Inherited Cancer Early Diagnosis (ICED) Study

NCT06163365 | Unknown

• 2 other identifiers: CCR5595304173
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

ICED is a prospective sample collection research study, aiming to develop or validate a blood/urine biomarker which could potentially detect cancers early in individuals at high risk of developing cancers, due to certain germline alterations.

Conditions

Li Fraumeni Syndrome; Lynch Syndrome; Hereditary Diffuse Gastric Cancer; Cowden Syndrome; Peutz-Jeghers Syndrome; Familial Adenomatous Polyposis; SMAD4 Gene Mutation; MutYH-associated Polyposis

Outcome Measures

Primary Outcomes (1)

• Primary hypothesis

  Cancer specific genetic and epigenetic changes will be combined to provide a circulating tumour DNA signal that is present in patients who receive a confirmed diagnosis of cancer and not in patients who do not develop cancer

  2 years

Secondary Outcomes (1)

• Secondary hypothesis

  2 years

Study Arms (2)

Cohort 1. Li Fraumeni (TP53 mutations carriers)

Patients with a germline TP53 alteration included in this study will undergo their usual surveillance with their treating team. In addition to their routine scans or examinations, they will provide blood samples at enrollment, during the study (optional) and at the end of their participation (at 12 months). The results of any radiological scan undergone during this period will be collected retrospectively and added to their data collection, which will allow for a correlative analysis between the genetic and epigenetic results and radiological outcomes.

Cohort 2. Gastro-intestinal (GI) cohort

Patients with underlying germline conditions at high risk of developing a GI malignancy (approximately 40-50 patients) * Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM genes) * PTEN * STK11 (Peutz-Jeghers syndrome) * CDH1 and APC gene alterations carriers prior to their risk-reducing surgery if such is performed. * SMAD4 * MUTYH\* (\*biallelic variants) Carriers of CDH1 and APC pathogenic mutation are invited to give blood and optional urine samples before and after their surgery, if they undergo this intervention, with no need for sequential samples. Samples should be taken when convenient for the patient prior to and post-surgery.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Anyone in the general population who are a confirmed carrier of a pathogenic/likely pathogenic variant in any of the following genes: TP53, Mismatch Repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM), PTEN, STK11 (Peutz-Jeghers syndrome), CDH1, APC, SMAD4, MUTYH\* (\*biallelic carriers).

You may qualify if:

• Patients over the age of 18 years old, with no active cancer
• Carriers of a pathogenic/likely pathogenic variant in any of the following genes: TP53, Mismatch Repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM), PTEN, STK11 (Peutz-Jeghers syndrome), CDH1, APC, SMAD4, MUTYH\* (\*biallelic carriers).
• Able to consent to the study.

You may not qualify if:

• Carriers of a variant associated with reduced penetrance (in the view of a geneticist) or a variant of uncertain significance.
• Patients with a malignancy diagnosed in the previous 5 years \[except non-melanomatous skin cancer or cervical carcinoma in situ (CIS)\].

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead

Study Sites (1)

The Royal Marsden NHS Foundation Trust

London, United Kingdom

RECRUITING

Related Publications (18)

• Clarke CA, Hubbell E, Kurian AW, Colditz GA, Hartman AR, Gomez SL. Projected Reductions in Absolute Cancer-Related Deaths from Diagnosing Cancers Before Metastasis, 2006-2015. Cancer Epidemiol Biomarkers Prev. 2020 May;29(5):895-902. doi: 10.1158/1055-9965.EPI-19-1366. Epub 2020 Mar 30.

  PMID: 32229577 BACKGROUND

• Kratz CP, Achatz MI, Brugieres L, Frebourg T, Garber JE, Greer MC, Hansford JR, Janeway KA, Kohlmann WK, McGee R, Mullighan CG, Onel K, Pajtler KW, Pfister SM, Savage SA, Schiffman JD, Schneider KA, Strong LC, Evans DGR, Wasserman JD, Villani A, Malkin D. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clin Cancer Res. 2017 Jun 1;23(11):e38-e45. doi: 10.1158/1078-0432.CCR-17-0408.

