Hormonal contraception and breast cancer,what more do we need to know?

Abstract

Most women use hormonal contraception for more than 30 years and for many, this may involve exposure in their older reproductive years when baseline breast cancer risk rises steeply. Overall, the risk of breast cancer diagnosis with exposure to hormonal contraception is very small and outweighed by its contraceptive benefits but despite this, there are still outstanding questions for all methods used in clinical practice due to paucity of available evidence, lack of which should not be taken to imply safety. This is exemplified by the following assumptions: the progestogen-only pill and long-acting reversible contraceptives are ‘breast-safe’ options in peri-menopausal women, use of the levonorgestrel intrauterine system for the management of endometrial pathology in breast cancer survivors is less likely to promote disease recurrence and the benefit all hormonal contraceptive methods confer in reducing unplanned pregnancy in women at high familial risk outweigh the risk of breast cancer diagnosis. There is no data on risk with the concurrent prescription of hormone replacement therapy in women exhibiting climacteric symptoms who are still menstruating. Advice of GPs and Community Sexual & Reproductive Health specialists will inevitably be sought about some or all these issues and in the absence of conclusive evidence from clinical studies, caution should be applied and women counselled appropriately.

Keywords

Breast cancer hormonal contraception

Introduction

There is a small increased risk of breast cancer diagnosis associated with hormonal contraceptives but for most women who are at population risk, the benefit in reducing un-intended pregnancy and the risk of diagnosis of other cancers (i.e. ovary, endometrium) is considered to prevail over this potential concern.¹ Overwhelmingly, evidence is restricted to the combined oral contraceptive (COC), which is the most commonly used method by women in England with a usage of 45%.² In older reproductive women, however, long-acting reversible contraceptives (LARC) are more likely to be prescribed.² One of the strongest risk factors for breast cancer is increasing age with most being diagnosed in the post-menopause.³ This age-related increase, however, begins with a steep rise in incidence in women from their early 30s that levels off in the early fifties. Subsequent age-related incidence fluctuations reflect the impact of the NHS Breast Screening Programme and factors associated with presentation and diagnosis in women over 70.³ In older reproductive women, whose baseline risk of breast cancer is rising, there is paucity of clinical evidence about the risk of breast cancer diagnosis with LARC and the progestogen-only pill (POP) and in those who are still menstruating and require hormone replacement therapy (HRT) for alleviation of climacteric symptoms, an absence of evidence about the concurrent use of any hormonal contraception, including the levonorgestrel intrauterine system (LNG-IUS) on breast cancer outcomes.² There is also no data about breast cancer risk with combined vaginal or transdermal preparations although prescription is minimal across all age-groups having been introduced into clinical practice relatively recently.² Finally, with all hormonal contraception methods, uncertainty remains about their impact on the risk of diagnosis in women at elevated personal risk due to a high-risk benign breast condition or family history and risk of recurrence in breast cancer survivors.

The United Kingdom Medical Eligibility Criteria (UK-MEC), which was up-dated in May 2016, contains advice about safe clinical practice to prevent unwanted pregnancy by hormonal contraceptive type in the context of a diverse range of medical conditions, including the diagnosis and management of benign and malignant breast disease.⁴ As it was beyond the remit of the UK-MEC to provide an exhaustive summary of clinical evidence, the aim of this review is to clarify the information provided, including areas of remaining clinical uncertainty relevant for patient counselling.

What can be concluded about breast cancer diagnosis and mortality with hormonal contraception in women at population risk?

Combined oral contraceptives

The National Institute of Health and Clinical Excellence (NICE) published evidence statements about COC in their 2013 familial breast cancer guidance (CG164), which were as follows;

Use of oral contraceptives slightly increases the risk of breast cancer.

This increase in risk appears to be confined to current and recent use (with an associated relative risk of 1.24 for current users within 5–10 years).

Sub-group analyses suggest risk may be restricted to premenopausal women, particularly those who commence COC at a younger age, or with a longer duration of exposure prior to their first full-term pregnancy but this all requires confirmation. The main findings from all meta-analyses and reanalyses reviewed by NICE and meta-analyses published subsequently to the NICE guidance are summarised in Table 1.^5–8 Overall risk estimates, irrespective of whether they are statistically significant, are small (i.e. < 2).

