Introduction

Recently, in Japan, insurance coverage for microsatellite instability (MSI) testing as a companion diagnostic agent for immune-checkpoint inhibitors and comprehensive cancer genome profiling has highlighted the growing importance of Lynch syndrome (LS) awareness among gastroenterologists.

Aims & Methods

Our aim was to assess the shifts in knowledge regarding LS and practice trends among Japanese gastroenterologists. We conducted a questionnaire survey on physicians' knowledge and practice trends regarding LS in their facilities, collaborating with the councilors of the Japanese Society of Gastroenterology in 2020 and 2022. The knowledge survey on LS encompassed an understanding of the genetic background of LS, primary and secondary screening methods for LS, and spillover effects of comprehensive cancer genome profiling tests on LS practice. Meanwhile, the practice trends survey on LS examined information on the LS screening methods utilized, the number of patients screened for LS, and LS surveillance methods. Each questionnaire item was compared between the first and second surveys to determine the proportion of physicians who chose each option based on the total number of physicians who completed the questionnaire. The responses of physicians who participated in both surveys were analyzed to assess changes in their responses to each question.

Results

The knowledge survey was completed by 146 in the first survey and 228 doctors in the second survey. Besides, the practice trend survey was completed by 362 in the first survey and 195 doctors, respectively, in the second survey. The second survey revealed a significant increase in several key indicators compared to the first survey. These included the number of physicians opting for universal tumor screening as the primary screening method for LS (26/195 vs. 20/354) , the proportion of physicians conducting the BRAF V600E test for chemotherapy selection (100/195 vs. 137/354), the number of newly diagnosed patients with LS in the last 3 years per physician (1.64±4.15 vs. 0.96±3.27), and the number of patients with LS currently under surveillance per physician (2.00±5.09 vs. 1.15±4.03). Among physicians who participated in both surveys, the knowledge about primary and secondary screening methods, the proportion offering BRAF V600E testing in colorectal cancer tissue and performing screening tests for endometrial cancer, and the number of patients with LS currently under surveillance per physician were significantly higher in the second survey than in the first survey. Physicians who initiating or strengthening the inspection of primary and secondary screening for LS between the first and second surveys had a significantly higher proportions of increasing currently surviving patients with LS compared with those who continued or discontinued screening tests. (13/33 vs. 13/100, 11/33 vs. 13/100)

Conclusion

In conclusion, there has been a notable increase in both the number of patients diagnosed with LS and the number of patients screened for LS in Japan in recent years. This increase can be attributed to an increase in the number of physicians performing primary screening, such as universal tumor screening, and secondary screening utilizing MSI and immunohistochemistry for mismatch repair protein tests.

Disclosure

This study was supported by a research grant from The Japanese Society of Gastroenterology

Introduction

Lynch syndrome (LS) is associated with an increased risk of upper gastrointestinal (GI) cancers. While upper GI surveillance is recommended in several guidelines, there remains international variability and ongoing debate regarding its implementation, timing, and extent. This study evaluated the incidence of gastric (GC), duodenal (DC), and jejunal cancers (JC) in LS patients using data from the German Consortium for Familial Intestinal Cancer (GCFIC). In addition, the diagnostic yield of esophagogastroduodenoscopy (EGD) and push enteroscopy (PE), performed at a tertiary care center, was retrospectively analyzed.

Aims & Methods

A total of 960 endoscopic procedures (494 EGD, 466 PE) were retrospectively analyzed in 349 LS patients documented at a tertiary care center. Push enteroscopy (PE) was performed using a colonoscope to allow deeper insertion into the small intestine, enabling inspection of the proximal jejunum. Clinically relevant findings included intestinal metaplasia, Barrett’s esophagus, adenomas, and carcinomas. These findings were systematically compared between EGD and PE to evaluate diagnostic yield. The GCFIC database was evaluated to determine cancer incidence by genotype.

Results

In the GCFIC cohort (n=2859), the majority of GC (2.2%), DC (2.1%), and JC (1.9%) occurred in high-risk pathogenic variant carriers (PGV) (MLH1, MSH2, EPCAM). However, a small proportion of cancers was also observed in low-risk PGV carriers: GC in two MSH6 carriers, DC in five patients with MSH6 or PMS2, and JC in seven low-risk carriers (MSH6: 3, PMS2: 4). In the NZET cohort, 22% of procedures and 50 % of patients revealed relevant findings. Gastric adenomas were found in 3.7%, gastric cancer in 1.1%, and intestinal metaplasia in 28% of patients. Duodenal adenomas were found in 3.7% and cancer in 0.9%. Jejunal neoplasia was detected exclusively by PE (adenomas 1.7%, cancer 0.6%).

