Updates on Hereditary Breast Cancer Testing and Management
Advances in genetics provide opportunities to identify individuals who are at increased risk of cancer.
Hereditary cancer syndromes:
- Present at an earlier age
- Cause multiple cancers
- Exhibit rare cancers (e.g., ovarian, pancreatic, metastatic prostate)
- Demonstrate specific types of tumor pathology (triple-negative breast cancer, often seen in BRCA1)
- Tend to affect individuals with particular ethnic backgrounds (e.g., Ashkenazi Jewish ancestry), where BRCA mutations are 10 times more common (1/40)
Approximately, 5-10% of breast cancers are hereditary. Genes conferring high risk include BRCA1/2, CDH1, PALB2, PTEN, and TP53. The genes ATM and CHEK2 are moderate risk. Breast cancer mutations are inherited from either parent in an autosomal dominant way, meaning that parents, siblings, and children of affected individuals have a 50% chance of carrying the mutation. Changes in DNA are called pathogenic variants or mutations.
The best family member to test is the one diagnosed with cancer, especially when found at a young age or because it was rare, like ovarian or pancreatic cancer. Sometimes, when this person is unwilling or unable, first- and second-degree relatives can be tested instead. The importance of patient education and informed consent cannot be overstated. Identifying at-risk family members is essential.
Guidelines for Managing Breast Cancer Risk
The guidelines for managing breast cancer risk fall into three categories:
- Preventive Medication
- Risk-reducing Surgery
Studies of BRCA1/2 patients reported improved cancer detection with an MRI (77-94%) compared with mammography alone (33-59%). Annual MRI starting at age 25, with annual mammography (alternating with MRI every 6 months) starting at age 30, is the best way to detect hereditary breast cancer.
2. Preventive Medication
Oral contraceptives reduce ovarian cancer by 50% with little, if any, associated breast cancer risk. Selective estrogen receptor modulators (tamoxifen and raloxifene) and aromatase inhibitors (anastrazole and exemestane) reduce invasive breast cancer rates by 38-65%.
3. Risk-reducing Surgery
Patients at exceedingly high risk of breast or ovarian cancer may consider risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO). When ovaries and fallopian tubes are being removed, consideration should be given to hysterectomy as well to allow for treatment of menopause with estrogen alone, and not combination estrogen-progesterone. Additionally, both BRCA1 and BRCA2 variants have recently been shown to increase the risk of uterine cancer.
Risk-reducing mastectomy (RRM)
- RRM decreases breast cancer risk by at least 90%.
- A compelling family history may also warrant consideration for this surgery.
- In BRCA carriers, RRSO is associated not only with a 77% reduction in all-cause mortality, but with a 62% reduction in breast-cancer-related mortality.
- RRSO reduces not only ovarian cancer in BRCA carriers by up to 96%, but also breast cancer risk by 50-55% in premenopausal BRCA1 and BRCA2 positive patients.
Genetic testing may affect surgery choices for newly diagnosed cancer patients. BRCA mutations increase the risk of contralateral (opposite) breast cancer; those who choose bilateral over unilateral mastectomy are less likely to die from breast cancer.
Recommendations for Cancer Screening and Management
The table below matches gene variants with cancer diagnoses and screening approaches:
- Genes for which consideration of MRI screening is recommended
- Genes for which discussions about RRM and/or RRSO are recommended
- Those in whom pancreatic cancer screening can be considered
National Comprehensive Cancer Network (NCCN) Recommendations for Breast and Ovarian Screening & Management as a Function of Genetic Variant*
|Breast MRI with contrast*||BRCA1, BRCA2, PTEN, TP53, PALB2, CDH1, STK11, ATM, CHEK2, NF1|
|Consider risk-reducing mastectomy (RRM)||BRCA1, BRCA2, TP53, PTEN, PALB2|
|Consider risk-reducing salpingo- oophorectomy (RRSO)^||BRCA1, BRCA2, BRIP1, RAD51C, RAD51D,MLH1, MSH2, MSH6, PMS2, EPCAM|
|Consider pancreatic cancer screening||.STK11, P16 (independent of FH)|
.BRCA2 (one affected FDR or two family members of any degree)
.PALB2, ATM, BRCA1, MLH1, MSH2, MSH6 (with any affected FDR)
- * = Schedule MRI on days 7-15 of menstrual cycle in premenopausal patients, with age of first MRI dependent on gene variant and FH. Consider tomosynthesis with annual mammogram.
- ^ = Salpingo-oophorectomy is removal of ovaries and fallopian tubes (bilateral)
- FH = family history
- FDR = first-degree relative (mother, sister, daughter)
Whereas certain gene mutations increase the risk of cancer, identification of affected families is improving. Most breast cancer is unrelated to genes, and all patients with or at risk of cancer diagnosis need early consultations with specialists in breast medicine, cancer genetics and, often, psychological support.
Be Strong, Be Healthy, Be in Charge!
Roxanne B. Sukol, MD MS and Holly J. Pederson, MD
Roxanne B. Sukol, MD MS is a staff member of Medical Breast Services at Cleveland Clinic and an Assistant Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of CWRU. Her practice focuses on breast cancer risk assessment and management of patients at high risk, with special interest in prevention of chronic disease.
Holly J. Pederson, MD is the Director of Medical Breast Services at Cleveland Clinic and an Associate Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of CWRU. Her practice focuses on breast diagnostics, breast cancer risk assessment and management of the high risk patient.
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- What Your Family Health History Can Teach You