The Korean Society of Gynecologic Oncology, jointly with the International Gynecologic Cancer Society, has declared June as “Uterine Cancer Awareness Month” since 2023 to raise awareness of the seriousness of uterine cancer.

Uterine cancer, one of the top three gynecologic cancers along with ovarian cancer and cervical cancer, has recently become the number one gynecologic cancer due to a sharp increase in incidence.

Unlike cervical cancer, which is screened every two years for adult women over the age of 20, uterine cancer is not included in the national health screening program, remaining a neglected cancer due to the lack of awareness compared to cervical and ovarian cancers.

However, with the recent advent of immuno-oncology drugs, the treatment outcomes of uterine cancer have improved significantly, and the role of immuno-oncology drugs has moved to more advanced stages of treatment, suggesting their potential as backbone drugs.

Korea Biomedical Review interviewed Dr. Kim Jae-weon, professor of obstetrics and gynecology at Seoul National University Hospital and president of the Korean Society of Gynecologic Oncology, about the current status of uterine cancer in Korea and the role of immuno-oncology drugs, which have emerged after 50 years.

Question: What are the causes of uterine cancer and what are its characteristics?

Answer: The underlying cause is still not clearly understood. The problem is that the incidence of uterine cancer is on the rise not only in Korea but worldwide. The increase is more pronounced in developed countries, including Europe, and it is believed that it is due to the advanced living environment, earlier age of menstruation, and lower birthrate. Based on the most recent 2021 cancer registration statistics, there were more than 3,700 new cases of uterine cancer in Korea. This is a more than fivefold increase from the 700 cases 25 years ago.

Most uterine cancers are endometrial cancers, which is why the terms uterine and endometrial are sometimes used interchangeably. A common symptom of endometrial cancer is bleeding, and if you visit your doctor with bleeding, an ultrasound scan will reveal any thickening or protruding masses on the lining of the uterus, and a biopsy will confirm the diagnosis.

Three out of four new cases of endometrial cancer are usually diagnosed in the early stages, and usually stage 1, and surgery can cure more than 90 percent of early cases. However, when detected at an advanced stage, while some can be cured, a significant number of patients experience recurrence, and the five-year survival rate drops significantly for stage 3 or 4 recurrent cancer. Based on data published in 2021, the five-year relative survival rate for locally advanced cases is as high as 80 percent. However, it drops significantly to 35 percent for remote cases that have metastasized to other organs.

Q: Recent national and international guidelines recommend screening for mismatch repair (MMR) defects before treatment for endometrial cancer. Why?

A: MMR testing is a way to help ensure that patients receive the most effective treatment. People with mismatch repair deficiency (dMMR) are more likely to respond well to immuno-oncology drugs like Keytruda (pembrolizumab). Keytruda can also be used in patients with proficient mismatch repair (pMMR), but the combination of drugs used in both cases is different and requires an MMR test to confirm it. Just as PARP inhibitors are more effective in ovarian cancer in patients with BRCA gene mutations, MMR is a biomarker for immuno-oncology use in endometrial cancer.

Q: Given the history of immuno-oncology, development in endometrial cancer seems to have been slow.

A: A related point was made in Nature. If you look at the history of immuno-oncology, it started with melanoma and expanded step by step and now has become available in endometrial cancer. If clinical trials had been conducted in all cancers from the beginning, immuno-oncology would have been available for endometrial cancer much sooner. Recently, there has been some discussion about changing how cancers are categorized so that rare cancers are not discriminated against.

Q: The first immuno-oncology drug developed for endometrial cancer was Keytruda. How have survival rates changed for patients before and after Keytruda?

A: In the past, patients with advanced disease who received first-line treatment with conventional chemotherapy were expected to live about a year, but after Keytruda, survival has increased dramatically. As previously described, immuno-oncology works well in patients with defective mismatch repair (dMMR). In the KEYNOTE-158 study of patients with second-line or higher endometrial cancer, the median overall survival (mOS) was 65.4 months, a median of more than five years. We consider survival of more than five years a cure, so it's remarkable to see a median mOS of more than five years on two or more lines of treatment.

We're also seeing this change at the point of care. Whereas in the past, we didn't hear from most of our patients again after treatment ended, we now hear that they are in a nursing home. We are spending much more time with our patients and seeing a significant improvement in survival rates.

Q: Currently, immuno-oncology drugs are only reimbursed for the second-line treatment or beyond in advanced endometrial cancer in Korea. However, immuno-oncology drugs are already available for first-line treatment in the United States. This is where we’re looking forward to future advances in endometrial cancer treatment.

A: Right. In the U.S., Keytruda was approved in June for the first-line treatment of endometrial cancer as a combination therapy with conventional chemotherapy (paclitaxel + carboplatin). According to the U.S. approval, patients with newly diagnosed advanced or recurrent endometrial cancer, regardless of MMR status, can receive Keytruda combined with carboplatin and paclitaxel, followed by Keytruda alone. In a cohort analysis, progression-free survival (PFS) assessments showed a 70 percent reduction in the risk of disease progression and death in patients with mismatch repair defects (dMMR) and a 40 percent reduction in patients without repair defects (pMMR). This is a very encouraging result, as it confirmed progression-free survival in patients with and without mismatch repair defects.

However, it is not yet approved in Korea. We are waiting for the approval of Keytruda for the first-line treatment of endometrial cancer in Korea soon. As the treatment effect is good, we expect this indication will be approved and treated in Korea shortly. In addition, research is being conducted to add targeted antitumor drugs or antibody-drug conjugates (ADCs) to immuno-oncology drugs so I think there will be even greater advances in the future.

Q: Another immuno-oncology drug, Jemperli (dostalimumab), was recently approved in Korea for treating second-line endometrial cancer. How has that improved the treatment environment?

A: As mentioned earlier, Keytruda can also be used in patients without proficient mismatch repair (pMMR).

In the overall survival evaluation of the KEYNOTE-775 study, the Keytruda-lenvatinib arm demonstrated a 30 percent reduction in the risk of death compared to the chemotherapy arm, suggesting a significant treatment benefit.

Since Keytruda and Jemperli are both immuno-oncology drugs, I don't think there is much difference in side effects. However, in terms of managing side effects, there is a tendency to prioritize the more familiar drug.

Although it is not yet reimbursed, many patients have recently used private insurance to pay for Keytruda. It is unfortunate that even if there is a drug that has a dramatic effect, there are still limitations that prevent people from using it due to cost.