Conclusion

Upper gastrointestinal surveillance is essential in patients with Lynch syndrome. Push enteroscopy (PE) provides diagnostic value beyond conventional esophagogastroduodenoscopy (EGD), particularly in detecting jejunal neoplasia, and should be considered in high-risk surveillance protocols.

Disclosure

Robert Hüneburg was funded by Deutsche Krebshilfe (DECADE), and Wilhelm-Sander-Stiftung.
Jacob Nattermann was funded by Wilhelm-Sander-Stiftung.

Introduction

Lynch syndrome (LS) is a hereditary condition associated with an increased risk of early colorectal cancer (CRC), due to mutations in DNA mismatch repair (MMR) genes, accounting for 3-5% of all CRC. High-definition screening colonoscopies in specialized centers reduce CRC mortality in this setting.

Aims & Methods

We conducted a clinical audit in a large cohort of these patients, ultimately to enhance the quality of care provided. We performed a retrospective evaluation of the clinical characteristics and risk factors of LS patients under surveillance at our reference center. CRC surveillance program includes colonoscopy every 2 years, starting at ages 20–25 for MLH1/MSH2 carriers and 30–35 for MSH6/PMS2 carriers. We further analyzed compliance to surveillance protocol and its clinical outcomes – our primary endpoint was mortality rate due to CRC and secondary endpoints were time to first advanced colorectal lesion and CRC staging at diagnosis.

Results

A total of 508 patients were included (44% MSH2, 23% MLH1, 20% MSH6, and 13% PMS2). The mean age at surveillance initiation was 44.4 years, with 35.6% starting after the diagnosis of a Lynch syndrome-associated neoplasia. The mean surveillance duration was 5.6 years. Each patient underwent an average of four colonoscopies, with 50% performed within the recommended surveillance intervals.
During the follow-up period, 35 patients were diagnosed with CRC, with a mean time to first advanced colorectal polyp of 3.7 years and for the first CRC diagnosis of 4.8 years. Having any colonoscopy outside the established interval was not associated with higher CRC incidence (p = 0,647). CRC cases diagnosed prior to surveillance initiation (n=143) were more advanced (58.1% stage ≥ II) and were treated with segmental colectomy in 80% of cases. In contrast, CRC cases diagnosed during surveillance (n=48) were detected at earlier stages (64.6% Tis/T1) and managed with endoscopic resection (29%) or total colectomy (56%) (p < 0.001).
The incidence of CRC was higher in MLH1/MSH2 carriers compared to MSH6/PMS2 carriers (36% vs. 22%, p = 0.0020). The mean age at first CRC diagnosis was 45.6 years for MLH1/MSH2 carriers and 49.9 years for MSH6/PMS2 carriers (p = 0.053). The CRC-related mortality rate was 0.6% (n=3), all cases diagnosed before surveillance initiation.

Conclusion

Although adherence to the CRC surveillance program in LS patients can be optimized, our findings underscore its importance in specialized reference centers. Surveillance was associated with earlier CRC detection, less invasive therapeutic approaches, and reduced CRC-related mortality. Our results also show a lower incidence of CRC and an higher age at first CCR diagnosis in MSH6/PMS2 carriers, strengthening the personalized surveillance recommendations dependent on gene specificities.

References

Castillo-Iturra, J., Sánchez, A. and Balaguer, F. (2024) ‘Colonoscopic surveillance in Lynch Syndrome: Guidelines in perspective’, Familial Cancer [Preprint]
del Carmen, G. et al. (2023) ‘Colorectal surveillance outcomes from an institutional longitudinalcohort of Lynch syndrome carriers’, Frontiers in Oncology, 13
Kastrinos, F. et al. (2021) ‘Gene-specific variation in colorectal cancer surveillance strategies for Lynch syndrome’, Gastroenterology, 161(2)

Introduction

Individuals with Lynch syndrome (LS) are predisposed to different tumors, including gastric (GC) and duodenal (DC) cancer, especially those with specific mutations or familial aggregation. However, the role of esophagogastroduodenoscopy (EGD) in these patients is still uncertain, with heterogeneous recommendations among different guidelines.

