Genomics of gynaecological carcinosarcomas and future treatment options

Barker, Holly E.; Scott, Clare L.

doi:10.1016/j.semcancer.2019.10.006

Cited by 12 publications

(14 citation statements)

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“…Similarly, patients with advanced uterine and ovarian carcinosarcoma show low response rates to chemotherapy and overall have a poor prognosis. 16 Three out of nine patients with carcinosarcoma in our trial demonstrated durable responses to immunotherapy. A significant percentage of uterine carcinosarcomas shows mismatch repair protein (MMRP) deficiency/microsatellite instability which is associated with response to single-agent anti-PD-1/PD-L1 therapy.…”

Section: Discussionmentioning

confidence: 70%

Combination immunotherapy with nivolumab and ipilimumab in patients with rare gynecological malignancies: results of the CA209-538 clinical trial

Klein

Kee

Gao

et al. 2021

J Immunother Cancer

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BackgroundPatients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers.MethodsThis multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB).ResultsThe objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB.ConclusionsIpilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.

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Section: Discussionmentioning

confidence: 70%

Combination immunotherapy with nivolumab and ipilimumab in patients with rare gynecological malignancies: results of the CA209-538 clinical trial

Klein

Kee

Gao

et al. 2021

J Immunother Cancer

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“…Uterine carcinosarcoma incidence rates are five times higher than those of ovarian carcinosarcomas, resulting in fewer studies focusing on ovarian carcinosarcomas in the literature [ 41 , 42 ]. Whereas uterine carcinosarcomas are heterogeneous in their molecular profiling, ovarian carcinosarcomas represent a more homogenous group [ 7 ]. In an analysis of the transcriptome of ovarian carcinosarcomas, Gotoh et al found that the gene expression of ovarian carcinosarcomas most resembled that of high-grade serous ovarian cancer [ 17 ].…”

Section: Molecular Characterizationmentioning

confidence: 99%

“…However, recent molecular data that are reviewed in this article suggest that these tumors are more likely epithelial tumors that have undergone significant de-differentiation. The current biological theory posits that these tumors are either derived from a single progenitor that gives rise to carcinoma and sarcoma cells or from one progenitor carcinoma cell that undergoes a sarcomatous transformation [ 6 , 7 ]. These tumors are now considered epithelial in origin, and this designation has led to updated treatment algorithms that are similar to those of other epithelial endometrial and ovarian tumors.…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterizations of Gynecologic Carcinosarcomas: A Focus on the Immune Microenvironment

Borrego

Lengyel

Kurnit

2022

Cancers

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Gynecologic carcinosarcomas, specifically of endometrial and ovarian origin, are aggressive and rare tumors. Treatment data are limited and are often extrapolated from other histologies and smaller retrospective studies. While the optimal therapy approach remains contentious, treatment is often multimodal and may include surgery, chemotherapy, radiation, or a combination of multiple strategies. However, despite aggressive treatment, these tumors fare worse than carcinomas of the same anatomic sites irrespective of their stage. Recent studies have described in-depth molecular characterizations of gynecologic carcinosarcomas. Although many molecular features mirror those seen in other uterine and ovarian epithelial tumors, the high prevalence of epithelial-mesenchymal transition is more unique. Recently, molecular descriptions have expanded to begin to characterize the tumor immune microenvironment. While the importance of the immune microenvironment has been well-established for other tumor types, it has been less systematically explored in gynecologic carcinosarcomas. Furthermore, the use of immunotherapy in patients with gynecologic carcinosarcomas has not been extensively evaluated. In this review, we summarize the available data surrounding gynecologic carcinosarcomas, with a focus on the immune microenvironment. We end with a discussion of potential immunotherapy uses and future directions for the field.

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“…OCS tumorigenesis is thought to be based on the "conversion hypothesis" of sarcomatous transformation of a differentiated cancer cell-type (carcinoma) into undifferentiated (sarcomatous) malignancy (29,30). It is generally accepted that the transformation is not driven by somatic mutation, but via reprogramming of gene expression and associated with high level of genomic instabilities (see Figure 1B).…”

Section: Hgsoc and Ocs Are Often Regarded As "Class C" Tumors Where Tmentioning

confidence: 99%

T-Cell Receptor Therapy in the Treatment of Ovarian Cancer: A Mini Review

Dand

Doig

et al. 2021

Front. Immunol.

Self Cite

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Ovarian cancer, in particularly high-grade serous ovarian cancer (HGSOC) and ovarian carcinosarcoma (OCS), are highly aggressive and deadly female cancers with limited treatment options. These tumors are generally unresponsive to immune check-point inhibitor (ICI) therapy and are referred to as immunologically “cold” tumors. Cell-based therapy, in particular, adoptive T-cell therapy, is an alternative immunotherapy option that has shown great potential, especially chimeric antigen receptor T cell (CAR-T) therapy in the treatment of hematologic malignancies. However, the efficacy of CAR-T therapy in solid tumors has been modest. This review explores the potential of another cell-based therapy, T-cell receptor therapy (TCR-T) as an alternate treatment option for immunological “cold” OC and OCS tumors.

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Genomics of gynaecological carcinosarcomas and future treatment options

Cited by 12 publications

References 123 publications

Combination immunotherapy with nivolumab and ipilimumab in patients with rare gynecological malignancies: results of the CA209-538 clinical trial

Combination immunotherapy with nivolumab and ipilimumab in patients with rare gynecological malignancies: results of the CA209-538 clinical trial

Molecular Characterizations of Gynecologic Carcinosarcomas: A Focus on the Immune Microenvironment

T-Cell Receptor Therapy in the Treatment of Ovarian Cancer: A Mini Review

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