Recent progress in Lynch syndrome and other familial colorectal cancer syndromes.

The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.

Extent of investigation and management of cases of 'unexplained' mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus.

BACKGROUND: Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR. METHODS: This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance. RESULTS: We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS. CONCLUSION: Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.

Lynch Syndrome Genetics and Clinical Implications.

Lynch syndrome (LS) is one of the most prevalent hereditary cancer syndromes in humans and accounts for some 3% of unselected patients with colorectal or endometrial cancer and 10%-15% of those with DNA mismatch repair-deficient tumors. Previous studies have established the genetic basis of LS predisposition, but there have been significant advances recently in the understanding of the molecular pathogenesis of LS tumors, which has important implications in clinical management. At the same time, immunotherapy has revolutionized the treatment of advanced cancers with DNA mismatch repair defects. We aim to review the recent progress in the LS field and discuss how the accumulating epidemiologic, clinical, and molecular information has contributed to a more accurate and complete picture of LS, resulting in genotype- and immunologic subtype-specific strategies for surveillance, cancer prevention, and treatment.

Sarcoma in patients with Lynch syndrome and response to immunotherapy.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant genetic predisposition to multiple malignancies and is characterized by deficient DNA mismatch repair. Increased incidence of sarcomas is not formally ascribed to LS; however, increasing evidence suggests a preponderance of these malignancies in affected families. Sarcomas typically possess a low tumor mutational burden and incite a poor immune infiltrate, thereby rendering them poorly responsive to immunotherapy. METHODS: We searched the University of California, Los Angeles (UCLA) sarcoma program database for patients with a diagnosis of sarcoma and LS from 2016 to 2023. Three such patients were identified and all three were treated with PD1 blockade. RESULTS: We present three cases of LS-associated sarcomas (two soft tissue sarcoma and one osteosarcoma) with increased tumor mutational burdens. These patients were each treated with an anti-PD1 antibody and experienced a response far superior to that reported for non-LS-associated sarcomas. CONCLUSIONS: Increased mutational burden and immune infiltrate are observed for sarcomas associated with LS. Although unselected patients with sarcoma have demonstrated poor response rates to immunotherapy, our findings suggest that patients with Lynch-associated sarcomas are more likely to respond to treatment with anti-PD1. These patients should be given consideration for immunotherapy.

Neoadjuvant immunotherapy in a locally advanced colon cancer patient with MSI-H and suspected Lynch syndrome: A case report.

Carrilizumab, a PD-1 inhibitor, has shown therapeutic effectiveness in patients with late-stage or metastatic solid tumors exhibiting DNA mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). dMMR/MSI-H cancer patients are known to be responsive to PD-1 inhibitors. However, the use of carrilizumab for preoperative immunotherapy in early, unresectable MSI-H/dMMR primary colon cancer lesions is relatively underexplored. We present the case of a 46-year-old male who sought medical attention at our institution due to a history of hematochezia for two weeks, right-sided abdominal pain for one week, and loose stools. Imaging indicated duodenal involvement, and a biopsy confirmed ascending colon adenocarcinoma with MSI-H status. Given that the patient's family exhibited a history of more than three confirmed cases of colorectal cancer spanning two generations, Lynch syndrome was considered. After four cycles of PD-1 antagonist immunotherapy with carrilizumab, the patient's symptoms resolved, and physical examination revealed no abdominal tenderness or palpable masses. Following radical colectomy, the primary tumor exhibited a pathological complete response. This case highlights the potential of preoperative neoadjuvant immunotherapy to improve staging accuracy and increase surgical resection rates in T4b MSI-H colon cancer patients without distant metastasis, suggesting a need for reconsideration of the treatment approach.

[Novel Treatment Concepts in Patients with Colorectal Carcinomas and High Microsatellite Instability]. / Neue medikamentöse Konzepte bei Patienten mit kolorektalen Karzinomen und Mikrosatelliteninstabilität.

