Kathleen Moore, MD: I mentioned that our understanding of stage in a recurrence and now our emerging understanding of the molecular subtypes is really impacting how we assign adjuvant therapy with the diagnosis of endometrial cancer. You can look at 2 recently published manuscripts that come from different eras to get a sense of this. We’re excited that we saw Gynecologic Oncology Group [GOG] protocol 0209 finally published in 2020 by Dr David Miller. Congratulations.

However, this study was done over a decade ago. They enrolled women with advanced or recurrent disease. These could be patients whom we would consider adjuvant treatment—maybe they had a surgery with a positive node, all the way to stage IV disease. They randomized them to receive paclitaxel and carboplatin, which was the experimental arm at that time, vs the standard of care at the time, which was the triplet of paclitaxel, doxorubicin, and cisplatin given over 2 days. It was a noninferiority design and paclitaxel and carboplatin was found to be noninferior and, therefore, an established standard of care that many of us had moved to already many years ago. But now we have the data to back that up. When you look at the stratification in that study, there was no mention of molecular subtyping. We just weren’t doing that in that era.

Fast-forward to another publication from this year, which was the PORTEC-3 trial. This was a European study that was questioning the benefit of adding chemotherapy to radiation therapy in patients with stage I through III disease as adjuvant therapy. They did extensive molecular profiling as an exploratory analysis in about 500 women. They looked at the markers that I previously mentioned in this module. They looked at loss of TP53, at POLE, and mismatch repair deficiency. They also had a group of patients in whom no significant mutations were found. They looked at the prognostic significance of those 4 classifications then they looked at the significance of those classifications on whether a patient received chemotherapy with their radiation therapy.

As I mentioned previously, the groups definitely were prognostic. When you look at the patients who had loss of TP53, their 5-year recurrence-free survival was only 48%, compared with 98% for women whose tumors had a POLE mutation, 72% for women with mismatch repair deficiency, and 74% for those with no significant mutation noted. There definitely is a prognostic significance associated with TP53 and POLE, 1 negative and 1 positive.

Layered on to that are suggestions of predictive biomarker potential with these markers as well. If you look at the patients with loss of TP53 who did or didn’t receive chemotherapy with their radiation—everyone received radiation—the 5-year recurrence-free survival for chemotherapy was 59% vs only 39% if they only received radiation. This group of patients may receive more benefit from chemotherapy than those who don’t have a loss of a TP53. If you looked at the POLE, they all did so well that it was hard to show a difference. It was 100% vs 97% for chemotherapy vs no chemotherapy. If you looked at the patients with mismatch repair deficiency, it was 68% 5-year recurrence-free survival with chemotherapy vs 76% without. Those are pretty close. The confidence intervals overlap, so it’s probably not significant. The question we need to answer is whether we need to use chemotherapy in that group. Similarly, for those patients with no significant mutation profile, there wasn’t a statistically significant difference in the response.

This is an exploratory analysis so we can’t hang our hat on this, but if you look at the group of patients who have loss of TP53, the difference between 59% and 36% is a striking difference in recurrence-free survival and may give us more insight into who needs adjuvant chemotherapy with or without radiation with endometrial cancer.

If you think back to GOG-0249, which was based on high-intermediate risk criteria and added chemotherapy to radiation vs radiation alone, it did not show a difference in this high-intermediate risk group. Maybe that’s because we were still including a group of patients who were just too low risk for recurrence. It’s really focusing on potentially this group of patients with loss of TP53. That may be the group who needs chemotherapy. That will have to be validated in a study designed around that end point, but this PORTEC-3 exploratory analysis is certainly a step in the right direction. From a practice standpoint, being off–clinical trial gives you some information about when you add chemotherapy and when you potentially don’t need to in these patients. It’s very important information. I’m glad this was published this year.

Transcript Edited for Clarity