Uterine Serous Carcinoma (USC) represents a particularly insidious variant of endometrial cancer, comprising only 10% of diagnoses yet delivering the majority of mortality in the disease due to relentless recurrence and early spread. At Protheragen, we understand the critical need for a new generation of therapies to combat the challenges posed by USC. Our focus is on providing comprehensive preclinical research services to support the development of innovative diagnostics and therapeutics.
Overview of Uterine Serous Carcinoma (USC)
Uterine Serous Carcinoma (USC) is a rare but highly aggressive subtype of endometrial cancer, accounting for approximately 10% of all diagnosed endometrial cancers. Despite its relative rarity, USC is responsible for 40% of endometrial cancer-related deaths. Patients with USC are often diagnosed at earlier stages compared to those with endometrioid subtype endometrial cancer, but they remain at a higher risk of recurrence and have a poorer prognosis. USC is characterized by marked nuclear atypia, abnormal p53 staining in immunohistochemistry, and a high rate of lymphovascular space invasion, nodal involvement, and peritoneal surface involvement, even in early-stage disease.
Fig.1 Human epidermal growth factor receptor 2 (HER2) immunohistochemistry in endometrial serous carcinoma. (Buza N.,
et al., 2021)
Pathogenesis of Uterine Serous Carcinoma (USC)
The pathogenesis of uterine serous carcinoma (USC) draws upon a broad range of genetic and molecular changes. Genomic characterizations led by The Cancer Genome Atlas (TCGA) have placed USC into the "copy number high" subgroup. This subgroup exhibits extensive cell-cycle disturbances—typified by amplifications of CCNE1, MYC, PPP2R1A, PIK3CA, ERBB2, and deletions of CDKN2A—as well as near-universal mutations in TP53 (90%). USC frequently harbors additional perturbations within the PI3K/AKT/mTOR signaling axis and demonstrates HER2 overexpression in roughly 30% to 40% of specimens. Collectively, these aberrations fuel USC’s aggressive phenotype and drive its dismal long-term outcomes.
Diagnostics Development for Uterine Serous Carcinoma (USC)
- Histopathological Diagnosis
Histopathological assessment continues to be the gold standard for establishing the diagnosis of uterine serous carcinoma (USC). Pathologic diagnosis hinges on a triad of defining characteristics: prominent nuclear atypia, a distinctive papillary architectural pattern, and an aberrant p53 protein expression profile observed on immunohistochemical stains. In practice, a panel that includes p53, p16, PAX8, AE1/AE3, CK7, and select adjunct markers enhances diagnostic certainty and differentiates USC from other endometrial neoplasms. Notably, USC demonstrates a striking and uniform membranous positivity for CK7 and AE1/AE3, a finding that assists in the diagnosis.
- Molecular Testing
Molecular testing, chiefly focused on HER2 analysis, is vital for pinpointing those patients who stand to gain the most from targeted therapies. HER2 overexpression or gene amplification appears in around a quarter to a third of all uterine serous carcinoma specimens. To ensure an accurate diagnosis and appropriate patient stratification for these specific therapies, uniform HER2 testing and well-defined scoring guidelines are imperative. Both immunohistochemistry followed by fluorescence in situ hybridization have, to date, served a key role in the reliable identification of HER2-positive tumors and the subsequent initiation of anti-HER2 therapy.
Therapeutics Development for Uterine Serous Carcinoma (USC)
- Targeted Therapies
Currently, discussions in the oncology community are focusing on HER2 inhibitors—such as trastuzumab and SYD985—as well as small-molecule agents that inhibit the PI3K/AKT/mTOR pathway. Clinical trials highlight that HER2-directed interventions yield meaningful gains, translating into extended progression-free and overall survival. Data show that pairing trastuzumab with carboplatin and paclitaxel results in almost a nine-month increase in progression-free survival for patients with advanced HER2-positive tumors.
- Immunotherapies
Immunotherapy—especially the pembrolizumab and lenvatinib pairing—has delivered robust response rates in advanced or recurrent uterine serous carcinoma (USC). Current clinical trials continue to explore a range of immunotherapeutic drugs and combinations for patients with high-risk or recurrent endometrial cancer. Early findings show the pembrolizumab and lenvatinib regimen yielding a response rate of about 50% among USC subjects.
