Familial breast cancer

The offer of a gene panel test should be considered for individuals diagnosed with breast cancer that meets one or more of the following criteria. 

Patient diagnosed with 

• Breast cancer under age 40
• Bilateral breast cancer, both under age 60
• Triple negative breast cancer (TNBC), under age 60
• Breast cancer under age 45 with (at least) one 1st degree relative under age 45
• Breast cancer 'and' ovarian cancer, any age
• Male breast cancer, any age
• Breast cancer 'and' CanRisk score of 10% or more (all genes) OR a Manchester score  of 15 or more.

For eligibility criteria for testing in individuals affected with other cancers including ovarian, prostate, or pancreatic cancers, please refer to the Scottish Genomic Test Directory for eligibility criteria and appropriate panel details (Scottish Genomic Test Directories - Scottish Strategic Network for Genomic Medicine ). 

The hereditary breast cancer gene panel can be requested by Clinicians in Breast Surgery, Oncology and Clinical Genetics and includes the following genes: BRCA1, BRCA2, TP53, PALB2, PTEN, STK11, ATM, CHEK2, RAD51C and RAD51D.

CDH1 is not included in the panel routinely however can be added in patients diagnosed with lobular breast cancer when the following eligibility criteria are met: 

• Lobular breast cancer and Diffuse Gastric Cancer (DGC)* (both under 70 years) 

• Bilateral or multiple ipsilateral lobular breast cancer under 50 years 

• Lobular breast cancer under 70 years plus 1 or greater first degree relative or second degree relative with DGC* at any age 

• Lobular breast cancer and ≥1 first degree relative or second degree relative with DGC* (1 or more cases occurred under 70 years) 

*At least one diagnosis of DGC should be confirmed 

Founder variants: Individuals with Ashkenazi Jewish, Whalsay (Shetland) or Westray (Orkney) ancestry have a higher likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 due to the higher prevalence of specific variants in these populations (founder variants). 10 to 12% of people with breast cancer and Ashkenazi Jewish ancestry have a pathogenic variant in BRCA1 or BRCA2, rising to 1 in 3 where diagnosis is under 40 years of age. 

Please contact your local Clinical Genetics Service to discuss testing in patients affected with breast cancer who have known Ashkenazi, Whalsay or Westray ancestry. In addition, individuals with ancestry from Piscinisco in Italy (or the surrounding area) primarily (but not exclusively) families based in the Lothians are known to have a higher likelihood of harbouring a pathogenic variant in a cancer susceptibility gene and warrant referral to Clinical Genetics. This is due to having a high proportion of historic immigration from the Piscinisco region to the Southeast of Scotland. 

Individuals who can be offered genetic testing or where testing of relatives is advised: 

• Following a diagnosis of breast cancer where test eligibility criteria met:
  • Testing in affected patients to inform treatment or follow up should be undertaken by a registered healthcare professional involved in the patient’s care, following local protocols.
  • Testing is generally restricted to breast surgery and oncology teams.
  • If eligibility is uncertain, the patient can be referred to the Genetic Services for assessment of eligibility or additional discussion if deemed necessary.
  • All patients with a reported germline variant (‘Pathogenic’ or ‘likely pathogenic’) should be referred to their local Genetic Services for appropriate counselling and support.
  • All patients with a reported ‘Variant of Uncertain Significance (VUS)’ should be discussed with their local Genetic Service to determine if any further action is required. 

• In individuals with a family history of breast cancer but no personal history of cancer: genetic testing is always most informative in an individual affected with cancer. The person with no personal history of cancer should be advised to ask their relative to seek advice on testing (via their own cancer service or GP). If it is not possible to test a living affected relative, it may be possible for testing to be carried out in a deceased relative affected with breast or ovarian cancer, if there is 

• • A suitable tissue sample available for DNA extraction, 'and'
  • Pathology-adjusted Manchester score 17 or over or CanRisk score is 15% or over, 'and'
  • No living affected individual is available for genetic testing

If there is no living affected relative to test and no suitable tissue available from a deceased affected relative, then testing of an unaffected person can be offered (by clinical genetics only) when the following criteria are met:  

• • Manchester score 19 or over, OR CanRisk score 10% or over. 
    
    

• In individuals with a known pathogenic and/or likely pathogenic variant in the family:  If a pathogenic or likely pathogenic variant is identified in an individual, then relatives also at risk of inheriting the variant can be offered testing regardless of whether they have had cancer or not. The Clinical Genetics team assists in cascading the result through the family and undertakes predictive testing of at-risk relatives. 