  PMID: 28572266 BACKGROUND

• Saya S, Killick E, Thomas S, Taylor N, Bancroft EK, Rothwell J, Benafif S, Dias A, Mikropoulos C, Pope J, Chamberlain A, Gunapala R; SIGNIFY Study Steering Committee; Izatt L, Side L, Walker L, Tomkins S, Cook J, Barwell J, Wiles V, Limb L, Eccles D, Leach MO, Shanley S, Gilbert FJ, Hanson H, Gallagher D, Rajashanker B, Whitehouse RW, Koh DM, Sohaib SA, Evans DG, Eeles RA. Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls. Fam Cancer. 2017 Jul;16(3):433-440. doi: 10.1007/s10689-017-9965-1.

  PMID: 28091804 BACKGROUND

• Hanson H, Brady AF, Crawford G, Eeles RA, Gibson S, Jorgensen M, Izatt L, Sohaib A, Tischkowitz M, Evans DG; Consensus Group Members. UKCGG Consensus Group guidelines for the management of patients with constitutional TP53 pathogenic variants. J Med Genet. 2020 Jun 22;58(2):135-9. doi: 10.1136/jmedgenet-2020-106876. Online ahead of print.

  PMID: 32571901 BACKGROUND

• Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J; Hereditary CRC guidelines eDelphi consensus group. 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 Mar;69(3):411-444. doi: 10.1136/gutjnl-2019-319915. Epub 2019 Nov 28.

  PMID: 31780574 BACKGROUND

• Burn J, Sheth H, Elliott F, Reed L, Macrae F, Mecklin JP, Moslein G, McRonald FE, Bertario L, Evans DG, Gerdes AM, Ho JWC, Lindblom A, Morrison PJ, Rashbass J, Ramesar R, Seppala T, Thomas HJW, Pylvanainen K, Borthwick GM, Mathers JC, Bishop DT; CAPP2 Investigators. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet. 2020 Jun 13;395(10240):1855-1863. doi: 10.1016/S0140-6736(20)30366-4.

  PMID: 32534647 BACKGROUND

• Blair V, Martin I, Shaw D, Winship I, Kerr D, Arnold J, Harawira P, McLeod M, Parry S, Charlton A, Findlay M, Cox B, Humar B, More H, Guilford P. Hereditary diffuse gastric cancer: diagnosis and management. Clin Gastroenterol Hepatol. 2006 Mar;4(3):262-75. doi: 10.1016/j.cgh.2005.12.003.

  PMID: 16527687 BACKGROUND

• Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013 Nov 6;105(21):1607-16. doi: 10.1093/jnci/djt277. Epub 2013 Oct 17.

  PMID: 24136893 BACKGROUND

• Boardman LA, Thibodeau SN, Schaid DJ, Lindor NM, McDonnell SK, Burgart LJ, Ahlquist DA, Podratz KC, Pittelkow M, Hartmann LC. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. 1998 Jun 1;128(11):896-9. doi: 10.7326/0003-4819-128-11-199806010-00004.

  PMID: 9634427 BACKGROUND

• Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J Gastroenterol. 2006 Feb;101(2):385-98. doi: 10.1111/j.1572-0241.2006.00375.x.

  PMID: 16454848 BACKGROUND

• Betti M, Aspesi A, Biasi A, Casalone E, Ferrante D, Ogliara P, Gironi LC, Giorgione R, Farinelli P, Grosso F, Libener R, Rosato S, Turchetti D, Maffe A, Casadio C, Ascoli V, Dianzani C, Colombo E, Piccolini E, Pavesi M, Miccoli S, Mirabelli D, Bracco C, Righi L, Boldorini R, Papotti M, Matullo G, Magnani C, Pasini B, Dianzani I. CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma. Cancer Lett. 2016 Aug 10;378(2):120-30. doi: 10.1016/j.canlet.2016.05.011. Epub 2016 May 12.

