Breast cancer genetics and high-risk surveillance

01Role and principlesWho benefits and the main preventive aims.

Hereditary breast cancer is suggested by phenotype, not simply the number of affected women. Young age, bilateral disease, male breast cancer, ovarian cancer, triple-negative breast cancer at a relevant age and combinations with pancreatic or prostate cancer can indicate BRCA-related susceptibility. Other patterns point toward TP53, PTEN, CDH1, STK11 or rarer syndromes. Both parental lineages matter, and a sparse pedigree does not equal low risk when family size is small or relatives died young.

Genetic testing begins with consent, a verified pedigree and the most informative affected person. Panel choice reflects phenotype and current genomic-directory criteria. A pathogenic variant may establish management and enable precise cascade testing. A true negative for a known familial variant can return risk toward population or residual family risk. An unaffected negative result without a known familial cause cannot exclude heredity. A VUS is an unresolved laboratory observation, not a diagnosis.

Surveillance is calibrated to near-term risk and radiation sensitivity. Contrast-enhanced MRI is highly sensitive in dense young breasts and is central to many high-risk programmes; mammography contributes calcification detection and becomes more prominent with age. TP53 carriers require particular attention to radiation avoidance. Schedules change with gene, age, prior cancer, breast density and national guidance, so a written genetics-led plan is safer than a remembered generic annual scan.

Prevention decisions are preference sensitive. Bilateral mastectomy offers the largest breast-risk reduction but has irreversible sensory, reconstructive and psychosocial effects. Tamoxifen or anastrozole offers smaller subtype-specific reduction without surgery. BRCA-associated tubo-ovarian risk is best reduced with salpingo-oophorectomy at a gene- and age-appropriate time after reproductive planning; screening with CA125 and ultrasound has not replaced it. Premature menopause, bone, cardiovascular, sexual and fertility consequences require preparation and hormone-management discussion.

Key points

Take a three-generation history covering maternal and paternal relatives, cancer site, age at diagnosis, bilateral or multiple primaries, ancestry and confirmed pathology; small families and early deaths can hide inherited risk.
Test an affected relative first whenever possible because a negative result in an unaffected person is often uninformative when the familial cause is unknown.
Use an accredited germline multigene panel matched to the phenotype rather than ordering BRCA1 and BRCA2 reflexively for every family or using a consumer test.
Pathogenic and likely pathogenic variants can guide care; a variant of uncertain significance is managed from personal and family risk until laboratory reclassification.
BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1 and STK11 are important high-risk contexts, while ATM and CHEK2 often confer moderate risk modified by family and polygenic background.
First-line surveillance modality and start age are gene and risk specific. Younger high-risk patients commonly receive contrast MRI, with mammography added or substituted according to age, gene and radiation considerations.
Risk-reducing bilateral mastectomy substantially reduces but does not abolish breast-cancer risk and requires multidisciplinary genetic, surgical, reconstructive and psychological counselling.
Risk-reducing salpingo-oophorectomy is more effective than unproven routine ovarian screening for BRCA-associated ovarian risk; timing differs between genes and reproductive plans.
Tamoxifen before menopause and anastrozole after menopause can reduce ER-positive breast cancer in selected high-risk people, but gene biology and treatment toxicity determine usefulness.
A germline result may affect breast surgery, radiotherapy, ovarian prevention, systemic treatment and trials in a person who already has cancer, so referral should not be deferred until survivorship.
Cascade testing is targeted to the known familial variant and requires consent and support; clinicians facilitate family communication but do not disclose one person’s result casually.
Offer fertility and reproductive counselling, including prenatal and preimplantation options, before risk-reducing surgery or gonadotoxic treatment narrows choice.

02Assessment and patient selectionRisk features, eligibility and important cautions.

BRCA-related pattern

Young breast, ovarian, male breast, pancreatic and aggressive prostate cancers across either lineage support BRCA1 or BRCA2 assessment.

Li–Fraumeni pattern

Very early breast cancer plus sarcoma, brain, adrenocortical or multiple childhood cancers raises germline TP53 and changes imaging radiation decisions.

Syndromic physical clues

Macrocephaly and mucocutaneous lesions may suggest PTEN, while mucocutaneous pigmentation and hamartomatous polyps can suggest STK11.

Hereditary diffuse gastric pattern

Diffuse gastric carcinoma and lobular breast cancer in relatives should prompt CDH1-focused clinical genetics review rather than a breast-only panel.

Uninformative family structure

Few female relatives, adoption, unknown paternity or young deaths reduce observable cancers and can make simple counting underestimate risk.

Current symptomatic diseaseRed flag

A mutation carrier with a new lump enters urgent triple assessment; surveillance imaging is not a substitute for symptomatic diagnosis.

