Kathleen Moore, MD: We’ve learned a tremendous amount in the past 3 to 5 years about the importance of molecular profiling in patients with endometrial cancer, both in early stage and, probably more important, for treatment selection in advanced-stage and recurrent-stage disease. We’ll talk a little more about that throughout this module.

What we’ve really learned is that all patients, regardless of stage or histology at the time of diagnosis, must have their tumors tested for mismatch repair [MMR] proteins, plus or minus microsatellite instability, and every institution now has its own algorithms developed. I’m pleased to hear that this has rolled out very quickly both in the community and academic centers, so at least patients with a new diagnosis are having mismatch repair proteins tested. This is important because it identifies patients who are at risk for having Lynch syndrome, which is a genetic predisposition to developing endometrial cancer.

Regardless of risk for recurrence, if we diagnose women who have this genetic predisposition, we can prevent them from developing a colon cancer later in their life through appropriate risk-based screening once we’ve cured them from their endometrial cancer. We can do cascade testing for relatives and try to create “previvors” and do risk-reducing surgeries and screenings that prevent them from ever-developing Lynch-associated cancers, which also includes some ovarian cancers. This is incredibly important from a family testing standpoint and prevention standpoint but also in terms of identification of women who will potentially benefit from immunotherapies. We’ll talk about that a little later in this segment.

The same goes for women who are already advanced, have recurrent disease, or are at high risk for recurrent disease. We are testing everyone for mismatch repair proteins. This is less a must, but many of us are doing next-generation sequencing [NGS] for these patients. There, you get tumor mutational burden, microsatellite instability, and POLE. You also get some less frequent, but very important from a predictive biomarker standpoint, findings of ERBB2 or HER2 amplification, ERBB2 or HER2 mutations are less common but still present, and there are others. ARID1A may be targetable in the future. There are a number of these molecular findings that do impact selection of therapies in the recurrent setting. In the advanced or recurrent setting, next-generation sequencing is certainly warranted.

In terms of thinking about patients who are newly diagnosed and looking at their molecular subtype and histology, we are increasingly understanding the impact on prognosis. For many of you listening to this, it has been a journey. We’ve talked about patients who were intermediate risk if you think back to Gynecologic Oncology Group [GOG] protocol 33, and then high-intermediate risk was determined from GOG-99, based on grade, depth of invasion, and age. We ran clinical trials trying to figure out who was at higher risk for recurrence and how we could impact that recurrence based on risk stratification. Now, when you layer in the molecular profiling on top of that, we have an enriched manner by which we can assess someone’s prognosis and maybe even their appropriateness for adding chemotherapy to radiation therapy in an adjuvant setting based on these molecular subtypes.

When we’re talking about our patients who have loss of TP53, that’s mainly going to be your high-grade serous patients but also some high-grade endometrioid, patients who have POLE, patients who have mismatch repair deficiency, and a group of patients who have no significant mutations identified. The prognosis in each group varies if you use that group of patients with no mutations as the baseline. Our worst prognosis is among patients with loss of TP53. Our best is in POLE. Patients with mismatch repair are somewhat in the middle. We are starting to tailor therapies based on those molecular subtypes and moving a little from our prior way of looking at things by intermediate and high or immediate risk. It’s very much an emerging paradigm for selection of therapy for the right patient.

Transcript Edited for Clarity