Molecular characterization as new driver in prognostic signatures and therapeutic strategies for endometrial cancer.

Endometrial cancer (EC) incidence and mortality rates have been increasing, particularly among young females. Although more than 90% of ECs are sporadic, 5-10% are hereditary, a majority of which occurs within Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) or Lynch syndrome. The traditional histopathological classification differentiates EC between two main groups: type I (or endometrioid) and type II (including all other histopathological subtypes). However, this classification lacks reproducibility and does not account for the emerging molecular heterogeneity. In 2013, The Cancer Genome Atlas (TCGA) project proposed EC molecular classification defining four groups with different prognostic and predictive values and the current international guidelines are progressively establishing EC risk stratification and treatment based on both histopathological and molecular criteria. Our manuscript aims to summarize the current state of EC molecular characterizations, including germline alterations at the basis of hereditary EC predisposition, to discuss their clinical utility as prognostic and predictive markers.

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.

Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome.

PURPOSE: Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers. PATIENTS AND METHODS: To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx. RESULTS: We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies. CONCLUSIONS: Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.

Diagnosis and Management of Constitutional Mismatch Repair Deficiency Syndrome.

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare autosomal recessive genetic disorder that has little more than 200 total cases reported as of 2020. Whereas a single mutation in genes responsible for mismatch repair causes the autosomal dominant Lynch syndrome (LS), CMMRD is caused by biallelic heterozygous defects: distinct deleterious mutations on each allele for a single gene. As the disease is exceedingly rare and may present via a wide variety of signs, including neurofibromatosis type 1- and Lynch Syndrome-associated malignancies, diagnosis and subsequent surveillance are complex with suggested methods published by the International Replication Repair Deficiency Consortium. We report here the history and management of a patient whose newly diagnosed CMMRD was managed with both curative and prophylactic surgical treatment.

Somatic Sequencing and Microsatellite Instability Results From Mismatch Repair-deficient Endometrial Carcinoma Patients Without Lynch Syndrome ("Lynch-like" tumors): Implications for Heritable Cancer Screening, Molecular Prognostication, and Immunotherapeutic Vulnerability.

Immunostaining of endometrial carcinomas for mismatch repair (MMR) protein loss is standard-of-care for Lynch syndrome screening, but also identifies MMR-deficient tumors without germline pathogenic variants. While the majority show MLH1 hypermethylation ( MLH1hm ), somatic MMR pathogenic variants are increasingly recognized drivers of immunohistochemistry-germline discordance. Because MMR abnormalities with both germline and somatic origins have prognostic significance and impart susceptibility to immune checkpoint inhibitors, it is important to understand how frequently tumors with MMR immunohistochemical loss and normal germline testing ("Lynch-like" tumors) have underlying somatic MMR pathogenic variants. Somatic tumor sequencing±microsatellite instability (MSI) testing was performed on 18 endometrial cancers with MMR immunohistochemical loss but negative MMR germline results and negative MLH1hm where relevant. Tumor sequencing and MSI testing were successful in 94%. Where successful, 80% were MSI-high and 94% had a molecular correlate for the initial immunohistochemical interpretation. The single case without an identified somatic pathogenic variant was MSI-low and initially showed loss of MSH6 by immunohistochemistry but with extremely limited internal control staining. On review, MSH6 immunohistochemistry was reclassified as equivocal, and repeat staining revealed improved control expression with intact MSH6. Following reclassification of this case, 100% tumors with MMR deficiency by immunohistochemistry had at least 1 confirmed somatic MMR pathogenic variant, and 86% were MSI-high. These results demonstrate that when correctly interpreted immunohistochemistry is a strong surrogate for somatic MMR pathogenic variants and support its use as the frontline MMR biomarker in endometrial cancer for heritable screening, molecular prognostic classification, and immunotherapeutic biomarker testing purposes.

Lynch syndrome-associated chordoma with high tumor mutational burden and significant response to immune checkpoint inhibitors.

Chordoma is a rare malignant bone tumor arising from notochordal tissue. Conventional treatments, such as radical resection and high-dose irradiation, frequently fail to control the tumor, resulting in recurrence and re-growth. In this study, genetic analysis of the tumor in a 72-year-old male patient with refractory conventional chordoma of the skull base revealed a high tumor mutational burden (TMB) and mutations in the MSH6 and MLH1 genes, which are found in Lynch syndrome. The patient and his family had a dense cancer history, and subsequent germline genetic testing revealed Lynch syndrome. This is the first report of a chordoma that has been genetically proven to be Lynch syndrome. Chordomas usually have low TMB; however, this is an unusual case, because the TMB was high, and immune checkpoint inhibitors effectively controlled the tumor. This case provides a basis for determining the indications for immunotherapy of chordoma based on the genetic analysis. Therefore, further extensive genetic analysis in the future will help to stratify the treatment of chordoma.

