Systematic Review With Meta-analysis

The Effects of Family History on the Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma

Yonne Peters; Evi van Grinsven; Peter D. Siersema

Aliment Pharmacol Ther. 2021;54(7):868-879.

Abstract and Introduction

Abstract

Background: Current guidelines recommend different screening approaches for individuals with a family history of Barrett's oesophagus (BO) or oesophageal adenocarcinoma (OAC), varying from no screening to screening all individuals with a positive family history.

Aims: To determine evidence-based risk estimates for individuals with a family history of BO or OAC

Methods: We systematically searched Pubmed, Embase and Cochrane Library until October 2020 to identify all studies that reported on the association between family history and the risk of BO and OAC. Pooled summary estimates of adjusted relative risks and prevalence of familial BO/OAC with 95% confidence intervals (CIs) were calculated using a random effects model.

Results: Fourteen studies comprising 16 189 BO/OAC patients were analysed. Familial clustering was seen in 8.84% (95% CI: 5.54–13.82) and 4.37% (95% CI: 2.15–8.69) of patients with BO and OAC, respectively (nine studies). Screening first-degree relatives of BO patients had a diagnostic yield between 12% and 44% for BO (four studies). However, the yield for high-grade dysplasia and OAC was low (<2%). Individuals with a positive family history had a higher risk of having BO (aRR 3.26; 95% CI 1.43–7.40; I ² = 46%; three studies) and OAC (aRR 2.19; 95% CI 1.14–4.21; I ²= 48%; five studies) compared to individuals without a family history.

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline characteristics of the included studies
Author	Year	Country	Enrolment date	Study design	Index population	Age range (y)	Control group	Cases (n)	Controls (n)	FH assessment	Type of relative	Diagnoses in relatives	FH confirmed
Ash³²	2011	United States	NS	R	BO ± dysplasia, OAC	NS	None	603	—	Medical reports Interview	FDR	BO, OC	No
Chak³³	2002	United States	1999–2000	CC	BO ≥3 cm, OAC, OGJAC	≥18	Hospital-based GERD	58	106	Survey	FDR/SDR	BO ≥3 cm, OAC, OGJAC	Most
Chak³⁴	2004	United States	NS; 3 y	P	BO ≥3 cm, OAC	NS	None	62 FDR	—	Endoscopy	FDR	BO, OAC	Yes
Chak³⁵	2006	United States	NS; 1–4 y	CS	BO ≥3 cm, OAC	≥18	None	392	—	Survey	FDR/SDR	BO ≥3 cm, OAC	Yes
Dhillon³⁶	2001	United States	1993–1995	CC	OAC	30–79	Population-based	293	695	Interview	FDR	OC	No
Jiang³⁷	2014	United States	1992–1997	CC	OAC	30–74	Population-based	147	1297	Interview	FDR	OC	No
Juhasz³⁸	2011	United States	NS	P	HGD, OAC	≥19	None	47 FDR	—	Endoscopy	FDR	BO	Yes
Kharazmi³⁹	2018	Sweden	1958–2015	R	OAC	NS	Cancer database	13.325^a	NS	Registry	FDR	OAC	Yes
Lagergren⁴⁰	2000	Sweden	1995–1997	CC	OAC	<80	Population based	189	816	Interview	FDR	OC	No
Mussetto⁴¹	2013	Italy	2009	P	BO	≥18	None	18 FDR	—	Endoscopy	FDR	BO	Yes
Romero⁴²	2002	United States	1996–1999	P	BO ± OAC	≥18	Hospital-based GERD	100 FDR	100	Endoscopy	FDR	BO ≥3 cm	Yes
Rubenstein⁴³	2020	United States	2008–2011	P	CRC screenees (BO)	50–80	Screening based	70	751	Survey	Any FH	OC	No
Tofani⁴⁴	2019	United States	2006–2016	R	Dysplastic BO	NS	None	282	—	Medical reports	FDR	OAC	No
Verbeek⁴⁵	2014	The Netherlands	2000–2011	CS	BO ≥2 cm, OAC	All	None	603	—	Survey	FDR/SDR	BO or OAC	Yes

Abbreviations: BO, Barrett's oesophagus; CC, case-control study; CS, cross-sectional study; OAC, oesophageal adenocarcinoma; OC, oesophageal cancer; OGJAC, oesophagogastric junctional adenocarcinoma; FDR, first-degree relatives; FH, family history; GERD, gastro-oesophageal reflux disease; NS, not stated; P, prospective cohort study; R, retrospective cohort study; SDR, second-degree relatives; ±, with or without.
^aOesophageal cancer patients.

