BRCA mutation in ovarian cancer.pptx

Ovarian cancer

1. BRCA mutation in ovarian cancer Prepared by: Zul Azmi Sutaji Supervisor: AP Dr Mohamad Nasir Shafiee

2. Outlines Introduction Role of BRCA in ovarian cancer development Implication of BRCA testing in ovarian cancer Role of prophylactic surgery in BRCA mutation patients Oral contraceptives and BRCA mutation carriers Treatment consideration in germline BRCA mutation carriers PARP inhibitors Conclusion

3. Introduction Ovarian cancer: 4 th common women cancer, approximately 700 new cases per year in Malaysia Incidence peak: 45 -70 years old 56% presented at late stage (Stage 3, 4) 90% is epithelial type, which accounts ~70% is in high-grade serous carcinoma (HGSC) form One of the most significant risk factor: genetic mutation of BRCA1/2 gene HGSC highly mutated cancer, 96% most notably had mutation at p53 and BRCA1/2 gene Among women with BRCA1/2 mutation, risk developing ovarian cancer is 44% and 17% respectively 1. Malaysian National Cancer Registry Report 2007-2011 2. Hasmad et a l., (2016)

4. BRCA gene is a tumour suppressor gene, 2 types been identified BRCA1 has the cytogenetic location 17q21, while BRCA2 is 13q12 Both genes produce proteins that important in helping repair damaged DNA due to double-strand break (DSB) by keeping genetic material stable and functional Majority BRCA1/2 mutation leads preferentially to cancer of breast and ovary Women with mutation in BRCA1 or BRCA2 gene have a risk of breast cancer about 5 times, and risk of ovarian cancer about 10-30 times than normal population 1. Kuchenbaecker et al., (2017)

5. Role of BRCA in ovarian cancer development Two mechanisms of BRCA gene action in repair a double-strand break: Non-homologous end joining : Causes open ends of the DNA to attach binding protein and ultimately reconnect the sides of the DNA Homologous recombination : Repairing unaltered reading frame. From the open ends, a single strand 3’ opening is formed BRCA1 is a part of a larger complex molecule that helps to survey the DNA for DSB damage Role of BRCA2 is less clear, but it likely has direct role in repair by assisting the RAD51 complex in attaching to repair site Mutation in BRCA gene mean that the protein that repairs DNA damage changes shape and is non-functional. This can increase the chances of cancer developing Gudmundsdottir et al ., (2006) Yang et at ., (2002) O’Connor et al., (2015)

6. Of all patients who are diagnosed with serous ovarian carcinoma, over 15% will have a germline BRCA mutation (g BRCA mut) present The average cumulative risk of developing ovarian cancer with a BRCA1/2 mutation was 40% and 11% respectively, for those with g BRCA mut Davies et al ., (2001) Antoniou et al ., (2003) Risch et al ., (2001) There is evidence of age discrepancy for onset of disease; BRCA1 mutation – Increase risk after 40 years old BRCA2 mutation – Increase risk after 50 years old This become important when counselling patients regarding options for risk reduction

7. Implication of BRCA testing in ovarian cancer BRCA mutation testing, provide an opportunity to screen family members earlier, and in some cases carry out preventative measures to greatly reduce the risk of developing cancer Some professional guidelines recommended , BRCA mutation testing and genetic counselling should be offered in patient with epithelial ovarian cancer at the time of diagnosis However, testing for germline BRCA mutations in patients with ovarian cancer with mucinous, borderline or non-epithelial histology not recommended because the frequency of BRCA mutations in these group is similar to that in the general population National Comprehensive Cancer Network (NCCN), (2014) Risch et al ., (2006)

8. 1. Neff et al., (2017)

9. Role of prophylactic surgery in BRCA mutation patients for ovarian cancer risk reduction Prophylactic surgery in patients with g BRCA mut has been shown to be beneficial in prevention of ovarian cancer The risk reduction for ovarian cancer is 35–50% with a salpingectomy alone Patients who were at high risk for a breast or a BRCA -related gynaecologic malignancy, that chose risk-reducing salphingo-oophorectomy (RRSO), had a 75% decreased risk of developing ovarian cancer following surgery A large meta-analysis confirmed the significant reduction in ovarian cancer risk among patients with BRCA who undergo an RRSO Falconer et al ., (2015) Kauff et al ., (2002) Rebbeck et al ., (2009)

10. Oral contraceptives and BRCA mutation carriers Oral contraceptive pills ( OCP) have been studied as a type of ‘ chemoprophylaxis ’ shows reduction in risk of ovarian cancer by 50% A meta-analysis confirmed that the benefit of OCP use among patients with a BRCA mutation may be similar or better than the general population However, the use of OCP has to be weighed against the risk of or impact on breast cancer and hormonal manipulation Whether OCP use increases the risk of breast cancer in BRCA mutation carriers is conflicting Narod et al ., (1998) Moorman et al ., (2013) Lee et al ., (2008)

11. Treatment consideration in germline BRCA mutation carriers Currently, surgical tumor debulking followed by adjuvant chemotherapy platinum-based and taxane is the standard treatment for advanced ovarian cancer BRCA -mutant cells have shown higher response rates to platinum-based treatment Therefore, prognosis BRCA1/2 germline mutations were shown to have a definitive improvement in overall survival compared to patients without a mutation For BRCA2 mutation carriers , the mean 5-year overall survival was 52 % compared to 36% in non-carriers Tan et al ., (2008) Bolton et al ., (2012)

12. PARP inhibitor Poly (ADP-ribose) polymerase ( PARP ) is a member of the collection of proteins that aides in the homologous recombination repair of double-strand breaks of DNA In patients with known BRCA1/2 mutations, single-agent treatment with olaparib showed a 63% clinical benefit. Olaparib are proven, the progression free survival was 11 months compare with 4 months in placebo group. Hence, its use in the maintenance setting for patients with recurrent HGSC who are platinum sensitive Fong et al ., (2009) Ledermann et al ., (2014)

13. Rucaparib , a PARP-1/2 inhibitor, was tested in a population with recurrent HGSOC. It was recently approved for use in germline or somatic BRCA mutation patients who have had ⩾2 lines of therapy Niraparib is a third PAR P inhibitor that involves inhibition of PARP-1 , PARP-2 , and PARP-3 . Recently approved niraparib to be used in the maintenance setting for platinum-sensitive HGSOC, regardless of BRCA status FDA grants accelerated approval to new treatment for advanced ovarian cancer (2016) Mirza et al ., (2016)

14. Conclusion Understanding the role BRCA mutations play in the development, treatment response, and prognosis is an exciting and developing area in the treatment of ovarian cancer Identification of a BRCA mutation may not only help the afflicted patient, but also allows for genetic testing to be performed on relatives, allowing for the potential to prevent ovarian cancer PARP inhibition has an opportunity to significantly improve outcomes in women who harbor germline or somatic BRCA mutations, as well as tumors that display a high degree of homologous recombination deficiency