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States. Some of the poor prognostic factors for metastatic CRC (mCRC) include BRAF V600E mutation and microsatellite instability (MSI) that result from mutation or loss of mismatch-repair genes. While the prognostic value of MSI-high CRC for early-stage patients treated with resection and adjuvant chemotherapy is favorable, the prognostic value of BRAF mutation is still unclear. Furthermore, the impact of BRAF mutation with concurrent microsatellite instability on overall survival has not been well investigated. Methods: Here, we collected BRAF mutation status and MSI status of stage II/III CRC patients (n=106) treated at the University of Kansas Cancer Center between September 2009 and July 2020 and compared overall survival between 4 subtypes:MSI-H/BRAF mutant (n=16), MSS/BRAF mutant (n=4), MSI-H/BRAF WT (n=17) and MSS/BRAF WT (n=69), further stratifying patients by age at diagnosis and tumor location. Molecular data were obtained from molecular oncology laboratory as PCR or IHC-based or acquired from outside records. Subgroup analyses were done for stage II and stage III cancers. Results: Table shows the patient characteristics. From our preliminary analysis, MSI-H CRC was found to be primarily a right-sided tumor (MSI-H/BRAF mutant: 94% and MSI-H/BRAF WT 76%). On the contrary, MSS CRC had a more heterogenous localization, spanning left colon, right colon and rectum. In our patient cohort, median survival was not reached for stage II patients whereas for stage III patients, BRAF mutation was associated with poor median survival irrespective of MSI status (MSS/BRAF mutant: 27 months and MSI-H/BRAF mutant 29 months). Median overall survival was found to be 87 months, not reached, 27 months and 29 months for MSS/BRAF WT, MSI-H/BRAF WT, MSS/BRAF mutant and MSI-H/BRAF mutant, respectively. Although associated with poor survival, MSI-H/BRAF mutant displayed later age at diagnosis (mean age 73) compared to MSS/BRAF mutant (mean age 60, p-value<0.029). Conclusions: Our finding suggests that BRAF mutation has poor prognosis even at earlier stages of the disease and that MSS/BRAF mutation, in particular, has the worst prognostic features. These findings highlight the need for BRAF-targeted therapy for CRC at any stage. Due to small sample size, however, our results warrant validation in a larger cohort. [Table: see text]

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Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: A meta-analysis of 22 studies

European Journal of Cancer ◽

10.1016/j.ejca.2010.05.022 ◽

2010 ◽

Vol 46 (15) ◽

pp. 2781-2787 ◽

Cited By ~ 63

Author(s):

Li-Xin Qiu ◽

Chen Mao ◽

Jian Zhang ◽

Xiao-Dong Zhu ◽

Ru-Yan Liao ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Prognostic Value ◽

Meta Analysis ◽

Kras Mutations ◽

Colorectal Cancer Patients ◽

Predictive And Prognostic Value

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Prognostic Value of KRAS Mutations in Codons 12 and 13 in South Egyptian Colorectal Cancer Patients

Journal of Cancer and Tumor International ◽

10.9734/jcti/2015/20417 ◽

2015 ◽

Vol 2 (4) ◽

pp. 182-195 ◽

Cited By ~ 1

Author(s):

Alia Attia ◽

Hosny Badrawy ◽

Hisham Hamza ◽

Tarek Elsaba

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Prognostic Value ◽

Kras Mutations ◽

Colorectal Cancer Patients

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BRAF and KRAS mutations as additional risk factors in the context of clinical parameters of patients with colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3522 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3522-3522

Author(s):

Vlad Calin Popovici ◽

Eva Budinska ◽

Arnaud Roth ◽

Fred Bosman ◽

Sabine Tejpar ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Braf Mutation ◽

Kras Mutation ◽

Prognostic Value ◽

Tumor Site ◽

Kras Mutations ◽

P Values ◽

Significance Level ◽

Survival After Relapse

3522 Background: The BRAF and KRAS mutations have been proposed as prognostic markers in colorectal cancer (CRC). Of them, only the BRAF V600E mutation has been validated as prognostic for overall survival and survival after relapse, while the value of KRAS mutation is still unclear. Methods: In a cohort of 1423 stage II-III patients from the PETACC-3 clinical trial, the prognostic value of the BRAF and KRAS mutations was retrospectively assessed in all possible stratifications defined by the 5 factors (T and N stage, tumor site and grade, and microsatellite instability status), by log rank test for overall survival (OS), relapse-free survival (RFS), and survival after relapse (SAR). The presence of interactions was tested by Wald test. The significance level was set to 0.01 for Bonferroni-adjusted p-values (P*), and a second level for a trend towards statistical significance was set at 0.05 for unadjusted p-values (P). Results: BRAF mutation was a marker of poor OS only in microsatellite stable (MSS) and left-sided tumors, with no prognostic value in microsatellite instable (MSI-H) or right-sided tumors. In MSS/left-sided tumors, BRAF mutation represents a marker of higher risk than previously reported: OS HR=6.4 [95% CI: 3.6-11.5], P* < 0.0001. For SAR, BRAF was prognostic in more stratifications, with higher risk in MSS/left-sided tumors (HR=3.9 [95% CI: 2.1-7.2], P* = 0.0002) than in MSS/right-sided (HR=2.3 [95% CI: 1.2-4.4], P=0.01). A novel observation was that BRAF mutation was prognostic also for RFS, but only in MSS/left-sided tumors (HR=3.6 [95% CI:2-6.3], P*=0.0005]). Additionally, heterogeneity in OS and RFS among BRAF mutants was observed. In general, KRAS mutation did not reach the significance level required, but showed a trend to become a prognostic marker for RFS in MSS tumors with early lymph node involvement (N1) (HR=1.6 [95% CI:1.1-2.2], P=0.01). Conclusions: The prognostic utility of the BRAF and KRAS mutations has to be interpreted in the context of other factors. For the BRAF mutation, a clear interaction with MSI status and tumor site was observed, with BRAF mutation indicating a much higher risk in MSS/left-sided tumors than previously considered.

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