Rates of genotyping for KRAS, NRAS, BRAF, microsatellite instability (MSI), and mismatch repair (MMR) in metastatic colon cancer patients: Gaps and implications.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15123-e15123
Author(s):  
Martin Gutierrez ◽  
Kristin Sedgwick Price ◽  
Richard B. Lanman ◽  
Rebecca Nagy ◽  
Irfan Shah ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Real World ◽  
The United States ◽  
Treatment Selection ◽  
Optimal Treatment ◽  
Braf V600e ◽  
Metastatic Colon Cancer ◽  
Molecular Genotyping

e15123 Background: Molecular genotyping is essential to optimal treatment selection in metastatic colon cancer (mCC) as mutations in exons 2,3,4 of KRAS and NRAS (expanded RAS) and BRAF V600E predict lack of response to anti-HER2 therapy, and microsatellite instability high (MSI-H) predicts positive response to immune checkpoint inhibitor (ICPI)s. The National Comprehensive Cancer Network (NCCN) first recommended molecular genotyping for mCC in 2009 and by 2016 recommended all pts with mCC have expanded RAS, BRAF, and mismatch repair deficiency (MMRd) testing. This study updates genotyping rates in metastatic colon cancer (mCC) in a real-world practice setting. Methods: We performed a retrospective review of genomic testing patterns from pts with mCC diagnosed between January 2013 and December 2017 from 22 academic and community health centers in the United States who contributed to COTA’s de-identified Real World Evidence database. Results: 563 pts with mCC were identified in the Cota database over the 5-year period. 341 (61%) pts with mCC had testing for KRAS, 130 (23%) for NRAS, 177 (31%) for BRAF, and 297 (53%) for MMRd. Testing rates for NRAS, BRAF and MMRd all increased from 2013 to 2017 but remained suboptimal with undergenotyping rates of 48%, 45% and 12% respectively by 2017. 33 (6%) pts received cetuximab and/or panitumumab without prior testing for both KRAS and NRAS, despite established lack of benefit. Between 2016 and 2017, when NCCN recommended testing for KRAS, NRAS, BRAF and MMRd, only 24% of mCC pts were tested for all biomarkers. Conclusions: Although molecular genotyping rates increased over the described 5-year period, since 2016, less than one quarter of all mCC pts in this cohort received guideline recommended genotyping. Approaches that may improve complete genotyping rates in mCC, such as plasma-based comprehensive genomic profiling, may improve optimal treatment selection and should be tested in prospective trials.

scholarly journals Genomic Profiling for KRAS, NRAS, BRAF, Microsatellite Instability, and Mismatch Repair Deficiency Among Patients With Metastatic Colon Cancer

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Martin E. Gutierrez ◽  
Kristin S. Price ◽  
Richard B. Lanman ◽  
Rebecca J. Nagy ◽  
Irfan Shah ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
De Novo ◽  
The United States ◽  
Metastatic Colon Cancer ◽  
Mismatch Repair Deficiency ◽  
National Guidelines ◽  
Repair Deficiency ◽  
Biomarker Testing

PURPOSE Genomic testing is recognized in national guidelines as essential to guide appropriate therapy selection in metastatic colorectal cancer. Previous studies report adherence to testing guidelines is suboptimal, but current testing rates have not been assessed. This study reports testing rates in metastatic colon cancer (mCC) for guideline-recommended biomarkers in a US-based population. MATERIALS AND METHODS A retrospective review of data extracted from electronic medical records was performed to identify patients with pathologically confirmed mCC and describe patterns of guideline-aligned biomarker testing. Data were extracted from the electronic health records of 1,497 patients treated at 23 practices across the United States. Both community and academic centers were represented. RESULTS A total of 1,497 patients with mCC diagnosed between January 1, 2013 and December 31, 2017 were identified. Guideline-aligned biomarker testing rates for RAS, BRAF, and microsatellite instability/mismatch repair deficiency over this study period were 41%, 43%, and 51%, respectively. Patients were more likely to have guideline-aligned testing for RAS and BRAF if they were treated at an academic center, were diagnosed with de novo metastatic disease, and were female. In addition, patients < 65 years of age were more likely to have guideline-aligned RAS testing. Of the 177 patients (12% of cohort) who received anti–epidermal growth factor receptor therapy, only 50 (28%) had complete guideline-aligned biomarker testing. CONCLUSION Despite guideline recommendations and significant therapeutic implications, overall biomarker testing rates in mCC remain suboptimal. Adherence to guideline-recommended biomarker testing would potentially reduce exposure to expensive and ineffective therapies, resulting in improved patient outcomes.

Profiling for microsatellite instability (MSI) and mismatch repair (MMR) among patients with colon cancer in real world settings.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e15622-e15622
Author(s):  
Tracy Ann Proverbs-Singh ◽  
John Marshall ◽  
Marian M Varda ◽  
Ibrahim Nakhoul ◽  
Bhavesh Balar ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Real World

Sporadic Colon Cancer: Mismatch Repair Immunohistochemistry and Microsatellite Instability in Omani Subjects

2008 ◽  
Vol 53 (10) ◽  
pp. 2723-2731 ◽  
Author(s):  
Hassan Ashktorab ◽  
Hassan Brim ◽  
Marwa Al-Riyami ◽  
Anand Date ◽  
Kamla Al-Mawaly ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Sporadic Colon Cancer

Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

2009 ◽  
Vol 27 (13) ◽  
pp. 2129-2136 ◽  
Author(s):  
Friedemann Honecker ◽  
Hendrik Wermann ◽  
Frank Mayer ◽  
Ad J.M. Gillis ◽  
Hans Stoop ◽  
...  
Keyword(s):  
Germ Cell ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Braf Mutation ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Braf V600e ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Mmr Deficiency

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). Conclusion We report for the first time a correlation between a gene mutation—BRAF V600E—and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.

scholarly journals Immunotherapy, Inflammation and Colorectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 618 ◽  
Author(s):  
Charles Robert Lichtenstern ◽  
Rachael Katie Ngu ◽  
Shabnam Shalapour ◽  
Michael Karin
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
The United States ◽  
Chemotherapeutic Agents ◽  
Adoptive T Cell Therapy ◽  
Current Status ◽  
Cancer Type ◽  
T Cell Therapy

Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR–MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR–MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).

