Discovery of a novel and a rare Kristen rat sarcoma viral oncogene homolog (KRAS) gene mutation in colorectal cancer patients

e14558 Background: Epithelial growth factor receptor (EGFR) inhibitors are not effective in KRAS mutant colorectal tumors. In these tumors the k-ras protein is activated by post-translational modification by binding farnesyl (C15) and geranylgeranyl (C17) moieties. Both are products of the mevalonate pathway, as is cholesterol. Statins (HMG-CoA-reductase inhibitors) not only inhibit synthesis of cholesterol, but also of C15 and C17 and thus may relevantly inhibit post-translational activation of ras proteins. Therefore, statins may inhibit the expression of the mutant KRAS phenotype and normalize the phenotype into KRAS wild type. In a phase II study we investigated whether simvastatin treatment renders KRAS mutant colorectal tumors sensitive to panitumumab. Methods: Major eligibility criteria were advanced or metastatic colorectal cancer failing prior 5FU, oxaliplatin and irinotecan containing regimens, with a mutation in codon 12, 13 or 61 of KRAS gene on tumor sample. Patients were treated with simvastatin 80mg once daily and panitumumab 6mg/kg every 2 weeks. Primary objective was to investigate the percentage of patients free from progression and alive 11 weeks after the first administration of panitumumab. This phase II study was performed in a Simon two stage design, performing an interim analysis after the enrolment of 15 patients. When at least 6 of these patients (i.e. 40%) were to be alive and free from progression free at 11 weeks after the first administration of panitumumab (similar to the results of the KRAS wild type population of the phase III study), another 31 patients would be included during stage 2. Results: Fifteen evaluable patients were enrolled by 4 study sites. Only one patient was free from progression 11 weeks after start of panitumumab treatment (6.7%). Mean progression free survival was 9.1 weeks (range 5-17 weeks). Most frequent reported side effect was skin toxicity (40%), one patient experienced myositis grade 3. Conclusions: Simvastatin 80mg once daily was not able to inhibit the KRAS mutant phenotype sufficiently to reach sensitivity to panitumumab in colorectal cancer patients with a mutation in the KRAS gene. Clinical trial information: NCT01110785.

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Clinic-pathological characteristics of MMR protein, KRAS-NRAS-BRAF gene mutation, HER-2 and PD-L1 status in 3822 Chinese colorectal cancer patients

10.21203/rs.3.rs-49998/v1 ◽

2020 ◽

Author(s):

Li Zhang ◽

Nan Chen ◽

Zhongwu Li ◽

Aiwen Wu ◽

Jie Chen

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Gene Mutation ◽

Female Group ◽

Medical Database ◽

Braf Gene ◽

Arms Pcr ◽

Poorly Differentiated ◽

Her 2 ◽

Colorectal Cancer Patients

Abstract ObjectivesColorectal cancer is one of the most common cancers. It is a heterogeneous tumor. The aim of this study was to investigate MMR protein expression, KRAS-NRAS-BRAF gene mutation, HER-2 and PD-L1 status in large Chinese CRC patients. MethodsWe reviewed all CRC patients who underwent surgery in Peking University Cancer Hospital between 2010 and 2018 from a prospective collected medical database. We analyzed the clinic-pathological factors associated with immunohistochemistry profiles. We analyzed KRAS-NRAS-BRAF gene changes through ARMS-PCR. ResultsIn our study, d-MMR frequency of CRC was 8%. d-MMR was more common in poorly differentiated colorectal cancer (p = 0.000), and d-MMR was more likely to occur in stage T3 + T4( p = 0.026), and p-MMR was more likely to have lymph node metastasis(p = 0.000). d-MMR was more likely to occur in the right colon, and p-MMR patients usually occur in the rectum sigmoid colon(p = 0.000). p-MMR patients were more likely to have distant metastasis (p = 0.000). We analyzed all 3822 patients with-BRAF status available by IHC, the frequency of BRAF positive expression ration was 1.4%. A total of 1068 colorectal cancer patients had gene analysis by ARMS-PCR. 484 of them had KRAS gene mutation, 28 NRAS gene mutation, 20 BRAF mutation and 536 patients had no mutation. The percentage was 45%, 2.6%, 2%, and 50%, respectively. d-MMR patients usually had BRAF gene mutation (p < 0.001). KRAS and NRAS gene mutations were not associated with MMR status (p = 0.846, p = 0.438). PD-L1 expression was higher in the female group (p = 0.034), poorly differentiated adenocarcinoma group(p = 0.026), and d-MMR group (p = 0.005). The ratio of HER-2 3 + was 1.9%, and HER-2 3 + was usually found in p-MMR group(p = 0.043). ConclusionOur data can improve deeper understanding of colorectal cancer carcinogenic factors and future therapies for colorectal cancer.

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Use of Molecular Tumor Characteristics to Prioritize Mismatch Repair Gene Testing in Early-Onset Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.671 ◽

2005 ◽

Vol 23 (27) ◽

pp. 6524-6532 ◽

Cited By ~ 139

Author(s):

Melissa C. Southey ◽

Mark A. Jenkins ◽

Leeanne Mead ◽

Jonathan Whitty ◽

Melanie Trivett ◽

...

Keyword(s):

Colorectal Cancer ◽

Family History ◽

Protein Expression ◽

Cancer Patients ◽

Gene Mutation ◽

Early Onset ◽

Amsterdam Criteria ◽

Colorectal Cancer Patients ◽

Early Onset Colorectal Cancer ◽

Mmr Proteins

Purpose The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. Methods We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. Results Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. Conclusions Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation–carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

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