Table 1.

Combined oral contraceptives and risk of breast cancer diagnosis.^a

Combined oral contraceptives: Breast cancer risk ratio with 95% confidence intervals or +/− standard deviation^5–9
				Postmenopausal		Parity		First full-term pregnancy
		All ages	Premenopausal or aged < 45	Including age > 45	Age > 45 < 60 years	Nulliparous	All parous	Use before	Use after
Ever use		1.06 (0.98–1.14)	1.14 (1.05–1.24)	1.22 (0.55–2.71)		1.21 (0.99–1.47)	1.03 (0.95–1.13)	1.17 (1.06–1.30)
		1.06 (0.92–1.22)	1.16 (1.07–1.25)	1.03 (0.94–1.13)
		1.06 (1.02–1.12)	1.15 (1.08–1.23)
		1.08 (0.55–1.61)
		1.07 (+/− 0.017)
		1.08 (1.00–1.17)
		1.08 (0.99–1.17)
		1.08 (0.96–1.23)
Age at first use	<20 years		1.22 (+/−0.044)
	<25 years		1.25 (1.10–1.44)
Current use		1.24 (+/−0.038)	1.30 (1.13–1.49)			1.30 (+/− 0.098)		1.33 (+/−0.081)	1.21 (+/− 0.054)
Recency (time since last use)	1–4 years	1.16 (+/− 0.038)
		1.10 (0.93−1.29)
	5–9 years	1.07 (+/− 0.024)
		1.15 (0.94–1.40)
	≥10 years	1.07 (0.95–1.19)
		1.13 (0.97–1.31)
		1.01 (0.90–1.20)
	10-14 years	0.98 (+/− 0.022)
	≥15 years	1.03 (+/−0.025)
	>20 years	1.02 (0.88–1.18)
Duration	<1 year	0.95 (0.83–1.09)
		1.07 (+/− 0.023)
	<2 years	1.04 (0.94–1.16)
	<5 years	1.05 (+/−0.018)			1.06 (NS)			1.72 (1.36–2.19) in women < 46
		1.03 (0.92–1.15)
	5–10 years	1.09 (+/−0.022)
		1.01 (0.90–1.13)
	<8 years				1.07 (NS)
	>8 years	1.27 (1.12–1.44)
	>10 years	1.04 (0.93–1.17)
		1.14 (0.90–1.42)
	10-14 years	1.16 (+/−0.033)			1.07 (NS)^b
	≥15 years	1.08 (+/−0.044)

Statistically significant results are indicated in bold font.

< 12-years’ use.

Almost exclusively evidence is based on monophasic and multiphasic COC formulations no longer used in UK clinical practice.^10–13 As an example, the increased risk of diagnosis reported with moderate and high dosages of ethinyl oestradiol and mestranol refers to obsolete preparations.¹³ Risk estimates by progestogen class (i.e. estrane or gonone-derived) or first, second and third generation progestogens are inconsistent and there is no data about COC containing fourth generation progestogens in current use.^10–13 The diverse range of COC formulations now available means future observational evidence will likely be based on small numbers of breast cancer events, which may limit the reliability of reported outcomes.

The progestogen-only pill^9,10,14–16

There is no consistent evidence for an increased risk of breast cancer diagnosis with exposure but this is based on limited observational data (four observational studies and one re-analysis) without specification of formulations used (Table 2). This means there is uncertainty that results are directly applicable to oral progestogens in current UK use (i.e. desogestrel, norethisterone and levonorgestrel).

Table 2.

Progestogen-only contraception and risk of breast cancer diagnosis.

