Professors Nadeem Qureshi and Gareth Evans explain how decisions on surveillance and treatment strategies for people with familial breast cancer are based on level of risk


NICE Accreditation Mark

NICE Clinical Guideline 164 on 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 has been awarded the NICE Accreditation Mark.

This Mark identifies the most robustly produced guidance available. See evidence.nhs.uk/accreditation for further details.

T he recently updated NICE Clinical Guideline (CG) 164 on familial breast cancer (see www.nice.org.uk/guidance/cg164) has been the subject of front-page headlines, such as ‘Breast cancer drugs offered to women at high risk’.1,2 At the same time, reports about actress Angelina Jolie’s preventative bilateral mastectomy have increased the population’s awareness of the risk associated with familial breast cancer.3

Prevalence and risk

Familial breast cancer is the most common neoplasm in women, with a lifetime risk as high as one in 8–10;1 the risk for men is <1 in 1000.4 Up to 27% of breast cancers are predicted to have an inherited component,5 of which around 20% of this is due to BRCA1 or BRCA2 mutation;6 a mutation in the BRCA1 or BRCA2 genes accounts for about 2%–3% of breast cancers in women and 7%–15% in men.7,8 These genes have a classical Mendelian inheritance pattern, with both men and women in each generation having a one in two chance of inheriting the genetic mutation. Those with the BRCA1 mutation (reportedly the mutation that Jolie has3) have a 60%–90% risk of developing breast cancer in their lifetime, as well as a 40%–65% risk of developing ovarian cancer.9,10 Men with BRCA2 mutations have a 6%–10% risk of breast cancer and a 20% risk of prostate cancer.11,12

TP53 mutations are also associated with a very high risk of breast cancer and are also linked to malignancies of the soft tissue and bone (sarcomas), malignant gliomas, and adrenal cancer,13 particularly in people in their twenties and thirties.

Risk classification

The NICE guideline on familial breast cancer provides risk categories to identify people at:1

  • ‘near population risk’
  • moderate risk
  • high risk.

Initial assessment is based on the nature of the family history recorded, and is a basic history-taking skill that is well established in British general practice.

Women with a lifetime risk of breast cancer based on their family history of:1

  • ≥30% are classified as at high risk in the NICE guideline and should be referred to (tertiary) clinical genetic services for further investigation and possible intervention
  • 17%–29% are classified as at moderate risk and should be assessed by secondary specialist care services (see Table 1).
Table 1: Risk category for breast cancer1*
Risk groupRisk
Near populationModerateHigh
Lifetime from age 20 years <17% >17% but <30% ≥30%
Age 40–50 years <3% 3–8% >8%
  • * Risk of a person developing breast cancer, calculated as a percentage and using a proven risk assessment ‘scoring’ method
  • † Includes patients with known BRCA1, BRCA2, and TP53 mutations and rare conditions that carry an increased risk of breast cancer, such as Peutz–Jeghers syndrome (STK11 mutation), Cowden syndrome (PTEN mutation), and familial diffuse gastric cancer (E-cadherin mutation).
  • NICE. 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. Clinical Guideline 164. Reproduced with kind permission from NICE.
  • Available at: www.nice.org.uk/CG164

Key recommendations for general practice and primary care

Collecting a family history

The 2013 update of the NICE guideline has retained the recommendation from the previous 2004 guideline that a detailed family history should be collected for women with concerns about their risk of breast cancer because of family history and symptoms.1,14 A family history can also be collected when it is clinically relevant—for example, during routine checks for a woman taking hormone replacement therapy (HRT).1

Family history should be investigated in all cases of male breast cancer. Women newly diagnosed with breast cancer should also have been assessed under specialist care, but if they are missed, the patient may approach their GP and should be managed as indicated in Figure 1.

When a relevant family history in a relative is identified, the GP or practice nurse should elicit, as per good clinical genetic practice:1

  • age at which the relative’s cancer was diagnosed
  • patient’s relationship to the affected relative
  • ethnicity of the patient and their relatives
  • nature of the cancer (e.g. site of cancer, multiple sites, and associated cancers).

When assessing the nature of the breast cancer in relatives, it is important to identify whether or not the affected relatives are from the maternal or paternal side of the family.1 It is clearly unrealistic to obtain this level of detail in a 10-minute consultation, so this could be facilitated by a self-administered family history questionnaire in paper or electronic format15—for example, a
web-based tool has been introduced by the US Surgeon General’s Family History Initiative.16 The use of online or paper-based questionnaires also means that the patient has the opportunity to discuss information about their family history with the extended family and populate the questionnaire with these details prior to returning to the GP.

