BRCA PATHOGENIC/LIKELY PATHOGENIC VARIANT-POSITIVE MANAGEMENT

Breast awareness:
- Starting at age 18 years:
  - Women should be familiar with their breasts and promptly report changes to their health care provider:
    - Periodic, consistent breast self-exam (BSE) may facilitate breast self-awareness
      - Premenopausal women may find BSE most informative when performed at the end of menses

Clinical breast exam, every 6 to 12 months:
- Starting at age 25 years:
  - Randomized trials comparing clinical breast exam versus no screening have not been performed:
    - Rationale for recommending clinical breast exam every 6 to 12 months is the concern for interval breast cancers
Breast screening:
- Age 25 to 29 years:
  - Annual breast MRI screening with contrast:
    - or Mammogram with consideration of tomosynthesis:
      - Only if MRI is unavailable:
        Breast MRI is preferred due to the theoretical risk of radiation exposure in pathogenic /likely pathogenic variant carriers
  - Individualized based on family history if a breast cancer diagnosis before age 30 is present
- Age 30 to 75 years:
  - Annual mammogram with consideration of tomosynthesis and breast MRI screening with contrast:
    - The criteria for high-quality breast MRI include:
      - A dedicated breast coil
      - The ability to perform biopsy under MRI guidance
      - Radiologists experienced in breast MRI
      - Regional availability
    - Breast MRI is preferably performed on:
      - Days 7 to 15 of a menstrual cycle for premenopausal women
- Age greater than 75 years:
  - Management should be considered on an individual basis
- For women with a BRCA pathogenic / likely pathogenic variant who are treated for breast cancer and have not had a bilateral mastectomy:
  - Screening with annual mammogram with consideration of tomosynthesis and breast MRI should continue as described above
    - The appropriateness of imaging modalities and scheduling is still under study. Lowry KP, Lee JM, Kong CY, et al. Cancer 2012;118:2021-2030.
    - Lehman CD, Lee JM, DeMartini WB, et al. Screening MRI in women with a personal history of breast cancer. J Natl Cancer Inst 2016;108.
Discuss option of risk-reducing mastectomy:
- Counseling should include a discussion regarding:
  - Degree of protection
  - Reconstruction options, and risks
- In addition, the family history and residual breast cancer risk with age and life expectancy should be considered during counseling
Recommend risk-reducing salpingo-oophorectomy (RRSO):
- Given the high rate of occult neoplasms:
  - Special attention should be given to sampling and pathologic review of the ovaries and fallopian tubes
- Typically between 35 and 40 years, and upon completion of child bearing
- Because ovarian cancer onset in patients with BRCA2 pathogenic / likely pathogenic variants is an average of 8 to 10 years later than in patients with BRCA1 pathogenic / likely pathogenic variants:
  - It is reasonable to delay RRSO for management of ovarian cancer risk:
    - Until age 40 to 45 years in patients with BRCA2 pathogenic / likely pathogenic variants unless age at diagnosis in the family warrants earlier age for consideration of prophylactic surgery.
  - Counseling includes a discussion of:
    - Reproductive desires
    - Extent of cancer risk
    - Degree of protection for breast and ovarian cancer
    - Management of menopausal symptoms
    - Hormone replacement therapy, and related medical issues
  - Salpingectomy alone is not the standard of care for risk reduction, although clinical trials of interval salpingectomy and delayed oophorectomy are ongoing:
    - The concern for risk-reducing salpingectomy alone is that women are still at risk for developing ovarian cancer
    - In addition, in premenopausal women, oophorectomy likely reduces the risk of developing breast cancer but the magnitude is uncertain and may be gene-specific
Limited data suggest that there may be a slightly increased risk of serous uterine cancer among women with a BRCA1 pathogenic / likely pathogenic variant.
- The clinical significance of these findings is unclear
- Further evaluation of the risk of serous uterine cancer in the BRCA population needs to be undertaken
- The provider and patient should discuss the risks and benefits of concurrent hysterectomy at the time of RRSO for women with a BRCA1 pathogenic / likely pathogenic variant prior to surgery
- Women who undergo hysterectomy at the time of RRSO are candidates for estrogen alone hormone replacement therapy, which is associated with a decreased risk of breast cancer compared to combined estrogen and progesterone, which is required when the uterus is left in situ (Chlebowski R, et al. JAMA Oncol 2015;1:296-305)

Address psychosocial and quality-of-life aspects of undergoing risk-reducing mastectomy and /or salpingo-oophorectomy
For those patients who have not elected RRSO:
- Transvaginal ultrasound combined with serum CA-125 for ovarian cancer screening:
  - Although of uncertain benefit, may be considered at the clinician’s discretion starting at age 30 to 35 years
Consider risk reduction agents as options for breast and ovarian cancer, including discussion of risks and benefits