Progestogen-only pill: Breast cancer risk ratio with 95% confidence intervals or +/− standard deviation^9,10,15,16
		All ages	30–39 years	40–49 years	Postmenopausal
Ever use		1.10 (0.73–1.50)			0.97 (0.80–1.17)
Ever use		1.10 (0.80–1.70)
Current use		1.60 (1.00–2.40)	1.70 (0.80–3.70)	1.60 (0.90–2.60)
Recency	>5 years	1.17 (+/− 0.09)
	>10 years	0.99 (+/−0.13)
Injectable progestogen (DMPA): breast cancer risk ratio with 95% confidence intervals or +/− standard deviation ⁹ ^, ¹⁴ ^, ¹⁷ ^– ²²
		All ages
Ever use		1.10 (0.97–1.40)
		1.00 (0.80–1.30)
		1.21 (0.96–1.52)
		0.90 (0.70–1.20)
		1.23 (0.88–1.73)
		1.20 (0.90–1.60)
Current use		2.00 (1.50–2.80)
		1.65 (1.08–2.52)
		1.83 (1.31–2.55)
		1.60 (1.10–2.30)
		All ages	≤ 34 years	35-44 years	≥45 years
Recency	≤ 4 years	2.02 (1.35–3.01)	2.19 (1.23–3.89)	1.42 (0.72–2.82)	1.20 (0.27–5.29)
	<5 years	1.17 (+/0 0.13)
	>4-8 years	1.24 (0.81–1.90)	0.81 (0.36–1.84)	1.31 (0.72–2.39)	1.14 (0.44–2.92)
	>8-13 years	0.90 (0.60–1.36)	1.08 (0.46–2.55)	0.70 (0.37–1.33)	0.87 (0.43–1.77)
	>10 years	0.94 (+/0 0.13)
		All ages	<25 years	25–39 years	≥30 years
Duration of use	<2 years	1.1 (0.84–1.5)	1.50 (0.77–2.80)	0.78 (0.44–1.40)	1.30 (0.84–1.90)
	2-5 years	0.72 (0.42–1.20)	0.62 (0.13–2.90)	0.85 (0.33–2.20)	0.68 (0.34–1.40)
	≥6 years	1.20 (0.59–2.20)	4.20 (1.1–16.20)	0.77 (0.20–2.90)	0.87 (0.35–2.10)
		All ages
Duration among	<12 months	0.50 (0.10–1.60)
recent users	≥12 months	2.20 (1.20–4.20)
		–	25–39 years	30–34 years	≥35 years
Age at first use		–	1.40 (0.80–2.30)	0.80 (0.40–1.50)	2.00 (0.90–4.60)
Inter-uterine progestogen: breast cancer risk ratio with 95% confidence intervals or +/− standard deviation ¹⁶ ^, ²³ ^– ²⁷
		All ages	Premenopausal	Postmenopausal
Ever vs. never use		Post-marketing survey: no difference in age specific incidence rates	0.79 (0.54–1.17)	1.48 (1.10–1.99)
		1.53 (1.33–1.75)
		0.99 (0.88–1.12)

	≥1 LNG-IUS purchase	1.19 (1.13–1.25)
	≥2 LNG-IUS purchase	1.40 (1.24–1.57)
		All ages	30–39 years	40–49 years
Current use		0.85 (0.52–1.39)	0.72 (0.43–1.21)	1.02 (0.9–1.16)
			40–44 years	45–49 years	50–54 years
Age at first use and time since first purchase	1–5 years		1.09 (0.90–1.28)	1.08 (0.91–1.23)	1.31 (1.10–1.53)
	≥5 years		1.09 (0.90–1.3)	1.33 (1.07–1.63)	1.28 (1.14–1.42)
	≥10 years		1.40 (0.90–2.06)	1.39 (1.23–1.55)	1.37 (1.14–1.61)
Progestogen implant (1 study) ²¹
		All ages
Ever use		8.59 (1.92–38.4)
Time since first use	≤ 5 years	1.20 (0.07–19.50)
Time since first use	5–9 years	13.7 (1.74–108.06)

Note: Statistically significant results are indicated in bold font.

Long-acting reversible hormonal contraception^9,14,–27

As for the POP, there is a paucity of clinical evidence (Table 2). The only conclusions that can be made are:

Associations of breast cancer risk with ever or current use for all administration routes (implant, injectable, intrauterine) are inconsistent.

