Lynch Syndrome Patients Research Articles

P204 - Creating a screening method for known Lynch Syndrome patients to detect Upper Tract Urothelial Carcinoma

P204 - Creating a screening method for known Lynch Syndrome patients to detect Upper Tract Urothelial Carcinoma

Tumor Testing and Genetic Analysis to Identify Lynch Syndrome Patients in an Italian Colorectal Cancer Cohort.

Lynch syndrome (LS) is an inherited cancer susceptibility syndrome caused by germline mutations in a DNA mismatch repair (MMR) gene or in the EPCAM gene. LS is associated with an increased lifetime risk of colorectal cancer (CRC) and other malignancies. The screening algorithm for LS patient selection is based on the identification of CRC specimens that have MMR loss/high microsatellite instability (MSI-H) and are wild-type for BRAFV600. Here, we sought to clinically and molecularly characterize patients with these features. From 2017 to 2023, 841 CRC patients were evaluated for MSI and BRAFV600E mutation status, 100 of which showed MSI-H. Of these, 70 were wild-type for BRAFV600. Among these 70 patients, 30 were genetically tested for germline variants in hereditary cancer predisposition syndrome genes. This analysis showed that 19 of these 30 patients (63.3%) harbored a germline pathogenic or likely pathogenic variant in MMR genes, 2 (6.7%) harbored a variant of unknown significance (VUS) in MMR genes, 3 (10%) harbored a VUS in other cancer-related genes, and 6 (20%) were negative to genetic testing. These findings highlight the importance of personalized medicine for tailored genetic counseling, management, and surveillance of families with LS and other hereditary cancer syndromes.

The prevalence of lynch syndrome (DNA mismatch repair protein deficiency) in patients with primary localized prostate cancer using immunohistochemistry screening

BackgroundProstate cancer is one of the most heritable human cancers. Lynch syndrome is an autosomal dominant inheritance caused by germline mutations in DNA mismatch repair (MMR) genes, which are also associated with an increased incidence of prostate cancer. However, prostate cancer has not been defined as a Lynch syndrome-associated cancer. The proportion of Lynch syndrome patients in primary prostate cancers is unclear. In this study, we investigated MMR protein loss using universal immunohistochemical screening to determine the prevalence of Lynch syndrome in patients with localized prostate cancer who underwent radical prostatectomy.MethodsOne hundred twenty-nine surgical specimens from radical prostatectomy performed at Toranomon Hospital between 2012 and 2015 were retrospectively tested using universal screening with immunohistochemistry staining for expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6. For all suspected MMR-deficient patients, germline genetic tests focusing on MMR genes were performed.ResultsMMR protein loss was found in only one patient (0.8%) who showed dual MSH2/MSH6 loss. This patient showed a single nucleotide pathogenic germline mutation from c.1129 C to T (p.Gln377*) at exon 7 in the MSH2 gene. He was diagnosed with a primary prostate cancer at 66 years of age. He had a documented history of Lynch syndrome (Muir–Torre syndrome) with previous colon cancer, sebaceous tumor, and keratoacanthoma as well as subsequent bladder cancer, all of which also showed dual MSH2/MSH6 loss. He also had a strong family history of colorectal and other Lynch syndrome-associated cancers. The pathological stage was pT3aN0M0, and the pathological grade was Gleason 7(4 + 3) with tertiary pattern 5.ConclusionsIn this study, immunohistochemical screening of MMR proteins for Lynch syndrome was performed in a series of prostate cancer cases. The prevalence of Lynch syndrome in localized prostate cancer was 0.8%, which is low compared with other Lynch syndrome-associated cancers.

Emotional Regulation Strategies in Lynch Syndrome Diagnosis Psychological Adjustment – A Review

"The purpose of this article is to investigate the role of emotional regulation (ER) as a process underlying a variety of symptoms associated with Lynch syndrome (depression, anxiety, fear of cancer recurrence (FCR), insomnia, fatigue, pain, and subjective cognitive difficulties in patients with Lynch syndrome. Firstly, we provided an overview of the main psychopathological symptoms found in cancer patients and their impact, and then an overview of emotional regulation strategies and discussed the main impact ER strategies have on cancer patients, especially emotional suppression and experiential avoidance, as found in evidence-based studies. Recent research has shown that two ER strategies generally considered maladaptive, emotional suppression and experiential avoidance were significantly associated with higher levels of anxiety, depression, FCR, fatigue, and cognitive difficulties. We propose that experiential avoidance and emotional suppression may be common transdiagnostic mechanisms for a common set of psychological symptoms in Lynch syndrome patients, a hypothesis to be tested in a future study."

