Incorporating Molecular Features into Choosing Adjuvant Therapy

Brad Monk, MD, FACOG, FACS: I’d like to incorporate the molecular features into the selection of adjuvant therapy. Ketta, talk to us a little about PORTEC-4a and the TAPUR trial? Thank you.

Domenica Lorusso, MD, PhD: The PORTEC-3 trial gave us a lot of interesting information. Even though there was retrospective analysis, it suggested that, according to the molecular feature that the tumor presented, the response to treatment may be quite different. In particular, the patients with POLE mutations have a good prognosis; they probably don’t need any adjuvant treatment. On the contrary, the TP53 mutations tumors had a worse prognosis and seem to benefit with chemotherapy. The intermediate prognosis is that the MMR (mismatch repair) deficient population seems not to have such a good response to chemotherapy when we combine chemotherapy plus radiation treatment. These patients would require another kind of treatment, like I/O [immuno-oncology] therapy. The last group—the group with no specific molecular characteristics—gained a little benefit from chemotherapy. Taking in consideration all these aspects, we are designing a new generation of clinical trials that use this information to guide adjuvant treatment. The first trial using this information was the PORTEC-4a trial. It was very interesting because the PORTEC-4a trial was an adjuvant radiotherapy trial for patients with stage I intermediate-risk endometrial cancer. Most of us do not consider radiotherapy a treatment to offer to this patient because it increases local control but has no impact on overall survival. According to only clinical characteristics, we risk overtreating a lot of patients when we offer radiotherapy to all of them.

PORTEC-4a is very interesting because it divides patients into 3 groups according to the molecular characteristic: low risk, intermediate risk, and high risk. The study doesn’t offer any treatment—no radiation—to the low-risk group while offering radiation treatment only to the intermediate- and high-risk groups. This trial represented the first example of a trial that used the molecular characteristics of the tumor to guide adjuvant treatment. It’s the first but not the only 1; a lot of trials are arriving. In particular, there’s a huge international project called the RAINBOW trial. They use different treatments according to the molecular characteristic in the adjuvant setting. In this scenario, patients with tumors who have TP53 mutations receive chemotherapy and then PARP inhibitors for 2 years. Those with MMRD [mismatch repair–deficient] tumors received radiation treatment and then immunotherapy for 1 year. Those with MMSP [malignant melanoma of soft parts] tumors received radiation treatment and hormonal treatment, with adjuvant as maintenance. Those with POLE tumors do not receive any adjuvant treatment, so it’s a completely different way to approach treating endometrial cancer. It is straightforward in the treatment of the disease.

Brad Monk, MD, FACOG, FACS: We’re excited about that. That’s on topic with the adjuvant treatment. There’s another international trial that ENGOT [European Network of Gynaecological Oncological Trial groups] and the GOG [Gynecologic Oncology Group] are collaborating on. It’s called KEYNOTE-B21, and it’s basically taking patients with newly diagnosed endometrial cancer positive nodes—even patients with T53 mutations, to your point about molecular characterization—and treating them with chemotherapy and adding a placebo or pembrolizumab. Radiation is elective. This whole adjuvant space and molecular partitioning are both really important.

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