An increased risk with injectable progestogen may be restricted to recent or longer duration use in younger women.

There is no reliable evidence for the safety or otherwise of progestogen implants. Just one study has been published but the number of cancer events was so small and confidence intervals so wide, the veracity of the large, eightfold increased risk is very doubtful.²¹

The LNG-IUS may not be risk-free. An increased risk of diagnosis in women aged over 45 who had purchased the device at least twice, implying a duration effect, has been reported.^25–27

Hormonal contraceptives and breast cancer mortality

Observational evidence exploring associations between hormonal contraceptive use at breast cancer diagnosis and subsequent disease-specific mortality has evaluated COC only. While risk is increased with current or recent exposure, there is no evidence to support an association with more advanced disease at presentation or an increased risk of breast cancer mortality compared with those not exposed to COC at the time of diagnosis.^14,28 Limitations with all observational evidence that confound interpretation and could reduce a potential adverse impact include lack of information about breast cancer treatment in COC-users and non-users and the fact that the former tends to be of higher social class and more health more health conscious hence likelier to present early with breast symptoms.

Hormonal contraceptives and absolute risk of cancer diagnosis

The absolute risk of hormonal contraceptives will be determined by a woman’s individual baseline risk. For younger reproductive women, this is low and although it rises with increasing age, the associated excess risk with exposure to COC, POP and LARC is still small and comparable in degree with that conferred by other known modifiable risk factors for hormone sensitive breast cancer in premenopausal women (Table 3^{10,13,14,20,21,25,29–32}). For completion, Table 3 also includes modifiable factors associated with risk reduction. Combined oral contraceptives are also associated with a decreased risk of diagnosis of ovarian, endometrial and colorectal cancer.^1,33 Their use in the UK, in 2010, was attributed to account for 1600 fewer female cancer diagnoses overall.¹ Currently, there is insufficient data about the impact of the POP or LARC on the risk of diagnosis of cancers other than breast to know whether there is similar associated benefit or not.

Table 3.

Absolute excess risk of estrogen receptor positive breast cancer diagnosis in reproductive women at population risk associated with modifiable risk or protective factors.¹

		Excess cancers per 1000 women exposed by 5-year age group^a
	Risk ratio	25–29 years	30–34 years	35–39 years	40–44 years	45–49 years	50–54 years
Baseline risk per 1000 women²⁹		1	3	6	13	22	28
Modifiable reproductive and lifestyle factors
Current smoking	1.12	0.1	0.4	0.7	1.6	2.6	3.4
Former smoking	1.09	0.1	0.3	0.5	1.4	2.0	2.5
Smoking initiated before first full term pregnancy	1.21	0.2	0.6	1.3	2.7	4.6	5.9
Alcohol consumption (3–6 glasses per week)	1.15	0.2	0.5	0.9	2.0	3.3	4.2
Alcohol consumption (2 glasses per day)	1.51	0.5	1.5	3.1	6.6	11.2	14.3
Age at first live birth (>24 years)	1.15	0.2	0.5	0.0	2.0	3.3	4.2
Breast feeding (6-12 months vs. never)	0.90	−0.1	−0.3	−0.6	−1.3	−2.2	−2.8
Late age at menarche (≥15 vs. <11 yrs)	0.77	−0.2	−0.7	−1.4	−3.0	−5.1	−6.4
Parity (≥1 live birth vs. nulliparity)	0.75	−0.3	−0.8	−1.5	−3.3	−5.5	−7.0
Hormonal contraceptives – ever use
COC	1.07	0.1	0.2	0.4	0.9	1.5	2.0
POP	1.10	0.1	0.3	0.6	1.3	2.2	2.8
DMPA	1.17	0.2	0.5	1.0	2.2	3.7	4.8
LNG-IUS all ages	1.53	0.5	1.6	3.2	6.9	11.7	14.8
LNG-IUS premenopausal	0.97	0.0	−0.1	−0.2	−0.4	−0.7	−
LNG-IUS postmenopausal	1.48	−	−	−	−	−	13.4
Injectable^b	8.59	7.6	22.8	45.5	98.7	167	212.5
Hormonal contraceptives – current use
COC	1.24	0.2	0.7	1.4	3.1	5.3	6.7
POP	1.60	0.6	1.8	3.6	7.8	13.2	16.8
DMPA	2.00	1.0	3.0	6.0	13.0	22.0	28.0
LNG-IUS all ages	0.85	−0.2	−0.5	−0.9	−2.0	−3.3	−4.2
LNG-IUS premenopausal	0.72	−0.3	−0.7	−1.7	−3.6	−6.2	–
LNG-IUS postmenopausal	1.02	–	–	–	–	–	0.56
Injectable	No data	–	–	–	–	–	–

