search

Fertility Issues and Preservation in Brca Mutated/carriers

Download

Please note! This essay has been submitted by a student.

Download PDF

Introduction

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 [1]. 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 and Fertility

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 [2]. 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 [3].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].

Essay due? We'll write it for you!

Any subject

Min. 3-hour delivery

Pay if satisfied

Get your price

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 [6].

Prophylactic Risk Reduction Surgery

The fact that women with germline mutation BRCA genes have an increased lifetime risk of developing ovarian and breast cancer is well established [7]. 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.

Fertility Preservation Strategies

  1. Oocyte &/or embryo cryopreservation. It is the most established and reliable method (after pubertal onset).In order to limit estradiol rise induced by ovarian stimulation, specifically in estrogen sensitive diseases, such as breast or endometrial cancer, specific co-treatment with aromatase inhibitor (letrozole) is currently proposed.There is no increased risk of gynecologic or breast cancers, even in healthy BRCA mutation carriers.
  2. Ovarian tissue cryopreservation. Only strategy allowing for preservation of both fertility and endocrine ovarian function.Considering the general recommendation of bilateral salpingo-oophorectomy before the age of 40 or 5 years, before the age of the earliest case of ovarian cancer in the family, OTC should by itself be questioned. However, if one might consider this option, very young patients would be the best candidates, in particular if embryo/oocyte cryopreservation following controlled ovarian hyperstimulation (COH) cannot be performed.

Preimplantation Genetic Diagnosis (PGD) – Procedure and Ethical Concerns

In 2003 the European Society of Human Reproduction and Embryology (ESHRE) ethics taskforce considered PGD acceptable for conditions like hereditary breast and ovarian cancer [8]. 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.

Conclusion

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.

References

  1. Mahajan N. Fertility preservation in female cancer patients: An overview. J Hum Reprod Sci 2015;8:3-12.
  2. Grynberg M, Raad J, Comtet M, Vinolas C, Cédrin-Durnerin, Sonigo C. Future Oncol. 2018 Feb;14(5):483-490.
  3. Antoniou, A., Pharoah, P. D., Narod, S., Risch, H. A., Eyfjord, J. E., Hopper, J. L.,Easton, D. F. (2003). Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. American Journal of Human Genetics, 72(5), 1117–1130.
  4. Lord, C.J. and Ashworth, A. BRCAness revisited. Nat Rev Cancer. 2016; 16: 110–120.
  5. Prakash, R., Zhang, Y., Feng, W., and Jasin, M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb Perspect Biol. 2015; 7: a016600.
  6. de la Noval BD. Potential implications on female fertility and reproductive lifespan in BRCA germline mutation women. Arch Gynecol Obstet. 2016;294(5):1099–1103.
  7. De Felice F, Marchetti C, Di Pinto A, Musella A, Palaia I, Porpora MG, Muzii L, Tombolini V,Panici PB, Tomao F. Fertility preservation in gynaecologic cancers. Ecancermedicalscience. 2018 Jan 16;12:798.
  8. Shenfield F, Pennings G, Devroey P, Sureau C, Tarlatzis B, Cohen J. ESHRE ethics task force. Taskforce 5: preimplantation genetic diagnosis. Hum Reprod 2003;18:649–651.
72
writers online
to help you with essay
banner clock
Clock is ticking and inspiration doesn't come?
We`ll do boring work for you. No plagiarism guarantee. Deadline from 3 hours.

We use cookies to offer you the best experience. By continuing, we’ll assume you agree with our Cookies policy.