BRCA associated Hereditary Breast and Ovarian Cancer Syndromes: Diagnosis, Prevention & Treatment


What is the importance of family history in breast and ovarian cancer?

Relative risk of breast cancer conferred by a First Degree Relative with breast cancer was 2.1. Risk increases with number of affected relatives, age at diagnosis, number of affected male relatives. Studies have shown an odds ratio of 3.1 for the risk of ovarian cancer with atleast one First Degree Relative with ovarian cancer.

They are usually transmitted either through mother’s or father’s side of the family, with an inheritance risk of 50%. Both males and females can inherit and transmit the disease. Not everyone with the predisposition develops cancer (incomplete penetrance and/or gender-restricted or gender-related expression).

Common characteristics of familial cancer

  • Multiple cancers within the family
  • Occur at an earlier age
  • Two or more primary cancers in a single individual
  • Cases of male breast cancer

Family syndromes associated with breast and/or ovarian cancer

  • Breast and Ovary CancerBRCA1BRCA2
  • Breast Cancer: Li Fraumeni (TP53), Cowden (PTEN). ATM, Peutz-Jegher’s
  • Ovary Cancer: Lynch, Gorlin, MEN1

BRCA1 and BRCA2 genes and their clinical implications

Mutations in BRCA1 and BRCA2 are responsible for disease in:

  • 45% of families with multiple cases of breast cancer
  • Upto 90% of families with both ca breast and ca ovary
Location 17q12-21 13q
Type of mutation Germline Germline
Associated malignancy breast, ovary, fallopian tube, male breast, pancreas, testicular, early onset ca prostate Breast, male breast, ovary, prostate, melanoma, pancreas
Function Tumor suppressor gene Tumor suppressor gene

Clinical criteria that predict likelihood of BRCA1 or BRCA2 mutation

Personal history Family history
Early onset breast cancer Multiple cases of breast cancer
Male breast cancer at any age Both breast and ovary cancer
Bilateral breast cancer One or more breast cancers in males
Both breast and ovary cancer Ashkenazi Jewish background

Typical characteristics of breast and ovarian cancer in BRCA mutations

Ca breast in BRCA1 mutation carriers:

  • ER-negative, PR-negative, HER2/neu receptor-negative (Triple Negative) .
  • Basal phenotype

CA ovary in BRCA1 mutation carriers:

  • High-grade
  • Serous histopathology

Breast cancer screening and prevention strategies for BRCA mutation carriers

Breast self examination Monthly self examination beginning in early adult life (18-21y) to establish a regular habit and allow familiarity with normal characteristics of breast tissue.
Clinical breast examination Annual/semi-annually beginning at 25-35 years of age
Annual MRI  25-29y of age
Annual MRI and mammography  Between 30y to 75y of age

Risk Reduction strategies for breast cancer in BRCA mutation carriers

Risk Reducing Mastectomy (RRM)

It may be a Subcutaneous mastectomy in which 90-95% of breast tissue is removed or Simple (total) mastectomy in which nipple-areolar complex is also removed. Bilateral mastectomy reduces the risk of breast cancer by approximately 90%.

Risk Reducing Salpingo-ophorectomy

In this, bilateral ovaries and fallopian tubes are removed after childbearing is complete. Reduction in Ca breast risk of upto 75%.

Most effective strategy is RRM at age 25y and RRSO at age 40 years.


Tamoxifen (synthetic anti-estrogen) reduces the risk of invasive breast cancer by about 50%, mainly in ER positive breast cancer. It also causes 50% risk reduction in BRCA1 mutation carriers & 58% risk reduction in BRCA2 mutation carriers for cancer in contralateral breast. But it is rarely associated with an increased incidence of endometrial cancer and thrombotic events.

Ovarian cancer screening and prevention strategies for BRCA mutation carriers

Transvaginal ultrasound (TVUS)

It has a lower specificity in premenopausal women which can cause difficulty in interpretation.

CA-125 plus an ovarian cancer symptom index

Positive symptom index :bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly, more than 12 times per month occurring only within the prior 12 months.

CA-125 values greater than 30 U/mL are considered abnormal.

Women at inherited risk of ovarian cancer who are carriers of a deleterious BRCA1 mutation should undergo TVUS and serum CA-125 screening every 6 to 12 months, beginning at age of 25 to 35 years.


Risk Reduction strategies for ovary cancer in BRCA mutants

Risk Reducing Salpingo-ophorectomy (RRSO)

In this, bilateral ovaries and fallopian tubes are removed after childbearing is complete.


Oral contraceptives cause significant risk reduction in ovarian cancer risk. Maximum protection is at 3-5 years of use with 36% reduction in risk for each additional 10 years of use. There is no association with breast cancer and use of oral contraceptives formulated after 1975.


Risk of second malignancies in BRCA mutation carriers?

10y risk of developing ca ovary after ca breast in BRCA1 mutation carriers 12.7%
In BRCA2 mutation carriers 6.8%
Lifetime risk of additional breast cancer in BRCA1 mutation carriers 44.1%
In BRCA2 mutation carriers 33.5%
10y risk of subsequent breast cancer after ca ovary in BRCA1 12%
In BRCA2 mutation carriers 2%

Other family syndromes associated with Breast and/or Ovarian cancer

Lynch syndrome

It is an Autosomal Dominant disorder characterized by germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2). This syndrome predisposes to right-sided colon cancer, endometrial cancer, ovarian cancer, renal cancer, ureter cancer, small bowel cancer, pancreatic cancer, etc.

Li-Fraumeni syndrome

It is characterized by germline mutations in TP53 gene. It predisposes to premenopausal breast cancer, childhood sarcoma, brain tumors, leukemia, adrenocortical carcinoma. It is characterised by early age of onset and multiple primaries.

Cowden syndrome

It is caused by germline mutations in PTEN gene. (chr 10q23). It predisposes to bilateral breast cancer with young age of onset, skin disorders like trichilemmomas, oral fibromas, papillomas, acral, palmar and plantar keratoses, and CNS abnormalities like macrocephaly, developmental delay, gangliocytomas of the cerebellum,etc.

Peutz-Jeghers syndrome

It is an Autosomal Dominant disorder caused due to germline mutations in STK11 gene (chr 19p13.3). It may cause melanocytic macules on the lips, or multiple GI polyps (hamatomas and adenomas).

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