Statistically significant risk ratios are indicated in bold font.

Based on only 15 breast cancers diagnosed in women exposed to progestogen implant vs. 2 breast cancers in controls.

What should women be advised if they develop breast symptoms while using hormonal contraceptives?

National cancer waiting targets aim for all women over the age of 30 presenting with breast symptoms necessitating evaluation to be seen within two weeks of receipt of referral by their local breast unit, where diagnosis is confirmed by triple assessment (i.e. clinical breast examination, breast imaging with tissue biopsy as appropriate).^34,35 Benign and malignant breast conditions can present with similar symptoms such as a lump, pain, nipple discharge, contour and skin change so it can be difficult to make a diagnosis based on clinical examination alone, especially in women in their fourth and fifth decades, when presentation with benign symptoms is high and breast cancer incidence is increasing.³ Given the short national target times for referral and time to diagnosis, continuation of hormonal contraception is highly unlikely to have any significant, further impact on outcome, in the event of a subsequent breast cancer diagnosis, so there is no need for cessation if referral is indicated. Non-hormonal contraception can be discussed if a breast cancer is diagnosed. Even though short duration of exposure would unlikely have any adverse effect, it would not be prudent to commence hormonal contraception in a woman if she has symptoms warranting referral. The UK-MEC guidance has been revised to reflect this.⁴

Hormonal contraception in women at high risk

Benign breast conditions

These are categorised by histological biopsy findings and on this basis, subsequent estimated risk of being diagnosed with breast cancer. For most, the estimated risk ratio is less than two, which is not considered significant and women are advised as if they are at population risk. High-risk benign pathology refers to the non-precursor conditions of epithelial atypia and Lobular carcinoma in situ (LCIS), which are associated with a significant up to 5-fold and 10-fold increase in baseline risk, respectively.^36,37 Limited observational data, restricted to COC only and confounded by inconsistency in the classification of benign breast conditions, have not shown an additive impact on the risk of breast cancer diagnosis in women with any benign breast condition.^38,39 The UK-MEC does not recommend restriction of hormonal contraception in the presence of a benign breast condition but given the greater potential absolute excess risk conferred in women with atypia and LCIS, discussion in those confirmed to have a high-risk lesion should reflect this. Absolute risk estimates based on risk ratios from studies in women at population risk, are summarised in Table 4. Despite the higher associated absolute risk, most women exposed will not be diagnosed with breast cancer; however, for some women, this risk may be unacceptable and non-hormonal methods preferred.

Table 4.

Absolute excess risk of breast cancer diagnosis in premenopausal women at elevated risk exposed to hormonal contraceptives.