S307 Chromoendoscopy vs Regular Endoscopy for Lynch Syndrome Patients: Systematic Review With Meta-Analysis of Randomized Controlled Trials

S307 Chromoendoscopy vs Regular Endoscopy for Lynch Syndrome Patients: Systematic Review With Meta-Analysis of Randomized Controlled Trials

Lynch Syndrome – An Overview of the Worldwide Management of This Silent Killer Within Our Genes

"Lynch syndrome, also known as hereditary non-polyposis cancer syndrome, represents the most common autosomal dominant genetic predisposition for the early onset development of several malignancies. Nearly three decades ago, the discovery of microsatellite instability, a distinctive feature of pathogenic variants within genes encoding mismatch repair proteins, marked a significant leap forward in understanding cancer biology and the underlying spectrum of cancers triggered by these mutations – typical of Lynch syndrome. In recent years, a new treatment paradigm, using immune checkpoint inhibitors, as well as preventive measures has drastically improved the survival rates. Identifying individuals with an inherent predisposition to cancer, through diagnostic protocols followed by personalized screening and treatment algorithms, holds the potential to mitigate premature cancer-related fatalities as well as preventable mortality. It is estimated that only a limited number of patients have been diagnosed, underscoring the importance of implementing specific screening programs for early detection of malignancies to which these patients are susceptible. This article aims to underline the importance of a national protocol tailored to guide a Western-inspired practice for Lynch syndrome patient management, the main aim of the Romanian Society for Lynch Syndrome, by providing an overview of similar initiatives throughout the world."

The English National Lynch Syndrome transformation project: an NHS Genomic Medicine Service Alliance (GMSA) programme

ObjectiveIn England, through the Genomic Medicine Service Alliances (GMSAs), a national transformation project aims to embed robust pathways to deliver universal Lynch syndrome (LS) testing for patients with colorectal and...

B-210 Spectrum of Germline Mutation with Characteristic MLH1 Hotspots and High Concordance with MMR Deficiency Phenotype in Lynch Syndrome Patients in Taiwan

Abstract Background Patients carried defects on cancer susceptibility genes or had cancer family history have at least twice the risk of developing cancer than the general population, with both early onset and multiple cancers features. For elucidating the carrier rate of cancer susceptibility genes in patients with inherited colorectal cancer (CRC) and endometrial cancer (EnCa) in Taiwan, we established a NCCN guided 30-gene panel which included four DNA Mismatch Repair (MMR) genes to detect the germline mutation of patients with Lynch Syndrome. Correlation of genotype and phenotype of MMR enzymes are under investigation as well. Methods Sixty-eight blood samples were collected from unrelated cancer patients, 42 of them were from patients with inherited colon cancer, 13 from patients with diagnosis of both CRC and endometrial cancer and 13 from patients with early onset EnCa. 30-gene panel was performed by next generation sequencing (NGS) platform and variants were annotated following ACMG guideline. MMR protein expression in tumor tissue sections were identified by conventional immunohistochemistry (IHC) stain. Loss of nuclear staining were classified as MMR deficiency. Results Average age of first tumor onset of 68 patients were 49.2 years old. 54% (37/68) of the subjects had at least one germline mutations with pathogenic effect or deleterious variant predicted by in silico protein function software. Five of them carried two heterozygous mutations. Total 42 mutations appeared majority on three MMR genes, MLH1 (17/42, 40%), MSH2 (10/42, 24%) and MSH6 (6/42, 11%) with notified three hotspots on MLH1 p.R265C (7/17, 41%); p.T117M (2/17, 12%) and p.K618del(2/17, 12%). The rest mutations spread sporadically on nine genes (PMS2, TP53, CHEK2, POLE, POLD1, ATM, EPCAM, MLH3 and RNF43). For exploring the effect of germline mutation on MMR protein expression status on tissue, we compared the MMR IHC results and the germline mutation pattern. As high as 57% concordance between phenotype and genotype were found. We also collected six blood samples from relatives of our CRC cohort to demonstrate the inheritance and pathogenesis of the germline mutation. Exactly the same germline mutations can be found in diseased relatives among different generation or siblings. Conclusion In spite of having founder mutations on MLH1 gene in Taiwanese Lynch syndrome, most of the germline mutations randomly occurred in MMR-related genes. Comprehensive cancer susceptible gene screening panel by NGS is a cost-effective way to identify the inherited status of individuals with family cancer history and serves as a surrogate tool to predict MMR protein expression. Genetic counseling and prophylactic therapeutic information can be provided for positive cases for better cancer prevention.