  PMID: 27181379 BACKGROUND

• Jafri M, Wake NC, Ascher DB, Pires DE, Gentle D, Morris MR, Rattenberry E, Simpson MA, Trembath RC, Weber A, Woodward ER, Donaldson A, Blundell TL, Latif F, Maher ER. Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma. Cancer Discov. 2015 Jul;5(7):723-9. doi: 10.1158/2159-8290.CD-14-1096. Epub 2015 Apr 14.

  PMID: 25873077 BACKGROUND

• Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer Clinical guideline Your responsibility Your responsibility Contents Contents [Internet]. 2013. Available from: www.nice.org.uk/guidance/cg164

  BACKGROUND

• Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA Jr. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008 Sep;14(9):985-90. doi: 10.1038/nm.1789. Epub 2007 Jul 31.

  PMID: 18670422 BACKGROUND

• Kwapisz D. The first liquid biopsy test approved. Is it a new era of mutation testing for non-small cell lung cancer? Ann Transl Med. 2017 Feb;5(3):46. doi: 10.21037/atm.2017.01.32.

  PMID: 28251125 BACKGROUND

• Church TR, Wandell M, Lofton-Day C, Mongin SJ, Burger M, Payne SR, Castanos-Velez E, Blumenstein BA, Rosch T, Osborn N, Snover D, Day RW, Ransohoff DF; PRESEPT Clinical Study Steering Committee, Investigators and Study Team. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. 2014 Feb;63(2):317-25. doi: 10.1136/gutjnl-2012-304149. Epub 2013 Feb 13.

  PMID: 23408352 BACKGROUND

• Hitchins MP, Vogelaar IP, Brennan K, Haraldsdottir S, Zhou N, Martin B, Alvarez R, Yuan X, Kim S, Guindi M, Hendifar AE, Kalady MF, DeVecchio J, Church JM, de la Chapelle A, Hampel H, Pearlman R, Christensen M, Snyder C, Lanspa SJ, Haile RW, Lynch HT. Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome. BMJ Open Gastroenterol. 2019 May 28;6(1):e000299. doi: 10.1136/bmjgast-2019-000299. eCollection 2019.

  PMID: 31275589 BACKGROUND

• Klein EA, Richards D, Cohn A, Tummala M, Lapham R, Cosgrove D, Chung G, Clement J, Gao J, Hunkapiller N, Jamshidi A, Kurtzman KN, Seiden MV, Swanton C, Liu MC. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol. 2021 Sep;32(9):1167-1177. doi: 10.1016/j.annonc.2021.05.806. Epub 2021 Jun 24.

  PMID: 34176681 BACKGROUND

Related Links

• Link to PubMed ID: 9634427
• Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer Clinical guideline
• Link to PubMed ID: 34176681

Biospecimen

Retention: SAMPLES WITH DNA

Blood sample for ctDNA and epigenetic studies\* \*(for CDH1 and APC carriers who undergo surgery, samples before and after their surgery) Urine sample for ctDNA and epigenetic studies\* \*(for CDH1 and APC carriers who undergo surgery, samples before and after their surgery)

MeSH Terms

Conditions

Li-Fraumeni Syndrome; Colorectal Neoplasms, Hereditary Nonpolyposis; Stomach Neoplasms; Hamartoma Syndrome, Multiple; Peutz-Jeghers Syndrome; Adenomatous Polyposis Coli

Condition Hierarchy (Ancestors)

Neoplastic Syndromes, Hereditary; Neoplasms; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Stomach Diseases; Hamartoma; Neoplasms, Multiple Primary; Intestinal Polyposis; Lentigo; Melanosis; Hyperpigmentation; Pigmentation Disorders; Skin Diseases; Skin and Connective Tissue Diseases; Adenomatous Polyps; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Study Officials

• Angela George

  The Royal Marsden

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elena Cojocaru

CONTACT

020 3186 5384; elena.cojocaru@rmh.nhs.uk

Lydia Taylor

CONTACT

020 3186 5384; lydia.taylor@rmh.nhs.uk

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Target Duration: 12 Months
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2023
• First Posted: December 8, 2023
• Study Start: July 26, 2022
• Primary Completion: July 26, 2024
• Study Completion: July 26, 2025
• Last Updated: December 8, 2023

Record last verified: 2023-11

Locations

GB (1)