Britta Weigelt, PhD
Among the main histologic subtypes of epithelial ovarian carcinoma, high-grade serous carcinoma, clear cell carcinoma, and endometroid carcinoma have associated hereditary cancer syndromes with which molecular testing can be used to tease out the best intervention for patients.
In identifying these mutations, it’s important to understand the difference between germline and somatic mutations, said Britta Weigelt, PhD, in a presentation during the 2019 OncLive®
State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma.
At the meeting, Weigelt, director of the Gynecology DMT Research Laboratory at Memorial Sloan Kettering Cancer Center, explained that the presence of both germline and somatic mutations confer potential implications on treatment decisions, although germline mutations carry an added cancer risk.
High-Grade Serous Carcinoma
Approximately 70% of all epithelial ovarian cancers are high grade, and are predominantly characterized by somatic TP53
mutations, with rare somatic mutations in BRCA1/2
, and NF1
. Additionally, high-grade cancers are characterized by high levels of genomic instability measured by the number of copy alterations, said Weigelt.
Homologous Recombination Deficiency
Another common feature of high-grade serous cancers is defects in the homologous recombination DNA repair pathway. Approximately one-third of high-grade serous cancers have germline and somatic mutations in the BRCA1/2
gene, as well as silencing via hypermethylation in BRCA1
. However, there are several other genes that play a role in homologous recombination deficiency, including BRIP1
, and PALB2
, all of which are now accounted for on multi-panel germline tests.
“About 50% of high-grade serous cancers have an alteration or defect in homologous recombination,” said Weigelt.
As such, anyone who has been diagnosed with ovarian cancer, particularly high-grade serous cancer, should undergo testing for germline and somatic mutations in BRCA1/2
as it may indicate eligibility for PARP inhibitor therapy as well as illuminate individual and familial risk of future ovarian and breast cancer.
Exploitation of these vulnerabilities via the use of targeted therapies has resulted in dramatic benefit, explained Weigelt. Specifically, the use of PARP inhibitors has shown to result in significant responses in patients with BRCA1/2
Most recently, olaparib (Lynparza) demonstrated a 70% reduction in the risk of disease progression or death compared with placebo in patients with newly diagnosed, BRCA1/2
-mutant advanced ovarian cancer in the phase III SOLO-1 trial.1
In December 2018, the FDA approved the agent as frontline maintenance therapy for patients with platinum-sensitivity, and either a germline or somatic mutation in BRCA1/2
, joining rucaparib (Rubraca) and niraparib (Zejula) in this indication.
DNA Mismatch Repair Deficiency/Microsatellite Instability
The DNA mismatch repair (dMMR) pathway allows for genomic stability by correcting DNA mismatches generated during DNA replication, said Weigelt. The major proteins housed within the dMMR pathway include MLH1, MSH2, MSH6, and PMS2. If a somatic or germline mutation develops in one of these genes or gives rise to epigenetic silencing, DNA mismatches go uncorrected, leading to an increased mutation rate and microsatellite instability (MSI).
Although the risk varies by study and mutation, women carry a 10% to 12% lifetime risk of developing ovarian cancer and Lynch syndrome if they harbor a germline dMMR mutation versus 1.6% of the overall population.2
Although the risk is of greater variability among women with somatic dMMR/MSI mutations, these mutations have been linked with non-serous clear cell and endometrioid histologies as well as synchronous and metachronous ovarian and endometrial cancer, said Weigelt.
In this context, a dMMR/MSI-H tumor is not only indicative of risk, but of eligibility for immunotherapy. In May 2017, the FDA approved the PD-1 inhibitor, pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic, dMMR/MSI-H solid tumors regardless of histology, becoming the first tumor agnostic approval for patients who have progressed on prior therapy.3
For patients with non-serous, clear cell or endometrioid cancers, Weigelt recommends testing for dMMR via immunohistochemistry as it may indicate amenability to immune checkpoint inhibition. Additionally, a germline mutation in the MMR gene is linked to hereditary non-polyposis colorectal cancer (CRC) or Lynch syndrome. If found, patients should be followed indefinitely as these mutations most commonly manifest in CRC and endometrial cancers.
Among the many ways to test for BRCA1/2
or dMMR/MSI, the MSK-IMPACT assay is commonly used at Memorial Sloan Kettering Cancer Center, said Weigelt. This test, first introduced in November 2017, has the capacity to sequence over 468 cancer related-genes via blood and tissue to extract information about actionable cancer targets, she concluded.
- Moore K, Colombo N, Scambia G, et al. Olaparib maintenance therapy following first-line platinum-based chemotherapy in patients with FIGO stage III–IV ovarian cancer (OC) with a BRCA1/2 mutation (BRCAm): Phase III SOLO1 trial. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA7_PR.
- Jensen KC, Mariappan MR, Putcha GV, et al. Microsatellite instability and mismatch repair protein defects in ovarian and epithelial neoplasms in patients 50 years of age and younger. Am J Surg Pathol. 2008;32(7):1029-1037. doi: 10.1097/PAS.0b013e31816380c4.
- FDA Approves Merck’s KEYTRUDA (Pembrolizumab) for Adult and Pediatric Patients with Unresectable or Metastatic, Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient Cancer. Merck. Published May 23, 2017. https://bit.ly/2rzdPYQ. Accessed April 3, 2019.