scholarly journals Study of Ras Mutations’ Prognostic Value in Metastatic Colorectal Cancer: STORIA Analysis

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1919
Author(s):  
Alessandro Ottaiano ◽  
Nicola Normanno ◽  
Sergio Facchini ◽  
Antonino Cassata ◽  
Anna Nappi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Median Survival ◽  
Prognostic Value ◽  
Primary Tumour ◽  
Eastern Cooperative Oncology Group ◽  
Rank Test ◽  
Wild Type ◽  
Kras Mutations ◽  
Thermo Fisher Scientific ◽  
Fisher Scientific

Background: Colorectal cancer (CRC) is the second most common cause of cancer-specific death in both sexes in Western countries. KRAS mutations occur in about 50% of metastatic CRCs (mCRCs). The prognostic value of specific KRAS mutations still remains unexplored and unclear. Methods: Two hundred and forty KRAS wild-type and 206 KRAS/NRAS mutant consecutive unresectable mCRC patients with PS Eastern Cooperative Oncology Group (ECOG) 0 or 1, aged < 80 years, and with a life expectancy >3 months entered into this study. DNA was extracted from paraffin-embedded formalin-fixed tumour tissues, and it was sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Data were analysed using the Torrent Suite Software v5.0 (Thermo Fisher Scientific). The primary outcome was the analysis of the prognostic role of different KRAS mutations in terms of overall survival (OS). Results: There were no significant differences among the most prevalent mutations (p.G12D, p.G12V, p.G13D, p.G12A, p.G12C, and p.G12S) in terms of age (<65 vs. ≥65 years), gender (male vs. female), grading (G1/G2 vs. G3), side of primary tumour (left vs. right), pT, and pN. At the median follow-up of 25.6 months, there were 77 deaths in KRAS-mutated patients and 94 in wild-type patients. Three homogeneous prognostic groups were identified: wild-type patients (group A, median survival: 27.5 months), p.G13D/p.G12A/p.G12V/p.G12D mutants (group B, median survival: 17.3 months), and p.G12C/p.G12S mutants (group C, median survival: 5.0 months, p < 0.0001 according to Log Rank test). Upon multivariate analysis, metastatic involvement and p.G12C/p.G12S KRAS mutation group C (vs. other mutations) emerged as independent prognostic variables for survival. Conclusions: We show that mutant KRAS is a negative prognostic factor and that p.G12C/p.G12S variants present the worst clinical courses. This information suggests a clear difference among KRAS mutations, and it will be useful to test potentiated and/or innovative therapeutic strategies in p.G12C/p.G12S metastatic CRC patients.

Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3520-3520 ◽  
Author(s):  
David Tougeron ◽  
Thierry Lecomte ◽  
jean-Christophe Pages ◽  
Christine Collin ◽  
Claire Villalva ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Direct Sequencing ◽  
Prospective Trial ◽  
Growth Factor Receptor ◽  
Rank Test ◽  
Wild Type ◽  
Limit Of Quantification ◽  
Kras Mutations ◽  
The Impact

3520 Background: Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are standard components of treatment algorithms in metastatic colorectal cancer (mCRC). It is already well established that only patients with wild-type KRAS tumors benefit from treatment with an anti-EGFR agent. Pyrosequencing is now used for a precise determination of KRAS mutation burden and a conservative cutoff of 10% was defined as the lower limit of quantification for the assignment of mutation status. Up to now, the impact of low-signal KRAS mutations below 10% on the response to anti-EGFR therapy in mCRC has not been evaluated. Methods: All consecutive patients treated by anti-EGFR for a mCRC between January 2006 and June 2011 have been retrospectively analyzed by pyrosequencing using the therascreen KRAS Pyro Kit (Qiagen). All patients were defined wild-type (WT) for KRAS status using direct sequencing. The PFS data were plotted as Kaplan–Meier curve and compared by the log-rank test. Results: A total of 141 patients treated by anti-EGFR for a mCRC were included in the study. Mean age was 64.1 ± 14.8 years and a majority of patients had synchronous metastases (68.6%). Patients benefited from anti-EGFR in first-line chemotherapy (30.7%), second-line (22.9%), third-line (35%) or later (11.4%). Majority of patients benefited from anti-EGFR combined with cytotoxic chemotherapy (91.4%), mostly irinotecan (78.6%). Using pyrosequencing, 117 tumors had a KRAS WT status and 24 tumors had low-signal mutation, between 2 and 10% (KRAS lowMT). Response rate according RECIST criteria were 13.6% versus 35.4% partial response, 13.6% versus 37.2% stabilization and 72.7% versus 27.1% progression (p<0.01), for KRAS lowMT versus KRAS WT respectively. The PFS was respectively 2.6 ± 0.2 months for KRAS lowMT versus 6.0 ± 0.5 months for KRAS WT (p=0.024). Overall survival was not different between the two groups (27.4 months versus 33.0 months, p=0.4). Conclusions: Patients with tumors harboring KRAS lowMT benefit less of anti-EGFR therapy than patients with tumor harboring KRAS WT. While these results invite to consider low-signal tumors as positives, generalization awaits a large prospective trial.