Aims & Methods

To estimate the overall incidence of GC and DC in individuals with LS, to determine the incidence of GC and DC in higher-risk subgroups within these patients, as well as to clarify the usefulness of screening or surveillance by EGD.

Systematic search of Pubmed and Embase for cohort studies and clinical trials from inception to April 2024. Incidences of GC and DC were calculated, as well as the relative risk (RR) and their respective 95% confidence intervals in those studies comparing patients under surveillance with EGD vs without. A meta-analysis was performed using a random-effects model. Heterogeneity was assessed with the I² statistic.

Results

A total of 584 studies were obtained, of which 30 were finally included, with a total of 31264 patients with LS. The overall incidence of GC was 2.04% (95%CI 1.63-2.45). The incidence of GC was 2.60% (95%CI 1.61-3.60) in MLH1 carriers and 2.91% (95%CI 1.63-2.45) in MSH2 carriers. In those with LS and family history, the incidence of GC was 25.94% (95%CI 15.01-36.87). The incidence of DC was 1.61% (95%CI 1.21-2.00).
Only 3 studies compared patients with LS in follow-up with EGD vs those without follow-up, evidencing a protective effect of EGD for GC [RR 0.31 (95%CI 0.14-0.69)], but not for DC [RR 0.65 (95%CI 0.22-1.32)].

Conclusion

The incidence of GC and DC in patients with LS is higher than that of the general population, especially in those patients with MLH1, MSH2 mutations or family aggregation. Surveillance with EGD could help to reduce this incidence through the diagnosis of premalignant lesions.

Introduction

The role of capsule endoscopy (CE) for the surveillance of small-bowel (SB) cancer in asymptomatic Lynch syndrome (LS) patients has been questioned in recent years, with contradicting results. The overall lifetime risk of SB cancer in this population is around 4-5%, with an age-dependent pattern [1]. Besides, recent data highlight that, depending on the affected path_MMR gene, the frequencies of tumors other than colorectal cancer vary and that affected patients develop subsequent cancers later in life. The aim of this meta-analysis is to evaluate the diagnostic yield (DY) of CE as a screening tool in asymptomatic LS patients.

Aims & Methods

A systematic literature search was conducted in Pubmed, Embase and Web of Science to identify all studies evaluating SB cancer surveillance with CE in asymptomatic LS patients. The primary outcome was the evaluation of the DY of CE in consecutive screening rounds, for both CE-identified pathology and histologically-confirmed pathology (i.e., adenoma or adenocarcinoma). Pooled estimates of DY were calculated from random effects models.

Results

Five studies including 583 patients were identified for data extraction and statistical analysis [2-6] [Table]. The estimated pooled DY for CE-identified pathology was 8% in the first screening round (95% confidence interval [CI] 4-12%) and 6% in the second (95% CI 2-10%). Limiting the analysis to histologically-confirmed pathology, the pooled DY of the second-round screening dropped to 0% (95% CI 0-6%). The time interval between screening rounds was approximately 2 years.
Adenomas were detected in 8 patients (4 males) with a median age of 47.5 years (interquartile range [IQR] 19), while adenocarcinomas were diagnosed in 8 patients (5 males) with a median age of 62.5 years (IQR 17.25). MLH1 was the most involved path_MMR pathogenic variant (9 out of 16 patients), followed by MSH2 and MSH6 (5 and 2 patients, respectively). No adenocarcinomas were detected in MSH6 carriers, as only adenomas were found in 2 patients, with a considerably higher median age than MSH2 and MLH1 adenoma carriers (70.5 years versus 43.5 and 45). No predominance was observed according to the anatomical location (duodenum, n=6; jejunum, n=6; ileum, n=4).

Conclusion

The detection of adenocarcinoma appeared to have a 15-year delay compared to adenomas, supporting a rather slow adenoma to carcinoma transition.
A surveillance strategy starting from the age of 50, with a time interval between procedures lengthened to at least 5 years (instead of 2) could likely be more effective in reducing the burden of advanced disease, both in terms of cost-effectiveness and efficacy. Prospective data may reveal whether a potential SB surveillance might benefit from gene-associated differences in cancer risk, similar to the recent de-escalation of CRC screening recommendations in MSH6 and PMS2 carriers [7].
In conclusion, although the DY of CE is high in detecting SB lesions in LS, the low number of positive examinations eventually resulted in an even lower number of true-positive patients, with a pooled yield proximate to 0%.
The results of this study confirm that SB cancer surveillance with CE with a 2-year interval in asymptomatic LS individuals is not an effective screening strategy.

