RARE DISEASE
Rare uterine cancer
Rare uterine cancer
Rare uterine cancer
Synonyms: Rare cancer of uterus, Rare malignant tumor of uterus, Rare uterine malignant tumor
Synonyms: Rare cancer of uterus, Rare malignant tumor of uterus, Rare uterine malignant tumor
Synonyms: Rare cancer of uterus, Rare malignant tumor of uterus, Rare uterine malignant tumor
Drug discovery
1
drug
With orphan designation
Overview
Rare uterine cancers encompass aggressive histologies like uterine serous carcinoma, clear-cell carcinoma, carcinosarcoma, and sarcomas (leiomyosarcoma, endometrial stromal sarcoma), representing <5% of uterine malignancies [1][15][20]. These tumors often present at advanced stages, resist standard therapies, and account for >70% of uterine cancer mortality [8][11].
Burden
5-year survival: 35-55% for sarcomas vs 81% overall for endometrial cancer [1][11][15]
Responsible for ~3.1/100,000 deaths annually; non-Hispanic Black women experience 9.5/100,000 mortality (vs 4.7 in White women) [2][7][19]
DALY rates increased 40% globally (1990-2019), driven by aging populations and obesity [4][11][13]
Therapies
Primary: Total hysterectomy with BSO ± lymph node assessment [1][10][16]
Adjuvant: Platinum-based chemotherapy (carboplatin/paclitaxel) ± radiation; targeted therapies (lenvatinib/pembrolizumab) for advanced dMMR/MSI-H tumors [12][16]
Emerging: RNR inhibitors (gemcitabine) for PP2A-mutant serous carcinoma; HER2-directed therapies in clinical trials [3][12]
Categories: rare gynecological and obstetric diseases, rare neoplastic diseases
Research Papers
920 drug discovery papers about Rare uterine cancer, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
920 drug discovery papers about Rare uterine cancer, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-14 | Case Report: A case series on actionable genomic alterations guiding effective targeted therapy in rare sarcomas.
Advanced sarcomas have limited systemic therapy options, but genomic profiling can uncover actionable mutations. This case series illustrates the promise and limitations of next-generation sequencing (NGS) and targeted therapies in clinical practice across three sarcoma histologies. Case 1: A 36-year-old woman received local therapies for an angiosarcoma in her breast. Six months later, she developed osseous metastatic disease, and NGS revealed a GOPC-ROS1 fusion. She had a partial response to crizotinib. This ROS1 inhibitor and one course of radiation for oligometastatic progression controlled her disease for 12 months. Subsequent lines of therapy included pembrolizumab for high PD-L1 status, with suspected hyperprogression. Repotrectinib was trialed to overcome her ROS1 G2032R resistance mutation, but it had limited efficacy. She ultimately succumbed to her disease. Case 2: A 30-year-old woman with Neurofibromatosis Type 1 developed a high-grade, ALK-rearranged peripheral malignant nerve sheath tumor at her left antecubital fossa. Following resection, pulmonary metastases were identified. RNA transcriptome analysis revealed an EML4-ALK rearrangement. She had a prolonged partial response to alectinib. The ALK inhibitor and two courses of radiation for oligoprogression have continued to control her disease at 48 months. Case 3: A 51-year-old woman with uterine leiomyosarcoma developed pulmonary metastases shortly after completing adjuvant radiation. NGS revealed a BRCA2 deep deletion. After progressing on multiple lines of systemic therapies, her widely metastatic disease has been controlled for 62 months with niraparib and local therapies for oligoprogression. Three patients with advanced sarcomas achieved partial responses to NGS-guided targeted therapies, with disease control lasting from 1 to over 5 years. Two cases involved novel, targetable mutations not previously identified in these sarcoma subtypes. However, the limitations of targeted therapies are highlighted by one patient's lack of response to a novel ROS1 G2032R-directed treatment, and another patient's repeated oligometastatic progression despite using an ALK inhibitor without resistance mutations. Simply suppressing a driver-mutation clone with targeted therapy may be insufficient for long-term disease control in sarcoma. Local therapies can be critical adjuvants in achieving improved outcomes for aggressive sarcomas. We recommend careful consideration of NGS testing for all sarcomas as we continue to explore their vast mutational landscape, response to targeted therapies, and mechanisms of resistance.