Although not included in the NICE recommendations, another consideration is the opportunity to collect family history in other settings—for example, most general practices now collate some information about family history when the patient registers with the practice. If a person volunteers that they have a family history of breast cancer in this proactive setting, how much detail of the family history should be collated by the practice nurse or GP? The role of general practice ancillary staff in collecting information about family history was recognised by the Royal College of General Practitioners over 30 years ago.17 Perhaps this is the time to look at the extraordinary potential of other members of the general practice team to collate data on family history.

Interpreting the family history

The next challenge is to interpret and act on the family history that has been collected. The criteria for referral to secondary care, which can be found in the NICE guideline1 and online as a NICE Pathway (pathways.nice.org.uk/pathways/familial-breast-cancer)18 is shown in Figure 1. Decision support software—for example, Family History Risk Assessment Software (FaHRAS; www.fahras.co.uk)19—is available, but the logistics of entering information on family history into such software still needs to be considered.

It may be relatively straightforward to give the patient an assessment of their risk if they can only identify one or two relatives with breast cancer; however, other cancers that suggest a hereditary cancer syndrome may also emerge (see Figure 1). In such circumstances, general practice may want to discuss the case with a specialist, and so key contacts in each area should be identified.

Risk-reduction strategies

The 2013 guideline update expands on previous versions of the guideline by including recommendations to improve health surveillance of women at increased risk of familial breast cancer (see Figure 2).1

Risk associated with hormone-based therapies

With regard to co-prescribing, although evidence is of low quality, the NICE guideline development group recognised that the risk of breast cancer is increased in older women taking the combined oral contraceptive (COC). Specifically, women aged older than 35 years with a family history of breast cancer should be informed of the potential additional risk of breast cancer associated with COCs. Similarly, women with a family history of breast cancer who are considering HRT should be advised about the increased risk of breast cancer with different types and durations of treatment.1


Chemoprevention

One of the major headlines that has emerged since publication of the updated NICE guideline is the recommendation that women with a high risk of familial breast cancer should be offered chemoprevention with tamoxifen or raloxifene; women at moderate risk should be considered for chemoprevention. Similar to other specialist areas, the responsibility for hospital-initiated prescribing will eventually pass to GPs.

Before chemoprevention is offered, the specialist will have performed a full risk assessment and checked for contraindications—particularly whether there is an increased risk of thromboembolism for either drug and an increased risk of endometrial cancer for tamoxifen. Premenopausal women at high risk of breast cancer should be offered tamoxifen, while postmenopausal women should be offered tamoxifen if they do not have a uterus, and raloxifene if their uterus is intact. At the time of publication (June 2013), tamoxifen and raloxifene did not have a UK marketing authorisation for this indication. The prescriber should consult the summary of product characteristics and follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented.

The recommendations for women at high familial risk are based on high-quality randomised trials, but consensus opinion from the guideline development group suggested that women with a moderate risk of familial breast cancer within the next 10 years should also be considered for chemoprevention.1

During follow-up review, it is essential that the clinician responsible for prescribing identifies emerging contraindications, particularly symptoms suggestive of thromboembolic risk and endometrial cancer (such as intermenstrual and postmenopausal bleeding). Furthermore, the guideline advises that women stop chemoprevention 2 months before trying to conceive, and 6 weeks prior to elective surgery.1 One area of concern, which is likely to be picked up by area prescribing committees, is that neither drug holds a product licence for chemoprevention in women at increased familial risk. However, tamoxifen is widely used for the treatment of breast cancer (with substantial effects in terms of secondary prevention) and raloxifene for the prevention of osteoporosis.

Helping women to reduce their risk

Women with high familial risk will benefit from support provided by their GP when making difficult decisions—not only about surveillance and chemoprevention, as discussed above, but also about risk-reducing surgery. This includes considering the risks and benefits of risk-reducing mastectomy and bilateral salpingo-oophorectomies for women with known or suspected BRCA1, BRCA2, orTP53 gene mutations.

Issues that the GP should cover include the psychological impact of mastectomy and the implications of surgical induction of menopause in women who have bilateral oophorectomies.