Red flags requiring action

Breast cancer at a young age, bilateral primaries, male breast cancer or breast and ovarian cancer in one lineage suggests inherited susceptibility.
Ovarian, pancreatic, metastatic or high-risk prostate cancer alongside breast cancer can be part of a BRCA-related family pattern.
Sarcoma, brain tumour, adrenocortical cancer and very early breast cancer in a family raises TP53-associated Li–Fraumeni syndrome.
Diffuse gastric cancer with lobular breast cancer raises CDH1-associated hereditary diffuse gastric cancer and needs specialist gene-specific management.
A variant of uncertain significance must not drive irreversible surgery or predictive testing of healthy relatives.
New symptoms in a mutation carrier require diagnostic imaging even when a recent surveillance MRI or mammogram was normal.

03Baseline assessmentMeasurements that guide the plan and track progress.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line three-generation pedigreeFirst stepFirst line
Why
Identify syndromic patterns, the most informative person to test and relatives who may benefit from cascade care.
Interpretation and limitations
Record exact primary sites, ages, bilateral disease and lineage and verify pathology where possible; calculate risk rather than relying on family-count intuition.
02
Validated carrier and breast-risk model
Why
Estimate pathogenic-variant probability and age-specific breast risk when no familial result is yet available.
Interpretation and limitations
Use a current model such as CanRisk or BOADICEA with complete inputs; estimates change as pathology, family ages and polygenic or lifestyle information changes.
03
Reference accredited germline panel
Why
Detect inherited pathogenic variants in genes justified by personal and family phenotype and national testing criteria.
Interpretation and limitations
Test an affected relative first when possible and classify with current laboratory standards; confirm mosaic or technically complex findings where required.
04
Tumour genomic or immunohistochemical testing
Why
Identify a treatment biomarker or clue that may trigger germline testing, such as homologous-recombination or mismatch-repair findings.
Interpretation and limitations
A tumour result is not automatically inherited; confirm suspected germline variants in a constitutional sample with counselling.
05
First-line gene-specific breast imagingFirst line
Why
Detect preclinical breast cancer at the interval and with the modality appropriate to current absolute risk.
Interpretation and limitations
Use MRI and mammography according to gene, age and previous treatment; surveillance results use a diagnostic pathway when suspicious and do not justify prophylactic surgery without tissue.
06
Risk-reduction fitness assessment
Why
Define surgical, reproductive, bone, cardiovascular and menopausal consequences before preventive intervention.
Interpretation and limitations
Include breast and gynaecological surgical review, fertility goals, reconstruction, DEXA when relevant, psychological support and a plan for premature menopause and HRT eligibility.

04InterventionsLifestyle, treatment and escalation options.

01ReferralBuild the pedigree before orderingFirst stepPersonal or family cancer features suggest inherited breast-cancer susceptibility.

1Collect cancers, ages, bilateral and multiple primaries, ancestry and both parental lineages and verify key pathology or death records where feasible.
2Use current genomic-testing criteria and a validated risk model to determine genetics referral and identify the most informative living affected relative.
3Provide pre-test counselling on possible positive, negative, uncertain and incidental results, data use, family implications and the limits of insurance or direct-to-consumer tests.

02ResultTranslate classification into actionA germline laboratory report returns a pathogenic variant, true negative, uninformative negative or VUS.

1Confirm gene, variant classification, inheritance and phenotype fit with clinical genetics and avoid compressing distinct negative-result meanings into a single reassurance.
2Create a written gene-specific plan covering breast imaging, risk-reducing surgery, ovarian or other organ risk, current cancer treatment and reproductive options.
3For a pathogenic familial variant, support consented cascade communication and targeted testing; for a VUS, continue management from clinical risk and await formal reclassification.

03Breast preventionCompare surveillance, medicine and surgeryA healthy carrier or high-risk person is deciding how to reduce breast-cancer morbidity.

1Estimate age-specific risk and provide the exact MRI and mammography schedule, explaining interval cancer, contrast, false-positive and radiation considerations.
2Discuss tamoxifen or anastrozole where ER-positive prevention is biologically and clinically appropriate, quantifying VTE, uterine, bone and menopausal trade-offs.
3Offer bilateral risk-reducing mastectomy counselling when appropriate, including residual risk, reconstruction, sensation, complications, body image, timing and the option not to operate.

04Ovarian and reproductiveTime prevention around gene and fertilityA BRCA or other relevant carrier is approaching the gene-specific ovarian-risk period or planning a family.