Approximately 15% of patients with colorectal cancer show high microsatellite instability (MSI-high) in their tumour tissue. For one third of these patients, there is a hereditary cause for this finding - that leads to the diagnosis of Lynch Syndrome. In combination with clinical findings such as the Amsterdam or the revised Bethesda criteria, MSI-high status has been used as a tool in identifying patients at risk. Today, MSI-status has gained much more importance, due to its impact on treatment decisions. Patients with UICC II cancers should not receive adjuvant treatment. For patients with distant metastases and MSI-high status, immune checkpoint inhibitors can be given as first line therapy - with tremendous success. Novel data show a deep response for immune checkpoint antibodies in patients with locally advanced colon as well as rectal cancer in a neoadjuvant setting. Especially for patients with MSI-high rectal cancer, there might be a novel therapeutic regimen utilising immune checkpoint inhibitors without neoadjuvant radio-chemotherapy and even without surgery. This could lead to a relevant reduction in morbidity in this patient cohort. In conclusion, universal MSI-testing is essential for identifying patients at risk for Lynch syndrome and for optimal decision making in treatment planning.

Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology.

Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in the mismatch repair genes and is the most common etiology of hereditary colorectal cancer. While Lynch syndrome was initially defined by the clinical Amsterdam criteria, these criteria lack the sensitivity needed for clinical utility. This review covers the evolution of screening for Lynch syndrome from the use of tumor microsatellite instability and/or somatic alterations in mismatch repair protein expression by immunohistochemistry to the newest methods using next-generation sequencing. Additionally, it discusses the clinical implications of the diagnosis of Lynch syndrome as it affects cancer therapeutics and the role of screening in noncolorectal Lynch-associated cancers. As molecular oncology continues to evolve, it is crucial to remain current on the increasing complexity of Lynch syndrome diagnostics and treatment options.

Gene-Specific Variation in Colorectal Cancer Surveillance Strategies for Lynch Syndrome.

BACKGROUND AND AIMS: Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance with colonoscopy every 1-2 years starting at age 25 years for all carriers of Lynch syndrome-associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost. METHODS: Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25-40 years), and surveillance intervals (1-5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold. RESULTS: Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively. CONCLUSIONS: We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome-associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome-associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.

Mapping psychosocial interventions in familial colorectal cancer: a rapid systematic review.

BACKGROUND: Approximately 5% of colorectal cancer (CRC) cases are part of a well-defined inherited genetic syndrome and up to approximately 30% of these cases have a clinically defined familial basis. Psychosocial interventions in familial colorectal cancer address aspects mainly focused on affective, cognitive and behavioural outcomes. The present review aims to systematically map out the available psychosocial interventions for individuals with a family history of CRC and describe the current state of the research. METHODS: An extensive electronic search was conducted to investigate the literature published until June 2020. Inclusion criteria consisted of quantitative studies published in English that explored the impact of psychosocial interventions for familial CRC, clearly defined the psychosocial intervention offered and included participants with a family history of CRC. RESULTS: The analysis included 52 articles. Genetic counselling, educational interventions, psychological interventions and multimodal interventions were identified across the studies. In terms of diagnoses, Lynch Syndrome, Familial Adenomatous Polyposis, Familial Colorectal Cancer were the main conditions included in the studies. Affective, cognitive, behavioural aspects and quality of life emerged as the most frequently explored outcomes. The studies included individuals with both personal and familial history of CRC or family history alone. CONCLUSIONS: Our rapid review provides an overview of the literature exploring the impact of psychosocial interventions for familial CRC. The psychosocial interventions identified had an overwhelmingly positive impact across all types of outcomes measured. Genetic counselling appeared to be most beneficial, and this is expected as it is purposively designed to address genetic conditions. Further quantitative analysis of primary empirical research is needed to determine the efficacy and effectiveness of psychosocial interventions as well as the mechanisms through which they exert their effect.

