Introduction

Familial adenomatous polyposis (FAP) is a dominantly inherited disorder that predisposes to colorectal cancer. However, after the introduction of prophylactic colectomy and endoscopic surveillance, as well as genetic screening of first-degree family members, the risk of CRC has decreased dramatically with subsequent prolonged expected life expectancy^.1 Current guidelines solely aim at preventing cancer, which has been the focus for decades.^2-3 From a patient perspective, mental aspects of the disease, which might decrease quality of life may be equally important. However, knowledge and focus on mental well-being in FAP patients is limited. If FAP patients are at increased risk of mental stress and ultimately of developing psychiatric disorders, a potential possibility of early intervention is missed. The Danish Polyposis Register has for over 40 years included data from all Danish FAP patients. Consequently, the register is free of referral and selection bias. We aimed this study at estimating the impact on educational level and risk of psychiatric disorders in a nationwide cohort of patients with FAP compared to a matched background population.

Aims & Methods

Known Danish FAP patients by April 2021 were identified from the Danish Polyposis Register and paired with four matched controls based on matched on sex, birth year, and zip code at birth. Using national registries, educational status, psychiatric contacts or diagnoses, and need for antidepressants, anxiolytics, or antipsychotics were compared between FAP patients and controls. Follow-up of patients started on the date of their first being identified as having FAP or on 1^st January 1996, whichever came last. Follow-up ended on the date of any of the listed outcomes, emigration, death, loss to follow-up or the end of the study on 1^st January 2020, whichever came first. Relative risk for any of the listed outcomes was quantified by hazard ratios (HR); these were estimated using Cox proportional hazards regression, with age as the underlying timescale, and used the variables of exposure status, year of outcome, sex, cancer, and education for the multiple regression model. Cancer was included as a time-varying covariate in the Cox proportional hazards regressions.

Results

The analysis included 445 FAP patients and 1,538 controls. The highest attained education was significantly lower for FAP patients (p<0.001). When comparing FAP patients and controls and adjusting for cancer diagnosis, an increased risk was observed for a psychiatric contact (1.69, CI 95%, 1.25–2.29, p<0.001), any psychiatric prescription (1.39, CI 95%, 1.17–1.66, p<0.001), receiving a psychiatric diagnosis (1.64, CI 95%, 1.19–2.26, p=0.002), as well as facing any psychiatric event (HR 1.55, CI 95%, 1.32–1.83, p<0.001). An increased risk was specifically seen for affective (1.76, CI 95%, 1.09–2.83, p=002) and behavioral disorders (2.01, CI 95%, 1.10–3.69, p=0.02) as well as prescription of antidepressants (1.59, CI 95%, 1.24–2.03, p<0.001) and antipsychotics (1.85, CI 95%, 1.26–2.70, p=0.002). For FAP patients, the median age for affective and behavioral disorders was 32.7 years (range 15.0–73.6 years) and 14.7 years (range 5.5–47.7 years), respectively, which did not differ from controls.

Conclusion

Compared to controls, FAP patients have a significantly reduced educational level and an increased risk of developing affective and behavioural disorders with increased needs for antidepressants and antipsychotics. This calls for further exploratory and interventional trials.

References

1 Karstensen JG, Burisch J, Pommergaard HC, et al. Colorectal Cancer in Individuals With Familial Adenomatous Polyposis, Based on Analysis of the Danish Polyposis Registry. Clin Gastroenterol Hepatol 2019; 17(11): 2294-300 e1.
2 Monahan KJ, Bradshaw N, Dolwani S, et al. 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). Gut 2020;69(3):411-44.
3 van Leerdam ME, Roos VH, van Hooft JE, et al. Endoscopic management of polyposis syndromes: European society of gastrointestinal endoscopy
(ESGE) guideline. Endoscopy 2019;51:877–95.

Disclosure

JGK is consultant for SNIPR BIOME

Introduction

Heterozygous pathogenic germline variants in CDH1 or CTNNA1 cause hereditary tumor syndromes associated with a high risk for diffuse gastric cancer (DGC) and only for CDH1 carriers female lobular breast cancer (LBC). Carriers of a pathogenic variant often show multiple foci of gastric signet ring cell carcinoma (SRCC) at early age and are offered prophylactic total gastrectomy (PTG), especially if there is a positive family history for DGC. Endoscopic surveillance can inform the timing of PTG through detection of microscopic SRCC foci.

Aims & Methods

Individuals with heterozygous causative germline variants in CDH1 or CTNNA1 were evaluated at eight centers from the German Consortium for Familial Intestinal Cancer from 2008 through April 2023. Endoscopy findings, pathological data, personal and family cancer history, and demographics were recorded. Gastric cancer detection by endoscopy and gastrectomy and cancer-specific events were assessed. We evaluated outcomes of endoscopic surveillance for carriers with and without a family history of DGC.

