Combined immunotherapy of colorectal cancer in young patient with microsatellite instability (clinical case)

Background: Lynch Syndrome is an autosomal dominant trait that accounts forapproximately 3% of all cases of colorectal cancer (CRC). It is caused by mutations in DNA mismatch repair (MMR) genes, most commonly MLH1 or MSH2. These MMR defects cause high levels of microsatellite instability (MSI-H) in the tumours. MSI testing of all CRCs to identify potential Lynch Syndrome cases is not practical, so the Bethesda Guidelines, which use clinical and pathological features, were created to identify those tumours most likely to be MSI-H^1. In 2007 Jenkins et. al. created MsPath, a tool based on the pathological features described in the rarely used 3^rd Bethesda criterion, to improve prediction of MSI-H tumours among CRC cases diagnosed before age 60 years^2. Methods: We collected a population-based cohort of 716 CRC cases diagnosed before age 75 years in Newfoundland. For each of these cases we collected family history, performed MSI analysis, and scored a number of pathological features for the purpose of evaluating the accuracy of the Bethesda Criteria and MsPath at predicting MSI-H tumours. Results: Our work validates the MsPath tool in the Newfoundland population for the same age group used to create the tool. We found it identified MSI-H cases with a sensitivity of 95% and specificity of 35% in our population of CRCcases diagnosed before age 60 years (n=290). We also tested this tool on our older population of CRCcases, diagnosed at ages 60 to 74 years (n=426). We found it to be at least as predictive in this population,with a sensitivity of 95% and a specificity of 42%. We then used our entire cohort (N=716) to compare MsPath with the other Bethesda criteria.Bethesda criteria 1, 2, 4 and 5 together predicted MSI-H cases with a sensitivity of 67% and a specificity of 51%. MsPath was better at identifying these cases, with a sensitivity of 95% and a specificity of 39%. Conclusions: We conclude that MsPath can be extended to include patients diagnosed with CRC before age 75 years. As well, we have found that MsPath is a better predictive tool than the Revised Bethesda Guidelines for identifying MSI-H cases within a population-based setting of colorectal cancer. References: 1. Umar, A. et. al. J Natl Cancer Inst 2004;96:261-8 2.Jenkins, M.A. et. al. Gastroenterology 2007;133:48-56

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The microsatellite instability and budding intensity in colorectal cancer

10.26226/morressier.5b4709846f4cb30010951e04 ◽

2018 ◽

Author(s):

Zsolt Kovacs ◽

Laura Banias ◽

Simona Gurzu

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability

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Genetic Abnormalities and Microsatellite Instability in Colorectal Cancer

Cancer Detection and Prevention ◽

10.1046/j.1525-1500.1998.00049.x ◽

1998 ◽

Vol 22 (5) ◽

pp. 383-395 ◽

Cited By ~ 5

Author(s):

Pilar Iniesta ◽

Carmen de Juan ◽

Trinidad Caldes ◽

Francisco-Jose Vega ◽

Maria-Jose Massa ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Genetic Abnormalities

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The Role of the CpG Island Methylator Phenotype in Colorectal Cancer Prognosis Depends on Microsatellite Instability Screening Status

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-09-2594 ◽

2010 ◽

Vol 16 (6) ◽

pp. 1845-1855 ◽

Cited By ~ 126

Author(s):

Anna M. Dahlin ◽

Richard Palmqvist ◽

Maria L. Henriksson ◽

Maria Jacobsson ◽

Vincy Eklöf ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Cpg Island ◽

Cancer Prognosis ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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Decreased mean platelet volume is associated with microsatellite instability in colorectal cancer: A propensity score-matched analysis

Cancer Biomarkers ◽

10.3233/cbm-203250 ◽

2021 ◽

pp. 1-9

Author(s):

