Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released - Under Revision 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: CDH1
• Condition: Hereditary Diffuse Gastric Cancer
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• CDH1 ⇔ 0100488 (cdh1-related diffuse gastric and lobular breast cancer syndrome): Limited Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric. The limited actionability assertion in the pediatric population is based on low likelihood and effectiveness.

Final Consensus Scores

Gene Condition Pairs: CDH1 ⇔ 0100488 (OMIM:137215)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Mortality from gastric cancer / Endoscopic surveillance to detect gastric cancer or precursors and guide gastric cancer treatment and/or gastrectomy	2	0C	1B	2	5CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Approximately 1-3% of diffuse gastric cancers are attributable to hereditary diffuse gastric cancer (HDGC). The population prevalence of HDGC is rare, estimated at <0.1 per 100,000 in the general population. [1, 2]

Clinical Features

HDGC associated with pathogenic variants in CDH1 is characterized by the development of diffuse (signet ring cell) gastric cancer. Early stage HDGC is characterized by the presence of multiple microscopic foci of diffuse gastric cancer, which initially spreads within the mucosa only and at a later stage invades the gastric wall. Symptoms associated with this early stage are nonspecific and by the time specific symptoms appear, affected individuals are typically in an advanced stage of the disease. Symptoms in the late stage may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. Late in the course of gastric cancer, a palpable mass may be present. Tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures. Female carriers of CDH1 mutations have an additional risk of developing lobular breast cancer. There is some evidence that these patients are also at increased risk of signet ring cell colon cancer. [1, 2, 3, 4, 5, 6, 7, 8, 9]

Natural History

Pathogenic CDH1 variants are found in all ethnicities, though large clusters have been identified in certain geospatial locales such as New Zealand (Maori population) and Canada. It is estimated that early stage cancer in HDGC typically develops in most carriers before 20-30 years of age, while advanced disease is generally prolonged with an increasing risk with age: 1% at age 20, 4% for men and women at age 30 and 21% in men and 46% in women at age 50. The average age of diagnosis of gastric cancer for HDGC is around 37-40 years, with a reported range of 14 to 85 years. The earliest reported death from HDGC-associated gastric cancer is 14. The average age of onset for lobular breast cancer is 53 years, with the incidence rising after age 40.
When sporadic (i.e., non-hereditary) diffuse gastric cancer (DGC) is detected early prior to invasion into the stomach wall, the 5-year survival rate can be greater than 90%. However, the 5-year survival rate drops to lower than 30% when the diagnosis is made at a late stage. Survival of individuals with CDH1 pathogenic variants is believed to be the same as in individuals with sporadic DGC. [1, 2, 3, 4, 5, 6, 7, 8, 10]

2. How effective are interventions for preventing harm?

Patient Management

It is of great importance to centralize the intensive care for HDGC families in specialized centers with multidisciplinary medical teams. The team should include a surgeon specializing in upper gastrointestinal (UGI) cancer surgery, a gastroenterologist, a clinical geneticist, a nutritionist/dietician, pathologist and a counselor or psychiatrist. (Tier 2) [7, 8]

Carriers of pathogenic CDH1 mutations are currently advised to undergo risk-reducing total gastrectomy due to their high lifetime risk of developing gastric cancer and the limited efficacy of surveillance modalities. Most guidelines recommend gastrectomy after age 18 and before age 30-40, though the timing may be guided by patient preferences and age at onset within the family. Some guidelines permit consideration of gastrectomy prior to age 18. (Tier 2) [1, 3, 5, 6, 7, 8]

The results of a recent systematic review indicated that of 220 previously reported patients who were positive for CDH1 pathogenic variants, 77% underwent a prophylactic gastrectomy while 23% declined. However, there was a high rate of gastric cancer detection at the time of prophylactic gastrectomy. Of the 169 patients who underwent prophylactic gastrectomy, 63% were asymptomatic and had negative preoperative endoscopic and radiologic imaging findings, while 12% tested positive for cancer in their preoperative screening. The final pathology results displayed positive histology in 87% of all cases. This systematic review did not report recurrence rates in individuals undergoing gastrectomy, or long-term outcomes of individuals declining gastrectomy. (Tier 1) [10]