1Provide fertility, pregnancy and preimplantation or prenatal genetics counselling early and discuss how breast-cancer treatment or surgery may affect ovarian reserve and timing.
2Plan risk-reducing bilateral salpingo-oophorectomy after family completion at the gene-specific recommended age, with experienced pathology and peritoneal assessment.
3Explain why CA125 and transvaginal ultrasound do not offer equivalent mortality prevention and prepare bone, cardiovascular, sexual and hormone support for surgical menopause.

05Cancer diagnosisUse germline information during treatmentA patient with current breast cancer meets testing criteria or already carries a pathogenic variant.

1DefinitiveObtain genetics input early enough to inform bilateral surgery, radiation sensitivity, ovarian decisions and systemic treatment rather than after definitive therapy.
2Separate contralateral-risk reduction from treatment of the index cancer and explain that bilateral mastectomy does not treat distant micrometastatic risk.
3Use PARP, platinum or other gene-linked treatment only within the exact tumour, stage and funded indication and maintain cascade and long-term organ surveillance beyond cancer treatment.

05Medicines and treatment safetyRegimens, contraindications and review points.

Reduces ER-positive primary breast cancers without preventive mastectomy and can be used while ovarian function continues.

Tamoxifen for premenopausal risk reduction

Give tamoxifen 20 mg orally once daily for 5 years when preventive treatment is chosen for an eligible premenopausal person at increased breast-cancer risk.

Assess VTE history, abnormal uterine bleeding, pregnancy plans and interacting CYP2D6 inhibitors; provide non-hormonal contraception, investigate uterine symptoms and pause only through an individual perioperative plan.

Lowers oestrogen synthesis and reduces ER-positive breast cancer without tamoxifen-related uterine and thrombotic exposure.

Anastrozole for postmenopausal risk reduction

Give anastrozole 1 mg orally once daily for 5 years when NICE preventive criteria are met in a postmenopausal person and bone and symptom risks are acceptable.

Confirm postmenopausal status, measure and protect bone density when indicated and review arthralgia, vaginal symptoms, lipids and adherence; it does not prevent ER-negative BRCA1-predominant biology reliably.

06Targets, monitoring and follow-upResponse, safety and longer-term review.

Maintain a written lifelong schedule by gene, age and organ and update it after new family diagnoses, pregnancies, surgery, treatment and variant reclassification.
Track MRI and mammography attendance, recalls, biopsies and interval symptoms and ensure a new lump enters triple assessment immediately.
During chemoprevention, review adherence, VTE and uterine symptoms with tamoxifen and bone, joint and menopausal effects with anastrozole.
After risk-reducing mastectomy, review reconstruction, sensation, pain, body image and any residual chest-wall or axillary symptom rather than assuming zero risk.
After premenopausal salpingo-oophorectomy, monitor menopause, sexual function, bone density, cardiovascular risk and HRT plan and retain awareness of small residual primary peritoneal risk.
Recontact families when laboratory classification or national management guidance changes and document who owns this responsibility.
Review cascade uptake and barriers without pressuring disclosure, supporting the tested person with accurate family letters and genetics contact routes.

07Special situationsVariants, exceptions and circumstances that change the usual approach.

Paternal history counts equally

BRCA and most susceptibility variants are autosomal dominant, so few affected women on a paternal side can conceal substantial inherited risk.

Negative has several meanings

A true negative for a known familial variant differs fundamentally from an unaffected uninformative negative when no family mutation has been identified.

VUS is not a surgical indication

Uncertain variants are common on broad panels and must not prompt prophylactic mastectomy or predictive testing until reclassified as pathogenic.

MRI and mammography see different signals

MRI detects vascular enhancement sensitively, while mammography can reveal calcification; gene and age determine how the complementary methods are combined.

Prevention does not become compulsory

A high estimated risk justifies options and support, not coercion; surveillance and surgical choices can change over time with informed preference.

One result can change active treatment

Germline findings may alter bilateral surgery, radiotherapy or systemic options and therefore need clinically useful turnaround during a new cancer pathway.

08Common pitfallsFrequent interpretation and management errors.

01
Taking only a maternal family history or counting only breast cancer.
02
Testing an unaffected person first when an informative affected relative is available.
03
Treating an uninformative negative panel as proof that familial risk is absent.
04
Using a variant of uncertain significance to justify irreversible surgery or cascade testing.
05
Giving every carrier the same screening modality and starting age regardless of gene and age.
06
Using annual ovarian ultrasound and CA125 as an equivalent alternative to proven risk-reducing surgery.
07
Planning premenopausal oophorectomy without fertility, bone, cardiovascular, sexual and hormone support.
08
Assuming bilateral mastectomy eliminates every breast and systemic cancer risk.
09
Waiting until breast treatment ends before obtaining a result that could change surgery or systemic therapy.
10
Disclosing a patient’s genetic result to relatives without consent or a lawful justification.