Association between KRAS mutation and lung metastasis in advanced colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 494-494
Author(s):  
Allan Andresson Lima Pereira ◽  
Juliana Florinda De Mendonga Rego ◽  
Van Karlyle Morris ◽  
Michael J. Overman ◽  
Cathy Eng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lung Metastasis ◽  
Kras Mutation ◽  
Lung Metastases ◽  
Lymph Node Involvement ◽  
Rank Test ◽  
Cancer Center ◽  
Wild Type ◽  
Kras Mutations ◽  
Kras Status

494 Background: The role of KRAS status in the time-dependent pattern of metastasis in colorectal cancer (CRC) patients has been reported but not validated in independent series of unresectable metastatic CRC. We aimed to determine its potential value as a predictive factor for development of lung metastasis. Methods: We retrospectively evaluated data from MD Anderson Cancer Center from 494 patients diagnosed with metastatic CRC with KRAS mutation testing (codons 12, 13, 61) by Sanger sequencing or mass spectroscopy genotyping in 2008 through 2010. Medical records and image reports were assessed to determine date of lung metastasis diagnosis, pattern of lung involvement and presence of thoracic lymph nodal metastasis. Time-to-lung metastasis (TTLM), lung-metastasis-free survival (LMFS) and overall survival (OS) were calculated from the time of diagnosis of first metastasis in any site according to the Kaplan-Meier method and were compared by log-rank test. Results: We included 494 patients (41% female) with a median age of 55 years. 292 tumors were KRAS wild type (WT, 59%) and 202 (41%) were KRAS mutants. OS was not different between the groups (45.5 months for KRAS mutants vs. 50.6 months for KRAS wild type; p=0.6). At the time of diagnosis of metastatic disease, 36% of patient had lung metastases, with 1.6-fold higher odds of lung metastases with a KRAS mutation (p=0.013, 95% CI 1.1 – 2.4). Compared to KRAS WT, KRAS mutations were associated with a shorter TTLM (15.2 vs. 22.4 months; p=0.002) and LMFS (12.9 vs. 16.7 months; p= 0.019). There was no difference in thoracic lymph node involvement (p= 0.18), number of lung metastasis (p=0.71), lung lobes involved (p=0.19) or disease in bilateral lung (p=0.27) according to KRAS status. There were no differences in lung metastasis frequency or pattern between codons 12, 13, and 61 mutations. Conclusions: In this retrospective analysis, lung metastases were more common at diagnosis of mCRC in KRAS mutant patients and more likely to develop during the disease course. This data suggests a potential role for KRAS mutations in determining a metastatic tropism of CRC to the lung and can be used to risk stratify patients.

Analysis of the p53/BAX Pathway in Colorectal Cancer: Low BAX Is a Negative Prognostic Factor in Patients With Resected Liver Metastases

1999 ◽  
Vol 17 (5) ◽  
pp. 1364-1364 ◽  
Author(s):  
Isrid Sturm ◽  
Claus-Henning Köhne ◽  
Gerhard Wolff ◽  
Henrik Petrowsky ◽  
Timo Hillebrand ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Relative Risk ◽  
Protein Expression ◽  
Liver Metastases ◽  
Prognostic Marker ◽  
Median Survival ◽  
Prognostic Value ◽  
Hepatic Metastases ◽  
Wild Type ◽  
Frameshift Mutations