Lynch syndrome in urological practice: diagnosis, therapeutic strategies, and screening for upper tract urothelial carcinoma.

PURPOSE OF REVIEW: To provide a comprehensive overview of diagnosis, treatment, and screening for upper tract urothelial carcinoma (UTUC) among Lynch syndrome patients. RECENT FINDINGS: Lynch syndrome is an autosomal dominant disorder resulting from the germline mutation in the mismatch repair (MMR) system. The Lynch syndrome predisposes to early onset of a broad spectrum of tumours, among which UTUC represents the third most frequent malignancy. Since up to 10% of UTUC can be attributed to Lynch syndrome, a correct recognition of this disease provides the opportunity for patients and their relatives to be properly treated for UTUC and to be followed up for other Lynch syndrome-related malignancies. SUMMARY: UTUC patients less than 65 years, or UTUC patients with personal history of Lynch syndrome-related cancer, or with one first-degree relative (FDR) less than 50 years with Lynch syndrome-related cancer, or two FDRs with Lynch syndrome-related cancer regardless of age should be referred to molecular testing and subsequent DNA sequencing to confirm Lynch syndrome diagnosis. Considering the increased risk of metachronous recurrence, treatments other than radical nephroureterectomy, such as ureteroscopic laser ablation may represent valuable therapeutic strategies. As Lynch syndrome patients exhibit an approximate 14-fold increased risk of developing UTUC compared with general population, expert recommendations are urgently required in order to point out appropriate screening protocols.

Hereditary gynecologic tumors and precision cancer medicine.

Gynecologic cancers are more often caused by genetic factors than other cancers. Genetic testing has become a promising avenue for the prevention, prognosis, and treatment of cancers. This review describes molecular features of gynecologic tumors linked to hereditary syndromes, gives an overview of the current state of clinical management, and clarifies the role of gynecology in the treatment of hereditary tumors. Typical hereditary gynecologic tumors include hereditary breast and ovarian cancer, Lynch syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. Multigene panel testing, which analyzes a preselected subset of genes for genetic variants, has recently become the first-choice test because it can provide more accurate risk assessment than a single test. Furthermore, comprehensive genomic cancer profiling enables personalized cancer treatment and aids in germline findings.

European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.

BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged. METHODS: The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. RESULTS: Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. CONCLUSION: The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.

The diversity of tumours with microsatellite instability: molecular mechanisms and impact upon microsatellite instability testing and mismatch repair protein immunohistochemistry.

Microsatellite instability (MSI) as a distinct molecular phenotype in human neoplasms was first recognised in 1993. Since then there has been tremendous progress in our understanding of this phenotype, including its genomic drivers and functional consequences. Currently, the multiple lines of investigation on MSI seem to have converged upon one important facet: its diversity, both genotypically and phenotypically, and both within and across tumour types. This review article offers a pathologist's perspective on our current understanding of this diversity, and highlights its potentially significant impact on the effective use of our current MSI detection tools: PCR- or sequencing-based MSI testing and mismatch repair protein immunohistochemistry.

Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance.

Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors.

Pancreatic Cancer Progression in a Patient With Lynch Syndrome Receiving Immunotherapy: A Cautionary Tale.

Pancreatic ductal adenocarcinomas (PDACs) with DNA mismatch repair deficiency (MMRd) respond preferentially to immune checkpoint inhibitors (ICIs). However, a subset of MMRd PDACs does not respond to these agents. This report describes a patient with PDAC who experienced rapid disease progression suggestive of hyperprogressive disease. The case involved a 63-year-old man carrying a pathogenic germline PMS2 mutation who developed metastatic PDAC. His tumor showed isolated loss of PMS2 expression by immunohistochemistry (IHC). He was treated with pembrolizumab, but his disease rapidly progressed. Whole-genome and transcriptome sequencing of a liver metastasis biopsy, acquired at disease progression, showed a retained wild-type PMS2 allele and hallmarks of microsatellite stability, including low tumor mutational burden and low MSIsensor score. PCR-based microsatellite instability (MSI) testing of the treatment-naïve tumor showed microsatellite stability. The ICI-treated tumor had a lower density of CD8+ T-cell infiltration than the treatment-naïve tumor, which is contrary to the expected evolution with ICI responsiveness. Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.