Risk assessments can impact treatment, follow up and eligibility for risk reducing options such as surgery and screening for individuals affected with cancer and their close relatives.  Therefore, there is a growing need for these to be individualized. A Family History Service with a patient-facing electronic family history data collection tool and electronic pedigree drawing is necessary in undertaking risk assessments efficiently. Utilisation of pedigree drawing software and individualised risk prediction programmes to undertake risk assessments will maximise efficiency and enable more personalised management. Individualised risk assessments can be facilitated using a validated risk assessment tool such as CanRisk (see ‘Definition of Risk Categories’ for further guidance). For further guidance on agreed data input please see CanRisk in Scotland .

Following identification of a Likely pathogenic and/ or pathogenic variant

All patients who are identified as carrying a pathogenic and/ or likely pathogenic variant in a gene increasing their risk of breast cancer, should be referred to Clinical Genetics for an individualised risk assessment and discussion of risk management options.

The laboratory report must be available and issued from a UK diagnostic service which meets appropriate quality standards.

Where available, UKCGG management guidelines for gene carriers should be followed (UKCGG leaflets and guidelines - Cancer Genetics Group ).

The UK Cancer Genetic Group have developed guidelines  for the following genes:

• BRCA1
• BRCA2
• PTEN
• PALB2
• TP53
• ATM
• CHEK2

The following outcomes of germline testing will confer a very high risk (over 40% lifetime risk) of breast cancer in females†

• Heterozygous pathogenic/likely pathogenic variants in BRCA1, BRCA2, TP53, PALB2, STK11, PTEN and CDH1. 
• Heterozygous c.7271T>G variant in ATM
• Homozygous or compound heterozygous pathogenic/likely pathogenic variants in ATM and CHEK2.

Heterozygous ‘pathogenic’ or ‘likely pathogenic’ variants in ATM, CHEK2, RAD51C and RAD51D are generally considered to confer a moderately increased risk in females† (lifetime risk between 17 to 30%) but can be assessed at a higher risk following an individualised risk assessment particularly in there is a significant family history. 

Assessing risk following identification of a ‘Variant of Uncertain Significance (VUS) 

In this event, the variant cannot be used in the risk assessment which should be based on personal and family history alone. In addition testing cannot be offered to relatives to aid clinical decision making as further evidence is required to help clarify the pathogenicity of the variant. However, testing may be undertaken in relatives as part of segregation studies to aid variant interpretation. All patients reported to have a ‘VUS’ should be discussed with Clinical Genetics to determine if further action is indicated.

Assessing risk following genetic testing where no causative variant identified or where genetic testing has not been undertaken as eligibility criteria have not been met

Risk assessment should be undertaken by a family history service with consideration of testing in other relatives where appropriate. Following discharge from cancer services, females† affected with breast cancer, who are either not eligible for genetic testing or who have not been found to carry an actionable variant on testing, should receive surveillance equivalent to those with the same family history but without a personal history of breast cancer. 

The individual being assessed should be a first-degree relative of an affected family member or a second-degree relative through an unaffected male. Affected individuals should be first-degree relatives of each other or related through unaffected males.

A first-degree relative is mother, father, daughter, son, sister or brother. A second-degree relative is grandmother, grandfather, granddaughter, grandson, aunt, uncle, niece, nephew, half-sister or half-brother. Please note that a case of bilateral breast cancer should be treated as the equivalent of 2 affected relatives.

Confirmation of family history 

For accurate risk estimation, the following are required:  

• age of diagnosis of affected relatives and cancer site and type. 
• current age or age of death of unaffected close relatives.  

Confirmation of relatives’ cancer diagnosis using medical records, cancer registry or death certificates should be performed for abdominal malignancies wherever possible. In general, it is not necessary to validate breast cancer-only histories. However, when substantial management decisions, i.e. risk-reducing surgery, are being considered and no causative variant has been identified, breast cancer history should be verified. Where no family history verification is possible, agreement by a multidisciplinary team should be sought before proceeding with risk-reducing surgery.

The following risk categories apply to those assigned female† at birth and who have not had any masculising or gender affirming treatments. Any patient who has had such treatment requires an individualised approach and should be discussed with Clinical Genetics. 

Very high risk: 

High risk

Moderate risk

Low risk

Very high risk 

• Heterozygous 'pathogenic' or 'likely pathogenic' variant in BRCA1, BRCA2, PALB2, STK11, PTEN and CDH1.
• Heterozygous c.7271T>G ATM
• Biallelic 'pathogenic' or 'likely pathogenic' variants in CHEK2
• Female† with a lifetime risk of developing breast cancer of 40% or more (see category definitions)

*To qualify for screening under 30 years, female† must be a BRCA1, BRCA2 or PALB2 carrier 'and' have an 8% or greater 10 year risk at the age when entered. 

