Infertility and Risk of Breast Cancer in Men

A National Case-Control Study in England and Wales

Anthony J. Swerdlow; Cydney Bruce; Rosie Cooke; Penny Coulson; Michael E. Jones

Breast Cancer Res. 2022;24(29)

Abstract and Introduction

Abstract

Purpose: Breast cancer is uncommon in men and its aetiology is largely unknown, reflecting the limited size of studies thus far conducted. In general, number of children fathered has been found a risk factor inconsistently, and infertility not. We therefore investigated in a case–control study, the relation of risk of breast cancer in men to infertility and number of children.

Patients and Methods: We conducted a national case–control study in England and Wales, interviewing 1998 cases incident 2005–17 and 1597 male controls, which included questions on infertility and offspring.

Results: Risk of breast cancer was statistically significantly associated with male-origin infertility (OR = 2.03 (95% confidence interval (CI) 1.18–3.49)) but not if a couple's infertility had been diagnosed as of origin from the female partner (OR = 0.86 (0.51–1.45)). Risk was statistically significantly raised for men who had not fathered any children (OR = 1.50 (95% CI 1.21–1.86)) compared with men who were fathers. These associations were statistically significantly present for invasive tumours but not statistically significant for in situ tumours.

Conclusion: Our data give strong evidence that risk of breast cancer is increased for men who are infertile. The reason is not clear and needs investigation.

Introduction

Breast cancer is comparatively rare in men, and its aetiology is largely unknown. There are several commonalities with the disease in women, including a genetic component with several specific genes and SNPs known^[1] and a relation to anthropometric factors.^[2] There is a very high risk in men with Klinefelter syndrome,^[3] and this, along with the relation to anthropometrics, suggests that sex hormone-related factors might be involved, as they are in women, and a raised risk of breast cancer has been found in the only cohort analysis able to examine prior oestradiol levels in men who subsequently developed breast cancer.^[4] In women, reproductive-related factors are important in breast cancer aetiology,^[5] notably a reduced risk in parous women, and although that relates to the hormonal consequences of parity, which could not plausibly apply in men, it nevertheless seems worth investigating whether male fertility relates to male breast cancer risk. Klinefelter syndrome is associated with infertility,^[6] and there is some, but not definitive, evidence that testicular abnormalities may also be associated with male breast cancer risk.^[2] Infertility is generally defined as the inability to conceive after at least 12 months of regular unprotected sexual intercourse and can be of male origin or female or contributions from both.^[7]

Investigation of the relation of male infertility and reproductive history to breast cancer risk has been hampered, however, by the rarity of the tumour. Few studies have investigated infertility^[8–10] or reproductive history,^[2,11–15] the largest based on 227 cases of whom 7 reported male infertility.^[8] A pooled analysis has been published,^[2] but is difficult to interpret because the small studies aggregated had very varied case and control selection criteria, and varied also in definitions of infertility. No significant relation to infertility was found, but there was a significant relation to whether the subject had any children. We have conducted a case–control study in England and Wales covering almost 2000 cases nationally incident over a 12.7 year period and present here the results relating to fertility and children.

