Changes

March 2024 — reviewed. A literature search was conducted in January 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. More detail on risk factors has been added. No major changes to clinical recommendations have been made.

Update

Goals

To support primary healthcare professionals to:

• Make an assessment of a person's risk of developing breast cancer.
• Refer appropriately to secondary care or other specialist service.
• Provide appropriate information and advice to the person.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

NICE quality standards

What is it?

• Familial breast cancer is defined as breast cancer occurring in a woman with a family history of the disease [NICE, 2023]. A family history of breast cancer is a strong risk factor for developing the disease [Collaborative Group on Hormonal Factors in Breast Cancer, 2001; NICE, 2023].
  • The risk increases with the number of relatives affected and the age at diagnosis of the relative (the younger the age of diagnosis, the greater the risk) and is modified by other breast cancer risk factors.
  • A person's risk can be calculated based on their family history by the use of specialist computer programs in secondary care or in specialist genetic clinics.
  • Given the high prevalence of breast cancer, many people have a relative with the disease, but this may be due to chance rather than to genetic or shared lifestyle factors. Most women with a family history of breast cancer are not at a substantially increased risk of breast cancer.
• Hereditary breast and ovarian cancer syndrome (HBOC) is a genetic predisposition to developing breast and ovarian cancer, demonstrated by family history criteria and/or known variants in specific genes [Sessa, 2023]. In some families, this may also be associated with an increased susceptibility to other cancers, such as prostate cancer, malignant melanoma and pancreatic cancer [ACOG, 2019].
• When an increased risk is suggested by family history or genetic testing, measures may be offered to attempt to reduce the risk of developing breast cancer through education, enhanced screening, and preventative treatments [ACOG, 2019; NICE, 2023].

How common is it?

• Breast cancer is the most common cancer in the UK, accounting for 15% of all new cancer cases [Cancer Research UK, 2021].
  • It is the most common cancer in women in the UK, accounting for 30% of all new cancer cases in women.
  • 99% of breast cancer cases in the UK are in women. In men in the UK, breast cancer is uncommon and not among the 20 most common cancers.
  • Between 2016 to 2018, there were, on average, 55,920 cases diagnosed per year in the UK (55,545 in women and 375 in men).
  • In the UK, the lifetime risk of developing breast cancer is about 14% (1 in 7) for women born in 1961 [Cancer Research UK, 2021]. The lifetime risk is less than 0.1% for men [NICE, 2023]. 
• The incidence of breast cancer is strongly related to age, with the highest incidence rates being in older people. In the UK [Cancer Research UK, 2021]:
  • In 2016 - 2018, on average, each year, 24% of new cases were in people aged 75 years and older.
  • Incidence rates in the UK are highest in people aged 90 or more.
  • Age-specific incidence rates rise steadily from around age 25-29, then more steeply from age 35-39 in women and from age 60-64 in men.
• A positive family history increases the risk of breast cancer [Cancer Research UK, 2021; NICE, 2023]. 
  • People with a family history of breast, ovarian, or related cancer might have a higher lifetime risk than the general population. 
  • Breast cancer risk is around twice as high in women with one first-degree relative with breast cancer compared to women with no first-degree relative affected.
  • Risk increases with the number of relatives affected and the age of diagnosis of the relative (younger age confers greater risk) and is modified by other risk factors.
  • However, over 85% of women with a first-degree relative with breast cancer will never develop breast cancer themselves, and 87% of women with breast cancer have no first-degree relative affected.
• Inherited mutations in specific genes substantially increase the risk of breast cancer. The most common mutations are those of BRCA1 and BRCA2.
  • Women with a BRCA1 or BRCA2 have a 45 to 65% risk of developing breast cancer by the age of 70 [Cancer Research UK, 2021].
• Cancer Research UK estimate that 23% of cases of breast cancer in the UK are preventable [Cancer Research UK, 2021].
  • In 2015, 8% of cases were caused by overweight and obesity, 8% by alcohol and 1% by ionising radiation.
  • See the section on risk factors for other risk factors, some of which may be modifiable.
  • Risk may also be reduced in certain high-risk individuals by treatment with medication or surgery.

What are the risk factors?

