What is the diagnosis and treatment for Hereditary (genetic) Breast Cancer?

From the Guidelines

Genetic breast cancer is primarily linked to mutations in the BRCA1 and BRCA2 genes, which significantly increase a person's risk of developing breast cancer, and management should be guided by the most recent and highest quality evidence, such as the 2021 St. Gallen International Consensus Guidelines for treatment of early breast cancer 1.

Key Considerations

• Women with BRCA1 and BRCA2 mutations have a 45-72% lifetime risk of breast cancer compared to about 12% in the general population.
• Regular screening is essential for early detection, including annual mammograms starting at age 30 and breast MRIs starting at age 25, as recommended by the ESO-ESMO 4th International Consensus Guidelines for breast cancer in young women 1.
• For high-risk individuals, preventive options include chemoprevention with medications like tamoxifen (20mg daily for 5 years) or raloxifene, and prophylactic surgeries such as bilateral mastectomy, which can reduce breast cancer risk by over 90% 1.
• Genetic counseling is strongly recommended before testing to understand implications and options, and should be preceded by consultation with a genetics counselor or other trained professional to assure full discussion of the risks and benefits 1.
• Other genes associated with increased breast cancer risk include PALB2, ATM, CHEK2, and TP53, and lifestyle modifications like maintaining a healthy weight, limiting alcohol, and regular exercise can also help reduce risk.

Management Recommendations

• For survivors harbouring a BRCA1/2 or (other) strongly predisposing mutation, bilateral risk-reducing mastectomy may be considered, although there is no definite evidence that it leads to a survival benefit 1.
• Risk-reducing salpingo-oophorectomy (RRSO) should be discussed from the age of 35 provided that the woman has completed family planning, and for BRCA1 mutation carriers RRSO is recommended between age 35-40 and for BRCA2 mutation carriers around age 40, always respecting patient’s preferences and considering the family history 1.
• Indications and timing of risk-reducing salpingo-oophorectomy for other highly penetrant mutations should follow available international/national guidelines.
• The degree of penetrance of the gene, and the age of the woman with a genetic diagnosis, affected the recommendations for prophylactic mastectomy, and consideration of risk-reducing mastectomy for women harboring highly penetrant genes (e.g. BRCA1, BRCA2, TP53, and PALB2) is recommended 1.

From the Research

Genetic Breast Cancer Overview

• About 5%-10% of breast cancer is hereditary, with BRCA1 and BRCA2 being the most common genes associated with hereditary breast cancer (HBC) 2
• Several additional genes have been associated with HBC, including highly penetrant genes (TP53, PTEN, CDH1, STK11, and PALB2) and moderately penetrant genes (CHEK2, ATM, BARD1, BRIP1, NBN, NF1, RAD51D, and MSH6) 2

Screening and Risk-Reduction Strategies

• Screening breast MRI is recommended for women at >20% lifetime risk, which includes women with mutations in highly penetrant genes and the majority of moderately penetrant genes 2
• Consideration of chemoprevention is recommended for women with mutations in high and moderately penetrant genes 2
• Risk-reducing mastectomy can be considered for women with highly penetrant genes, but is associated with significant morbidities 2
• Alternating magnetic resonance imaging and digital mammography screening is a cost-effective approach for BRCA1 and BRCA2 gene mutation carriers, particularly when started at age 30 3

Surveillance Methods

• Magnetic resonance imaging (MRI) is more sensitive for detecting breast cancers than mammography, ultrasound, or clinical breast examination (CBE) alone in BRCA1 and BRCA2 mutation carriers 4
• A combined sensitivity of 94% for MRI plus mammography has been demonstrated, compared to 39% for mammography alone 5
• Novel imaging modalities, including abbreviated protocol MRI and contrast-enhanced digital mammography, are being investigated for surveillance in unaffected BRCA1/2 mutation carriers 6

Management for BRCA1/2 Mutation Carriers

• Surveillance includes annual magnetic resonance imaging (MRI) and mammogram (MG) for unaffected BRCA1/2 mutation carriers 6
• Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) should be considered for unaffected BRCA1/2 mutation carriers 6
• For BRCA1/2 mutation carriers with breast cancer, breast-conserving therapy (BCT) is an appropriate treatment option, but mastectomy and contralateral risk-reducing mastectomy should be considered to reduce the risk of second primary breast cancer 6