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Breast Cancer Res. 2022;24(29) © 2022 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Descriptive characteristics of male breast cancer cases and controls participating in the study
Characteristic	Cases		Generations study husband controls		Non-blood relative controls		All controls
Characteristic	No.	%	No.	%	No.	%	No.	%
Index age (years)^a
< 40	47	(2.4)	8	(0.8)	76	(12.4)	84	(5.3)
40–9	159	(8.0)	13	(1.3)	135	(22.1)	148	(9.3)
50–9	385	(19.2)	118	(12.0)	165	(26.9)	283	(17.7)
60–9	729	(36.5)	564	(57.3)	162	(26.4)	726	(45.5)
70–9	678	(33.9)	281	(28.6)	75	(12.2)	356	(22.3)
Socio-economic group (ACORN)^b
1 (highest)	710	(35.5)	594	(60.4)	271	(44.2)	865	(54.2)
2	120	(6.0)	35	(3.5)	25	(4.1)	60	(3.8)
3	633	(32.2)	279	(28.4)	204	(33.3)	483	(30.2)
4	318	(15.9)	57	(5.8)	77	(12.5)	134	(8.4)
5 (lowest)	183	(9.2)	12	(1.2)	32	(5.2)	44	(2.7)
Uncategorised^c	24	(1.2)	7	(0.7)	4	(0.7)	11	(0.7)
Region of residence
North	375	(18.8)	172	(17.5)	91	(14.5)	263	(16.5)
North-West	368	(18.4)	193	(19.6)	98	(15.6)	291	(18.2)
Mids, East and Wales	379	(18.9)	154	(15.7)	131	(20.9)	285	(17.8)
London & SE	465	(23.3)	270	(27.4)	159	(25.3)	429	(26.9)
South West	411	(20.6)	195	(19.8)	149	(23.7)	344	(21.6)
Year of interview
2007–9	447	(22.4)	214	(21.7)	229	(37.4)	443	(27.7)
2010–14	807	(40.4)	533	(54.2)	245	(40.0)	778	(48.7)
2015–20	744	(37.2)	237	(24.1)	139	(22.7)	376	(23.6)
Marital status
Married or cohabiting	1600	(80.1)	984	(100.0)	556	(90.7)	1540	(96.4)
Not married	398	(19.9)	0	(0.0)	57	(9.3)	57	(3.6)
Year of diagnosis
2005–9	682	(34.1)
2010–14	851	(42.6)
2015–17	465	(23.3)
Breast cancer
Invasive	1838	(92.0)
In situ	160	(8.0)
ER
+ ve	1844	(92.3)
− ve	28	(1.4)
Not known	126	(6.3)
Total	1998	(100)	984	(100)	613	(100)	1597	(100)

ER, Oestrogen receptor
^aAge at diagnosis of cases; equivalent age for controls (see Methods)
^bAcorn score based on postcode of residence [20]
^cGeographic areas not covered by Acorn (Isle of Man, Channel Islands), and residence in an institution or other non-household location

Table 2. Risk of breast cancer in men in relation to infertility
Infertility	Cases No. %		Controls No. %		Odds ratio^a (95% CI) All subjects	P	Odds ratio^a (95% CI) excluding men with potentially confounding conditions^b	P
No	1810	90.6	1503	94.1	1.00		1.00
Yes	112	5.6	80	5.0	1.29 (0.94–1.77)	0.11	1.11 (0.78–1.58)	0.55
Source: self	50	2.5	22	1.4	2.03 (1.18–3.49)	0.01	1.59 (0.82–3.10)	0.17
Source: partner	31	1.6	34	2.1	0.86 (0.51–1.45)	0.58	0.92 (0.54–1.56)	0.75
Source: not known or other	31	1.6	24	1.5	1.26 (0.71, 2.24)	0.44	1.05 (0.56–1.98)	0.87
Not known if infertile	76	3.8	14	0.9	1.53 (0.80–2.93)	0.20	1.40 (0.73–2.70)	0.31
Total	1998	100.0	1597	100.0

CI, confidence interval
^aAdjusted for age, socio-economic status (Acorn score [20]), year of interview, marital status and geographical region of residence
^bExcluding 11 men with Klinefelter syndrome, 9 with potentially confounding prior cancers, 29 who were severely obese at age 20 (2) or at age 40 (27), and 169 with testicular diseases

Table 3. Risk of breast cancer in men in relation to number of biological children
	Cases No. %		ControlsNo. %		Odds ratio^a (95% CI) All subjects	P	Odds ratio^a (95% CI) excluding potentially confounding conditions^b	P
Fatherhood (i.e. any children)
No	383	19.2	174	10.9	1.00^c		1.00
Yes	1615	80.8	1423	89.1	0.67 (0.54–0.82)	< 0.001	0.70 (0.56–0.88)	0.003
No. of children
0	383	19.2	174	10.9	1.00		1.00
1	296	14.8	172	10.8	0.94 (0.71–1.25)	0.69	0.97 (0.73–1.31)	0.94
2	789	39.5	798	50.0	0.60 (0.48–0.75)	< 0.001	0.64 (0.50–0.81)	< 0.001
≥ 3	530	26.5	453	28.4	0.66 (0.52–0.84)	< 0.001	0.69 (0.54–0.89)	0.006
Linear trend per child, including 0					0.85 (0.79–0.92)	< 0.001	0.86 (0.80–0.94)	< 0.001
Linear trend per child, excluding 0					0.89 (0.79–1.00)	0.04	0.89 (0.79–1.00)	0.053
Total	1998	100.0	1597	100.0