There is at least one report of gastric cancer following gastrectomy in residual gastric mucosal tissue. (Tier 2) [1]

Risk-reducing mastectomy could be considered, but is not uniformly recommended, as it may be a reasonable option for some women who carry CDH1 mutations. Literature about prophylactic mastectomy in HDGC is scarce, and it is reasonable to consider prophylactic mastectomy on a case-by-case basis, taking into account the family pedigree. (Tier 2) [6, 9, 11, 12]

No direct evidence on the effectiveness of risk-reducing surgery in patients with CDH1 pathogenic variants was identified. Findings from 2 observational studies and 3 decision analysis studies suggest that risk-reducing subcutaneous/total mastectomy has a beneficial effect in terms of significantly reducing the risk of breast cancer in women with a family history of breast cancer, or with BRCA1/2 pathogenic variants. One of the observational studies found that risk-reducing mastectomy was also associated with a reduction in breast cancer mortality in women with a family history of breast cancer. Among the two observational studies, one found no cases of invasive breast cancer among women who had undergone bilateral total mastectomy over 3 years (compared to 8/63 patients undergoing surveillance only). The second study showed a reduction in the risk of breast cancer of 89.5% in moderate-risk women who had undergone mastectomy and a reduction of 90-94% among high-risk women. The risk reduction for death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women. (Tier 1) [11]

For individuals who have not undergone bilateral risk-reducing mastectomy, pharmacotherapeutic chemoprevention should be offered according to guidelines for high-risk women. (Tier 2) [6, 11]

No direct evidence on the effectiveness of pharmacotherapeutic chemoprevention in patients with CDH1 pathogenic variants was identified. Evidence cited in guidelines was based on patients defined as high-risk based on a family history of breast, ovarian or related (prostate/pancreatic cancer) or with a BRCA1/2 and/or TP53 pathogenic variant. In these populations, high quality evidence from two randomized trials suggests the incidence of breast cancer is lower in patients given tamoxifen than in those given a placebo (RR=0.65; 95% CI: 0.56-0.74). Longer term follow-up from one of these trials found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83; p<0.0001). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10; p=0.8). (Tier 1) [11]

Surveillance

Gastric cancer surveillance may be used before prophylactic gastrectomy and for patients who decline gastrectomy. It is recommended that at risk individuals undergo screening every 6–12 months beginning at age 16 to 20, depending on guideline, or 5–10 years before the earliest cancer diagnosis in the family. The surveillance protocol should include gastroscopy with high definition endoscope by an experienced multidisciplinary team, extensive mucosal inspection, multiple random biopsies (minimum 30) throughout the anatomical regions plus multiple biopsy of any mucosal abnormalities, and H. pylori testing and eradication. However, the efficacy of surveillance is uncertain, with failure to detect existing gastric cancer occurring in approximately 50% of patients, and should be used with caution. (Tier 2) [1, 3, 5, 6, 7, 8]

When sporadic (i.e., non-hereditary) diffuse gastric cancer (DGC) is detected early prior to invasion into the stomach wall, the 5-year survival rate can be greater than 90%. However, the 5-year survival rate drops to lower than 30% when the diagnosis is made at a late stage. Survival of individuals with CDH1 pathogenic variants is believed to be the same as in individuals with sporadic DGC. (Tier 3) [4]

Referral to a high risk breast clinic is recommended. Monthly breast self-examinations (beginning age 30), biannual clinical breast exams (starting age 20-30, depending on guideline), and annual breast imaging (starting at age 20-35, depending on guideline) are recommended. Breast imaging modalities vary by guideline, with most guidelines recommending MRI which may be combined with mammogram, due to the limited ability of mammography to detect the lobular breast carcinoma histology that is most common in CDH1 pathogenic variant carriers. There is currently insufficient data on the role and outcome of breast cancer screening in CDH1 pathogenic variant carriers, so recommendations are based on the high lifetime risk of breast cancer, particularly the lobular subtype, and the precedents established in other hereditary breast cancer syndromes (e.g. due to BRCA1/2 pathogenic variants). (Tier 2) [1, 3, 5, 6, 7, 9, 11, 12, 13]

