BRCA Focus in Ovarian Cancer Turns to Preventive Testing for Inherited Mutations

Douglas A. Levine, MD

The frequency of hereditary mutations that convey an increased risk of ovarian cancer suggests that many cases of the disease are preventable, according to Douglas A. Levine, MD.

During the 17th Biennial Meeting of the International Gynecologic Cancer Society held in Kyoto, Japan, Levine explained some of the clinical implications of BRCA mutations in patients with ovarian cancer and of carriers of BRCA mutations. DOUGLAS A. LEVINE, MD “All women with ovarian cancer or who have a first- degree relative with ovarian cancer should be tested for BRCA1 and BRCA2 germline mutations,” suggested Levine, the director of the Division of Gynecologic Oncology and head of the Gynecology Research Laboratory at Perlmutter Cancer Center, NYU Langone Medical Center. By testing and gaining a greater understanding of family members with carrier mutations and increased risk, investigators could prevent increased rates of ovarian and other cancers.

In an analysis of genomic sequencing in 390 patients with ovarian carcinomas, germline or somatic mutations in homologous recombination genes were identified in 31% of cases; 24% were deleterious germline mutations, and 9% were somatic mutations.¹ These mutations included one or more of 13 homologous recombination genes, most notably BRCA1/2. Additionally, the rates were similar across both serous and nonserous histologies.

A second study looked at mutational frequency in 1915 cases of ovarian carcinoma and found that 18.1% of patients with ovarian cancer are carriers of germline mutations in genes associated with increased risk for ovarian cancer (Table).² Specifically, 14.6% of patients had mutations in BRCA1/2.

Table. Inherited Mutations in Ovarian Cancer-Associated Genes²

“We have been successful in identifying women at very high risk for ovarian cancer,” he said, as many of the possible drivers of ovarian cancer development are known and able to be identified. These women can then undergo treatment with risk-reducing salpingo-oophorectomy, potentially with added hysterectomy for an added benefit of reducing the risk of breast cancer and aggressive subtypes of endometrial cancer, he noted.

Of the possible drivers of ovarian cancer, Levine calculated that BRCA1/2 mutations and methylation account for about 32% of events. In addition, investigators have identified the distal fallopian tube as a potential common origin point for many ovarian cancers.

According to a multicenter integrated analysis of advanced-stage tumors, about half of high-grade serous carcinomas, which account for 70% to 74% of ovarian cancer cases, are associated with precursor serous tubal intraepithelial carcinoma lesions.³ The implications need to be considered further with additional confirmation; however, the study authors suggested that other proposed precursors for ovarian cancer should also be considered.

Beyond risk-reducing surgery, long-term oral contraceptive use has also shown benefit in reducing the risk of developing ovarian cancer. In an analysis of more than 5000 patients with ovarian cancer from the Ovarian Cancer Cohort Consortium, researchers noted an association with oral contraceptive use.⁴ For those women who used oral contraceptives for 5 to 10 years, the risk of invasive epithelial ovarian cancer was reduced by 23% (relative risk [RR], 0.77; 95% CI, 0.67-0.84), and by 33% (RR, 0.67; 0.58-0.75) for more than 10 years. Additionally, the risk of serous ovarian cancer was reduced by 28% (RR, 0.72; 0.64-0.83) by 5 to 10 years of oral contraceptive use and by 36% (RR, 0.64; 95% CI, 0.54-0.74) by more than 10 years of use.

For women with BRCA mutations, patients in the phase III Gynecologic Oncology Group trials who harbored BRCA2 mutations demonstrated longer progression-free survival (HR, 0.60; P <.001) and overall survival (HR, 0.39; P <.001) rates compared with those without BRCA mutations.2 Additionally, treatment with PARP inhibitors is also helping to improve survival rates for patients with BRCA mutations. “PARP inhibitors are active in both germline and somatic BRCA tumors,” Levine commented.

In the phase II ARIEL2 trial, patients with recurrent, platinum-sensitive, highgrade ovarian carcinoma were classified by BRCA mutation status and genomic loss of heterozygosity. In the BRCA-mutant subgroup, consisting of 40 patients who were treated with rucaparib (Rubraca), responses were seen in patients with germline and somatic mutations. The confirmed objective RR for patients with germline mutations was 85% and 74% for patients with somatic mutations.⁵

Levine suggested that both germline and somatic testing for BRCA mutations will likely become standard of care, especially as a result of PARP inhibition.

References

1. Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20(3):764-775. doi: 10.1158/1078-0432.CCR-13-2287.
2. Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2(4):482-490. doi: 10.1001/ jamaoncol.2015.5495.
3. Ducie J, Dao F, Considine M, et al. Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma. Nat Commun. 2017;8(1):990. doi: 10.1038/s41467-017-01217-9.
4. Wentzensen N, Poole EM, Trabert B, et al. Ovarian cancer risk factors by histologic subtype: an analysis from the ovarian cancer cohort consortium. J Clin Oncol. 2016;34(2):2888-2898. doi: 10.1200/JCO.2016.66.8178.
5. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87. doi: 10.1016/ S1470-2045(16)30559-9.