References

[1] Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 2020;22:15–25.
[2] Saurin J-C, Pilleul F, Soussan EB, et al. Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with Lynch syndrome. Endoscopy 2010;42:1057–62.
[3] Haanstra JF, Al-Toma A, Dekker E, et al. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Gut 2015;64:1578–83.
[4] Haanstra JF, Al-Toma A, Dekker E, et al. Incidence of small bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Endosc Int Open 2017;5:E622–E626.
[5] Perrod G, Samaha E, Perez-Cuadrado-Robles E, et al. Effectiveness of a dedicated small bowel neoplasia screening program by capsule endoscopy in Lynch syndrome: 5 years results from a tertiary care center. Ther Adv Gastroenterol 2020;13:1756284820934314.
[6] DeJesse J, Vajravelu RK, Dudzik C, et al. Uptake and outcomes of small intestinal and urinary tract cancer surveillance in Lynch syndrome. World J Clin Oncol 2021;12:1023–36.
[7] Peltomäki P, Nyström M, Mecklin J-P, et al. Lynch syndrome genetics and clinical implications. Gastroenterology 2023 Jan 24;S0016-5085(23)00050-1. doi:10.1053/j.gastro.2022.08.058 [Online ahead of print]

Introduction

Colonoscopic surveillance reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. Still, its invasiveness and high costs highlight the need for a non-invasive approach to predict the presence of neoplastic lesions.

Aims & Methods

This study aimed to identify faecal bacterial biomarkers to discern between carriers with colorectal lesions and those with normal colon.
Two independent Spanish cohorts (a training and a validation cohort) were recruited through two multicenter studies (Table 1). Participants provided a faecal sample before surveillance colonoscopy to quantify the abundance of F. prausnitzii (FPRA) and its phylogroups I and II (PHGI and PHGII), P. stomatis (PTST), B. fragilis (BCTF), B. thetaiotaomicron (BCTT), B46 (best BLAST match S. variabile), G. morbillorum (GMLL), B48 (best BLAST match R. faecis), and E. coli (ECO) through qPCR. Eubacteria (EUB) was quantified as the total bacterial load. Participants were classified based on colonoscopy findings as normal colonoscopy (NC), non-advanced adenoma (NAA), and advanced neoplasia (AN, including advanced adenoma and CRC). A bacterial signature for neoplasia prediction was defined and validated in the training and validation cohorts, respectively.

Table 1. Main characteristics of the study participants. NC, normal colonoscopy; NAA, non-advanced adenoma; AA, advanced adenoma; CRC, colorectal cancer.

Results

The bacterial abundances were analysed in the training cohort according to age, sex, body mass index (BMI), germline mutation, and colonoscopy findings. Significant moderate positive correlations were identified between the abundances of BCTF and age (r=0.325, p=0.040), and PHGII and BMI (r=0.399, p=0.010). A significant negative correlation was identified between GMLL abundance and BMI (r=-0.331, p=0.036). Patients harbouring MLH1 mutations exhibited a significantly higher abundance of FPRA compared to PMS2 carriers (p=0.048). Patients with neoplasia (NAA+AN) presented significantly lower abundances of BCTF (p=0.027) and B48 (p=0.038) than patients with NC. Patients with AN presented a significantly lower abundance of PTST compared to patients with NC or NAA (p=0.032).
Although all the bacterial markers achieved a sensitivity of 100% to predict the presence of neoplasia, none of them presented a specificity higher than 25% by itself. To maintain sensitivity and increase specificity a bacterial signature was defined including ECO, BCTF, GMLL, FPRA, PHGI, PHGII, and B46 combined with the inherited mutation. The signature showed 100% sensitivity (SS), 52.50% specificity (SP), 34.48% positive predictive value (PPV), and 100% negative predictive value (NPV). This signature was subsequently validated demonstrating 100% SS, 56.45% SP, 53.44% PPV, and 100% NPV.

Conclusion

A new faecal bacterial signature to predict the presence of colorectal neoplasia in LS carriers has been identified, showcasing its potential usefulness to improve and personalise LS surveillance, optimising endoscopic resources, and providing a less invasive and cost-effective approach.

Disclosure

S. Taboada-López, M. Malagón, S. Ramió-Pujol and M. Serra-Pagès are employees of GoodGut.