PURPOSE: To determine the prognostic value of the central downstream apoptosis effector BAX in relation to its upstream regulator p53 in R0-resected hepatic metastases of colorectal cancer. PATIENTS AND METHODS: Retrospective analysis of 41 patients who underwent potentially curative resection of liver metastases from colorectal cancer was performed. Tumor DNA was screened for p53 mutations by single-stranded conformational polymorphism polymerase chain reaction and for BAX frameshift mutations by fragment length analysis. Protein expression of BAX, p21, and p53 was investigated by immunohistochemistry. RESULTS: Overall median survival was 40.2 months. Tumors with BAX frameshift mutations were considered microsatellite mutator phenotype–positive and were excluded from further prognostic analyses. Patients with high BAX protein expression had a median survival of 53.6 months compared with 35.4 months for patients with low BAX expression (P < .05). The negative prognostic value of low BAX expression was more evident in those patients with wild-type p53 (median survival, 54.0 v 23.3 months for BAX-negative tumors; P < .01). Low BAX expression was an independent negative prognostic marker in multivariate regression analysis for all patients independent of the p53 status (relative risk, 3.03, P = .03), especially for p53 wild-type tumors (relative risk, 8.21; P = .0095). CONCLUSION: We conclude that low BAX expression is an independent negative prognostic marker in patients with hepatic metastases of colorectal cancer. The best survival was seen in patients with an intact p53-to-BAX pathway; ie, wild-type p53- and BAX-positive tumors. Thus, analysis of apoptosis signaling pathways (here, p53 in concert with its downstream death effector, BAX) might yield more prognostic power in future studies as compared with analysis of single genes such as p53 alone.

scholarly journals KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Alessandro Ottaiano ◽  
Guglielmo Nasti ◽  
Mariachiara Santorsola ◽  
Vincenzo Altieri ◽  
Giuseppina Di Fruscio ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Median Survival ◽  
Good Prognosis ◽  
Primary Tumors ◽  
Circulating Free Dna ◽  
Hazard Ratios ◽  
Thermo Fisher Scientific ◽  
Evolutionary Trajectories ◽  
Prognostic Power ◽  
Fisher Scientific

BackgroundWe previously reported that loss of KRAS mutations (“regressive” mutational trajectories) from primary tumors to metastases associated with the oligo-metastatic status in colorectal cancer (CRC). The present study was undertaken in order to analyze the mutational trajectories of KRAS in a well-characterized cohort of CRC patients who developed poly- or oligo-metastatic disease.Material and MethodsPatients were treated and followed-up according to European Society of Medical Oncology guidelines. Primary CRC FFPE tissue and metastatic circulating-free DNA were extracted using the QIAamp DNA specific kits (Qiagen, Hilden, Germany). Samples were sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Plasma collection for liquid biopsy was done from 1 to 14 days before starting first-line chemotherapy. Analysis of the prognostic power of KRAS evolutionary trajectories was done with uni- and multivariate analyses.ResultsOne-hundred-fourteen patients were enrolled. Sixty-three patients presented with mutated KRAS (mutKRAS) and 51 with wild-type KRAS (wtKRAS). KRAS mutational concordance was high (70.1%).Two divergent subsets were identified: mutKRAS in primary tumors and wtKRAS in metastatic ones (regressive: mutKRAS → wtKRAS in 8.8% of patients), and vice versa (progressive: wtKRAS → mutKRAS in 21.1% of patients). An association between KRAS regressive trajectory and the oligo-metastatic status (P &lt;0.0001) was found. At multivariate analysis, regressive and progressive mutational trajectories emerged as independent prognostic factors for survival, with Hazard Ratios of 0.22 (CI 95%: 0.08–0.61; median survival: not reached) and 2.70 (CI 95%: 1.11–6.56, median survival: 12.1 months), respectively.ConclusionsOur data provide evidence that the evolutionary trajectories of KRAS can have a strong clinical prognostic role and that they can be involved in discriminating between poly-metastatic aggressive vs oligo-metastatic indolent CRC.

scholarly journals The prognostic value of KRAS mutations in patients with colorectal cancer

2012 ◽  
Vol 28 (5) ◽  
pp. 1579-1584 ◽  
Author(s):  
YASUHIRO INOUE ◽  
SUSUMU SAIGUSA ◽  
TAKASHI IWATA ◽  
YOSHINAGA OKUGAWA ◽  
YUJI TOIYAMA ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Value ◽  
Kras Mutations

Overall survival based on MSI and BRAF mutation status for stage II/III colorectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 132-132
Author(s):  
Sophiya Karki ◽  
Rashna Madan ◽  
Sarah Schmitt ◽  
Ziyan Y. Pessetto ◽  
Andrew K. Godwin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Microsatellite Instability ◽  
Median Survival ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Stage Ii ◽  
Age At Diagnosis ◽  
Mutation Status ◽  
Braf Mutant

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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