**Breast density should be reviewed annually from 50years. If the mammogram shows an entirely fatty breast (BI-RADS A, see the BI-RADS Atlas - Reporting System ), MRI is unlikely to add value and their screening protocol should change to mammography only for the remainder of their screening.   

Heterozygous TP53 ‘pathogenic’ or ‘likely pathogenic’ variant Carriers (Li Fraumeni syndrome) 

Biallelic ATM ‘pathogenic’ or ‘likely pathogenic’ variants (Ataxia Telangiectasia) 

Mammography is contraindicated.

Untested females† with 50% or greater risk of a pathogenic/likely pathogenic variant in a high-risk gene

• Very High-Risk gene specific protocol should be offered up to age 50 when this should be reviewed.
• If the female† remains untested after age 50 years, they move to the High-Risk protocol.

High risk 

*Screening starts at 35 years or 5 years earlier than the youngest age of onset in the family (but not before 30 years) 

Moderate risk 

*Screening starts at 40 years or 5 years earlier than the youngest age of onset in the family (but not before 35 years)

Low risk (population risk)

Equates to 17% or less lifetime risk

Screening age 71 or over

Females† age 71 or over no longer receive breast screening invitations from the National Breast Screening Programme (NBSP) can self-refer for breast screening every 3 years. Females† assessed to be very high risk should continue to have access to annual screening if requested via locally agreed pathways.

Recommendations for all females† having surveillance 

• All screening mammography should be digital and performed at centres providing mammography to NBSP standards. 
• It should be ensured that individual strategies are developed for all females† having mammographic surveillance and that surveillance is: 
  • To NBSP standards 
  • Audited 
  • Reviewed at regular intervals
  • Only undertaken after written information is given about risks and benefits. 
• MRI surveillance should include MRI of both breasts performed to NBSP standards. 
• A robust recall system should be in place equivalent to NBSP. 

Hormone Replacement Therapy (HRT) and hormonal contraceptives are not contraindicated in females† who are not at ‘very–high’ risk of breast cancer. For those with a very high risk (≥40% lifetime risk), referral to specialist clinic for further discussion is advised.

Printable version of Risk Category and Screening Protocols Summary

Risk reducing bilateral mastectomy is appropriate only for females† with a very high breast cancer risk and a small proportion of females† from high-risk families. This should be managed by a multidisciplinary team. Any patients considering risk reducing surgery because of a genetic variant or an increased familial risk should have had their risk assessed recently by Clinical Genetics and have access to a Breast Nurse Specialist and Clinical Psychology. All females† considering risk reducing mastectomy should be reviewed by Clinical Genetics to confirm risk assessment prior to referral to breast services.

Females† affected with breast cancer 

Contralateral mastectomy is not generally advised for those with unilateral cancer due to doubling risks with no survival benefit. However, where there is increased risk of contralateral cancer conferring a lifetime risk of breast cancer of 30% or greater, it can be considered.

The risks and benefits of risk-reducing contralateral mastectomy should be considered on a case-by-case basis following MDT discussion in females† undergoing breast cancer treatment with at least one of the following:

• A known 'pathogenic' or 'likely pathogenic' variant* conferring a 30% or greater ('high' or 'very high') lifetime risk of contralateral breast cancer following an individualised risk assessment.  Consideration of remaining (residual) risk and clinical history should be included in MDT discussion.
• A family history of breast cancer estimated to confer a 30% or greater ('high' or 'very high') remaining (residual) risk of contralateral breast cancer following an individualised risk assessment, with all breast cancer diagnoses confirmed in the family where possible.

For patients with an active cancer who are deemed at 'very high' risk of further breast cancers due to a 'pathogenic' or 'likely pathogenic' variant, the treatment of the cancer may outweigh the need for Clinical Genetics review. However, discussion with Clinical Genetics should be offered to the patient where feasible.

Females† with no personal history of breast cancer  

Prophylactic bilateral risk reducing mastectomy can be considered for females† who are estimated to have a ‘high’ or ‘very high’ lifetime risk of breast cancer following an individualised risk assessment. 

The risks and benefits of prophylactic bilateral mastectomy should be considered on a case-by-case basis following MDT discussion with at least one of the following: 

• A known ‘pathogenic’ or ‘likely pathogenic’ variant conferring a 30% or greater (‘high’ or ‘very high’) lifetime risk of breast cancer*. Consideration of remaining (residual) risk and clinical history should be included in MDT discussion.

• A family history of breast cancer estimated to confer a 30% or greater remaining (residual) risk of breast cancer, with all breast cancer diagnoses confirmed in the family where possible**.  