2026-07-10 | A High-Fidelity and Ancestrally Inclusive Patient-Derived Organoid Platform Resolves Cancer Cell Plasticity in Uterine Carcinosarcoma.
Uterine carcinosarcoma (UCS) is a rare but extremely lethal endometrial cancer that metastasizes early and resists current treatment modalities. It is biphasic, built from malignant epithelial and mesenchymal cells. Genomic studies indicate that these tumors are clonal, and that the mesenchymal cells arise from the epithelial cells through cancer cell plasticity. This biology has been hard to study, because faithful patient-derived models are scarce. The gap is widened by inequity. Women of African ancestry carry the greatest burden of UCS, yet are underrepresented in existing models. To address this, we established patient-derived organoids (PDOs) from an ancestrally inclusive UCS cohort, alongside matched normal endometrial PDOs. The organoids reproduced the biphasic histology of the original tumors. Across four sequencing platforms, they retained the tumor mutation and copy-number landscape, remained stable across passages, and expanded for up to 28 months. At single-cell resolution, UCS PDOs captured both malignant compartments and traced continuous transcriptional trajectories along the epithelial-to-mesenchymal axis, capturing patient-specific cancer cell plasticity. The models also nominated candidate vulnerabilities in proof-of-concept therapeutic testing. UCS PDOs were enriched for CREB-family transcriptional programs, and CREB inhibition reduced their viability. Combined FGFR and YAP inhibition outperformed either agent alone. Together, this work delivers a histologically, genomically, and transcriptionally faithful, ancestrally inclusive, and lineage-resolved UCS organoid platform for studying cancer cell plasticity and its vulnerabilities in an aggressive and inequitably burdened cancer.
2026-07-03 | Integrative analysis of small cell carcinoma of the uterine cervix reveals its heterogeneity and provides novel predictive markers.
Small cell carcinoma of the uterine cervix (UCSCC) is a rare and aggressive HPV-linked neuroendocrine malignancy with limited therapeutic options and poor prognosis. Through integrative analysis of whole-exome sequencing (WES), single-cell RNA-seq (scRNA-seq), PinpoRNA-HPV, bulk RNA-sequencing, and immunohistochemistry (IHC), we delineated its molecular architecture. Genomic profiling unveiled the dysregulation of 10 core oncogenic pathways and an exceptionally high tumor mutational burden (TMB), along with frequent alterations in DNA repair genes. ScRNA-seq analysis identified nine distinct malignant subclusters characterized by lineage plasticity (ASCL1/NEUROD1/UCHL1) alongside active HPV18 transcription. The tumor microenvironment exhibited a paradoxical immune landscape: dense infiltration of CD8+ T cells and CD163+ tumor-associated macrophages (TAMs) in the complete absence of tumoral PD1/PD-L1 expression. Cell-cell communication analysis revealed that malignant subclusters specifically overexpress CD47, engaging SIRB1 on TAMs and SIRPG on T cells. IHC validation confirmed a CD8+/CD163+/PD-L1-phenotype and demonstrated that transcriptional CD47 enrichment in malignant clones implicated the CD47-SIRB1 axis as the primary immune checkpoint. These findings indicated UCSCC as an HPV-driven, heterogeneous tumor that might employ CD47 as an alternative immune evasion pathway in the absence of PD-L1, providing a strong rationale for exploring CD47 blockade as a novel potentially therapeutic strategy.
2026-06-29 | Unusual morphologic features in molecularly defined high-grade sarcomas of the uterus.