Defective mismatch repair proteins and microsatellite instability in young Mexican patients with colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14708-e14708
Author(s):  
Arturo Quintanilla Guzman ◽  
Arturo Luevano Gonzalez ◽  
Augusto Rojas Martinez ◽  
Juan Pablo Flores Gutierrez ◽  
Juan Francisco Gonzalez Guerrero ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Young Patients ◽  
Gene Promoter ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Braf Mutations ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Msi Analysis

e14708 Background: Colorectal carcinoma (CRC) is prevalent malignancy and a third of the cases affect young patients. 15% of CRC have microsatellite instability (MSI) due to disruptions in mismatch repair (MMR) genes, like germline mutations (3%) and hypermethylation of the MLH1 gene promoter associated to the BRAF V600E mutation (12%). The aim of this work was to assess MMR abnormalities in tumors of Mexican CRC patients under 50 years old. Methods: CRC paraffin-embedded tissues of 47 patients with available demographic/clinical data were studied by immunohistochemistry (IHC) for MLH1/MSH2, qPCR with specific probes/sequencing for the BRAF V600E mutation, and conventional PCR (5 markers) for MSI analysis. Results: Female:Male ratio was 0.81:1. Most of the cases were classified as TNM Stage II, were located in the cecum, invaded the serous coat, and showed intestinal-type histology. 20 samples showed alterations in MMR protein expression. MLH1, MSH2, and combined deficiency of both proteins were detected in 17, 4, and 4 tumors, respectively. No BRAF mutations were detected. MSI analysis restricted to the 20 altered IHC samples showed MSI in 10 tumors (3 MSI-low and 7 MSI-high tumors). The four cases with MLH1/MSH2 deficiency, showed MSI-high pattern. Conclusions: We found 42.6% cases with defective MMR expression. No epigenetic abnormalities associated to BRAF V600E mutation were registered. The lack of MSI in ten tumors with deficient MMR may be due to alternate DNA repair mechanisms. Acknowledgments. Work supported by the CHIBCHA Project (European Commission7FP grant #223678).

Algorithm for identifying various second- and third-line chemotherapy regimens in elderly U.S. Medicare patients with metastatic colon cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 553-553
Author(s):  
Kaloyan A Bikov ◽  
C. Daniel Mullins ◽  
Ebere Onukwugha ◽  
Brian S. Seal ◽  
Nader Hanna
Keyword(s):  
Colon Cancer ◽  
Sensitivity Analysis ◽  
Real World ◽  
Face Validity ◽  
Metastatic Colon Cancer ◽  
The Face ◽  
Medicare Patients ◽  
Utilization Patterns ◽  
Third Line ◽  
Clinical Rules

553 Background: Patients with metastatic colon cancer (mCC) often receive multiple lines of chemotherapy treatment (TX) in response to disease progression or toxicities. A claims-based algorithm that identifies TX lines can provide information on “real world” clinical practice patterns that may not be captured by clinical trials. Methods: Our claims-based algorithm was applied to SEER-Medicare data of elderly mCC patients diagnosed in ‘03-‘07 and followed through ‘09. The algorithm included 17 clinical rules for identifying the beginning and end TX lines. The face validity of the algorithm was assessed by 1) examining the output against a TX map for a random sample of patients; 2) evaluating the overall results; and 3) conducting a sensitivity analysis, which evaluated the variability in the number of detected TX lines as a function of key algorithm parameters. Results: Of 7,951 mCC patients, 3,266 (41%) received TX; 1,440 (18% of all, 44% of TX) and 274 (3% of all, 8% of TX) received 2nd and 3rd line TX, respectively. Fewer than 1% of treated patients had a 4th TX line. The utilization patterns in terms of number and type of TX lines were robust to changes in the algorithm parameters. OX±BEV (45%), 5FU/LV±BEV (33%) and IRI±BEV (16%) were the three most common initial TXs. 2nd line TX most commonly consisted of IRI±BIOLOGIC (62%) and OX±BIOLOGIC (26%), but 6% of patients received only BIOLOGICS. CETUX (19%), PANIT (15%), IRI alone (17%) and OX alone (12%) were the most common 3rd line TXs. OX to IRI (49%), IRI to OX (14%), 5FU/LV to OX (12%), and 5FU/LV to IRI (12%) were the most frequent TX progressions for those with 2nd line TX. 5FU/LV to OX to IRI (26%), OX to IRI to BIOLOGICS alone (25%), 5FU/LV to IRI to OX (14%) and IRI to OX to BIOLOGICS alone (6%) were the most frequent TX progressions for those with 3rd line TX. Conclusions: Our claims-based algorithm suggests that during 2003-2009 relatively few elderly mCC patients received 2nd and 3rd line TX. Sensitivity analysis confirmed the robustness of the algorithm. Future observational studies should address the “real world” benefits and risks of 2nd and 3rd line TX among elderly mCC patients.

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