[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 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.

Mismatch Repair Screening of Gastrointestinal Cancers: The Impact on Lynch Syndrome Detection and Immunotherapy.

INTRODUCTION: Mismatch repair immunohistochemistry (MMR IHC) or microsatellite instability (MSI) testing is now routinely performed in patients with colorectal cancer (CRC) to select those requiring Lynch syndrome testing. MMR IHC is also carried out on CRC and upper gastrointestinal (GI) cancers to select patients for immunotherapy. We review the Royal Marsden Hospital's pathway of molecular to germline testing for Lynch syndrome in the context of NICE guidance and the National Test Directory. METHODS: We conducted (i) a retrospective audit of adherence to NICE guidance DG27 for patients diagnosed with CRC March 2017-August 2018 and (ii) a retrospective service evaluation of MMR IHC/Lynch syndrome testing in patients diagnosed with upper GI cancers January 2019-2020. RESULTS: Of 394 patients with CRC, 346 (87.8%) had MMR IHC testing. Thirty-eight of 346 (10.9%) were MMR deficient (MMR-D) and 5 (1.4%) were found to have pathogenic germline variants causing Lynch syndrome. Of 405 patients with upper GI cancers, 221 (54.6%) had MMR IHC testing. Ten of 221 (4.5%) were MMR-D and 1 (0.5%) had a pathogenic germline variant causing Lynch syndrome. DISCUSSION: This study highlights the small but significant number of patients, with CRC or upper GI cancers, which were caused by Lynch syndrome. It also highlights weaknesses in our testing pathway that limit access to germline testing. As MMR testing increases, it is important that clinicians are aware that patients with MMR-D tumours require reflex somatic testing or referral for germline testing. We have incorporated the guidelines into a pathway for use in clinics and multidisciplinary teams.

Oncology Informatics for Lynch Syndrome Research and Care: A Literature Review.

PURPOSE: This study aims to review and evaluate available informatics platforms for research and management purposes of Lynch syndrome (LS) to identify gaps and needs for future development. METHODS: LS informatics tools were identified through literature search in four publication databases (1 and Scopus). First, the LS and functional elements of every informatics tools for LS were introduced. Then, current existing LS informatics tools were reviewed and explained. RESULTS: A detailed review of implemented studies shows that many types of informatics platforms are available for LS management (ie, prediction model, clinical decision support system, database website, and other tools for research and management purposes of LS). Moreover, several dimensions of existing LS informatics tools were discussed and features and positive findings were reported. CONCLUSION: Reviewing the literature reveals that several LS informatics tools were focused on gene-specific estimate, cancer risk prediction, identifying/screening patients, supporting personalized care of individuals with LS, and storing mismatch repair mutations information. Nevertheless, these platforms do not fully cover the care and research purposes. For instance, future developments of LS tools require more attention to dynamic knowledgebase, extra-colonic lynch-related cancers on the basis of precision medicine, variants of unknown significance, and support from diagnosis to surveillance for patient follow-up. Insights and recommendations provided in this study could help researchers and developers to meet the existing challenges in future developments.

Lynch syndrome; towards more personalized management?

Lynch syndrome is the most common inherited cause of colorectal (lifetime risk up to 70%) and endometrial cancer. The diagnosis of Lynch syndrome facilitates preventive measures aimed at reducing the incidence and mortality of cancer. Colonoscopic surveillance for colorectal cancer, aspirin, and prophylactic hysterectomy and bilateral salpo-oopherectomy for endometrial and/or ovarian cancer have demonstrated to effectively reduce cancer mortality in this population. However, the lifetime risk of each cancer in people with Lynch syndrome is gene-specific and may be modified by environmental factors. Furthermore, the benefits of surveillance strategies need to be balanced against the risk of over-diagnosis and be supported by evidence of improved outcomes from cancer diagnosis in surveillance. Therefore, people with Lynch syndrome may benefit from a personalized management approach.

DNA Mismatch Repair-deficient Rectal Cancer Is Frequently Associated With Lynch Syndrome and With Poor Response to Neoadjuvant Therapy.