Age group in years	Risk group		Baseline risk	Excess risk per 1000 women exposed to hormonal contraception^a
				COC risk ratio		POP risk ratio		DMPA risk ratio		LING-IUS risk ratio		Implant risk ratio
				Ever 1.07	Current 1.24	Ever 1.10	Current 1.60	Ever 1.17	Current 2.00	Ever 1.53	Current 0.85	Ever 8.59^b	Current No data
25–29	Population²⁹		1	0.1	0.2	0.1	0.6	0.2	1.0	0.5	−0.2	7.9	–
	Family history^5,40	1 affected FDR^c	3	0.2	0.7	0.3	1.8	0.5	3.0	1.6	−0.5	22.8	–
		BRCA 1	50	3.5	12.0	5.0	30.0	8.5	50.0	26.5	−7.5	379.5	–
		BRCA 2	20	1.4	4.8	2.0	12.0	3.4	20.0	10.6	−3.0	151.8	–
	High risk benign breast condition^36,37	Atypia	5	0.4	1.2	0.5	3.0	0.9	5.0	2.7	−0.8	38.0	–
	High risk benign breast condition^36,37	LCIS	10	0.7	2.4	1.0	6.0	1.7	10	5.3	−1.5	75.9	–
30–34	Population²⁹		3	0.2	0.7	0.3	1.8	0.5	3.0	1.6	−0.5	22.8	–
	Family history^5,40	1 affected FDR^c	9	0.6	2.2	1.0	5.4	1.5	9.0	4.8	−1.4	68.3
		BRCA 1	50	3.5	12.0	5.0	30.0	8.5	50.0	26.5	−7.5	379.5
		BRCA 2	50	3.5	12.0	5.0	30.0	8.5	50.0	26.5	−7.5	379.5
	High risk benign breast condition^36,37	Atypia	5	0.4	1.2	0.5	3.0	0.9	5.0	2.7	−0.8	38.0	–
	High risk benign breast condition^36,37	LCIS	10	0.7	2.4	1.0	6.0	1.7	10	5.3	−1.5	75.9
35–39	Population²⁹		6	0.4	1.4	0.6	3.6	1.0	6.0	3.2	−0.9	45.5	–
	Family history^5,40	1 affected FDR^b	15	1.1	3.6	1.5	9.0	2.6	15.0	8.0	−2.3	113.9	–
		BRCA 1	100	7.0	24.0	10.0	60.0	17.0	100.0	53.0	−15.0	759.0	–
		BRCA 2	50	3.5	12.0	5.0	30.0	8.5	50.0	26.5	−7.5	379.5	–
	High risk benign breast condition^36,37	Atypia	5	0.4	1.2	0.5	3.0	0.9	5.0	2.7	−0.8	38.0	–
		LCIS	10	0.7	2.4	1.0	6.0	1.7	10	5.3	−1.5	75.9	–
40–44	Population²⁹		13	0.9	3.1	1.3	7.8	2.2	13.0	6.9	−1.95	98.7	–
	Family history^5,40	1 affect ed FDR^c	26	1.8	6.4	2.6	15.6	4.4	26.0	13.8	−4.0	197.3	–
		BRCA 1	100	7.0	24.0	10.0	60.0	17.0	100.0	53.0	−15.0	759.0	–
		BRCA 2	100	7.0	24.0	10.0	60.0	17.0	100.0	53.0	−15.0	759.0	–
	High risk benign breast condition^36,37	Atypia	5	0.4	1.2	0.5	3.0	0.9	5.0	2.7	−0.8	38.0	–
	High risk benign breast condition^36,37	LCIS	10	0.7	2.4	1.0	6.0	1.7	10	5.3	−1.5	75.9	–
45–49	Population²⁹		22	1.5	5.3	2.2	13.2	3.7	22.0	11.7	−3.3	167.0	–
	Family history^5,40	1 affected FDR^b	44	3.1	10.6	4.4	26.2	7.5	44.0	23.3	−6.7	334.0	–
		BRCA 1	150	10.5	36.0	15.0	90.0	25.5	150.0	79.5	−22.5	1138.5	–
		BRCA 2	100	7.0	24.0	10.0	60.0	17.0	100.0	53.0	−15.0	759.0	–
	High risk benign breast condition^36,37	Atypia	5	0.4	1.2	0.5	3.0	0.9	5.0	2.7	−0.8	38.0	–
	High risk benign breast condition^36,37	LCIS	10	0.7	2.4	1.0	6.0	1.7	10	5.3	−1.5	75.9	–

Statistically significant risk ratios and estimated excess absolute risks are indicated in bold font.

Based on only 15 breast cancers diagnosed in women exposed to progestogen implant vs. 2 breast cancers in controls.

Mother, sister or daughter.

