Please note! This essay has been submitted by a student.
Although cancer incidence increases with advancing age,many young people are getting diagnosed with cancer every year. Approximately, 40-80% of females experience possible infertility as a result of their cancer treatments . This ontoward experience of gonadotoxic therapy related infertility can lead to psychological stress.With the latest advancements in cryopreservation techniques, female fertility preservation (FP) have now become the standard of care for all young patients diagnosed with diseases that might reduce fertility either naturally or as a result of treatment. Muatation in BRCA 1/2 (breast cancer susceptibility genes 1 and 2) genes increases the chances of developing breast and ovarian cancer later in life. As BRCA genes follows an autosomal dominant pattern of inheritance,chances that a child will be a carrier are 50%, though with variable penetrance.Hence,fertility issues are relevant for healthy BRCA mutation carriers, whose family-planning decisions are often influenced by the need of prophylactic bilateral risk reducing surgeries at young age.
BRCA 1/2 are tumor suppressor genes that belongs to the family of DNA double-strand breaks (DSBs) repair genes and plays a critical role in maintaining the DNA integrity . Mutations in these genes makes female carriers prone to develop breast and ovarian malignancies. There is a fivefold increased risk of developing breast cancer in female carriers harbouring these mutations,also chances of devloping malignancy are approximately 10 years earlier than those with non-hereditary disease.Carriers of mutations in BRCA 1/2 are estimated to have a lifetime risk of 65%–80% for developing breast cancer and up to 20%–45% of developing ovarian cancer .Approximately 5%–10% cases of breast and ovarian cancer are genetic, implying that this germline mutation is inherited in an autosomal dominant manner. In the general population,prevalence of BRCA deleterious mutations is generally 1:300-500 while in Ashkenazi Jews,1:40 is a carrier of one of three deleterious mutations in BRCA (BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT). Non-conservative forms of DNA repair, such as non-homologous end joining are used to repair DSBs when either BRCA1 or BRCA2 is defective.Such repairs are a relatively simple process in which the two broken DNA ends are joined without using a homologous DNA sequence to guide repair, and may therefore result in the introduction of DNA mutations [4,5].
Also controversy exists regarding the fertility potential in this setting of patients. In general, BRCA germline mutations seem to be related to a lower ovarian reserve and thus have a shorter reproductive lifespan compared to women without BRCA mutations. Further,the loss of BRCA function predisposes to DNA damage and subsequent accelerated follicular atresia and apoptotic oocytes .
The fact that women with germline mutation BRCA genes have an increased lifetime risk of developing ovarian and breast cancer is well established . In order to reduce the cancer risk and improve the survival, risk-reduction surgeries should be performed at 25 years old. As women with BRCA mutations are more likely to develop breast cancer at a younger age than ovarian cancer, decision regarding prophylactic risk reduction surgery i,e bilateral risk-reducing mastectomy (BRRM) and risk-reducing salpingo-oophorectomy (RRSO) should be evidenced-based.Risks and benefits of prophylactic surgical procedures should be throroughly narrated and discussed.Generally,to prevent ovarian cancer/fallopian tube cancer in BRCA mutation carriers,RRSO is recommended by 40 years of age or after completion of childbearing.This preventive strategy implies significant limitation in reproductive potential or premature menopause due to treatments received and may further require fertility assistance.
In 2003 the European Society of Human Reproduction and Embryology (ESHRE) ethics taskforce considered PGD acceptable for conditions like hereditary breast and ovarian cancer . Although knowledge regarding PGD for BRCA mutations is growing,its awareness varies among countries and is still persistenly low,especially in developing countries.
For PGD, the woman undergoes ovarian stimulation with subsequent oocyte harvesting, and sperm should be available for in -vitro fertilization (IVF). Once embryos are fertilized via IVF, they are allowed to develop in the embryology laboratory. At day five and/or six of development, the external cells of the blastocyst (trophectoderm cells, destined to become the placenta) can be biopsied and genetically tested for the presence of specific gene, such as BRCA1 or 2 mutations.
Besides the potential effects of PGD in BRCA carrier/mutated,ethical issues surround PGD.Issues regarding BRCA1/2 genes such as incompletely penetrant,their presence does not predict with certainty that the affected person will develop the disease,existing effective treatment and curability potential of the disease, raises concern regarding the ethical practice of PGD. In spite of these arguments, the anxiety and anguish involved in the need for lifetime preventive testing, ethically justifies PGD.
Fertility preservation discussions prior to initiating treatment, and preservation of the ability to have biological children, have been shown to increase quality of life and improve psychological outcomes for cancer patients. In particular, for young women with breast cancer, international guidelines recommend early referral to reproductive endocrinology and infertility specialists (REIs) to discuss reproductive goals. However, there are a number of potential barriers and concerns surrounding fertility preservation and subsequent pregnancy in BRCA carriers with or without a history of cancer including utility, efficacy, timing, and safety of any intervention.Fertility preservation by oocyte/embryo freezing employing specific ovarian stimulation protocols should be discussed. PGD is a medically and ethically acceptable way to eliminate the 50% risk of every offspring to inherit a deleterious BRCA mutation.A multidisciplinary team approach to this sensitive issue is warranted including oncology, reproductive endocrinology as well as psychosocial supportive providers to assist patients and their loved ones in making the best decisions for themselves in their medical and social situations.