Bringing Targeted Agents from Clinical Trials to the Clinic for Patients With Uterine Sarcoma

The diagnosis and classification of uterine sarcomas have been improved with the help of molecular profiling, according to a group of experts led by Matthew A. Ingham, MD. The research behind molecular profiling in this area has introduced many new targeted approaches.¹

Years of research have shown that there is an important role for next-generation sequencing to aid the diagnosis and detect genomic alterations that can be treated with targeted therapies. It has also become clearer through research that uterine leiomyosarcoma, a common subtype of uterine sarcoma, is a complex subtype for which novel therapies are needed. Other key components of uterine sarcoma pathogenesis, particularly for the endometrial stromal sarcoma subtype, are gene fusions.

“What we all want to try to do in the world of sarcoma is just understand it and develop new treatment approaches in clinical trials because it's such a rare disease. What the article tries to take home is how can we understand the biology of the disease, what are the genomic alterations or molecular abnormalities, and how we can take advantage of those vulnerabilities. I think that's really where we're trying to go with the field,” said Ingham, assistant professor of Medicine in the Division of Hematology and Oncology at New York Presbyterian Hospital/Columbia University Medical Center, in an interview with Targeted Oncology™.

Looking forward, Ingham et al suggest that preclinical studies assess uterine sarcoma models with consideration of new agents that may improve outcomes for patients.

Ingham explains the uniqueness of uterine sarcomas and how years of research around these tumors have led to advances in precision medicine for patients with uterine sarcoma during the interview.

TARGETED ONCOLOGY: Can you discuss uterine sarcoma and the need for new treatment options?

Ingham: When talking about uterine sarcoma, I think it reflects sarcoma, which means it's a rare disease. Uterine sarcoma has many different subtypes within it, and all these subtypes of uterine sarcoma are quite different biologically and clinically. What we need to do is try to understand them individually, so that we can treat them individually as well.

The most common subtype of uterine sarcoma is leiomyosarcoma, which is a sarcoma that comes from the smooth muscle of the uterus and that accounts for many uterine sarcomas, maybe about 70% to 80%. It's a difficult disease to treat, even after we remove it by surgery. It has a high risk of between 50% and 60% of coming back in the lungs or elsewhere in the body,so, it does have a high rate of metastatic relapse. One of the unmet needs in sarcoma research is to develop better systemic therapies for advanced uterine leiomyosarcoma.

Then the other types of uterine sarcoma are a little bit less common. There are high-grade and endometrial stromal sarcomas, there's a low-grade endometrial stromal sarcoma, and we have less common subtypes, which are adenosarcoma. Sometimes we'll see a type called PEComa, which arises in the uterus. Even after those, there are several ultra-rare uterine sarcomas. I think the challenge is just that it's a collection of rare diseases that are very distinct.

Can you talk about the genomic complexity of these tumors, and how to test these tumors?

In sarcoma, I think we find that molecular testing really can help us in 2 ways. First, it can help us from a diagnostic perspective. Some of the less common uterine sarcomas that I mentioned, like high-grade endometrial stromal sarcoma and low-grade endometrial stromal sarcoma, do harbor some characteristic gene fusions that we would only pick up with molecular testing. Sometimes, these diseases can be difficult to diagnose, just based on histology. I think the first use of molecular testing and sequencing is to help us make sure that we have the right diagnosis, so we can offer the patient the best treatment. The second aspect of it is that sometimes genomic and understanding the molecular basis of the tumor will also help us with treatment selection.

There are a couple of subtypes of uterine sarcoma where we find actionable alterations. For example, if it's PEComa, those tumors are characterized by loss of this gene called tuberous sclerosis [TST2]. It's important to make that diagnosis because they can be very sensitive to target a class of drugs called mTOR inhibitors. There was just a drug that was approved that's very efficacious, and probably much more so than chemotherapy. Then sometimes, we'll also find NTRK fusions, other highly actionable alterations that can help us with targeted treatment. Uterine leiomyosarcoma is a subtype of sarcoma where we have some recurrent genomic alterations, oftentimes, we see p53 and RB deletions. Those are the most common genomic events. Those are a little bit more challenging because we don't have a targeted drug that works directly against those alterations. What we're trying to do is understand the biological effects that some of those alterations have in uterine leiomyosarcoma if we can't target them directly. It seems that what they do is create a high level of replicative stress, and they have homologous recombination deficiency. That does appear that it could be targetable with a novel class of drugs called PARP inhibitors, which I think is 1 of the most recent exciting advances in how we treat uterine leiomyosarcoma.

What have been some of the most exciting clinical trials in this space recently?

To focus on uterine leiomyosarcoma, it is a challenging disease to treat when it's metastatic. We do have some chemotherapy options like doxorubicin and gemcitabine plus docetaxel. Those have kind of been the standard chemotherapy treatment for many years. They do certainly have some efficacy, but also have a fair amount of toxicity. Unfortunately, progression-free survival is relatively short with chemotherapy. I think what we're trying to do in research is understand the biology so that we can develop treatment approaches that are more targeted.

I think probably the most exciting development in the field is that it does seem that a subset of uterine leiomyosarcoma has a defect in their ability to repair their DNA. Many have probably heard about BRCA mutations in ovarian cancer and breast cancer, and what BRCA mutations do is that they impart a vulnerability and sort of a deficiency in the ability of the cancer to repair certain types of DNA damage, and it makes them sensitive to certain targeted treatment approaches with DNA damaging agents. We think that we've kind of found a BRCA-like phenotype in uterine leiomyosarcoma, and that's prompted several clinical trials that are looking at targeted drugs.

We ran a study at Columbia that is a good example of this. The study involves a combination of a PARP inhibitor called olaparib [Lynparza] with a low dose of chemotherapy called temozolomide. In this study, which was mostly patients who had progression on chemotherapy, we found that the treatment offered some activity. The response rate was about 27%, and the median progression-free survival was about 7 months. There are limitations but it seems to compare a little bit favorably to some of the existing drugs that we have after chemotherapy, like trabectedin, or pazopanib. We hope that it is starting to establish proof of principle that these targeted approaches with PARP inhibitors and DNA-damaging agents may be a new class of drugs that could help these patients.

You coauthored of an article that covered novel therapeutics in uterine sarcoma. What is the key takeaway from the article?

What we all want to try to do in the world of sarcoma is just understand it and develop new treatment approaches in clinical trials because it's such a rare disease. What the article tries to take home is how can we understand the biology of the disease, what are the genomic alterations or molecular abnormalities, and how we can take advantage of those vulnerabilities. I think that's really where we're trying to go with the field.

_REFERENCES:

_{Bose S, Schwartz GK, Ingham M, et al. Novel therapeutics in the treatment of uterine sarcoma. Am Soc Clin Oncol Educ Book. 2022 Apr;42:900-909. doi:10.1200/EDBK_350541.}