Herein we describe unusual or rare morphologic features in two high-grade uterine sarcomas with novel or uncommon genetic alterations, to bring attention to their morphologic diversity, diagnostic challenges, and potential therapeutic implications. We report an uterine sarcoma with a FGFR1::TACC1 fusion, the third reported case in the literature, exhibiting epithelioid morphology not previously documented and negativity for S100 and CD34 immunohistochemistry (IHC). We also report an uterine sarcoma with a novel ACOT7::ERBB4 fusion, which displayed spindle cell morphology and osteosarcomatous differentiation. S100 and SOX10 IHC were both negative. Molecular testing was highly informative in reaching a diagnosis in both cases, due to the unusual morphology and limited immunohistochemical support. Clinical follow-up revealed aggressive behavior in both cases, demonstrated by rapid disease progression and metastatic spread. These two cases expand on the known histologic and molecular spectrum of uterine mesenchymal neoplasms with tyrosine kinase receptor gene fusions. Recognition of these entities is important for appropriate classification, prognostication, and identification of patients eligible for targeted therapies such as TRK or FGFR inhibitors.
2026-06-23 | Fertility-sparing strategy in a rare case of uterine adenosarcoma and consecutive spontaneous pregnancy and livebirth.
We present the rare case of a 29-year-old patient with uterine adenosarcoma who received fertility-sparing treatment, subsequently conceived spontaneously, and gave birth to a healthy infant. In August 2022, the nulliparous patient presented with acyclic uterine bleeding. Diagnostic hysteroscopy and targeted resection of a polyp located at the cervicouterine junction revealed uterine adenosarcoma without sarcomatous overgrowth (FIGO stage T1a). Imaging confirmed no residual tumor or metastasis. A fertility-sparing management strategy was chosen, avoiding hysterectomy but involving close oncological surveillance with quarterly MRI scans. During follow-up, a concurrent diagnosis of symptomatic endometriosis introduced therapeutic challenges. The patient spontaneously conceived in 2023 and delivered a healthy infant by cesarean section at term in 2024. Subsequent hysteroscopy and imaging in 2025 showed no evidence of recurrence, therefore fertility-preserving management was continued. A short narrative of the patient's perspective on her initial diagnosis, possible fertility loss, and the emotional turmoil of pregnancy after uterine adenosarcoma is presented. Treating young patients diagnosed with uterine adenosarcoma poses a challenge to the treating physician due to the lack of guidelines and evidence regarding fertility-preserving treatment of this rare tumor. This report adds to the limited literature on successful pregnancy after uterine adenosarcoma and discusses indications and limitations of fertility-sparing treatment. Fertility preservation may be possible in selected early-stage uterine adenosarcoma cases without high-risk features such as sarcomatous overgrowth or myometrial invasion, with thorough counseling and strict follow-up. Further research is needed to develop standardized protocols and improve management in this context.
2026-07-14 | Case Report: A case series on actionable genomic alterations guiding effective targeted therapy in rare sarcomas.