Familial breast cancer

Risk is related to the strength of the family history and whether an individual has inherited a high-risk susceptibility gene, such as BRCA1 or BRCA2. In its 2013 familial breast cancer guidance (NG164), NICE concluded for COC “in women with a positive family history, the relative risk [of breast cancer] is consistent with findings in the general population”. There is no data for other hormonal methods.⁵ The following recommendations were made:

Up to the age of 35, women with a family history of breast cancer should be given general health advice on the use of COC as for women at population risk.

Over the age of 35, women should be informed risk of diagnosis with exposure to COC is increased as absolute risk increases with age.

Data from one case-controlled study, which showed an increased (but not additive) risk in BRCA1 but not BRCA2 mutation carriers under the age of 40 were used to inform the following recommendations in this group of women at very high baseline risk.⁵

Under the age of 40, discussion about COC should include the potential for an increased risk of breast cancer diagnosis as well as the potential for a decreased risk of subsequent ovarian cancer diagnosis.

While in some women with high familial risk, the potential for reducing the risk of diagnosis of ovarian cancer could exceed any associated increased risk of breast cancer diagnosis, COC is not indicated solely for ovarian cancer prevention.

COC should not be prescribed for the prevention of ovarian cancer to BRCA1 mutation carriers under the age of 40 who are considering prophylactic oophorectomy.

Two subsequent meta-analyses have reported inconsistent outcomes with COC exposure in BRCA1 and BRCA2 mutation carriers (all studies reviewed had a low number of cancer events).^41,42 An earlier age of breast cancer diagnosis in BRCA1 and BRCA2 mutation carriers using COC has been reported and hypothesised to result from delaying the age at first full-term pregnancy, or reduced parity but confirmation is required.⁴³

The UK-MEC advises “no restriction for use of any hormonal contraceptives for the purpose of contraception only in women with a family history” and recommends consideration of individual absolute risk when counselling women requesting contraceptive advice.⁴ For women at high familial risk, the theoretical or proven risks of COC are considered to “usually” outweigh the advantages (i.e. UK-MEC 3) but for the POP and LARC, including the LNG-IUS, the contraceptive benefits are considered to outweigh potential risks (i.e. UK-MEC 2) despite there being no direct clinical evidence regarding the latter. This should be made clear when counselling such women. In the absence of information about absolute risk in the UK-MEC guidance, estimates based on risk ratios from studies in women at population risk are summarised in Table 4.

Use of hormone replacement therapy in women taking hormonal contraceptives

There is no data about the concomitant use of hormonal contraceptives and HRT on the subsequent risk of breast cancer diagnosis in older reproductive women with climacteric symptoms who are still menstruating. Current recommendation is for continuation of contraception in such women until the age of 55, which does mean exposure to potentially higher dosages of exogenous sex hormones in an age group of women where individual risk for breast cancer is rising rapidly.^3,44 While there is no evidence supporting a dosage effect with HRT, there is for the estrogen content of COC (albeit with now obsolete preparations).¹² Women can be reassured; however, long-term use of COC followed by HRT does not appear to increase risk of breast cancer diagnosis over and above the separate contribution of each.⁴⁵

Hormonal contraception after a diagnosis of breast cancer

In younger women who have been treated for breast cancer and remain fertile, following treatment hormonal contraceptives are avoided to reduce the risk of promoting:³

Recurrence of previously diagnosed and treated hormone sensitive (i.e. estrogen receptor positive, ER+ve) disease

The development of a new contralateral ER+ve breast cancer.

A venous thrombotic event.