CI, confidence interval
^aAdjusted for age, socio-economic status (Acorn score [20]), year of interview, marital status and geographical region of residence
^bExcluding 11 men with Klinefelter syndrome, 9 with potentially confounding prior cancers, 29 who were severely obese at age 20 (n = 2) or at age 40 (n = 27), and 169 with testicular diseases
^ci.e. odds ratio raised (1.50 (1.21–1.86); p < 0.001) for childless men, if fathers are taken as the baseline

Table 4. Risk of breast cancer in men in relation to age at birth of first biological child
Age at birth of first child (years)	Cases No. %		Controls No. %		Odds ratio^a (95% CI) All subjects	P	Odds ratio^a (95% CI) excluding potentially confounding conditions^b	P
No children	383	19.2	174	10.9	1.00		1.00
< 20	65	3.3	30	1.9	1.14 (0.70–1.88)	0.60	1.33 (0.79–2.24)	0.28
20–4	426	21.3	300	18.8	0.79 (0.61–1.01)	0.06	0.82 (0.63–1.07)	0.15
25–9	588	29.4	614	38.4	0.57 (0.45–0.72)	< 0.001	0.60 (0.47–0.77)	< 0.001
30–4	317	15.9	344	21.5	0.56 (0.43–0.72)	< 0.001	0.59 (0.45–0.78)	< 0.001
≥ 35	169	8.5	117	7.3	0.84 (0.61–1.16)	0.30	0.88 (0.63–1.23)	0.47
Age not known	50	2.5	18	1.1	1.48 (0.80–2.71)	0.21	1.71 (0.88–3.30)	0.11
Linear trend per 5 years of age^c					0.97 (0.91–1.04)	0.38	0.96 (0.89–1.03)	0.27
Total	1998	100.0	1597	100.0

Table 5. Risk of invasive and in situ breast cancer in men in relation to infertility and number of children
	Invasive							In situ
	Cases No. %		Controls No. %		Odds ratio^a	(95% CI)	P	Cases No. %	Controls No. %	Odds ratio^a	(95% CI)	P
Infertility
No	1664	90.5	1503	94.1	1.00			146	1503	1.00
Yes	107	5.8	80	5.0	1.34	(0.97–1.85)	0.07	5	80	0.70	(0.28–1.79)	0.46
Not known	67	3.6	14	0.9	1.55	(0.79–3.02)	0.20	9	14	2.31	(0.88–6.10)	0.09
Source
Self	47	2.6	22	1.4	1.96	(1.13–3.41)	0.02	3	22	1.72	(0.50–5.94)	0.39
Partner	30	1.6	34	2.1	0.93	(0.55–1.58)	0.81	1	34	0.28	(0.04–2.09)	0.21
Not known	30	1.6	24	1.5	1.35	(0.75–2.44)	0.31	1	24	0.53	(0.07–3.98)	0.53
No. of children
0	353	19.2	174	10.9	1.00			30	174	1.00
≥ 1	1485	80.8	1423	89.1	0.65	(0.52, 0.81)	< 0.001	130	1423	0.87	(0.54, 1.41)	0.58
1	267	14.5	172	10.8	0.93	(0.69–1.24)	0.60	29	172	1.38	(0.76–2.52)	0.29
2	733	39.9	798	50.0	0.60	(0.48–0.76)	< 0.001	56	798	0.66	(0.39–1.12)	0.12
≥ 3	485	26.4	453	28.4	0.63	(0.49–0.81)	< 0.001	45	453	0.99	(0.57–1.71)	0.97
Linear trend per child, including 0					0.84	(0.78–0.91)	< 0.001			0.93	(0.78–1.12)	0.44
Linear trend per child, excluding 0					0.88	(0.78–0.99)	0.04			0.95	(0.71–1.26)	0.71
Total	1838	100.0	1597	100.0				160	1597

CI, confidence interval
^aAdjusted for age, socio-economic status (Acorn score [20]), year of interview, marital status and geographical region of residence