All right, well, thank you for everyone for allowing me to talk with you all this evening and hopefully this will be brief and just kind of high level in terms of some aspects of uterine sarcomas that I think can be helpful. I have no disclosures. By the end of today's discussion, I hope that you'd be able to describe the classification and features of various uterine sarcomas, understand the key components of the preoperative imaging for uterine mass concerning for sarcoma and understand some key studies concerning for treatment of uterine sarcomas. So first, just some brief background. As you all know, uterine mesenchymal tumors is the overarching category within which uterine sarcomas fall. And tumors are subcategorized as endometrial stromal tumors, tumors of the myometrium, mixed epithelial mesenchymal tumors or otherwise known as biphasic tumors. And then there are some other tumors that don't quite fit elsewhere, such as PCOMA. And also commonly known, lyomyomas are the most common uterine tumor. They are estimated to be clinically apparent in 25% of women and may be found following hysterectomy in up to 85% of reproductive age women and older. On the other hand, uterine sarcomas are quite rare and estimated to have an incidence of 0.5 cases for 100,000 women in the U.S. annually. With that in mind, the frequent concern is for incidentally identified sarcomas at the time of surgery for presumed benign fibroids. In a study from the 1980s, they looked at over 1,400 patients who had a hysterectomy for abnormal uterine bleeding or abdominal pain associated with uterine fibroids. And they determined how many of those patients were found to have a uterine sarcoma on final pathology. As you can see here, you can see that the risk of lyomyoma sarcoma is overall low, but does rise with each decade of life and is higher in the perimenopausal and postmenopausal women. Subsequently, in 2017, the Agency for Healthcare Research and Quality looked at data from 160 studies and determined that unexpected lyomyoma sarcoma occurs in approximately less than one to 13 of every 10,000 surgeries for symptomatic fibroids or symptomatic presumed fibroids. And so most typically, the risk of incidental finding of uterine sarcomas at the time of surgery for benign fibroids is typically quoted at 0.2%. Just some brief information about the various tumors that we're talking about. Low-grade endometrial sarcomas have a variety of appearances, but it's clinically classically tan to yellow color and soft consistency. They're differentiated from endometrial stromal nodules by having LVSI or myometrial invasion. High-grade endometrial stromal sarcomas form an intracavitary polyploid mass, often with hemorrhage and necrosis. And histologically, they are more expansile and infiltrative than we see with low-grade endometrial stromal sarcomas. Undifferentiated uterine sarcomas tend to be a fleshy intracavitary polyploid mass, commonly with hemorrhage and necrosis. And histologically, the cells have marked cellular atypia, numerous mitoses without differentiation towards endometrial stroma. The malignant tumor of the myometrium is the lyomyoma sarcoma, and LMS accounts for 1% of all uterine malignancies, but they are the most frequent malignant mesenchymal tumor of the uterus. Grossly, they usually present as one large dominant mass, often with hemorrhage and necrosis, and have severe nuclear and cytologic atypia, proliferative activity and necrosis. Of the biphasic tumors, adenosarcomas often present with tissue protruding through the cervical os, and the tumor is typically bulky and polyploid, usually involving the uterine fundus. The other biphasic tumor is carcinosarcoma, or malignant biphasic tumor is carcinosarcoma, however, this is no longer grouped with the sarcomas and instead classified with carcinomas. And lastly, picomas, which we won't discuss much here, but they can be considered benign or malignant. So touching on some highlights of preoperative imaging workup, the question is, does imaging help us to distinguish between a benign and malignant process? The first imaging that's typically completed is a pelvic ultrasound, and several sonographic features have been proposed to suggest sarcoma, and these are listed here. Unfortunately, many of these characteristics may also be found in benign leiomyomas. When features of increased vascularity plus large size plus degenerative cystic changes are used to identify sarcomas, the sensitivity ranges from 75 to 100%, but the positive predictive value is as low as 16%. In some studies, these factors did not distinguish between benign and malignant, and so using ultrasound to discern fibroid and sarcoma has had mixed results. And what about MRI? Well, there have been several MRI features that are listed here, which have been shown to correspond with uterine sarcomas. When using these features, the accuracy of MRI is quite high, anywhere from 84 to 94% for detecting uterine leiomyosarcoma and has a high sensitivity and specificity. So in 2022, this consensus paper was published on how to use MRI to assess for the risk of leiomyosarcoma, and in the consensus paper, they first described the MRI features that have strong association with leiomyosarcoma, some of which were