• Cancers usually result from the interaction of multiple causes, including genetic makeup and lifestyle factors. Risk factors are those which increase the chance of developing cancer; some are modifiable, others are not. When a person has an increased risk from one risk factor, such as family history or genetic makeup, management includes advice about other modifiable risk factors in order to reduce overall risk where possible.
• Risk factors which may further increase the risk of breast cancer in a person who has a family history of breast cancer or gene variants include:
  • Drinking alcohol —The risk increases with increasing units of alcohol. Breast cancer risk is 9% higher in women who drink up to 2 units per day and as much as 60% higher in those who drink 6 or more units per day compared to those who drink none. Those who have the highest lifetime intake have a 28% higher risk than those who have the lowest intake. (This is not the case in individuals with BRCA mutations).
  • Low levels of physical activity — Breast cancer risk is 13% lower in women with the highest level of total physical activity compared to those with the lowest. Evidence suggests that just 2.7 hours of moderate physical activity per week is associated with a 20% lower breast cancer risk in women with a family history of breast cancer.
  • Overweight and obesity (post-menopausal women) — This is a significant factor in the development of other cancers and, in the UK, is the second biggest cause of cancer, after smoking. In post-menopausal women, breast cancer is 13% higher per 5 units of body mass index (BMI) increase and 50% higher in those with the highest waist-to-hip ratio as compared to the lowest. Risk changes do seem to depend on whether the tumour is oestrogen receptor positive or negative and the use of hormone replacement therapy (HRT). (In pre-menopausal women, the opposite is true, and increased BMI is associated with reduced risk of breast cancer, however this is a much smaller influence on absolute risk, moreover, in women with high familial risk, there seems to be a larger difference in absolute risk depending on BMI than women at lower risk.)
  • Combined oral contraceptive use — Risk increases with years of use and declines after stopping, and may differ between different preparations.
  • Hormone replacement therapy (HRT) use — Risk is dependent on the type of HRT used and increases with duration of use.
  • Cigarette smoking — Evidence is mixed, and the risk/study outcomes may be confounded by other risk factors. Smoking may increase risk in those with BRCA2 mutations but not BRCA1. It is, however, the biggest modifiable cause of cancer overall in the UK.
  • Not breastfeeding. Risk is 16% lower in women who have ever breastfed compared to those who have never done so. (This association is not applicable to BRCA2 carriers.)
  • Ionising radiation — Radiotherapy and, to a lesser extent, diagnostic radiology. 1% of breast cancer cases in the UK are thought to be caused by ionising radiation. An estimated 0.1% of breast cancers under 75 years are caused by the lower exposure level of diagnostic X-rays. An estimated 0.03-0.06% of breast cancers are caused by having a mammogram, although mammography does not appear to be associated with breast cancer risk in women with BRCA mutations.
  • Younger age at menarche — Risk increases by 5% for each year younger at menarche. (Not applicable to BRCA2 carriers).
  • Older age at menopause — Risk increases by around 3% for each year older at menopause.
  • Older age at first giving birth — Risk increases by 3% for each year older a woman is when she first gives birth. The association may be different by tumour receptor type. (This risk is not applicable to individuals with BRCA mutations).
  • Not having given birth to children — Risk decreases with each live birth. (In those with BRCA mutations, the evidence for this risk is conflicting.)
  • Older age — Incidence rates of breast cancer are highest in people aged 90 or more, and around a quarter of all breast cancer cases are diagnosed in people aged 75 or more.

[Brown, 2018; Hopper, 2018; Kehm, 2020; Cancer Research UK, 2021; NICE, 2023]

What is known about the genetic risk factors?

• Between 5-10% of breast cancers are thought to be hereditary, caused by a genetic predisposition due to inherited pathogenic variants of specific high-risk genes. 
  • Hereditary cancer syndromes often result in cancer which affects more than one organ within the same individual or within a family.
  • Onset at an early age, a high incidence of bilateral disease, and an association with other malignancies (such as ovarian cancer) usually characterize hereditary breast cancer.
• The most commonly implicated genes are the BRCA1 and BRCA2 genes (BReast CAncer 1 and 2 genes; these are genes normally involved in preventing tumours and excessive cell division, but abnormal mutations within them increase the risk of several cancers, including breast cancer.) 
  • Women with BRCA1 and BRCA2 mutations have a 45-65% risk of developing breast cancer by the age of 70, and a higher risk than the general population across all age groups. Breast cancer risk in these individuals may be modified by other factors such as family history and lifestyle.
  • How many women are affected by these gene mutations varies with ethnicity and country of origin. In the UK, it has been estimated that 0.11% (BRCA1) and 0.12% (BRCA2) of the general population are affected; around 1 in 450 women. Some populations have much higher carrier frequency, for example, 2.5% (1 in 40) of Ashkenazi Jews.
• Other genes which may contain mutations leading to increased risk of breast cancer include the PALB2, ATM, CHEK2, TP53, STK11, CDH1 and PTEN genes. These may also confer risk of other cancers, for example:
  • TP53 gene mutation (Li–Fraumeni syndrome) — most women with this mutation develop breast cancer by 50 years of age. TP53 is also associated with sarcomas of childhood, leukaemias, adrenocortical carcinomas, and brain tumours.
  • PTEN gene mutation (Cowden's syndrome) — this predisposes to breast, thyroid, and uterine cancers and hamartomatous lesions of the skin.
  • STK11 gene mutation (Peutz-Jeghers syndrome) — this predisposes to increased risk of breast, ovarian, cervical, uterine, pancreatic, lung, gastric and colon cancer.

[Antoniou, 2003; ACOG, 2019; Cancer Research UK, 2021; Sessa, 2023]

Scenario: Breast cancer - managing family history

From age 16 years onwards.

Search strategy

Scope of search

This CKS topic is primarily based on the National Institute for Health and Care Excellence (NICE) guideline Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. A literature search was conducted for guidelines and systematic reviews relevant to managing family history of breast cancer in primary care. 

Search dates

December 2018 - March 2023

Key search terms

The terms listed below are the core search terms that were used for EBSCOhost MEDLINE (searched 12th December 2018). These terms were combined with search filters for systematic reviews and guidelines in EBSCOhost MEDLINE. The strategy was adapted for The Cochrane Library databases. 

S11    S3 AND S10
S10    S4 OR S5 OR S6 OR S7 OR S8 OR S9
S9    (MH "Genes, BRCA2")
S8    (MH "Genes, BRCA1")
S7    AB (mutation carrier*) OR TI (mutation carrier*)
S6    AB ( (familial or inherit* or hereditary or BRCA*) ) OR TI ( (familial or inherit* or hereditary or BRCA*) )
S5    AB family history OR TI family history
S4    (MH "Genetic Predisposition to Disease+")
S3    S1 OR S2
S2    AB ( (breast* N2 (neoplasm* or cancer* or tumor* or tumour* or metasta* or carcinoma*)) ) OR TI ( (breast* N2 (neoplasm* or cancer* or tumor* or tumour* or metasta* or carcinoma*)) )
S1    (MH "Breast Neoplasms+")

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.