Table 1. Ongoing trials on high-risk endometrial cancer and uterine serous papillary carcinoma. (Bogani G., et al., 2021)
| Agents |
Type of study |
Mechanism of Action |
Participants |
Primary endpoint |
Estimated completion date |
| Atezolizumab (NCT03178842) |
Phase III |
Immunotherapeutic agent (anti-PD-1) |
550 pts. with advanced or recurrent EC, including also USCP |
Overall survival Progression-free survival |
July 2022 |
| Avelumab |
Phase II |
Immunotherapeutic agent (anti-PD-1) |
120 pts. with advanced or recurrent EC, including also USCP |
Progression-free survival |
December 2023 |
| AZD1775 |
Phase II |
Blocks the activity of Weel |
80 pts. with USCP |
Objective response rate, Progression-free survival |
June 2023 |
| Capivasertib |
Phase II |
PIK inhibitor |
11 pts. with endometrial cancer (with PIK3CA) |
Objective response rate |
June 2020 |
| Dostarlimab (TSR-042) |
Phase III |
Immunotherapeutic agent (anti-PD-1) |
470 pts. with advanced or recurrent EC, including also USCP |
Progression-free survival |
February 2026 |
| Durvalumab, Lenvatinib |
Phase II |
Immunotherapeutic agent (anti-PD-1) TKI |
20 pts. with advanced or recurrent EC, including also USCP |
Objective response rate, Progression-free survival |
May 2021 |
| IMGN853, Pembrolizumab (MK-3475) |
Phase II |
Antibody-drug conjugate Immunotherapeutic agent (anti-PD-1) |
35 pts. with USCP (micro satellite stable) |
Objective response rate, Progression-free survival |
October 2023 |
| Niraparib |
Phase II |
PARP inhibitors (maintenance after platinum-based chemotherapy) |
45 pts. with advanced or platinum-sensitive recurrent USCP |
Progression-free survival |
July 2025 |
| Nivolumab (BMS-986205) |
Phase II |
Anti PDL-1, IDO-inhibitor |
45 pts. with advanced or platinum-sensitive recurrent EC, including also USCP |
Overall response rate |
September 2022 |
| ONC201 |
Phase II |
ONC201 targets the G protein-coupled receptor DRD2 |
36 pts. with advanced or recurrent EC, including also USCP |
Objective response rate, Progression-free survival |
October 2022 |
| Pembrolizumab (MK-3475) |
Phase II |
Immunotherapeutic agent (anti-PD-1) |
20 pts. with clinical stage I, grade 3 EC, encompassing endometrioid, serous, and clear cell histologies |
Change in the number of Tumor Infiltrating Lymphocytes |
May 2022 |
| Pembrolizumab (MK-3475) |
Phase III |
Anti-PDL-1 (added to platinum-based chemotherapy) |
810 pts. with advanced or recurrent EC, including also USCP |
Progression-free survival |
June 2023 |
| Selinexor |
Phase III |
XPO1 inhibitors (maintenance after platinum-based chemotherapy) |
248 pts. with advanced or recurrent EC, including also USCP |
Progression-free survival |
March 2023 |
| Trastuzumab |
Phase II |
Anti HER-2 |
61 pts. with advanced or recurrent USCP |
Progression-free survival |
December 2021 |
| VSV-hIFNbeta-NIS, with/without Ruxolitinib |
Phase I |
Oncolytic viral stomatitis virus-human interferon beta-sodium iodide symporter |
77 pts. with advanced or recurrent EC, including also USCP |
Maximum tolerated dose of VSV-hIFNbeta-NIS |
June 2021 |
Abbreviations: EC, endometrial cancer; USPC, uterine serous papillary carcinoma; pts., patients; PD-1, Programmed cell death protein 1; TKI, Tyrosine Kinase Inhibitors; PARP, Poly (ADP-ribose) polymerase; PIK3, phosphatidylinositol-4,5-bisphosphate 3-kinase; IDO, Indoleamine 2,3-dioxygenase; XPO1, Exportin 1.
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers comprehensive services for the development of diagnostics and therapeutics for uterine serous carcinoma (USC). Our services encompass histopathological and molecular diagnostics, targeted therapies, and immunotherapies. We provide state-of-the-art preclinical research services, leveraging advanced technologies and methodologies to accelerate the development of effective therapeutics for USC.
Disease Models
- SARARK, ARK1 or ARK2 CDX Models
- Organoids from Ascites
- Intraperitoneal (IP) Tumor Animal Models
- PIK3CA Mutation Animal Models
Protheragen provides customized services for USC diagnostics and therapeutics development. Our services are designed to meet the unique requirements of each project, ensuring that our clients receive tailored solutions that address their specific needs. We offer comprehensive support throughout the development process, from initial concept to final validation, ensuring that each project is executed with the highest level of precision and efficiency. If you are interested in our services, please feel free to contact us.
References
- Buza, Natalia. "HER2 testing in endometrial serous carcinoma: time for standardized pathology practice to meet the clinical demand." Archives of pathology & laboratory medicine 145.6 (2021): 687-691.
- Bogani, Giorgio, et al. "Uterine serous carcinoma." Gynecologic oncology 162.1 (2021): 226-234.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