Table 2. Prevalence of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) in individuals with a first-degree relative with confirmed BO or OAC
Author	Screening population	Characteristics of first-degree relatives				FDRs screened	Diagnoses	BO length (cm)	Prevalence of BO/OAC in FDRs
Author	Screening population	Age (y)	Gender	Reflux	Obesity^a	FDRs screened	Diagnoses	BO length (cm)	Prevalence of BO/OAC in FDRs
Chak 2004³⁴	Only 1 affected FDR	Mean: 44.6	Male: 43%	77%	43%	35	BO: 2\|OAC: 0	LSBO: n = 0	5.7% (95% CI: 1.6–18.6)
Chak 2004³⁴	≥2 affected FDRs	Mean: 45.3	Male: 55%	78%	30%	27	BO: 10\|OAC: 1	LSBO: n = 5	40.7% (95% CI: 24.5–59.3)
Juhasz 2011³⁸	Asymptomatic FDRs	Mean: 44.4	Male: 61%	0%	Not reported	12	BO: 1\|OAC: 0	LSBO: n = 4	8.3% (95% CI: 1.5–35.4)
Juhasz 2011³⁸	Symptomatic FDRs			100%		35	BO: 12\|OAC: 0		34.3% (95% CI: 20.8–50.9)
Mussetto 2013⁴¹	FDRs with reflux	Mean: 52	Male: 44%	100%	Not reported	18	BO: 8\|OAC: 0	Mean: 1.3	44.4% (95% CI: 24.0–67.0)
Romero 2002⁴²	FDRs with reflux	36% >50 years	Male: 67%	100%	65%	100	BO: 12\|OAC: 1	LSBO: n = 8	12.0% (95% CI: 6.9–20.0)

Abbreviations: BO, Barrett's oesophagus; OAC, oesophageal adenocarcinoma; FDR, first-degree relative; LSBO, long-segment Barrett's oesophagus (BO segment >3 cm).
^aObesity was defined as a body mass index ≥27.8 kg/m² in males and ≥27.3 kg/m² in females.

Table 3. Subgroup analysis: risk of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) in individuals with a positive family history
Category	Studies (n)	RR (95% CI)	P value	I ² (%)	References
Barrett's oesophagus
All studies	3	3.26 (1.43–7.40)	0.005	46	33, 42, 43
Study design
Case-control	1	8.08 (2.53–25.78)	<0.001	NA	33
Cohort	2	2.26 (1.12–4.56)	0.02	0	42, 43
Study location
United States	3	3.26 (1.43–7.40)	0.005	46	33, 42, 43
Europe	0	NA	NA	NA
Verification of BO and OAC in relatives
Confirmed family history	2	3.76 (0.85–16.64)	0.08	70	33, 42
Verbal family history (no confirmation)	1	2.63 (1.07–6.47)	0.04	NA	43
Adjusted for age	2	2.26 (1.12–4.56)	0.02	0	42, 43
Adjusted for gender	1	1.77 (0.57–5.47)	0.32	NA	42
Adjusted for GERD	2	2.26 (1.12–4.56)	0.02	0	42, 43
Adjusted for obesity	2	2.26 (1.12–4.56)	0.02	0	42, 43
Oesophageal adenocarcinoma
All studies	5	2.19 (1.14–4.21)	0.02	48	33, 36, 37, 39, 40
Study design
Case-control	4	1.55 (0.80–3.00)	0.19	0	33, 36, 37, 40
Cohort	1	3.60 (2.52–5.14)	<0.001	NA	39
Study location
United States	3	1.69 (0.57–4.97)	0.34	29	33, 36, 37
Europe	2	2.57 (1.06–6.24)	0.04	64	39, 40
Verification of BO and OAC in relatives
Confirmed family history	2	3.64 (2.57–5.14)	<0.001	14	33, 39
Verbal family history (no confirmation)	3	1.17 (0.55–2.46)	0.69	0	35, 36, 39
Adjusted for age	3	1.92 (0.80–4.63)	0.15	71	36, 39, 40
Adjusted for gender	2	2.57 (1.06–6.24)	0.04	64	39, 40
Adjusted for GERD	1	1.40 (0.49–4.01)	0.53	NA	40
Adjusted for obesity	2	1.15 (0.52–2.56)	0.73	0	36, 40