Barrier methods or the Cu-IUD are the preferred contraceptive choices with acknowledgement use of emergency contraception is extremely unlikely to cause any harm (UK-MEC 2).⁴ The UK-MEC categorisation of ‘current’ or ‘previous’ breast cancer is used to inform recommendation any hormonal contraception represents an unacceptable health risk for ‘current’ breast cancer (UK-MEC 4) but if other methods are unavailable or unacceptable, in women with ‘previous’ breast cancer, hormonal contraception may be initiated but only with agreement of a woman’s breast specialist team (UK-MEC 3).⁴ This UK-MEC categorisation does require explanation, however, as presently, breast cancer management defines women depending on whether they have completed ‘active’ treatment or not, where ‘active’ treatment includes some, or all the modalities of surgery, chemotherapy, herceptin and radiotherapy. Subsequently, women with ER+ve disease commence anti-estrogenic adjuvant systemic therapy (i.e. tamoxifen, aromatase inhibitors) for 5 to 10 years, whereas no further treatment is indicated for those with ER-ve cancer.⁴⁶ Completion of active therapy irrespective of ensuing endocrine therapy does not guarantee cure. Approximately one-third of women with early-stage disease will develop recurrence, most within five years from diagnosis, a small cohort, usually with ER+ve cancer can present with late-onset recurrence after 10 years or more.⁴⁷ UK-MEC categorisation by ‘active’ treatment would probably provide greater clarity.

Use of the LNG-IUS for the management of gynaecological conditions after breast cancer

In women treated for breast cancer, clinical evidence supporting efficacy and safety of the LNG-IUS for the prevention of endometrial cancer in tamoxifen-treated patients is lacking, although a reduction in the diagnosis of benign polyps and endometrial hyperplasia has been reported.⁴⁸ If considered, use of the LNG-IUS should be discussed with a woman’s breast specialist team (UK-MEC 3) but there is no data to support the UK-MEC statement risk disease progression may be less with the LNG-IUS compared with COC or higher-dose LARC.⁴ In breast cancer, patients prescribed the LNG-IUS for the management of menorrhagia, endometrial thickening or as a contraceptive, one small cohort study reported an increased risk of breast cancer recurrence with a longer duration of exposure but this group of women had worse prognostic disease, so conclusions cannot be made.⁴⁹ No randomised trials evaluating the LNG-IUS for endometrial protection in tamoxifen-treated patients have been sufficiently powered to detect an impact on breast cancer recurrence rates.⁴⁸ In clinical practice, the risk of tamoxifen-associated endometrial cancer is small and women are advised to report any abnormal or unexpected vaginal bleeding to be investigated and treated as necessary.⁵⁰ If endometrial pathology is confirmed in women with ER+ve disease treated with tamoxifen, in the absence of robust clinical evidence, progestogens (intrauterine or oral) are not usually recommended and instead surgical or alternative endocrine manipulation (e.g. switching to a gonadotropin-releasing hormone agonist with an aromatase inhibitor) is offered following multi-disciplinary breast and gynaecology discussion.

Summary

Overall, the absolute risk of breast cancer diagnosis associated with exposure to hormonal contraceptives is small, similar in degree to other known modifiable risk factors and falls within a few years of cessation. Despite this, outstanding questions about risk remain, which are relevant for clinical practice if women, especially in the older reproductive age-group are to be adequately informed. Absence of evidence does not equate to safety and there is insufficient evidence to support a contention that progestogen-only contraception, particularly the LNG-IUS is without risk.

Footnotes

Declaration of conflicting interests

The author(s) is a council member of the British Menopause Society and British Association of Day Surgery, and was chief investigator the UK randomised trial of HRT in symptomatic women with early breast cancer. In the last two years the author has presented three lectures sponsored by Mylan.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Hormonal contraception and breast cancer,what more do we need to know?

Abstract

Keywords

Introduction

What can be concluded about breast cancer diagnosis and mortality with hormonal contraception in women at population risk?

Combined oral contraceptives

The progestogen-only pill9,10,14–16

Long-acting reversible hormonal contraception9,14,–27

Hormonal contraceptives and breast cancer mortality

Hormonal contraceptives and absolute risk of cancer diagnosis

What should women be advised if they develop breast symptoms while using hormonal contraceptives?

Hormonal contraception in women at high risk

Benign breast conditions

Familial breast cancer

Use of hormone replacement therapy in women taking hormonal contraceptives

Hormonal contraception after a diagnosis of breast cancer

Use of the LNG-IUS for the management of gynaecological conditions after breast cancer

Summary

Footnotes

Declaration of conflicting interests

Funding

References

The progestogen-only pill^9,10,14–16

Long-acting reversible hormonal contraception^9,14,–27