Advanced sarcomas have limited systemic therapy options, but genomic profiling can uncover actionable mutations. This case series illustrates the promise and limitations of next-generation sequencing (NGS) and targeted therapies in clinical practice across three sarcoma histologies. Case 1: A 36-year-old woman received local therapies for an angiosarcoma in her breast. Six months later, she developed osseous metastatic disease, and NGS revealed a GOPC-ROS1 fusion. She had a partial response to crizotinib. This ROS1 inhibitor and one course of radiation for oligometastatic progression controlled her disease for 12 months. Subsequent lines of therapy included pembrolizumab for high PD-L1 status, with suspected hyperprogression. Repotrectinib was trialed to overcome her ROS1 G2032R resistance mutation, but it had limited efficacy. She ultimately succumbed to her disease. Case 2: A 30-year-old woman with Neurofibromatosis Type 1 developed a high-grade, ALK-rearranged peripheral malignant nerve sheath tumor at her left antecubital fossa. Following resection, pulmonary metastases were identified. RNA transcriptome analysis revealed an EML4-ALK rearrangement. She had a prolonged partial response to alectinib. The ALK inhibitor and two courses of radiation for oligoprogression have continued to control her disease at 48 months. Case 3: A 51-year-old woman with uterine leiomyosarcoma developed pulmonary metastases shortly after completing adjuvant radiation. NGS revealed a BRCA2 deep deletion. After progressing on multiple lines of systemic therapies, her widely metastatic disease has been controlled for 62 months with niraparib and local therapies for oligoprogression. Three patients with advanced sarcomas achieved partial responses to NGS-guided targeted therapies, with disease control lasting from 1 to over 5 years. Two cases involved novel, targetable mutations not previously identified in these sarcoma subtypes. However, the limitations of targeted therapies are highlighted by one patient's lack of response to a novel ROS1 G2032R-directed treatment, and another patient's repeated oligometastatic progression despite using an ALK inhibitor without resistance mutations. Simply suppressing a driver-mutation clone with targeted therapy may be insufficient for long-term disease control in sarcoma. Local therapies can be critical adjuvants in achieving improved outcomes for aggressive sarcomas. We recommend careful consideration of NGS testing for all sarcomas as we continue to explore their vast mutational landscape, response to targeted therapies, and mechanisms of resistance.
2026-07-10 | A High-Fidelity and Ancestrally Inclusive Patient-Derived Organoid Platform Resolves Cancer Cell Plasticity in Uterine Carcinosarcoma.
Uterine carcinosarcoma (UCS) is a rare but extremely lethal endometrial cancer that metastasizes early and resists current treatment modalities. It is biphasic, built from malignant epithelial and mesenchymal cells. Genomic studies indicate that these tumors are clonal, and that the mesenchymal cells arise from the epithelial cells through cancer cell plasticity. This biology has been hard to study, because faithful patient-derived models are scarce. The gap is widened by inequity. Women of African ancestry carry the greatest burden of UCS, yet are underrepresented in existing models. To address this, we established patient-derived organoids (PDOs) from an ancestrally inclusive UCS cohort, alongside matched normal endometrial PDOs. The organoids reproduced the biphasic histology of the original tumors. Across four sequencing platforms, they retained the tumor mutation and copy-number landscape, remained stable across passages, and expanded for up to 28 months. At single-cell resolution, UCS PDOs captured both malignant compartments and traced continuous transcriptional trajectories along the epithelial-to-mesenchymal axis, capturing patient-specific cancer cell plasticity. The models also nominated candidate vulnerabilities in proof-of-concept therapeutic testing. UCS PDOs were enriched for CREB-family transcriptional programs, and CREB inhibition reduced their viability. Combined FGFR and YAP inhibition outperformed either agent alone. Together, this work delivers a histologically, genomically, and transcriptionally faithful, ancestrally inclusive, and lineage-resolved UCS organoid platform for studying cancer cell plasticity and its vulnerabilities in an aggressive and inequitably burdened cancer.
2026-07-03 | Integrative analysis of small cell carcinoma of the uterine cervix reveals its heterogeneity and provides novel predictive markers.
Small cell carcinoma of the uterine cervix (UCSCC) is a rare and aggressive HPV-linked neuroendocrine malignancy with limited therapeutic options and poor prognosis. Through integrative analysis of whole-exome sequencing (WES), single-cell RNA-seq (scRNA-seq), PinpoRNA-HPV, bulk RNA-sequencing, and immunohistochemistry (IHC), we delineated its molecular architecture. Genomic profiling unveiled the dysregulation of 10 core oncogenic pathways and an exceptionally high tumor mutational burden (TMB), along with frequent alterations in DNA repair genes. ScRNA-seq analysis identified nine distinct malignant subclusters characterized by lineage plasticity (ASCL1/NEUROD1/UCHL1) alongside active HPV18 transcription. The tumor microenvironment exhibited a paradoxical immune landscape: dense infiltration of CD8+ T cells and CD163+ tumor-associated macrophages (TAMs) in the complete absence of tumoral PD1/PD-L1 expression. Cell-cell communication analysis revealed that malignant subclusters specifically overexpress CD47, engaging SIRB1 on TAMs and SIRPG on T cells. IHC validation confirmed a CD8+/CD163+/PD-L1-phenotype and demonstrated that transcriptional CD47 enrichment in malignant clones implicated the CD47-SIRB1 axis as the primary immune checkpoint. These findings indicated UCSCC as an HPV-driven, heterogeneous tumor that might employ CD47 as an alternative immune evasion pathway in the absence of PD-L1, providing a strong rationale for exploring CD47 blockade as a novel potentially therapeutic strategy.