Results

We identified 117 heterozygous carriers of a CDH1 variant and 4 carriers of a pathogenic germline CTNNA1 variant (73 female (60%)). A personal history of LBC was reported in 22/73 (30%) CDH1 positive female patients. A family history of gastric cancer was apparent in 93/121 patients (77%; 1^st degree relative in 77/93; 2^nd degree 69/93).
A total number of 177 endoscopic examinations was conducted (range 1-7). In 34/121 (28%) patients (age range 14-53 years), DGC was detected during endoscopy by either targeted (20/34 (59%) patients) and/or multiple random biopsies (15/34 (44%) patients; number of biopsies taken median 31 [range: 2-100). A total number of 14/121 (12%) patients presented with metastatic disease (age range 16-62 years). In one patient, a targeted biopsy revealed a metastasis of a LBC. Omitting random biopsies in our cohort would have led to an under-diagnosis rate of 41%.
Gastrectomy was performed in 29/121 (24%) patients after endoscopic diagnosis of DGC. A PTG was done in 53/121 (44%) patients without prior endoscopic detection of SRCC. Here, a SRCC was detected in 31/53 (59%) patients, including multifocal SRCCs in 23/31 (74%) patients (number of cancer foci 1-15). All SRCCs were confined to the mucosa (pT1a).
Cancer foci were located in the cardia (8 patients with total number of 11 cancer foci), fundus (12 patients with 32 foci), body (19 patients with 41 foci) and antral region (6 patients with 7 foci).
Twenty participants died during follow-up, 17 due to either gastric or lobular breast cancer. All the deceased patients due to gastric cancer were diagnosed at their initial endoscopy.

Conclusion

More than two third of the individuals with pathogenic germline variants in CDH1 or CTNNA1 had histopathologic evidence of DGC in endoscopy and/or gastrectomy specimens. In our cohort, we observed no incident tumors (>pT1a) if no macroscopic cancer was apparent at initial endoscopy. Random biopsies are crucial to sufficiently detect SRCCs, despite the low number of random biopsies taken in our real-life cohort.

Introduction

Several therapeutics are in development for familial adenomatous polyposis (FAP) to reduce polyp burden, the incidence of cancer and prevent or postpone intestinal surgery. However, there is limited consensus on the optimal method for measuring intestinal disease activity in FAP.

Aims & Methods

We aimed to systematically review existing endoscopic severity indices for FAP.
We searched MEDLINE, EMBASE and the Cochrane Library from inception to February 2023 to identify studies that evaluated endoscopic disease activity and severity in children and adults with FAP.

Results

A total of 94 studies were included. We evaluated component items of scoring indices, such as polyp count, polyp size and histology, and the scoring indices for the upper- and lower gastrointestinal tract . Partial validation was observed for polyp count and size. The most common reported scoring index was the Spigelman classification system, which was used for assessing the severity of duodenal disease. A single study reported an almost perfect inter- and intra-observer agreement for this system. The InSIGHT polyposis staging system, which was used for assessing colorectal polyp burden has been partially validated. It showed substantial inter-observer agreement, however it lacked the analysis of the intra-observer agreement. The SPACE criteria is a novel system to identify high-risk gastric polyps and was assessed for the inter-observer agreement; however it showed a moderate level of inter-observer agreement.

Conclusion

There are no fully validated endoscopic disease severity indices for FAP. Development and validation of reliable and responsive endoscopic disease severity instrument will be useful for clinical care, research and to assess the impact of pharmacological therapies on polyp burden in FAP.

Disclosure

Hicham Bouchiba: nothing to disclose
Anna L. Silverman: nothing to disclose
Arthur S. Aelvoet: nothing to disclose
John K. MacDonald: nothing to disclose
Brian G. Feagan: BGF has received grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG, and UCB; consulting fees from Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestle, Nextbiotix, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., and Zyngenia; speakers bureau fees from Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts, and UCB Pharma; is a scientific advisory board member for Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestle, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, and UCB Pharma; and is the Senior Scientific Officer of Alimentiv Inc. (formerly Robarts Clinical Trials, Inc.).
Vipul Jairath: has received has received consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso pharmaceuticals, Takeda, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi
CM: has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Takeda; royalties from Springer Publishing; research support from Ferring, Pfizer.
Evelien Dekker: Endoscopic equipment on loan of FujiFilm. Research grant FujiFilm. Honoraria for consultancy from Olympus, Fujifilm, Ambu and InterVenn, and speakers' fees from Olympus, GI Supply, Norgine, IPSEN, PAION and FujiFilm.
Jewel Samadder: Consulting or Advisory Role: Janssen Research & Development, Cancer Prevention Pharmaceuticals, Recursion Pharmaceuticals

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

CDH1 gene mutations are associated with gastric and breast cancer. The risk of colorectal cancer may be increased in the presence of this mutation, although evidence is scarce.

Aims & Methods

Aims: To assess the presence of high-risk colorectal polyps (polyp with ≥10mm or with high-grade dysplasia, ≥5 adenomas, any serrated polyp ≥10mm or with dysplasia) and colorectal cancer in patients on surveillance program with mutation in CDH1 gene.
Methods: Retrospective study in patients with CDH1 gene mutation followed in a family risk appointment in a tertiary care hospital.

Results

Data from 36 patients with a mean age of 44.22±14.77 years, 20 males, with a mean follow-up of 5.5 years. Twenty-seven patients had family history of gastric cancer and 9 of gastric and breast cancer; twelve patients had never undergone colonoscopy (age ≤ 40 years). Of the 24 patients who had already undergone at least one colonoscopy, 12 (50%) never removed polyps. Only 4 patients had high-risk polyps (age 30, 52, 59 and 77 years) and no patient presented with colorectal cancer during follow-up.

Conclusion

Although this is a small sample, our study revealed a low percentage of patients with hereditary diffuse gastric cancer with high-risk colorectal polyps (and only one patient with a high-risk polyp aged <50 years) and no patients with colorectal cancer, similar to a population without a CDH1 mutation. Further studies with larger sample sizes are needed to clarify the impact of CDH1 mutation on colorectal cancer.