Although genomic profiling successfully identifies those with microsatellite instability status who may benefit from PD-1 inhibitor therapy, a vast amount of women may be missed if they are not also tested for high tumor mutation burden too.
Microsatellite instability-high (MSI) testing alone may not accurately identify all women with recurrent ovarian cancer who would benefit from PD-1 inhibitor therapy, according to study results presented during the 49th Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancers held in New Orleans March 24-27.
In 2017, the Food and Drug Administration (FDA) approved Keytruda (pembrolizumab), a PD-1 inhibitor, to treat MSI-H tumors.
“MSI status in a tumor has really been something that has been a recent focus within the immunotherapy world since pembrolizumab was approved,” Jacqueline Feinberg, M.D., third-year resident at Yale New Haven Hospital and School of Medicine, said in an interview with CURE.
More recently, studies have suggested that tumor mutation burden (TMB) alone may predict responses to PD-1 inhibitors as well. In particular, TMB-high status may have more clout in predicting responses compared with MSI status as an immunotherapy biomarker.
“There actually might be other markers in tumors that can help to predict responses to pembrolizumab,” Feinberg said. “And the biggest one that we focused on was the tumor mutation burden — which is the actual number of mutations that a tumor has – and it has actually been shown in a few other cancers, like lung and bladder cancers, that tumor mutation alone was a good predictor of response to pembrolizumab and other PD-1 inhibitors.”
Therefore, Feinberg and colleagues identified patients most likely to respond to PD-1 therapy using a single comprehensive genomic profiling assay to test 4,140 tumors to simultaneously assess MSI status, TMB and up to 315 genomic alterations.
Overall, 2,872 tumors were either clear cell, endometrioid, mixed type or high grade serous ovarian cancer.
In total, 20.7 percent of endometrioid tumors, 9 percent of clear cell tumors, 9.7 percent of mixed ovarian cancers, and 7.8 percent of high grade serous tumors were TMB-high. Of those, only 6.3 percent were identified as MSI-H.
“Who are these groups of patients that could be missed if we’re only saying MSI status is a marker for response to pembrolizumab?” questioned Feinberg. “There is this big percentage of ovarian tumors that could potentially be responders to pembrolizumab and other PD-1 inhibitors.”
The researchers found just 252 cases of TMB-high and microsatellite stable cases across each histology, of which the most common genomic alterations were BRCA1, ARID1A, TP53, MLL2 and KRAS.
Lastly, endometrioid ovarian cancer appeared to have the highest prevalence of MSI-H and TMB-high status, which means these patients would be most responsive to PD-1 inhibitors, followed by clear cell and mixed ovarian cancers. “The next step of course would be to give PD-1 inhibitors to these patients,” noted Feinberg.
However, the researchers noted that either way, patients with recurrent ovarian cancer should be screen for both TMB and MSI status before considering treatment with PD-1 inhibitors.