Genomic Testing Has Impact on Treatment Decisions in Ovarian Cancer

Author(s):

Genomic testing to guide treatment decisions for women with ovarian cancer is in its early days. However, as more platforms become commercially available, physicians will need to understand the similarities and differences between tests.

Shannon Westin, MD

In November 2017, the FDA approved FoundationOne CDx as a companion diagnostic across multiple solid tumor types. That same month, the agency also approved MSK-IMPACT, a 468-gene assay developed by Memorial Sloan Kettering Cancer Center. Several genomic testing platforms have come on the market since then, each with its own benefits, drawbacks, and unique features.

Westin highlighted the features of some of these tests, all of which perform next-generation sequencing, can detect microsatellite instability (MSI) status and tumor mutational burden, and provide treatment recommendations. Each platform sequences roughly 300 to 600 genes, except for the new GPS Cancer test, which sequences 20,000 genes.

“It's unknown how many of those are actually actionable, but at some point, we may need that kind of information,” said Westin, professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center.

National Comprehensive Cancer Network Guidelines state that for patients who have recurrent ovarian, fallopian tube, or primary peritoneal cancer, tumor molecular testing is recommended prior to initiation of therapy for persistent/recurrent disease. Additionally, validated tests should be performed in a Clinical Laboratory Improvement Amendments-approved facility using the most recent available tumor tissue and include BRCA1/2, homologous recombination pathway genes, and microsatellite instability (MSI) and/or DNA mismatch repair.

The tissue requirements are also similar between platforms. "This is important because you have to know what you need to send and how much tissue these companies need to churn out a good result,” she said. “The majority are going to be around 10 slides and they want at least 20% tumor in those slides.”

The GPS Cancer and Tempus xT platforms offer germline screening. Westin said germline screening is important because it can help physicians determine whether a BRCA mutation is somatic or germline, and help identify other actionable mutations.

“In general, if the mutation is in the germline, it's not as helpful to target,” she said. “BRCA notwithstanding, but with the majority of the other genes we can see mutated, if we know that [mutation] is in the germline, it may not be as actionable as we would hope.”

Following genomic analysis, patients may be eligible to receive PARP inhibition as a treatment as well. Rucaparib (Rubraca) is approved for use in patients with BRCA-positive advanced ovarian cancer who have received ≥2 prior lines of chemotherapy, and olaparib (Lynparza) is available as a treatment for those with BRCA-positive advanced ovarian cancer following treatment with ≥3 or more prior lines of chemotherapy.

Niraparib (Zejula), olaparib, and rucaparib are all approved by the FDA as a maintenance therapy for patients who are in a complete or partial response to platinum-based chemotherapy.

Most recently, in December 2018, the FDA approved olaparib as a maintenance treatment for patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy, as approved by the FDA-approved BRACAnalysis CDx assay.

Westin pointed out that ovarian cancer is an extremely heterogeneous disease that can be serous, mucinous, endometroid, or clear cell, among a host of other characteristics. Nonetheless, most patients are treated with carboplatin and paclitaxel. Genomic testing can help the field move away from the one-size-fits-all approach.

“Maybe now if we can start identifying these abnormalities, we can start being a little bit smarter about how we're treating these patients,” she said. “There are multiple ongoing trials where patients [have] low-grade disease, [and we are looking at] MEK inhibitors, [or] for patients with endometroid tumors looking at PI3-kinase pathway inhibitors, so it does help us to get these tests so we know what we're dealing with.”

The other advantage of molecular testing, she said, is that it can drive participation in clinical trials, particularly umbrella and basket trials. In her presentation, Westin cited a study by Dung T. Le, MD, and colleagues published in the New England Journal of Medicine in 2015. Any patient with mismatch repair deficiency (dMMR) was eligible to receive pembrolizumab (Keytruda) regardless of tumor type.² Results of the study found that responses in patients with MMR-deficient noncolorectal cancer were similar to those of patients with dMMR colorectal cancer (CRC).

“It didn't matter if they had colorectal or noncolorectal [cancer],” she said. “They had a benefit if they had the aberration.”

The results of this study helped lead to the 2017 FDA approval of pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-high or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

Unselected testing in these types of trials can uncover patients who would not be expected to respond to a treatment. Westin noted that 40% of MSI-high patients are found in tumors with frequencies of <2%.

"Many of those patients aren't going to have [the aberration], but for the 2% you identify, they get an impact,” she said. “That's why unselected testing may help.”

References

Westin, SN. PARPi in recurrent ovarian cancer, and the role of somatic tumor testing. In: Proceedings from the 2019 SGO Annual Winter Meeting; January 17-19, 2019; Lake Tahoe, CA.
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520. doi: 10.1056/NEJMoa1500596.