mentioned on the previous slide. So first in this picture A, we see that if there's evidence of peritoneal implants, then this is concerning for cancer, not surprisingly. Additionally, in B, if there are abnormal lymph nodes, and that is highly concerning for cancer. In C, we see that if there's a high signal on T2-weighted images, then we should start thinking about it, but it's not definitive. So that's these bright areas are intermediate to high signals on T2-weighted images. And then in D, we see an example of a high DWI signal, which is defined as being equal to or higher than the endometrium. So in this example, we see this. On the left is the tumor compared to the endometrium, so it's equal to or higher than. And then last, sorry, last, the apparent diffusion coefficient, or the ADC, is calculated, and I'll leave that to the radiologist to calculate. But if that is less than 0.905, then that is concerning for malignancy. And so this paper also put out this algorithm that uses those features to gauge their level of concern for malignancy. And if you walk through this algorithm, you can put yourself out on either benign or concerning for malignancy. And so that can be helpful to think through preoperatively. And so just wrapping up, we'll touch on a treatment. For uterine sarcoma, the treatment of uterine-confined disease is often surgical, followed by observation. When it comes to advanced or recurrent disease, the treatment for low-grade endometrial stromal sarcoma and adenosarcoma without sarcomatous overgrowth is primarily centered on surgery and possibly hormonal therapy and radiation therapy, depending on the exact scenario. For high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, Lyme-myosarcomas, and adenosarcomas with sarcomatous overgrowth, beyond stage one, systemic therapy is often a component of treatment. Unfortunately, however, this group of advanced or recurrent uterine sarcomas, the five-year overall survival is less than 30% and likely as low as 12%. Preferred first-line regimens only have an objective response of around 30% with additional therapies that have been studied have reporting around 10% objective response. For over 40 years, treatment of uterine sarcomas has largely been anthracycline-based. In 2009, GEOG performed a single-arm phase two study evaluating the use instead of gemcitabine and docetaxol for the treatment of uterine LMS. Based on RESIST criteria, approximately 36% of patients experience objective response to treatment. As you can see here, the median PFS was 4.4 months, and the median overall survival was 16.1 months. However, myelosuppression was noted as the major toxicity of this regimen with grade three or four neutropenia occurring in 17% of patients. Additionally, 74% experience fatigue, 14% experience GI complaints, and 9% experience pulmonary toxicity. More recently, in 2014, the European Organization for Research and Treatment of Cancer performed a randomized controlled trial comparing doxorubicin to doxorubicin plus diphosphamide. This was a study of soft tissue sarcoma patients, 25% of which had some form of Laumeyer sarcoma, but not necessarily uterine. It wasn't described. There was no significant difference in overall survival, but the median OS was 12.8 months in the control group versus 14.3 months in the experimental arm. The median PFS was significantly higher in the doxorubicin and IFOS group compared to control, with the experimental group having a PFS of 7.4 months compared to 4.6 months. More patients in the doxorubicin IFOS group went into remission and fewer progressed, with an overall response of 14% in the control group compared to 26% in the doxorubicin IFOS group. On the flip side, patients on the experimental arm were more likely to require a dose reduction in our treatment interruption with 32% requiring a dose reduction, and more were likely to discontinue treatment due to toxicity. However, those in the doxorubicin group were more likely to discontinue treatment due to progression. Based on this information, the study concluded that the results do not support the use of intensified doxorubicin and IFOS for palliation of sarcoma, unless there's a specific goal of tumor shrinkage, like when considering its use for neoadjuvant chemotherapy with the goal of later achieving a surgical debulking surgery, surgical debulking. Then in 2017, doxorubicin was compared in a randomized controlled trial to gemcitabine docetaxel. This study showed no difference in PFS or OS, with some taking this data to suggest that doxorubicin should remain the standard first line treatment for most patients with advanced soft tissue sarcomas. However, this study did utilize a lower dose regimen of gemcitabine and docetaxel compared to the previous phase two trial that I showed you, which some suggest may explain the equivalence of these two regimens. However, despite this modified dosing, treatment adherence to gemdosee was inferior to doxorubicin, and patients in the gemdosee group experienced more dose delays, lower dose intensity, fewer cycles of treatment, and more treatment discontinuation due to toxicity. And most recently, a promising study is this French randomized controlled trial evaluating doxorubicin versus doxorubicin and trabectadine, followed by trajectomy maintenance in soft tissue and uterine leiomyosarcoma, with 45% of the patients represented were uterine leiomyosarcomas. In this trial, the combined treatment group experienced a significantly longer PFS of 12.2 months compared to 6.2 months. Overall survival has not yet been assessed, but PFS was their primary endpoint. The combo treatment did experience more dose reductions and more discontinuations due to toxicity. 