Quality of care provided by specialist services

General practice is not expected to use risk-assessment tools to assess the probability of a person carrying a genetic mutation associated with breast cancer, but GPs, as commissioners, have a responsibility to ensure that acceptable mutation assessment tools are being used and that the correct genetic testing threshold is adopted and resourced. Commissioners also need to ensure that risk-reducing mastectomy is provided only by surgeons with specialist skills in oncoplastic surgery and breast reconstruction.

NICE CG164 recommends that genetic mutation testing should be offered only by specialist genetic centres, with the threshold for genetic testing reduced from a 20% chance of a genetic mutation to 10% in the 2013 guideline.1 The guideline recommends that specialist services use acceptable tools such as the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA)20 and Manchester Scoring System.21

Figure 1: Care and management of people in primary care1
Care and management of people in primary care

National Collaborating Centre for Cancer (NCC-C). 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. Update of Clinical Guideline 14 and 41. Clinical Guideline 164.

Reproduced with kind permission from the NCC-C. Available at: www.nice.org.uk/CG164

Figure 2: Surveillance in secondary care1
Surveillance in secondary care

MRI=magnetic resonance imaging
National Collaborating Centre for Cancer (NCC-C). 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. Update of Clinical Guideline 14 and 41. Clinical Guideline 164.
Reproduced with kind permission from the NCC-C. Available at: www.nice.org.uk/CG164

Impact on primary care

Increasing workload

Although the revised guideline does not recommend that primary care proactively identifies women with a family history of breast cancer, the recommendations could still increase workload. For example:

  • women previously diagnosed with a moderate risk of familial cancer may approach GPs due to the new recommendation that they should be considered for chemoprevention with tamoxifen or raloxifene
  • women at high risk of familial cancer who have previously declined preventative measures, such as bilateral mastectomy, could approach GPs to be considered for chemoprevention
  • women previously diagnosed with breast cancer under the age of 40 years may return to their GP for assessment of their family history.

In these and other circumstances, GPs should take a systematic approach to collecting and interpreting family history. Relevant integrated decision-support software is still not available.

The NICE guideline also refers to a needs assessment that was undertaken to provide a context to the guideline. It indicated that, based on responses to a European-wide survey of healthcare professionals, GPs in the UK would be willing to explore the family history of breast cancer proactively with all eligible women.22 This low technology approach may increase the workload for general practice, but it would reduce unnecessary morbidity and mortality in at-risk individuals, particularly those from lower socioeconomic backgrounds, who do not usually avail themselves of preventative services in primary care. Furthermore, current evidence suggests that systematic approaches to collecting family history do not lead to undue anxiety.23

Providing support to women and men

 

Irrespective of the approach taken to identify women and men at increased risk of familial breast cancer, once they have been assessed by primary or specialist services they will need continuing support from general practice. Both patients and GPs need to keep the family history up to date in case new relevant information on relatives emerges. As described earlier, the GP also needs to support women to make difficult decisions about the risks and benefits associated with surveillance, chemoprevention, risk-reducing surgery, and co-prescribing of hormonal treatment such as the COC or HRT.

Conclusion

There has been a perception that there is no point in identifying women at risk of familial breast cancer as there are no effective interventions. This third iteration of the NICE guideline on familial breast cancer has, hopefully, put this misconception to rest. Surveillance, chemoprevention, and/or risk-reducing surgery can reduce both morbidity and mortality in high-risk patients. As such, GPs will have an increasingly active role in identifying and supporting these patients.

NICE implementation tools

NICE has developed the following tools to support implementation of Clinical Guideline 164 (CG164) on 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. The tools are now available to download from the NICE website:
www.nice.org.uk/CG164

NICE support for commissioners

Costing reportCommissioning.eps
Costing reports are estimates of the national cost impact arising from implementation based on assumptions about current practice, and predictions of how it might change following implementation of the guideline.

Costing templateCommissioning.eps
Costing templates are spreadsheets that allow individual NHS organisations and local health economies to estimate the costs of implementation taking into account local variation from the national estimates, and they quickly assess the impact the guideline may have on local budgets.

NICE support for service improvement systems and audit

Baseline assessment toolAudit.eps
The baseline assessment is an Excel spreadsheet that can be used by organisations to identify if they are in line with practice recommended in NICE guidance and to help them plan activity that will help them meet the recommendations.