A one-stop approach to diagnosing hereditary colorectal cancer in the Chinese population.

The current procedure for identifying hereditary colorectal cancer (HCRC) is time consuming in clinical practice. This study aimed to develop a time-saving approach to diagnosing HCRC. A total of 100 suspected HCRC patients were prospectively enrolled (cohort 1) and 116 colorectal cancer patients with DNA mismatch repair-deficient were retrospectively included (cohort 2). Next-generation sequencing (NGS) tests were performed on tumors and matched white blood cells (WBCs) or normal tissues. Using the conventional method upon WBC/normal tissue-based NGS data as a reference, the performance of the ColonCore method using tumor-only-based NGS data in predicting germline variants was explored in cohort 1 and validated in cohort 2. In cohort 1, the ColonCore method diagnosed 17 Lynch syndrome (LS) and 14 familial adenomatous polyposis (FAP); and by the conventional method, the cases were 16 and 10, respectively. The ColonCore method showed sensitivities of 100% in diagnosing LS (positive predictive value [PPV] 94.1%) and FAP (PPV 71.4%). Moreover, two of seven patients with multiple adenomas/polyps who did not meet existing clinical criteria for HCRC were predicted to harbor germline variants in APC and MUTYH. Additionally, the sensitivity of the ColonCore method in identifying LS patients from cohort 2 reached 85.7% with a PPV of 85.7%. The ColonCore method might be an acceptable tool for predicting germline variants associated with HCRC. Our work indicates the essentiality of NGS tests in CRC patients for precision diagnosis and treatment.

Risk-stratified faecal immunochemical testing (FIT) for urgent colonoscopy in Lynch syndrome during the COVID-19 pandemic.

Lynch syndrome is a hereditary cancer disease resulting in an increased risk of colorectal cancer. Herein, findings are reported from an emergency clinical service implemented during the COVID-19 pandemic utilizing faecal immunochemical testing ('FIT') in Lynch syndrome patients to prioritize colonoscopy while endoscopy services were limited. An emergency service protocol was designed to improve colonoscopic surveillance access throughout the COVID-19 pandemic in England for people with Lynch syndrome when services were extremely restricted (1 March 2020 to 31 March 2021) and promoted by the English National Health Service. Requests for faecal immunochemical testing from participating centres were sent to the National Health Service Bowel Cancer Screening South of England Hub and a faecal immunochemical testing kit, faecal immunochemical testing instructions, paper-based survey, and pre-paid return envelope were sent to patients. Reports with faecal haemoglobin results were returned electronically for clinical action. Risk stratification for colonoscopy was as follows: faecal haemoglobin less than 10 µg of haemoglobin/g of faeces (µg/g)-scheduled within 6-12 weeks; and faecal haemoglobin greater than or equal to 10 µg/g-triaged via an urgent suspected cancer clinical pathway. Primary outcomes of interest included the identification of highest-risk Lynch syndrome patients and determining the impact of faecal immunochemical testing in risk-stratified colonoscopic surveillance. Fifteen centres participated from June 2020 to March 2021. Uptake was 68.8 per cent amongst 558 patients invited. For 339 eligible participants analysed, 279 (82.3 per cent) had faecal haemoglobin less than 10 µg/g and 60 (17.7 per cent) had faecal haemoglobin greater than or equal to 10 µg/g. In the latter group, the diagnostic accuracy of faecal immunochemical testing was 65.9 per cent and escalation to colonoscopy was facilitated (median 49 versus 122 days, χ2 = 0.0003, P < 0.001). Faecal immunochemical testing demonstrated clinical value for Lynch syndrome patients requiring colorectal cancer surveillance during the pandemic in this descriptive report of an emergency COVID-19 response service. Further longitudinal investigation on faecal immunochemical testing efficacy in Lynch syndrome is warranted and will be examined under the 'FIT for Lynch' study (ISRCTN15740250).