96% of patients experienced a grade three or four adverse event in the combo group, but this study was the first to show a more robust PFS benefit over single agent doxorubicin. So summarizing those studies, this is not an exhaustive list. There are some other combinations, including with the decarbazine, but you can see here that unfortunately, we see that our frontline regimens are not that effective with very short progression-free survivals and our objective response being overall fairly low. And so with much of cancer treatment, many targeted therapies are acceptable options in select situations. As we discussed at the beginning, the various uterine sarcomas are clinically distinct entities, and as such, they are biologically distinct with many different mutation and gene alteration patterns. Many of the commonly altered genes are biologically relevant but unfortunately, many are not actionable mutations, meaning that these mutations lead to the cancer but are not necessarily effective targets at this point in time, as far as we're aware with treatment. Currently, these are the few exceptions that are first-line potential regimens. For example, there's a rare subset of sarcomas that demonstrate an NTRK rearrangement. If this is identified with next-generation RNA or DNA sequencing or with fish, these tumors can be targeted with NTRK inhibitors. And then PCOMAs have a more predictable mutation in their TCS1 or TCS2 genes, which upregulates the mTOR pathway. And accordingly, mTOR inhibitors like sirulimus can be utilized in this treatment. And then there are several other pathways and mutations being explored as novel targets in the treatment of uterine sarcomas, some of which are pictured here. For example, 25% of biomass sarcomas may demonstrate homologous recombination deficiency, and 10% may have a bracket mutation. Therefore, PARP inhibitors may be an effective treatment option for these select patients, possibly in combination with other agents. And as with these PARP inhibitors, you can see some, including in these emerging studies, include using PARPs in combination with other alkylating agents so that when we're causing this DNA damage, we might be able to have a synergistic effect by inhibiting the DNA repair pathway. Comparatively, unfortunately, uterine sarcomas have shown low rates of microcellulite instability, and only on the order of one to two or MSI high, and often they're understandably similarly TNB low. And as such, immunotherapies have yet to be, to show much effect in sarcomas, with some studies having objective response rates on the order of like 3%. Otherwise, genomic studies in uterine larmor sarcomas have failed to demonstrate consistent oncogenic alterations in the receptor tyrosine kinases. And as such, this is precluded using highly targeted approaches that have had success in some other sarcomas that have more predictable alterations, like in just tumors or dermatofibrosarcomas. Instead, TKIs that are being explored for uterine sarcomas have a more broad activity and are being explored in combination with other agents. So in summary, I hope that you are able to gather that there are several distinct types of uterine sarcomas. Lyomyomas are common, but uterine sarcomas are quite rare. Preoperatively, a well-protocolled MRI may help distinguish lyomyosarcoma from benign fibroids. And unfortunately, advanced and recurrent uterine sarcomas have a poor prognosis. The available treatments have relatively low objective responses, but new targeted treatment regimens are continuing to be evaluated. And then on the Valentine's Day theme, thank you for allowing me to share with you. Thank you so much, Dr. Newton. And I know that you have a meeting, a GOG meeting or SGO committee meeting in two minutes. So anybody have a question for the last two minutes that Dr. Newton will be with us? The second time I heard this is Viet. Thank you so much for that presentation. Could you just quickly comment how you choose patient in a metastatic setting, say lung metastasis, when do you choose to operate instead of chemotherapy? Yeah, in a metastatic setting, I would reserve surgery for a palliative benefit. So if someone was having significant pain, significant bleeding that otherwise couldn't maybe be palliated with radiation, I might consider surgery. Unfortunately, in that setting, our effective treatments are not very effective and a surgery is unlikely to add a significant survival benefit to them. And so at that point, delaying treatment should often just be based on providing added value to their symptom. All right, very good. Thank you, Meredith. Yeah, thank you so much, Meredith. I know that you're gonna run off. I just wanna, you know, the last.

uterine sarcomas

leiomyomas

preoperative imaging

treatment options

research