The Role of Hormonal Replacement Therapy in BRCA Mutated Patients: Lights and Shadows

Simple Summary Advances in molecular genetics have radically changed all aspects of cancer prevention, screening and treatment and, today, women who are suspected of being at risk of hereditary cancer should always undergo genetic counselling. Furthermore, today there is growing attention on the tumor suppressor genes BRCA 1 and BRCA2. In addition, there is growing attention on women who carry mutations of the tumor suppressor genes BRCA 1 and BRCA2 and undergo a prophylactic risk-reducing salpingo-oophorectomy. This paper explores the pathobiology of BRCA1\2 cancer genes in a translational perspective, focusing on molecular aspects of hormonal therapy in early menopausal women as well as on the latest evidence-based guidelines for clinicians. Physicians should counsel motivated patients who ask for relief from early menopausal symptoms about the risks and benefits of hormonal therapy, as well as tailoring and appropriate treatment for selected patients. All cancers develop as a result of mutations in genes. DNA damage induces genomic instability and subsequently increases susceptibility to tumorigenesis. Women who carry mutations of BRCA 1 and BRCA2 genes have an augmented risk of breast and ovarian cancer and a markedly augmented probability of dying because of cancer compared to the general population. As a result, international guidelines recommend that all BRCA1\2 mutation carriers be offered risk-reducing bilateral salpingo-oophorectomy at an early age to reduce the risk of cancer and decrease the mortality rate of this high-risk population. NCCN guidelines recommend risk-reducing bilateral salpingo-oophorectomy in pre-menopausal women, between 35-40 years in BRCA1 mutation carriers and between 40-45 years in BRCA2 mutation carriers. Unfortunately, the well-documented reduction of cancer risk is counterbalanced by early sterility and premature ovarian failure with an early onset of secondary menopausal syndromes such as neuromotor, cardiovascular, cognitive and urogenital deficiency. Hormonal replacement therapy significantly compensates for hormonal deprivation and counteracts menopausal syndrome morbidity and mortality; however, some data suggest a possible correlation between hormonal medications and cancer risk, especially in BRCA1\2 carriers who undergo long-term regimens. Conversely, short-term treatment before the age of natural menopause does not appear to increase the cancer risk in BRCA1 mutation carriers without a personal history of breast cancer after prophylactic surgery. Few data are available on BRCA2 mutation carriers and more well-designed studies are needed. In conclusion, clinicians should propose short-term hormone replacement therapy to BRCA 1 carriers to counteract hormonal deprivation; personalized counselling should be offered to BRCA2 mutation carriers for a balance between the risks and benefits of the treatment.