June 2016, Vol. 5, No. 5
Inherited Ovarian Cancer: What Have We Learned?Genetic Counseling
Compared with other cancers, ovarian cancer is relatively rare, accounting for just 1.3% of all new cancer cases in the United States. However, it has a high death rate—the highest of any female reproductive system cancer. Only around 1 in 7 women with ovarian cancer are diagnosed at the local stage. For these women, the 5-year survival is optimistic at 92%. However, most women present with advanced disease, for which the overall 5-year survival is estimated to be 45%.1 The low survival rate is primarily due to the inability to detect ovarian cancer at an early, curable stage. Whereas the average woman has approximately a 1.5% chance of developing ovarian cancer in her lifetime, a high-risk woman with a BRCA mutation may have anywhere from a 15% to a 68% lifetime risk.2
Screening options for ovarian cancer are extremely limited, and, to date, there are no proven effective surveillance strategies. Both the US Preventive Services Task Force and the American College of Obstetricians and Gynecologists recommend against ovarian cancer screening in the general population.3 For women at high risk who have elected not to proceed with risk-reducing surgery, transvaginal ultrasound with CA-125 levels can be considered every 6 months beginning at age 30 years or 5 to 10 years earlier than the youngest age of ovarian cancer diagnosis in the family.4 Even in this population, however, available surveillance options have not been shown to decrease ovarian cancer morbidity or mortality.3 In fact, it has been suggested that providing women with the option of surveillance for ovarian cancer gives them false hope, and when surveillance is not offered, they are more likely to proceed with risk-reducing surgery.5
Although bilateral salpingo-oophorectomy is a proven ovarian cancer prevention strategy, it is also an invasive procedure, affects quality of life, and may have health hazards. Additionally, for bilateral salpingo-oophorectomy to be effective in high-risk women, they have to be identified, and the majority of women with inherited mutations do not know they have them.6 Moreover, as only 7% to 10% of ovarian cancer cases occur in mutation carriers, this would not be an effective public health strategy to reduce ovarian cancer mortality and morbidity.3 Therefore, additional surveillance and prevention options are needed.
Data have demonstrated that at least some high-grade serous carcinomas originate in the fallopian tube. Therefore, one suggestion is the option of bilateral salpingectomy in premenopausal, high-risk women and for all women at the time of routine gynecologic surgery.3 However, to determine the impact of this procedure in preventing ovarian cancer, the proportion of cancers arising in the fallopian tubes would need to be known. It would also need to be determined if there is a genotypic correlation, so that individuals receive appropriate genetic counseling. Presently, the only proven intervention is bilateral salpingo-oophorectomy. It is essential that new screening and imaging technologies be developed to improve the outcome and quality of life for women at high risk for ovarian cancer.
Due to the high mortality rate and lack of effective surveillance methods, identifying women at increased risk for ovarian cancer is crucial, as it allows them to have the option of risk-reducing surgery. Historically, it was believed that 5% to 12% of invasive ovarian carcinomas were due to hereditary susceptibility.7 The 2 most common hereditary ovarian cancer syndromes were believed to be hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome. HBOC is associated with mutations in the BRCA1 and BRCA2 genes, whereas Lynch syndrome is associated with mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. As has been seen with other disease sites, the availability of multigene inherited cancer tests and their incorporation into clinical practice has altered the understanding of hereditary cancer, and this is also true for ovarian cancer.
Studies continue to demonstrate that BRCA1/2 account for the majority of known inherited epithelial ovarian cancer cases. However, multigene testing options have demonstrated that the remaining identifiable mutations represent a diverse spectrum, with Lynch syndrome typically representing a small percentage of known mutations. This was initially demonstrated in 2011 by Walsh and colleagues, who screened an unselected cohort of 360 women with primary ovarian, peritoneal, or fallopian tube carcinoma for mutations in 21 genes.8 Approximately 1 in 4 (82 of 360) women were found to carry a germline, loss-of-function mutation, and a total of 85 mutations were identified. BRCA1/2 represented 74% of mutations, whereas mutations in genes associated with Lynch syndrome only represented 2% of mutations. The remaining 24% of mutations were found in 9 genes, with the greatest proportion being CHEK2 (5 of 85) and BRIP1 (4 of 85). Since this study was undertaken, several others have reported on the results of inherited cancer panels in specific patient populations. The cohorts analyzed have included those that have particular age of onset and/or family history criteria, those that meet defined clinical criteria, and patient samples submitted to a specific genetic testing company.9
A laboratory cohort presented at the 2014 meeting of the American Society of Clinical Oncology reviewed the mutation spectrum of 263 patients diagnosed with ovarian cancer who were tested with a 25-gene inherited cancer panel. Again, BRCA1/2 accounted for over half the mutations identified (59.6%), and mutations in genes associated with Lynch syndrome represented 5.8%. The remaining 35% of mutations were represented by 8 genes, with the most mutations being identified in ATM, BRIP1, and NBN.10 A cohort from a different laboratory analyzed data for the contribution of 19 genes in a BRCA1/2-negative population of 911 patients with a personal history of breast and/or ovarian cancer. When the patients with breast cancer only were removed from the data set, 558 patients remained (466 with a personal history of ovarian cancer and 92 with a personal history of breast and ovarian cancer). In 41 of these individuals, 42 mutations were found. Unlike the other reported data sets, the most mutations were found to be in the Lynch syndrome genes, followed by BRIP1, CHEK2, and ATM. The common theme in all of these data sets is that a variety of genes have a role in ovarian cancer risk, and simply testing for BRCA1/2 or Lynch syndrome will miss a large percentage of cases.