42606 Genetic Referral and Diagnosis of Lynch Syndrome in Patients with Cutaneous Sebaceous Lesions

42606 Genetic Referral and Diagnosis of Lynch Syndrome in Patients with Cutaneous Sebaceous Lesions

Identification of lynch syndrome in patients with endometrial cancer based on a germline next generation sequencing multigene panel test: Ethnicity updated epidemiology (2148)

Identification of lynch syndrome in patients with endometrial cancer based on a germline next generation sequencing multigene panel test: Ethnicity updated epidemiology (2148)

Immune microenvironment profiling of normal appearing colorectal mucosa biopsied over repeat patient visits reproducibly separates lynch syndrome patients based on their history of colon cancer.

Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC), increasing lifetime risk of CRC by up to 70%. Despite this higher lifetime risk, disease penetrance in LS patients is highly variable and most LS patients undergoing CRC surveillance will not develop CRC. Therefore, biomarkers that can correctly and consistently predict CRC risk in LS patients are needed to both optimize LS patient surveillance and help identify better prevention strategies that reduce risk of CRC development in the subset of high-risk LS patients. Normal-appearing colorectal tissue biopsies were obtained during repeat surveillance colonoscopies of LS patients with and without a history of CRC, healthy controls (HC), and patients with a history of sporadic CRC. Biopsies were cultured in an ex-vivo explant system and their supernatants were assayed via multiplexed ELISA to profile the local immune signaling microenvironment. High quality cytokines were identified using the rxCOV fidelity metric. These cytokines were used to perform elastic-net penalized logistic regression-based biomarker selection by computing a new measure - overall selection probability - that quantifies the ability of each marker to discriminate between patient cohorts being compared. Our study demonstrated that cytokine based local immune microenvironment profiling was reproducible over repeat visits and sensitive to patient LS-status and CRC history. Furthermore, we identified sets of cytokines whose differential expression was predictive of LS-status in patients when compared to sporadic CRC patients and in identifying those LS patients with or without a history of CRC. Enrichment analysis based on these biomarkers revealed an LS and CRC status dependent constitutive inflammatory state of the normal appearing colonic mucosa. This prospective pilot study demonstrated that immune profiling of normal appearing colonic mucosa discriminates LS patients with a prior history of CRC from those without it, as well as patients with a history of sporadic CRC from HC. Importantly, it suggests the existence of immune signatures specific to LS-status and CRC history. We anticipate that our findings have the potential to assess CRC risk in individuals with LS and help in preemptively mitigating it by optimizing surveillance and identifying candidate prevention targets. Further studies are required to validate our findings in an independent cohort of LS patients over multiple visits.

Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients

BackgroundProgrammed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. MethodsLS patients with CRC who had evaluable tumours and received at least 2 cycles of PD-1 inhibitors were retrospectively included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies, including anticytotoxic T-lymphocyte-associated antigen-4 treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analysed. ResultsA total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3–71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses and 42.7% (n = 32) partial responses. Four of five cases of LS CRCs displaying proficient MMR (pMMR) or microsatellite stable (MSS) were not responsive. Mucinous/signet-ring cell differentiation was associated with a lower ORR (P = 0.013). The 3-year overall survival and progression-free survival were 91.2% and 82.2%, respectively. A polyp was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment, and they were all larger than 7 mm. ConclusionPD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. Large LS adenomas may also be eliminated by anti-PD-1 treatment. Data Availability StatementDue to the privacy of patients, the related data cannot be available for public access but can be obtained from Pei-Rong Ding (dingpr@sysucc.org.cn) upon reasonable request. The key raw data have been uploaded to the Research Data Deposit public platform (www.researchdata.org.cn).

The MSH2 c.793-1G>A variant disrupts normal splicing and is associated with Lynch syndrome.

