Hereditary Breast and Ovarian Cancer Syndrome

Hereditary breast and ovarian cancer syndrome is an autosomal dominant predisposition, most often caused by germline BRCA1 or BRCA2 variants, with high lifetime risks of breast, ovarian, fallopian tube and peritoneal cancers. It also raises risks of prostate and pancreatic cancer.

Pathophysiology. BRCA1 and BRCA2 repair double strand DNA breaks by homologous recombination. Loss of the second allele causes genomic instability and cancer, and also confers sensitivity to PARP inhibitors and platinum drugs.

Lifetime risk of breast cancer is about 55 to 70% for BRCA1 and 45 to 70% for BRCA2 carriers. Ovarian cancer risk is about 40% (BRCA1) and 15% (BRCA2).

Risk reducing surgery and surveillance change outcomes, and treatment choices depend on carrier status.

• Breast cancer at a young age, bilateral disease, triple negative cancer in BRCA1
• Ovarian, tubal or primary peritoneal high grade serous cancer
• Male breast cancer, especially BRCA2
• Prostate cancer (aggressive, BRCA2) and pancreatic cancer
• Melanoma and other cancers in BRCA2 families
• Family history across generations, including paternal lines
• No physical signs before cancer

• Genetic testing of BRCA1, BRCA2 and related genes (PALB2, ATM, CHEK2, TP53, others) by multigene panel with deletion and duplication analysis, in people with relevant personal or family cancer history, or ovarian cancer at any age.
• Counselling before and after testing, with family tree assessment.
• Tumour testing for BRCA status in ovarian, breast, prostate or pancreatic cancer to guide treatment.
• Cascade testing of relatives from age 18.

Differential diagnosis.

• Other high penetrance syndromes: TP53 (Li-Fraumeni), PTEN hamartoma tumour syndrome, CDH1
• Lynch syndrome (ovarian and endometrial cancer)
• Moderate risk genes (PALB2, ATM, CHEK2)
• Sporadic breast and ovarian cancer
• Familial clustering without a detectable variant
• Peutz-Jeghers syndrome

• Breast surveillance: yearly breast MRI from 25 to 30 years, with yearly mammography added from 30 to 40 years, to about 70 to 75 years. Clinical examination every 6 to 12 months from 25 years.
• Risk reducing mastectomy: offered from 25 years, with reduction of breast cancer risk by 90% or more.
• Chemoprevention: tamoxifen 20 mg orally once daily for 5 years can be considered in selected BRCA2 carriers who decline surgery (limited evidence in BRCA1).
• Risk reducing salpingo oophorectomy: advised at 35 to 40 years for BRCA1 and 40 to 45 years for BRCA2 carriers, once childbearing is complete. Hormone replacement is acceptable until about 51 years in women without a breast cancer history.
• Men with BRCA2: yearly PSA from 40 years and breast awareness. Pancreatic surveillance with MRI or endoscopic ultrasound in families with pancreatic cancer.
• Treatment of BRCA-related cancers:
  • Olaparib 300 mg orally twice daily for BRCA-associated ovarian, breast, prostate or pancreatic cancer, and for 1 year as adjuvant therapy in high risk HER2-negative early breast cancer.
  • Niraparib 200 to 300 mg orally once daily (by weight and platelet count), rucaparib 600 mg twice daily, or talazoparib 1 mg orally once daily for breast cancer.
  • Platinum chemotherapy (carboplatin) is particularly effective in BRCA-related cancer.
• Reproductive options: prenatal diagnosis and preimplantation genetic testing can be discussed.
• Genetic counselling: 50% chance of the variant for each child, and rare biallelic BRCA2 disease causes Fanconi anaemia.

Special groups.

• Pregnancy and breastfeeding: delay risk reducing surgery until after childbearing, and use MRI without contrast if needed.

Monitoring. Breast MRI yearly, mammography yearly from 30 to 40 years, and ovarian and prostate risk review. Review of risk and surgical options yearly.

Referral and escalation. Refer to clinical genetics and a high risk breast and gynaecology service. Urgent for a breast lump, pelvic mass, ascites, or persistent bloating.