2026-06-29 | Unusual morphologic features in molecularly defined high-grade sarcomas of the uterus.
Herein we describe unusual or rare morphologic features in two high-grade uterine sarcomas with novel or uncommon genetic alterations, to bring attention to their morphologic diversity, diagnostic challenges, and potential therapeutic implications. We report an uterine sarcoma with a FGFR1::TACC1 fusion, the third reported case in the literature, exhibiting epithelioid morphology not previously documented and negativity for S100 and CD34 immunohistochemistry (IHC). We also report an uterine sarcoma with a novel ACOT7::ERBB4 fusion, which displayed spindle cell morphology and osteosarcomatous differentiation. S100 and SOX10 IHC were both negative. Molecular testing was highly informative in reaching a diagnosis in both cases, due to the unusual morphology and limited immunohistochemical support. Clinical follow-up revealed aggressive behavior in both cases, demonstrated by rapid disease progression and metastatic spread. These two cases expand on the known histologic and molecular spectrum of uterine mesenchymal neoplasms with tyrosine kinase receptor gene fusions. Recognition of these entities is important for appropriate classification, prognostication, and identification of patients eligible for targeted therapies such as TRK or FGFR inhibitors.
2026-06-23 | Fertility-sparing strategy in a rare case of uterine adenosarcoma and consecutive spontaneous pregnancy and livebirth.
We present the rare case of a 29-year-old patient with uterine adenosarcoma who received fertility-sparing treatment, subsequently conceived spontaneously, and gave birth to a healthy infant. In August 2022, the nulliparous patient presented with acyclic uterine bleeding. Diagnostic hysteroscopy and targeted resection of a polyp located at the cervicouterine junction revealed uterine adenosarcoma without sarcomatous overgrowth (FIGO stage T1a). Imaging confirmed no residual tumor or metastasis. A fertility-sparing management strategy was chosen, avoiding hysterectomy but involving close oncological surveillance with quarterly MRI scans. During follow-up, a concurrent diagnosis of symptomatic endometriosis introduced therapeutic challenges. The patient spontaneously conceived in 2023 and delivered a healthy infant by cesarean section at term in 2024. Subsequent hysteroscopy and imaging in 2025 showed no evidence of recurrence, therefore fertility-preserving management was continued. A short narrative of the patient's perspective on her initial diagnosis, possible fertility loss, and the emotional turmoil of pregnancy after uterine adenosarcoma is presented. Treating young patients diagnosed with uterine adenosarcoma poses a challenge to the treating physician due to the lack of guidelines and evidence regarding fertility-preserving treatment of this rare tumor. This report adds to the limited literature on successful pregnancy after uterine adenosarcoma and discusses indications and limitations of fertility-sparing treatment. Fertility preservation may be possible in selected early-stage uterine adenosarcoma cases without high-risk features such as sarcomatous overgrowth or myometrial invasion, with thorough counseling and strict follow-up. Further research is needed to develop standardized protocols and improve management in this context.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Rare uterine cancer.
1 orphan drug designation for Rare uterine cancer.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
cridanimod | small molecules | FDA | 2011-01-12 | — | Xenetic Biosciences, Inc. |
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