Wen Wang ◽

Guangyu Wang ◽

Shuang Fu ◽

Beibei Zhang ◽

Zengyao Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Propensity Score ◽

Microsatellite Instability ◽

Propensity Score Matching ◽

Mean Platelet Volume ◽

Innate Immune ◽

Platelet Volume ◽

Activated Platelets ◽

Medical University ◽

Potential Parameters

BACKGROUND: Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) generally have a better prognosis and a more effective immune response than patients with microsatellite stable (MSS) CRC. Moreover, activated platelets play a crucial role in modulating innate immune cells. Mean platelet volume (MPV) is an indicator of platelet activation. This study is to examine the association between MPV and MSI status in CRC. METHODS: We collected the clinical and pathological variables of 424 CRC patients diagnosed at the Harbin Medical University Cancer Hospital from January 2018 to December 2018. Associations between MPV levels and MSI status were examined. Propensity score matching (PSM) was performed to reduce the possibility of selection bias. RESULTS: 424 CRC patients were divided into low-MPV group and high-MPV group according to the optimal cut-off value of MPV. 131 high-MPV patients were matched to low-MPV counterparts in a 1:1 ratio by propensity score matching. As MPV levels increased, the percentage of patients with MSI-H reduced. Furthermore, compared with MSS group, the MSI-H group had a significantly lower MPV levels (p= 0.003 after matching). In addition, logistic regression analysis identified reduced MPV as an independent risk factor for MSI-H in CRC patients after controlling for other potential parameters. CONCLUSION: Lower MPV is associated with MSI-H subtype of CRC. Further study on MPV in MSI-H CRC is warranted.

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Pre-treatment CT-based radiomics nomogram for predicting microsatellite instability status in colorectal cancer

European Radiology ◽

10.1007/s00330-021-08167-3 ◽

2021 ◽

Author(s):

Qian Pei ◽

Xiaoping Yi ◽

Chen Chen ◽

Peipei Pang ◽

Yan Fu ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Pre Treatment

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Clinicopathological features of Egyptian colorectal cancer patients regarding somatic genetic mutations especially in KRAS gene and microsatellite instability status: a pilot study

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-019-0028-z ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Neemat M. Kassem ◽

Gamal Emera ◽

Hebatallah A. Kassem ◽

Nashwa Medhat ◽

Basant Nagdy ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Cpg Island ◽

Human Cancer ◽

Statistical Significance ◽

Public Health Problem ◽

World Health ◽

Cpg Island Methylator Phenotype ◽

Number Of Patients ◽

The Impact

Abstract Background Colorectal cancer (CRC) is the third most common cause of cancer-related deaths which contributes to a significant public health problem worldwide with 1.8 million new cases and almost 861,000 deaths in 2018 according to the World Health Organization. It exhibits 7.4% of all diagnosed cancer cases in the region of the Middle East and North Africa. Molecular changes that happen in CRCs are chromosomal instability, microsatellite instability (MSI), and CpG island methylator phenotype. The human RAS family (KRAS, NRAS, and HRAS) is the most frequently mutated oncogenes in human cancer appearing in 45% of colon cancers. Determining MSI status across CRCs offers the opportunity to identify patients who are likely to respond to targeted therapies such as anti-PD-1. Therefore, a method to efficiently determine MSI status for every cancer patient is needed. Results KRAS mutations were detected in 31.6% of CRC patients, namely in older patients (p = 0.003). Codons 12 and 13 constituted 5/6 (83.3%) and 1/6 (16.7%) of all KRAS mutations, respectively. We found three mutations G12D, G12C, and G13D which occur as a result of substitution at c.35G>A, c.34G>T, and c.38G>A and have been detected in 4/6 (66.6%), 1/6 (16.7%), and 1/6 (16.7%) patients, respectively. Eleven (57.9%) patients had microsatellite instability-high (MSI-H) CRC. A higher percentage of MSI-H CRC was detected in female patients (p = 0.048). Eight patients had both MSI-H CRC and wild KRAS mutation with no statistical significance was found between MSI status and KRAS mutation in these studied patients. Conclusion In conclusion, considering that KRAS mutations confer resistance to EGFR inhibitors, patients who have CRC with KRAS mutation could receive more tailored management by defining MSI status. MSI-high patients have enhanced responsiveness to anti-PD-1 therapies. Thus, the question arises as to whether it is worth investigating this association in the routine clinical setting or not. Further studies with a larger number of patients are needed to assess the impact of MSI status on Egyptian CRC care.

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Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

Current Treatment Options in Oncology ◽

10.1007/s11864-021-00870-z ◽

2021 ◽

Vol 22 (8) ◽

Author(s):

Federica Pecci ◽

Luca Cantini ◽

Alessandro Bittoni ◽

Edoardo Lenci ◽

Alessio Lupi ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Cancer Progression ◽

Checkpoint Inhibitors ◽

Tnm Classification ◽

Standard Of Care ◽

First Line Therapy ◽

Combination Strategies ◽

The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

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