In addition to the diverse spectrum of mutations found in genes associated with a moderate or high risk of ovarian cancer, multigene testing options have also uncovered expanded phenotypes. In the Walsh study, none of the ovarian cancer patients found to have a mutation associated with Lynch syndrome or Li-Fraumeni syndrome had family histories consistent with the syndromes as currently described in the literature.8 Minion and colleagues also reported on individuals found to have germline mutations in Lynch syndrome genes that did not meet Lynch syndrome clinical criteria, as well as individuals meeting Lynch syndrome clinical criteria who were found to have mutations in other genes associated with increased ovarian cancer risk.11 Therefore, if clinicians rely on a testing strategy that analyze only genes associated with defined clinical criteria associated with a syndrome, they may miss an identifiable mutation.
Many of the genes analyzed in the previously mentioned data sets are part of the homologous recombination (HR) pathway. Cells contain multiple types of DNA repair mechanisms, and one of these is HR, which helps repair DNA damage, including single-stranded DNA, double-stranded DNA breaks, and DNA cross-links. Additionally, HR has a role with DNA replication forks. BRCA1/2 are involved in the repair of DNA double-strand breaks via HR, and studying genes in this pathway has uncovered other genes associated with breast and/or ovarian cancer risk. As BRCA1/2 are involved in the repair of DNA double-strand breaks via HR, cells with BRCA1/2 mutations have a decreased ability to repair double-strand breaks.
Ovarian cancers that have impaired HR ability are more sensitive to poly (ADP-ribose) polymerase, or PARP, inhibitors. PARP inhibitors keep cells from repairing themselves once they have been damaged by chemotherapy.12 Individuals with BRCA mutations start off with cells prone to problems repairing DNA, and PARP inhibitors make it even more difficult for tumor cells to correct themselves. Knowledge of the molecular mechanisms of BRCA1/2 has now permitted therapeutic interventions. On December 19, 2014, the FDA announced the approval of the first PARP inhibitor, Lynparza (olaparib), for patients with germline BRCA1/2 mutations and ovarian cancer who have had 3 or more lines of chemotherapy.13 Additional studies are needed to determine if the use of PARP inhibitors would be beneficial in other genes in the BRCA pathway or in other cancer sites.
- 1 in 4 ovarian cancers have an inherited, genetic component
- Identifying individuals at high risk of developing ovarian cancer is essential so these women can be offered risk-reducing procedures
- As the only effective intervention is bilateral salpingo-oophorectomy—which is an invasive procedure, can result in surgical menopause, and possibly has adverse health effects—new imaging and screening technologies are needed to improve the outcome and quality of life for women at high risk
- Lynparza (olaparib) became the first FDA-approved PARP inhibitor for women with BRCA mutations who have ovarian, fallopian tube, or primary peritoneal cancer and have had ≥3 lines of chemotherapy
- In addition to preventive opportunities, genetic testing for inherited ovarian cancer now has therapeutic implications for high-risk women
- National Cancer Institute. SEER Stat Fact Sheets: Ovary Cancer. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed March 19, 2015.
- Antoniou A, Pharoah PD, Narod S, et al. Average risk of breast and ovarian cancer associated with BRCA1 and BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-1130.
- Daly M, Dresher CW, Yates MS, et al. Salpingectomy as a means to reduce ovarian cancer risk. Cancer Prev Res (Phila). 2015;8:342-348.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. (NCCN Guidelines). Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2014. www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed March 19, 2015.
- van Driel CM, de Bock GH, Arts HJ, et al. Stopping ovarian cancer screening in BRCA1/2 mutation carriers: effects on risk management decisions & outcome of risk-reducing salpingo-oophorectomy specimens. Maturitas. 2015;80:318-322.
- Lancaster JM, Powell CB, Chen LM, et al; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2015;136:3-7.
- Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104:2807-2816.
- Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108:18032-18037.
- Kurian AW, Kingham KE, Ford JM. Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment. Curr Opin Obstet Gynecol. 2015;27:23-33.
- Langer LR, McCoy H, Moyes K, et al. A study of ovarian cancer patients tested with a 25-gene panel of hereditary cancer genes. J Clin Oncol. 2014;32:(suppl). Abstract 1511.
- Minion LE, Dolinsky JS, Chase DM, et al. Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2. Gynecol Oncol. 2015;137:86-92.
- Lupo B, Trusolino L. Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. Biochim Biophys Acta. 2014;1846:201-215.
- FORCE website. FDA review of olaparib. www.facingourrisk.org/our-role-and-impact/advocacy/current-actions/FDA-review-of-olaparib.php. Accessed March 19, 2015.
Multivitamin supplement use was associated with a reduction in chemotherapy-associated peripheral neuropathy in a subanalysis of the SWOG S0221 trial. Patients who were using multivitamins before chemotherapy had 40% less neuropathy, and those using them during or after treatment had a 23% reduced risk. The results were reported at the [ Read More ]
Women with clinicopathologic high-risk breast cancer received chemotherapy almost half as often with no increased risk of metastatic recurrence when a cancer gene assay was used to guide decision-making, results of a randomized trial showed. Patients at low risk by the 70-gene MammaPrint assay had a 5-year distant metastasis-free survival [ Read More ]