We evaluated 368 consecutively resected rectal cancers with neoadjuvant therapy for DNA mismatch repair (MMR) protein status, tumor response to neoadjuvant therapy, histopathologic features, and patient survival. Nine (2.4%) rectal cancers were mismatch repair-deficient (MMRD): 8 (89%) Lynch syndrome-associated tumors and 1 (11%) sporadic MLH1-deficient tumor. Of the 9 MMRD rectal cancers, 89% (8/9) had a tumor regression score 3 (poor response) compared with 23% (81/359) of MMR proficient rectal cancers ( P <0.001). Patients with MMRD rectal cancer less often had downstaging after neoadjuvant therapy compared with patients with MMR proficient rectal cancer (11% vs. 57%, P =0.007). In the multivariable logistic regression analysis, MMRD in rectal cancer was associated with a 25.11-fold increased risk of poor response to neoadjuvant therapy (tumor regression score 3) (95% confidence interval [CI]: 3.08-44.63, P =0.003). In the multivariable Cox regression analysis, the only variables significantly associated with disease-free survival were pathologic stage III disease (hazard ratio [HR]=2.46, 95% CI: 1.54-3.93, P <0.001), College of American Pathologists (CAP) tumor regression score 2 to 3 (HR=3.44, 95% CI: 1.76-6.73, P <0.001), and positive margins (HR=2.86, 95% CI: 1.56-5.25, P =0.001). In conclusion, we demonstrated that MMRD in rectal cancer is an independent predictor of poor response to neoadjuvant therapy and infrequently results in pathologic downstaging following neoadjuvant therapy. We also confirmed that MMRD in rectal cancer is strongly associated with a diagnosis of Lynch syndrome. Our results suggest that MMR status may help to provide a more patient-centered approach when selecting neoadjuvant treatment regimens and may help predict tumor response to neoadjuvant therapy.

Hereditary Colorectal Cancer.

Around 10% to 16% of colorectal cancer patients have a pathogenic variant in a cancer susceptibility gene. Some of these variants are in cancer genes that are associated with colorectal cancer while others are not. The hereditary colorectal cancer syndromes can be divided into two major categories, the nonpolyposis and the polyposis conditions. The nonpolyposis conditions can be divided into those that lead to colorectal tumors with defective mismatch repair and those that do not. The polyposis conditions are further divided by predominant histology into the adenomatous, hamartomatous, serrated, and mixed polyposis conditions. All of these conditions are described in detail herein.

Rectal Cancer in Patients with Hereditary Nonpolyposis Colorectal Cancer Compared with Sporadic Cases: Response to Neoadjuvant Chemoradiation and Local Recurrence.

BACKGROUND: This study aimed to assess the effect of neoadjuvant chemoradiation (nCXRT) on tumor regression and oncologic outcome of middle and low rectal cancer in patients of hereditary nonpolyposis colorectal cancer (HNPCC) compared to sporadic cases. STUDY DESIGN: This was a retrospective cohort study that compared the outcomes of patients with HNPCC presenting with middle or low rectal cancer indicated for nCXRT vs patients with sporadic rectal cancer. All patients received long-course nCXRT followed by total mesorectal excision. Primary outcome was pathologic tumor regression grade (TRG) assessed after resection. Secondary outcomes included disease-free survival and overall survival. RESULTS: Fifty-eight patients with HNPCC (24 female) were included in the study matched with 58 patients with sporadic rectal cancer (out of 166 using propensity score matching). Patients with HNPCC and sporadic rectal cancer were matched regarding tumor pathology TNM stage and lymphovascular invasion. In the HNPCC group, 36 patients (62%) had tumor regression (TRG3 = 6 (10.3%); TRG2 = 12 (20.6%); TRG1 = 18 (31%)) compared to 52 patients (92%) who had tumor regression in the control group (TRG4 = 9; TRG3 = 15; TRG2 = 18; TRG1 = 10) (p < 0.0007). After a median follow-up of 48 months, survival analysis revealed higher local recurrence and lower overall survival in patients with HNPCC compared to patients with sporadic rectal cancer. CONCLUSIONS: Rectal cancer in patients with HNPCC showed poorer response to nCXRT and was followed by higher local recurrence and lower overall survival than patients with sporadic rectal cancer. Tumor regression was detected in <65% of patients with HNPCC compared to >90% of patients with sporadic rectal cancer, and none of patients with HNPCC had a complete response.

Review article: Lynch Syndrome-a mechanistic and clinical management update.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to various cancers. AIM: To review the pathogenesis, clinical presentation, differential diagnosis and clinical strategies for detection and management of LS. METHODS: A narrative review synthesising knowledge from published literature, as well as current National Comprehensive Cancer Network guidelines for management of LS was conducted. RESULTS: LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. LS is one of the most common hereditary causes of cancer, and about 1 in 279 individuals carry a PV in an LS gene that predisposes to associated cancers. Individuals with LS have increased risks for colorectal, endometrial and other cancers, with significant variation in lifetime risk by LS-associated gene. CONCLUSIONS: As genetic testing becomes more widespread, the number of individuals identified with LS is expected to increase in the population. Understanding the pathogenesis of LS informs current strategies for detection and clinical management, and also guides future areas for clinical innovation. Unravelling the mechanisms by which these tumours evolve may help to more precisely tailor management by the gene involved.

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.

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.