*The laboratory report confirming the presence of an actionable variant must be available and issued from a UK diagnostic service which meets appropriate quality standards prior to surgery.  

**Where no family history verification is possible, bilateral risk reducing mastectomy should only be considered if there is agreement by a multidisciplinary team including Clinical Genetics, Breast Surgery and Clinical Psychology.   

The below recommendations are advised regarding risk reducing bilateral salpingo-oophorectomy in females† who may also have an increased risk of breast cancer:

• Discuss the risks and benefits of risk-reducing bilateral salpingo-oophorectomy with females† with a known 'pathogenic or 'likely pathogenic' variant in a gene known to also increase the risk of ovarian cancer in line with UK CGG guidelines (UKCGG leaflets and guidelines - Cancer Genetics Group ).
• Risk-reducing bilateral salpingo-oophorectomy may also be offered to those with a significant family history of ovarian cancer where individualised CanRisk assessment estimates the lifetime risk of ovarian cancer at 5% or more.
• Discussion should include the positive effects of reducing the risk of ovarian (and in some cases breast cancer) and the negative effects of a surgically induced menopause.
• Defer risk-reducing bilateral salpingo-oophorectomy until females† have completed their family.
• Where available, females† wishing to undergo risk-reducing bilateral salpingo-oophorectomy should be referred to a specialist clinic.

Contraindications to risk-reducing surgery

• Do not offer risk-reducing surgery to people with comorbidities that would considerably increase the risks of surgery.
• Do not offer risk-reducing surgery to people who have a limited life expectancy from their cancer or other conditions.

Some couples where one partner carries a ‘pathogenic’ or ’likely pathogenic’ variant in a cancer susceptibility gene might consider the option of Preimplantation Genetic Testing (PGT) to avoid passing the variant onto their children. PGT involves ‘in vitro fertilisation’ (IVF).

The embryos are then tested at an early stage for the familial variant and only embryos which do not carry the variant are transferred. Access to PGT is through the Clinical Genetics Service and only for couples meeting specified eligibility criteria. 

In 2018 the Association of British Insurers (ABI) agreed to an open-ended moratorium which means unaffected carriers of a 'pathogenic' or 'likely pathogenic' variant will not have to disclose the results of their predictive genetic test if taking out life or critical illness insurance after genetic testing. The Moratorium will be reviewed by the Department of Health and the ABI every 3 years. 

Those who are having genetic testing as part of their diagnostic process (e.g. a breast cancer patient) would be having a diagnostic genetic test. Insurers can use this to inform subsequent applications for life or critical illness insurance. However, the key element of insurance evaluation is likely to be a cancer diagnosis, rather than at-risk status. 

Horizon scanning 

Future content to include:

• Chemoprevention in females† with increased risk.
• Information and links to leaflets regarding hormone replacement therapy (HRT) and oral contraceptive pull (OCP) in females† with increased Breast Cancer risk.

Future service provision requiring consideration:

• Increased screening for moderate risk age 50 to 60 – see NICE Guidelines.
• Annual MRI screening in all very high-risk females† from 25 years (as per PHE).
• Development and/ or implementation of automation of patient facing family history questionnaire (FHQ) to pedigree drawing software and CanRisk in Scotland.
• Nationally organised screening programme for females† at increased risk.
• National database of individuals who carry a 'pathogenic' or 'likely pathogenic' variant in a cancer susceptibility gene.

Helpful links

• UKCGG leaflets and guidelines - Cancer Genetics Group
• Manchester (Evans) score — Knowledge Hub
• Scottish Genomic Test Directories - Scottish Strategic Network for Genomic Medicine
• Welcome to CanRisk
• Guidelines for use of CanRisk in Scotland | Right Decisions
• Women with a family history of breast cancer but without a personal history of cancer | Right Decisions
• Eligibility for genetic testing - algorithms | Right Decisions

References 

1. NICE CG164 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 Issued: June 2013
2. PHE Protocols for surveillance of women at very high risk of developing breast cancer - GOV.UK (www.gov.uk)
3. PHE Tests and frequency of testing for women at very high risk - GOV.UK (www.gov.uk)
4. HIS Familial breast cancer report (healthcareimprovementscotland.org)
5. UK Cancer Genetics Group (2018) Consensus for genes to be included on cancer panel tests offered by UK genetics services. Authors: Amy Taylor,1 Angela F Brady,2 Ian M Frayling,3,4 Helen Hanson,5 Marc Tischkowitz,1,6 Clare Turnbull,7,8,9 Lucy Side,10 on behalf of the UK Cancer Genetics Group (UK-CGG) 
6. Evans DG et al, 2017. Pathology update to the Manchester Scoring System based on testing in over 4000 families. J Med Genet 54: 674-681