NICE support for education and learning

Educational resourceEducation.eps

The educational resource is available as a PDF document, which summarises the recommendations from the familial breast cancer guideline on surveillance for women with no personal history of breast cancer.

PodcastEducation.eps

A podcast is available which covers:

  • the ‘strength’ of different recommendations
  • the reduction of the threshold for genetic testing
  • where carrier probability testing should be carried out and how
  • under what circumstances carrier probability testing should be carried out more quickly
  • changes to practice for genetic services and counsellors
  • areas for further research.

Key to NICE implementation icons

Commissioning.epsNICE support for commissioners

  • Support package for commissioners and others for quality standards
  • NICE guide for commissioners
  • NICE cost impact support for guidance (selection from national report/local template/costing statement, dependent on topic)

Audit.epsNICE support for service improvement systems and audit

  • Forward planner
  • 'How to' guides (generic advice on processes)
  • Local government briefings (with Centre for Public Health Excellence)
  • Baseline assessment tool for guidance
  • Audit support including electronic data collection tools
  • E-learning modules (commissioned)

Education.epsNICE support for education and learning

  • Clinical case scenarios
  • Learning packages including slide sets
  • Podcasts
  • Shared learning and other local best practice examples
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  2. The Telegraph. Women at high breast cancer risk to be given preventive drugs. www.telegraph.co.uk/health/women_shealth/10139438/Women-at-high-breast-cancer-risk-to-be-given-preventive-drugs.html (accessed 13 August 2013)
  3. BBC News website. Breast cancer: what is the risk?www.bbc.co.uk/news/world-us-canada-22520720 (accessed 2 August 2013).
  4. NICE. Familial breast cancer (breast cancer in the family). Information for the public. NICE, 2013. Available at: publications.nice.org.uk/familial-breast-cancer-breast-cancer-in-the-family-ifp164/familial-breast-cancer#close
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  6. Balmana J, Diez O, Rubio I, Cardoso F. On behalf of the ESMO Guidelines Working Group. BRCA in breast cancer: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22 (6): 131–134.
  7. Peto J, Collins N, Barfoot R. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 1999; 91 (11): 943–949.
  8. Fackenthal J, Olopade O. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 2007; 7 (12): 937–948.
  9. Antoniou A, Pharoah P, Narod S et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 222 studies. Am J Hum Genet 2003; 72 (5): 1117–1130.
  10. Ford D, Easton D, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998; 62 (3): 676–689.
  11. Evans D, Susnerwala I, Dawson J et al. Risk of breast cancer in male BRCA2 carriers. J Med Genet 2010; 47 (10): 710–711.
  12. Moran A, O’Hara C, Khan S et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer 2012; 11 (2): 235–242.
  13. Mai P, Malkin D, Garber J et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet 2012; 205 (10): 479–487.
  14. NICE. Familial breast cancer: the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care (partial update of CG14). London: NICE, 2006.
  15. Qureshi N, Carroll J, Wilson B et al. The current state of cancer family history collection tools in primary care: a systematic review. Genet Med 2009; 11 (7): 495–506.
  16. Carmona R, Wattendorf D. Personalizing prevention: the U.S. Surgeon General’s Family History Initiative. Am Fam Phys 2005; 71 (1): 36–39.
  17. Zander L, Beresford S, Thomas A. Medical records in general practice. London: Royal College of General Practitioners, 1978.
  18. NICE Pathways website. Familial breast cancer overview. pathways.nice.org.uk/pathways/familial-breast-cancer (accessed 24 July 2013).
  19. Family History Risk Assessment Software (FaHRAS) website. www.fahras.co.uk (accessed 24 July 2013).
  20. University of Cambridge website. BOADICEA model. ccge.medschl.cam.ac.uk/boadicea/model (accessed 2 August 2013).
  21. Evans D, Lalloo F, Cramer A et al. Addition of pathology and biomarker information significantly improves the performance of the Manchester scoring system for BRCA1 and BRCA2 testing. J Med Genet 2009; 46 (12): 811–817.
  22. Harris H, Nippert I, Julian-Reynier C et al. Familial breast cancer: is it time to move from a reactive to a proactive role? Fam Cancer 2011; 10 (3): 501–503.
  23. Wilson B, Qureshi N, Santaguida P et al. Systematic review: family history in risk assessment for common diseases. Ann Int Med 2009; 151: 878–885. G