Complete remission of heavily treated ovarian clear cell carcinoma with ARID1A mutations after pembrolizumab and bevacizumab combination therapy: a case report

Lin, Yu; Wen, Kuo Chang; Sung, Pi Lin; Chou, Yu‐Ting; Liew, Phui Ly; Chen, Lin Yu; Huang, Rui; Lai, Hung Cheng; Chang, Lu

doi:10.1186/s13048-020-00751-3

Cited by 13 publications

(8 citation statements)

References 16 publications

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“…Clinical trials and case reports suggest immune therapy; however, biomarker development to predict response to checkpoint inhibitor therapy has been challenging without consistent predictors (e.g., PD-L1 score) [ 94 ]. MMRd with a high tumor mutation burden and neoantigen expression are predictors of response to immune checkpoint blockade but do not explain all responsive cases.…”

Section: Molecular Subtypes Of Ovarian Carcinomasmentioning

confidence: 99%

The Evolution of Ovarian Carcinoma Subclassification

Köbel

Kang

2022

Cancers

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The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). Since histotypes arise from different cells of origin, cell lineage-specific diagnostic immunohistochemical markers and histotype-specific oncogenic alterations can confirm the morphological diagnosis. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish the five principal histotypes with high accuracy, and additional immunohistochemical markers can be used depending on the diagnostic considerations. Histotypes are further stratified into molecular subtypes and assessed with predictive biomarker tests. HGSCs have recently been subclassified based on mechanisms of chromosomal instability, mRNA expression profiles or individual candidate biomarkers. ECs are composed of the same molecular subtypes (POLE-mutated/mismatch repair-deficient/no specific molecular profile/p53-abnormal) with the same prognostic stratification as their endometrial counterparts. Although methylation analyses and gene expression and sequencing showed at least two clusters, the molecular subtypes of CCCs remain largely elusive to date. Mutational and immunohistochemical data on LGSC have suggested five molecular subtypes with prognostic differences. While our understanding of the molecular composition of ovarian carcinomas has significantly advanced and continues to evolve, the need for treatment options suitable for these alterations is becoming more obvious. Further preclinical studies using histotype-defined and molecular subtype-characterized model systems are needed to expand the therapeutic spectrum for women diagnosed with ovarian carcinomas.

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Section: Molecular Subtypes Of Ovarian Carcinomasmentioning

confidence: 99%

The Evolution of Ovarian Carcinoma Subclassification

Köbel

Kang

2022

Cancers

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“…Therefore, the combination of antiangiogenic drugs with other regimes might be a promising treatment strategy. A patient with refractory OCCC reached complete remission after nine cycles of pembrolizumab and bevacizumab combination therapy 42. Moreover, a retrospective real-world study showed that adding bevacizumab to chemotherapy in recurrent OCCC resulted in a remarkable benefit compared with high-grade serous ovarian carcinoma (PFS: 20 m vs 14 m) 43.…”

Section: Discussionmentioning

confidence: 99%

“…A patient with refractory OCCC reached complete remission after nine cycles of pembrolizumab and bevacizumab combination therapy. 42 Moreover, a retrospective real-world study showed that adding bevacizumab to chemotherapy in recurrent OCCC resulted in a remarkable benefit compared with high-grade serous ovarian carcinoma (PFS: 20 m vs 14 m). 43 Overall, antiangiogenic drug-containing regimens tend to be more effective in recurrent OCCC.…”

Section: Discussionmentioning

confidence: 99%

Sintilimab combined with bevacizumab in relapsed/persistent ovarian clear cell carcinoma (INOVA): an investigator-initiated, multicentre clinical trial—a study protocol of clinical trial

Liu

Song

et al. 2022

BMJ Open

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BackgroundOvarian clear cell carcinoma (OCCC) has an abysmal prognosis with a median overall survival (OS) of 25.3 months because of a low response to chemotherapy. The 5-year disease-specific survival rate after recurrence is 13.2%, with more than two-thirds of the patients dying within a year. Therefore, it is urgent to explore new therapeutic options for OCCC. Based on the characteristic immune-suppressive tumour microenvironment derived from the gene expression profile of OCCC, the combination of immunoantiangiogenesis therapy might have certain efficacy in recurrent/persistent OCCC. This trial aims to evaluate the efficacy and safety of sintilimab and bevacizumab in patients who have failed platinum-containing chemotherapy with recurrent or persistent OCCC.Method and analysisIn this multicentre, single-arm, open-label, investigator-initiated clinical trial, 38 patients will be assigned to receive sintilimab 200 mg plus bevacizumab 15 mg/kg every 3 weeks. The eligibility criteria include histologically diagnosed patients with recurrent or persistent OCCC who have been previously treated with at least one-line platinum-containing chemotherapy; patients with Eastern Cooperative Oncology Group (ECOG) performance status 0–2 with an expected survival greater than 12 weeks. The exclusion criteria include patients previously treated with immune checkpoint inhibitor and patients with contraindications of bevacizumab and sintilimab. The primary endpoint is the objective response rate. The secondary endpoints are progression-free survival, time to response, duration of response, disease control rate, OS, safety and quality of life. Statistical significance was defined as p<0.05.Ethics and disseminationThis trial was approved by the Research Ethics Commission of Tongji Medical College of Huazhong University of Science and Technology (2020-S337). The protocol of this study is registered at www.clinicaltrials.gov. The trial results will be published in peer-reviewed journals and at conferences.Trial registration numberNCT04735861; Clinicaltrials. gov.

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“…Finally, it should be noted that the lack of prognostic significance for ARID1A does not discount continued development of direct targeting, synthetic lethal strategies, and/or investigation into predictive value of ARID1A for immune-modulatory therapies [72][73][74][75]. As one of the most prevalent biomarkers in EAOCs it is a potentially high value biomarker with mechanisms of action that may be dependent on molecular context of the cancer (and subtype) in which alterations occur.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and Immunological Significance of ARID1A Status in Endometriosis-Associated Ovarian Carcinoma

Heinze

Nazeran

Lee

et al. 2021

Preprint

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ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumor suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumor-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p=0.012), and associated with MMRd (p<0.001), and presence of CD8+ TIL (p=0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOC we also observed an association between ARID1A loss-of-function mutation as a result of small indels (p=0.011, vs. single nucleotide variants). In ENOC, the association between ARID1A loss, CD8+ TIL, and age, appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance.

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Complete remission of heavily treated ovarian clear cell carcinoma with ARID1A mutations after pembrolizumab and bevacizumab combination therapy: a case report

Cited by 13 publications

References 16 publications

The Evolution of Ovarian Carcinoma Subclassification

The Evolution of Ovarian Carcinoma Subclassification

Sintilimab combined with bevacizumab in relapsed/persistent ovarian clear cell carcinoma (INOVA): an investigator-initiated, multicentre clinical trial—a study protocol of clinical trial

Prognostic and Immunological Significance of ARID1A Status in Endometriosis-Associated Ovarian Carcinoma

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