No direct evidence on the effectiveness of breast cancer surveillance in patients with CDH1 pathogenic variants was identified. Evidence cited in guidelines was based on patients with a BRCA1/2 pathogenic variant or a family history of breast cancer. One guideline summarizes that low quality evidence suggests a disease-specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study found that death from breast cancer was less likely in women aged less than 50 years with family history whose breast cancer was diagnosed during mammographic surveillance compared to a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR=0.24; 95% CI: 0.09-0.66]). Second, a study modelled death from breast cancer in a mammographic surveillance study in women with a family history aged less than 50 years and a control group from another study, using prognostic features at diagnosis and underlying risk. Projected ten-year death from breast cancer was lower in the mammographic surveillance group than in the control group of unscreened women of similar age (RR=0.80; 95% CI: 0.66-0.96). Third, a retrospective study found that death from any cause was less likely in BRCA1/2 pathogenic variant carriers aged between 28 and 77 years diagnosed with breast cancer during an intensive mammographic surveillance program than in those diagnosed outside this program (HR=0.44; 95% CI: 0.25-0.77]). (Tier 1) [11]

An individual patient data meta-analysis of high-quality observational studies shows that the use of breast MRI as an adjunct to mammography significantly increases the sensitivity of screening in women with BRCA1/2 pathogenic variants as compared with mammography alone (93.4 vs 39.6 %; p<0.001), though specificity is reduced. (Tier 2) [13]

Circumstances to Avoid

Surveillance should be accompanied by advice to minimize known gastric cancer risk factors such as smoking and the intake of salted, cured, and preserved foods, and to increase fresh fruit and vegetable intake. (Tier 2) [5]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

The population prevalence of CDH1 germline pathogenic variants was not available.

Pathogenic CDH1 variants are found in approximately 25-50% of all families fulfilling the HDGC clinical criteria, though this detection rate has reduced slightly over time, possibly due to initial selection bias and to broadening of the guideline criteria. (Tier 3) [2, 4, 5, 6, 7, 8]

Penetrance

Penetrance estimates have indicated a high penetrance for CDH1 pathogenic variants, with risk of gastric cancer by age 80 of 67-80% for men and 56-83% for women and risk of lobular breast cancer by age 80 of 23-68% for women. The combined risk for gastric and breast cancer in women was estimated as 90% by age 80. The risk of gastric cancer prior to age 20 is estimated to be <1%. (Tier 3) [1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 14]

Relative Risk

Information on relative risk was not available.

Expressivity

The age of onset is variable between and within families. (Tier 3) [4, 7]

4. What is the Nature of the Intervention?

Nature of Intervention

The major intervention is prophylactic gastrectomy, which has a low but existent perioperative mortality in a high volume cancer center (~1% for young healthy patients), and which has post-surgical, lifelong morbidity. Total gastrectomy can have a psychological, physiological, and metabolic impact on the patient. Eating habits must be altered, requiring support from a dietician; dumping syndrome can result in pain, nausea, fatigue, and diarrhea. Other complications may include lactose intolerance, fat malabsorption and steatorrhea, bacterial overgrowth, and post-prandial fullness. Lifelong vitamin B12 supplementation and close monitoring for anemia, hypocalcemia, osteoporosis, and trace element deficiencies are required. [2, 4, 5, 6, 7]

Endoscopic surveillance comes with a bleeding risk given the number of biopsies taken. [6]

Some female CDH1 pathogenic variant carriers who are at high risk of lobular breast cancer may elect risk-reducing mastectomy, which may have impacts on self-image, self-esteem, physical appearance, and feminine identity, though studies suggest favorable psychological outcome. [6, 12]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

