Follow-up recommendations and risk-reduction initiatives for Lynch syndrome

Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
Expert Review of Anti-infective Therapy (Impact Factor: 3.46). 10/2012; 12(10):1359-67. DOI: 10.1586/era.12.114
Source: PubMed


Lynch syndrome is the most common inherited colon cancer susceptibility syndrome. Lynch syndrome is characterized by a significantly increased risk for colon cancer and endometrial cancer and a smaller risk for several other associated cancers. Some periodic screening strategies, such as colonoscopy, reduce the incidence and mortality of Lynch syndrome. The aim of this review is to discuss the risks, surveillance tests and guidelines for the management of colonic and extracolonic tumors associated with Lynch syndrome. For extracolonic cancer, a benefit of surveillance is evident only for endometrial cancer. No definitive data show efficacy of chemopreventive drugs, although aspirin is a promising drug. In this review, the available evidence on the different screening strategies in Lynch syndrome will be discussed. Furthermore, the clinical and biological characteristics of this disease and their potential impact on prevention in individuals at risk are analyzed.

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    ABSTRACT: Endometrial cancer is the first malignancy in 50% of women with Lynch syndrome, an autosomal dominant cancer-prone syndrome caused by germline mutations in genes encoding components of the DNA mismatch repair (MMR) pathway. These women (2-4% of all those with endometrial cancer) are at risk of metachronous colorectal cancer and other Lynch syndrome-associated cancers, and their first-degree relatives are at 50% risk of Lynch syndrome. Testing all women newly diagnosed with endometrial cancer for Lynch syndrome may have clinical utility for the index case and her relatives by alerting them to the benefits of surveillance and preventive options, primarily for colorectal cancer. The strategy involves offering germline DNA mutation testing to those whose tumour shows loss-of-function of MMR protein(s) when analysed for microsatellite instability (MSI) and/or by immunohistochemisty (IHC). In endometrial tumours from unselected patients, MSI and IHC have a sensitivity of 80-100% and specificity of 60-80% for detecting a mutation in an MMR gene, though the number of suitable studies for determining clinical validity is small. The clinical validity of strategies to exclude those with false-positive tumour test results due to somatic hypermethylation of the MLH1 gene promoter has not been determined. Options include direct methylation testing, and excluding those over the age of 60 who have no concerning family history or clinical features. The clinical utility of Lynch syndrome testing for the index case depends on her age and the MMR gene mutated: the net benefit is lower for those diagnosed at older ages and with less-penetrant MSH6 mutations. To date, women with these features are the majority of those diagnosed through screening unselected endometrial cancer patients but the number of studies is small. Similarly, clinical utility to relatives of the index case is higher if the family's mutation is in MLH1 or MSH2 than for MSH6 or PMS2. Gaps in current evidence include a need for large, prospective studies on unselected endometrial cancer patients, and for health-economic analysis based on appropriate assumptions.
    No preview · Article · Sep 2013 · PLoS Currents
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    ABSTRACT: To determine whether wait time from histologic diagnosis of uterine cancer to time of definitive surgery by hysterectomy had an impact on all-cause survival. Women in Ontario with a confirmed histopathologic diagnosis of uterine cancer between April 1, 2000, and March 31, 2009, followed by surgery were identified in the Ontario Cancer Registry. Survival was calculated by using the Kaplan-Meier method. Factors were evaluated for their prognostic effect on survival by using Cox proportional hazards regression. Wait time was evaluated in a multivariable model after adjusting for other significant factors. The final study population included 9,417 women; 51.9% had surgery by a gynecologist, and 69.9% had endometrioid adenocarcinoma. Five-year survival for women with wait times of 0.1 to 2, 2.1 to 6, 6.1 to 12, or more than 12 weeks was 71.1%, 81.8%, 79.5%, and 71.9%, respectively. Wait times of ≤ 2 weeks were adversely prognostic for survival after adjusting for other significant factors in the multivariable model, and patients with wait times of more than 12 weeks had worse survival than those who had wait times between 2.1 and 12.0 weeks. To the best of our knowledge, this is the first report in a large population-based cohort demonstrating that longer wait times from diagnosis of uterine cancer to definitive surgery have a negative impact on overall survival.
    Full-text · Article · Nov 2013 · Journal of Clinical Oncology
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    ABSTRACT: Endometrial cancer is the most common malignancy of the female genital tract. Type and extent of disease at presentation and survival outcomes vary by race. The prevention of these cancers entails the prevention and treatment of associated precursor lesions. There are both modifiable and non-modifiable risks for endometrial cancer and their precursors, and preventive strategies should take this into consideration. This chapter is divided into sections on preventive strategies based on known and putative risk factors.
    No preview · Chapter · Jan 2014
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