Lynch syndrome (LS) is the most common inherited cancer predisposition disorder of colorectal cancer (CRC) which is associated with pathogenic variants in 4 mismatch repair (MMR) genes. Here, we reported a multi-generation Chinese family clinically diagnosed with LS. To identify the underlying pathogenic gene variants, 30 whole blood samples and 4 colorectal cancer tissue samples and their clinical data were obtained from this four-generation family. Microsatellite instability-high (MSI) testing, immunohistochemistry (IHC), and Whole-Exome Sequencing (WES) were performed to identify the MMR/MSI and the underlying gene variants. The minigene splicing assay and in vitro splicing assay were used to explore the function of this variant. MSI-H and dMMR was revealed by the MSI testing and IHC, Whole-Exome Sequencing (WES) in 3 patients successfully identified a splicing variant (c.793-1G>A) in intron 4 of MSH2. Sanger sequencing validated the WES results, and all the "healthy" individuals carrying the variant have been identified in the family by PCR. Bioinformatics analysis and in vitro minigene assay showed that the pathogenic variant affected the splicing process of MSH2 gene to generate 2 kinds defective transcription products, and consequently reduced the expression of MSH2 protein. The mutation carriers were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years because they both have a higher risk of LS. We found a pathogenic splicing variant (rs863225397, c.793-1G>A) of MSH2 gene, and furtherly confirmed that this mutation plays an important role in LS patients of this pedigree based on the vitro study. Our study indicates that one splicing mutation in the MSH2 gene (c.793-1G>A) causes LS and highlights the importance of LS gene testing.

Dietary behaviours of individuals with lynch syndrome at high risk of colorectal cancer: Results from the AAS-lynch study

Individuals with Lynch syndrome (LS) have a high lifetime risk of developing colorectal cancer (CRC) due to genetic alterations. Nutrition is one of the main modifiable risk factors for sporadic CRC, however this has not been established in LS patients. The present study aimed to give a detailed overview of dietary intakes in individuals with LS, and associated individual characteristics. Dietary behaviours of individuals with LS from the AAS-Lynch clinical trial (2017-2022) were obtained using a food frequency questionnaire. Dietary intakes, food group consumption and overall diet quality (dietary patterns, adherence to the Mediterranean diet) were described according to sociodemographic, anthropometric and clinical characteristics, and compared to participants without LS from the NutriNet-Santé study (matched on sex, age, BMI and region). 280 individuals with LS were included in this analysis and matched with 547 controls. Compared to controls, LS patients consumed less fibre, legumes, fruit and vegetables and more red and processed meat (all p<0.01). They also had a lower Mediterranean diet score (p=0.002). Among LS patients, men, younger patients, or those with disadvantaged situation had a diet of poorer nutritional quality with lower adherence to a "Healthy" diet (all p≤0.01). LS Patients with prevalent CRC had a higher consumption of dairy products than recommended, while those with prevalent adenoma consumed more vegetables, and less sugar and sweets (all p≤0.01). Although patients with LS were aware of their high lifetime risk of developing cancer, their diets were not optimal and included nutritional risk factors associated to CRC.

HGG-27. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON GLIOMAS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASK FORCE

Abstract Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation. MMRD-gliomas are resistant to chemoradiation but respond to immunotherapy. MMRD can occur somatically or be inherited as part of Lynch Syndrome (LS) or Constitutional Mismatch Repair Deficiency (CMMRD). However, the prevalence of MMRD in gliomas of children, adolescents, and young adults (CAYA), and impact of germline inheritance is unknown. We utilized functional genomic tools on population-based and validation cohorts from 3 large databases (Toronto, St-Jude and CBTN) to determine the prevalence, subgroup, and impact of germline mutations on MMRD-gliomas. Ongoing data on 998 pediatric-gliomas from Toronto reveals that MMRD is extremely rare in pediatric low-grade gliomas (PLGG) but common in pediatric high-grade gliomas (PHGG) (9%, p&amp;lt;0.0001). Similarly, data from St-Jude and CBTN (n=374) reveals that MMRD exists only in PHGG (8%). In both cohorts, MMRD-PHGG are enriched for RAS/MAPK, IDH, and TP53 mutations while pediatric-type fusions, BRAF-V600E and histone mutations are absent. In AYA-HGG (n=884), the most common groups include glioblastomas without chromosome-7/10 alterations (9%) and IDH1-astrocytomas, while MMRD is not present in IDH-oligodendrogliomas. All but 1 CAYA-MMRD-gliomas harbored germline MMR mutations. Data from the IRRDC on 174 patients reveal that LS is more common than CMMRD in gliomas, with the median age of onset 11 and 29 years in CMMRD and LS, respectively (p&amp;lt;0.001). Furthermore, CMMRD gliomas are commonly caused by germline PMS2 and MSH6 mutations, enriched for secondary polymerase mutations (60%, p&amp;lt;0.001), and exhibit ultra-hypermutation. In contrast, LS-gliomas are caused by MSH2 and MLH1 mutations, and enriched for IDH1 mutations (32%, p&amp;lt;0.025) with a lower mutational burden. Our data reveals high prevalence of MMRD in CAYA-HGG with alarming impact of germline predisposition. Specifically, unrecognized LS patients with AYA MMRD-HGG. These findings support universal screening for MMRD in HGG to identify patients for immunotherapy and surveillance.

Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.

Efficacy of PD-1 inhibitors for colorectal cancer and polyps in patients with Lynch syndrome.

e15521 Background: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. Methods: LS patients with CRC who had evaluable tumors and received ≥2 cycles of PD-1 inhibitors were included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies including anti cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analyzed. Results: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3 to 71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses (CRs) and 42.7% (n = 32) partial responses (PRs). Three cases of LS CRCs displaying pMMR/MSS or discordant MMR/MSI status were not responsive even with a high tumor mutation burden (TMB). Mucinous/signet-ring cell differentiation was associated with a lower ORR ( P= 0.013). The 3-year OS and PFS was 91.2% and 81.0%, respectively. Colorectal polyp/adenoma was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment and their maximum diameters were all larger than 7mm. Conclusions: PD-1 inhibitors are highly effective for dMMR/MSI-H LS CRCs, but not for pMMR/MSS LS CRCs or those displaying discordant MMR/MSI status or mucinous/signet-ring cell CRC. Some of the large LS adenomas may also be sensitive to anti-PD-1 treatment.

Associating patient perceptions to poor uptake of aspirin (ASA) chemoprevention in a single-center cohort of patients with Lynch syndrome (LS).

e15662 Background: LS is among the most common hereditary cancer (CA) syndromes, underlying 3% cases of colorectal CA (CRC) and 8% of CRC &lt; 50 yrs. Pts with LS have a very high lifetime risk of CRC, which has been shown to be decreased by intensive colonoscopy (COLO) surveillance. However, interval LS CRCs can still develop, and adjunctive therapies like ASA have been recognized for their chemoprev benefits, with 35% risk reduction associated with sustained ( &gt; 2 yrs) use. Existing data are scarce on uptake of ASA chemoprev in LS pts, as well as pt-level factors that may impact uptake. Methods: PREVENTLynch recruited LS participants in the Fox Chase Cancer Center (FCCC) Risk Registry, who were invited to complete a one-time e-survey after providing informed consent (1/2020-6/2020; IRB 20-8014). Demographic/personal/familial CA history were collected. Inconvenience (INC), side effects (SEs), prevention reassurance (PR), and likelihood of recommending (LoR) available and emerging CA prevention modalities were measured on 9-point scales (low = 1 vs high = 9). Results: 116 LS pts completed the survey. Mean age was 53 yrs [range 23-76 ]. 24.7% (33/116) reported being on ASA, with 24.2% (8/33) taking it for an unrelated cardiac indication. 96.6% (112/116) had completed COLO, with 60.5% getting annual screening and 39.5% getting screening in 2-3 yrs. No significant difference was noted among ASA users and non-users based on age, race and underlying genetic LS subtype. A majority of pts (61.6%) were on ASA 81 mg/day, while 24.3% and 12% reported taking 325 and 650 mg/day, respectively. LS pts both taking and not taking ASA perceived it to be convenient (mean INC: 1.18 ASA users vs 2.11 non-users, p = 0.01). Concern for SEs was lower in ASA users than non-users (mean 1.09 vs 2.30, p = 0.003) while PR of the protective benefits was higher in the ASA users (mean PR 5.94 vs 3.23, p &lt; 0.001). When comparing ASA to COLO, COLO was seen as more INC than ASA by both ASA users and non-users (mean COLO INC 3.0 and 3.1, p = 0.0001 and 0.017 compared to ASA INC, respectively). ASA users were more likely to recommend ASA to others (8.13 vs 4.09, p &lt; 0.001). Conclusions: ASA uptake is low among LS pts. ASA is perceived as a favorable modality of chemoprev in only a fraction of LS pts, with perceived SEs and low PR as barriers to uptake. There is a critical need to address negative perceptions of chemoprev in LS patients as more options are developed. [Table: see text]