A mismatch in care: results of a United Kingdom-wide patient and clinician survey of gynaecological services for women with Lynch syndrome.

OBJECTIVE: To describe the current testing practice, referral pathways and gynaecological services available to women with Lynch syndrome (LS) in the UK. DESIGN: Cross-sectional nationwide survey of gynaecological oncologists and women with LS. SETTING: United Kingdom. METHODS: Gynaecological oncologists were contacted directly. Women with LS were identified from national and regional clinical databases and the patient support group, Lynch syndrome UK. MAIN OUTCOME MEASURES: Gynaecological oncologists were asked to report rates of LS testing and current practice regarding risk-reducing strategies and gynaecological surveillance for women with LS. Women with LS were asked to describe their experiences of gynaecological care. RESULTS: In total, 41 gynaecological oncologists and 298 women with LS responded to the survey. Of the gynaecological oncologists surveyed, 37% were unfamiliar with any clinical guidelines for the management of LS. Only 29% of gynaecological oncologists supported universal testing of endometrial cancer for LS; one centre routinely performed such testing. In all, 83% said they perform risk-reducing gynaecological surgery and 43% were aware of a local gynaecological surveillance service for women with LS. Of women with LS, most had undergone a hysterectomy (n = 191/64.1%), most frequently to reduce their gynaecological cancer risk (n = 86/45%). A total of 10% were initially referred for LS testing by their gynaecologist and 55% of those eligible regularly attended gynaecological surveillance; however, 62% wanted more regular surveillance. Regional variation was evident across all standards of care. CONCLUSIONS: There is widespread variation in the services offered to women with LS in the UK. As a community, gynaecological oncologists should move towards a nationally agreed provision of services. TWEETABLE ABSTRACT: A mismatch in care for mismatch repair. Survey finds significant variation in gynaecological care for #Lynchsyndrome in the UK.

Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG).

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.

Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition.

BACKGROUND: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines. METHODS: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. RESULTS: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely. CONCLUSION: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.

The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome.

PURPOSE: There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients. METHODS: Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice. RESULTS: Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer. CONCLUSION: This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

Women's preferences for cancer risk management strategies in Lynch syndrome.

OBJECTIVE: We assessed preferences for cancer risk management strategies for Lynch syndrome (LS) in LS-affected women. METHODS: Women with LS aged ≥25 years evaluated 9 cancer risk management strategies using a visual analog scale (VAS) and modified standard gamble (SG). For the VAS, women ranked each strategy ranging from 0 (least preferred) to 100 (most preferred). VAS scores were calculated by dividing the corresponding number by 100. Scores closer to 1.0 reflected more favorable strategies. For the SG, participants were asked to specify their expected threshold of lifetime risk of endometrial or colorectal cancer, ranging from 0 to 100%, at which they would consider undertaking each strategy. Strategies included chemoprevention, cancer screening, and preventive surgery. Cancer worry and perceived cancer risk measures were collected on a subset of participants. RESULTS: Sixty-one women completed preference assessments. By VAS, annual combined screening was the most preferred, followed by annual screenings and chemoprevention with oral contraceptives. By SG, women were the most willing to endorse oral contraceptives and biannual screening strategies at the lowest threshold of lifetime risk followed by annual screening strategies. Surgical interventions were the least preferred strategies using both VAS and SG. Women with a family history of gynecologic or colorectal cancer were less likely to consider prevention or screening options compared to women without a family history. Cancer worry was higher among women with a positive family history of LS cancer. CONCLUSION: Understanding women's preferences may facilitate optimal use and adherence to cancer risk management strategies.