By the time specific symptoms of gastric cancer typically appear, affected individuals tend to be in an advanced stage of disease. In addition, the characteristic microscopic disease foci are often not readily detectable by routine upper endoscopy screening and random biopsies. Several studies have detected cancer foci in the gastrectomy specimens of CDH1 pathogenic variant carriers with negative preoperative biopsy results. (Tier 3) [2, 4, 14]

Because of the relative low incidence of gastric cancer, gastric surveillance is not routinely part of medical care in Western countries. (Tier 4) [7]

Date of Search: 06.04.2019

Reference List

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2. Oliveira C, Seruca R, Hoogerbrugge N, Ligtenberg M, Carneiro F. Clinical utility gene card for: Hereditary diffuse gastric cancer (HDGC). Eur J Hum Genet. (2013) 21(8).

3. Vangala DB, Cauchin E, Balmana J, Wyrwicz L, van Cutsem E, Guller U, Castells A, Carneiro F, Hammel P, Ducreux M, van Laethem JL, Matysiak-Budnik T, Schmiegel W. Screening and surveillance in hereditary gastrointestinal cancers: Recommendations from the European Society of Digestive Oncology (ESDO) expert discussion at the 20th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona, June 2018. Eur J Cancer. (2018) 104:91-103.

4. P Kaurah, DG Huntsman. Hereditary Diffuse Gastric Cancer. 2002 Nov 04 [Updated 2014 Jul 31]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1139

5. 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) 4(3):262-75.

6. van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, Caldas C, Schreiber KE, Hardwick RH, Ausems MG, Bardram L, Benusiglio PR, Bisseling TM, Blair V, Bleiker E, Boussioutas A, Cats A, Coit D, DeGregorio L, Figueiredo J, Ford JM, Heijkoop E, Hermens R, Humar B, Kaurah P, Keller G, Lai J, Ligtenberg MJ, O'Donovan M, Oliveira C, Pinheiro H, Ragunath K, Rasenberg E, Richardson S, Roviello F, Schackert H, Seruca R, Taylor A, Ter Huurne A, Tischkowitz M, Joe ST, van Dijck B, van Grieken NC, van Hillegersberg R, van Sandick JW, Vehof R, van Krieken JH, Fitzgerald RC. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. (2015) 52(6):361-74.

7. Kluijt I, Sijmons RH, Hoogerbrugge N, Plukker JT, de Jong D, van Krieken JH, van Hillegersberg R, Ligtenberg M, Bleiker E, Cats A. Familial gastric cancer: guidelines for diagnosis, treatment and periodic surveillance. Fam Cancer. (2012) 11(3):363-9.

8. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Gastric Cancer NCCN Evidence Blocks V2.2019. (2019) Accessed: 2019-06-04. Website: https://www.nccn.org/

9. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Genetic/Familial high-risk assessment: breast and ovarian V3.2019. (2019) Accessed: 2019-06-04. Website: http://www.nccn.org

10. Seevaratnam R, Coburn N, Cardoso R, Dixon M, Bocicariu A, Helyer L. A systematic review of the indications for genetic testing and prophylactic gastrectomy among patients with hereditary diffuse gastric cancer. Gastric Cancer. (2012) 15 Suppl 1:S153-63.

11. National Institute for Health and Care Excellence (NICE): National Collaborating Centre for Cancer (UK). Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People with a Family History of Breast Cancer.. (2013) Accessed: 2019-06-04. Website: https://www.ncbi.nlm.nih.gov/books/NBK247567/

12. Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F, Senkus E. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol. (2016) 27(suppl 5):v103-v110.

13. Llort G, Chirivella I, Morales R, Serrano R, Sanchez AB, Teule A, Lastra E, Brunet J, Balmana J, Grana B. SEOM clinical guidelines in Hereditary Breast and ovarian cancer. Clin Transl Oncol. (2015) 17(12):956-61.

14. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. GASTRIC CANCER, HEREDITARY DIFFUSE; HDGC. MIM: 137215: 2016 Aug 12. World Wide Web URL: http://omim.org.