dominant mode and are often characterized by early onset of disease.
1.9. Risks to family members: special consideration
Inheriting BRCA2 or PALB2 mutations from both parents causes specific types of Fanconi anemia. This rare condition is characterized by progressive bone marrow dysfunction, growth delay, variable congenital malformations, a high risk of leukemia and early solid tumors.
A woman and man with a confirmed BRCA2 or PALB2 mutation may therefore consider preconception genetic counseling to clarify the risks their partner has of also carrying a mutation in the same gene.
Current guidelines emphasize the importance of recognizing pancreatic cancer and the risk of prostate cancer associated with BRCA1/2 mutations. The risk of developing pancreatic cancer has been shown to be two to three times higher in patients with BRCA1 mutations and two to seven times higher in patients with BRCA2 mutations, respectively.
1.10. Monitoring
The surveillance recommendations for carriers of deleterious BRCA1/2 mutations according to the NCCN are as follows.
1.10.1. Women
There should be a breast awareness program9 from the age of 18. Clinical examination of the breasts should take place every 6–12 months10 from the age of 25 years and should include:
– breast monitoring11:- 25–29 years of age: annual breast cancer screening with contrast MRI12,13 (or mammography with consideration of tomosynthesis, only if MRI is not available) or individualized screening based on family history if breast cancer is diagnosed before the age of 30,- between 30 and 75 years of age: annual mammography taking into account tomosynthesis and breast MRI screening with contrast,- over 75 years of age: monitoring should be considered on an individual basis,- for women with a BRCA1/2 mutation who are being treated for breast cancer and have not undergone bilateral mastectomy, screening by annual mammography and breast MRI should continue as described above;
– discussing the option of risk-reducing mastectomy: the counseling should include a discussion of the degree of protection, reconstruction options and risks. In addition, family history and residual risk of breast cancer with age and life expectancy should be considered during counseling;
– recommending risk reduction by offering prophylactic14 bilateral adnexectomy (PBA), usually between 35 and 40 years of age and at the end of maternity. For the management of ovarian cancer risk in patients with BRCA2 mutations, it is reasonable to delay PBA until 40-45 years of age (ovarian cancer development in patients with BRCA2 mutations is on average 8-10 years later than in patients with BRCA1 mutations):- guidance includes a discussion of reproductive desires, the extent of cancer risk, the degree of protection against breast and ovarian cancer, management of menopausal symptoms, possible short-term hormone replacement therapy and related medical issues,- bilateral adnexectomy alone is not the standard of care for risk reduction, although clinical trials of bilateral prophylactic interval adnexectomy and delayed oophorectomy are ongoing. The only concern with bilateral adnexectomy is that women are still at risk of developing ovarian cancer. In addition, in premenopausal women, oophorectomy probably reduces the risk of developing breast cancer, but the extent of this reduction is uncertain and depends on gene alteration;
– addressing the psychosocial, social and quality of life aspects of prophylactic bilateral mastectomy and adnexectomy.
For patients who have not chosen PBA, transvaginal ultrasound combined with serum CA-125 for ovarian cancer screening, although of uncertain benefit, may be considered from 30 to 35 years of age.
Appropriate medication (e.g. tamoxifen, raloxifene, anastrozole and exemestane) can almost halve the risk of developing hormone-positive breast cancer. The decision to use such a drug requires discussion of the relative benefits and potential risk of side effects in the context of a woman’s general health, menopausal status and reproductive plans. In addition, the use of PARP inhibitors (e.g. olaparib, niraparib and rucaparib) is a potentially lethal synthetic therapeutic strategy and can be considered as targeted chemoprevention in patients with specific defects in DNA repair including BRCA1/2 mutations.
DEFINITION.– The term mastectomy refers to the surgical removal of all or part of the breast and sometimes the associated lymph nodes and muscles.
DEFINITION.– The term bilateral adnexectomy refers to a surgical procedure that involves the removal of the fallopian tubes and ovaries on both sides of the reproductive organ.
DEFINITION.– The term prophylactic here refers to a medical act that tends to prevent or inhibit the spread or occurrence of a cancerous disease.
1.10.2. Men15
It is recommended to practice breast self-examination from the age of 35.
A clinical breast examination is recommended every 12 months from the age of 35 onwards.
From the age of 45, the recommendations are as follows:
– recommended prostate cancer screening for BRCA2 carriers;
– considered screening for prostate cancer in BRCA1 carriers.
1.10.3. Men and women
People at risk need to be educated to recognize the signs and symptoms of cancer, particularly those associated with BRCA1/2 mutations.
There are no specific guidelines for screening for pancreatic cancer and melanoma, but screening can be individualized according to the cancer types observed in the family16.
1.10.4. Risks to relatives
Relatives should be advised about the possible risks of hereditary cancer, options for risk assessment and management.
It is necessary to recommend genetic counseling and to consider genetic testing for at-risk relatives.
Figure 1.4. Identifying at-risk individuals in the family (by testing family members (adults) who wish to be tested to reassure non-carriers and monitor carriers). The targeted test in the 36-year-old female was positive and the test in the 29-year-old female was negative
1.10.5. Reproductive options
For patients of childbearing age, it is recommended to advise them on options for prenatal diagnosis and assisted human reproduction, including preimplantation genetic diagnosis. The discussion should include the known risks, limitations and benefits of these technologies.
Biallelic mutations in some genes, such as BRCA2 and some other genes included in gene panels, may be associated with rare autosomal recessive conditions. Thus, for these types of genes, partner testing for mutations in the same gene would be considered if it were to be used as a basis for reproductive decision making and/or risk assessment and management.
Figure