Na Niu

Preclinical activity of sacituzumab govitecan in TROP2-positive low-grade serous ovarian cancer patient-derived xenograft models

Low-grade serous ovarian cancer is a rare epithelial ovarian cancer subtype characterized by high resistance to chemotherapy and an indolent disease course. The development of novel, effective, targeted treatments for recurrent, chemotherapy-resistant low-grade serous ovarian cancer remains an unmet medical need. We evaluated trophoblast cell-surface antigen 2 (TROP2) expression in a cohort of patients with low-grade serous ovarian cancer and assessed the preclinical activity of sacituzumab govitecan, an antibody-drug conjugate targeting TROP2, in vivo using a patient-derived xenograft (PDX) model. TROP2 expression was evaluated in 26 patients with low-grade serous ovarian cancer using immunohistochemistry. The efficacy of sacituzumab govitecan was assessed in vivo in severe combined immunodeficiency mice using a TROP2-positive low-grade serous ovarian cancer PDX model established from a patient with disease resistant to chemotherapy, aromatase inhibitors, and MEK inhibitors. TROP2 expression was observed in all low-grade serous ovarian cancer cases, with 21 of 26 (81%) samples demonstrating moderate to strong expression. In vivo studies in mice demonstrated that sacituzumab govitecan significantly inhibited tumor growth in a chemotherapy-, aromatase inhibitor-, and MEK inhibitor-resistant low-grade serous ovarian cancer PDX model compared to control animals treated with vehicle/saline (p < .0001). Median survival for control mice was 25 days, while it was not reached by the end of the experiment (day 50) in animals treated with sacituzumab govitecan. TROP2 is a novel biomarker highly expressed in low-grade serous ovarian cancer. Sacituzumab govitecan may represent a potentially effective new treatment option for patients with low-grade serous ovarian cancer progressing after standard treatment modalities. Further clinical trials in low-grade serous ovarian cancer treated with sacituzumab govitecan are warranted.

Folate receptor alpha as a successful biomarker in the treatment of low-grade serous ovarian cancer patients using preclinical and clinical models

Low-grade serous ovarian cancer is a rare epithelial ovarian cancer subtype characterized by high resistance to chemotherapy. Development of novel, effective, targeted treatments for recurrent low-grade serous ovarian cancer remains an unmet medical need. We evaluated FOLR1 expression in a cohort of low-grade serous ovarian cancer patients and the preclinical and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate targeting FOLR1, in vivo in a patient-derived xenograft model and in a heavily pretreated low-grade serous ovarian cancer patient progressing after chemotherapy, aromatase inhibitor, and MEK inhibitor treatment. FOLR1 expression was evaluated in 27 low-grade serous ovarian cancer patients using immunohistochemistry. The efficacy of mirvetuximab soravtansine was assessed in vivo in a low-grade serous ovarian cancer patient-derived xenograft model in severe combined immunodeficient mice, as well as in a patient harboring a recurrent low-grade serous ovarian cancer resistant to standard treatment modalities. FOLR1 expression was detected in all 27 (100%) low-grade serous ovarian cancer cases, with 21 of 27 (78%) of the samples demonstrating 2+/3+ in ≥75% of tumor cells. In vivo studies in mice demonstrated that mirvetuximab soravtansine inhibited tumor growth and prolonged survival in a low-grade serous ovarian cancer patient-derived xenograft model derived from a patient progressing after chemotherapy/aromatase inhibitor/MEK inhibitor. Clinical evidence further supported the therapeutic activity of mirvetuximab soravtansine in a FOLR1-positive low-grade serous ovarian cancer patient, as indicated by a prolonged partial response after 8 months of treatment. FOLR1 is overexpressed in a large percentage of low-grade serous ovarian cancers. Mirvetuximab soravtansine may represent a novel treatment option for low-grade serous ovarian cancer patients progressing after standard treatment modalities. Clinical trials with mirvetuximab soravtansine in FOLR1-positive low-grade serous ovarian cancers are warranted.

Diandric triploid partial mole versus digynic nonmolar triploidy: is morphological assessment sufficient for the diagnostic distinction?

AimsDiagnostic separation of diandric triploid gestation, i.e. partial mole from digynic triploid gestation, is clinically relevant, as the former may progress to postmolar gestational trophoblastic neoplasia. The aim of the study was to investigate if the combination of abnormal histology combined with ploidy analysis‐based triploidy is sufficient to accurately diagnose partial mole.Methods and ResultsA genotype–phenotype correlation study was undertaken to reappraise histological parameters among 20 diandric triploid gestations and 22 digynic triploid gestations of comparable patient age, gestational weeks, and clinical presentations. Two villous populations, irregular villous contours, pseudoinclusions, and syncytiotrophoblast knuckles, were common in both groups. Villous size ≥2.5 mm, cistern formation, trophoblastic hyperplasia, and syncytiotrophoblast lacunae were significantly more common in the partial hydatidiform mole. Cistern formation had the highest positive predictive value (PPV) (93%) and highest specificity (96%) for diandric triploid gestation, although the sensitivity was 70%. Cistern formation combined with villous size ≥2.5 mm or trophoblast hyperplasia or syncytiotrophoblast lacunae had 100% specificity and PPV, but a marginal sensitivity of 60%–65%. A moderate interobserver agreement (Kappa = 0.57, Gwet's AC1 = 0.59) was achieved among four observers who assigned diagnosis of diandric triploid gestation or digynic triploidy solely based on histology.ConclusionsNone of histological parameters are unique to either diandric triploid gestation or digynic triploid gestation. Cistern formation is the most powerful discriminator, with 93% PPV and 70% sensitivity for diandric triploid gestation. While cistern formation combined with either trophoblastic hyperplasia or villous size ≥2.5 mm or syncytiotrophoblast lacunae has 100% PPV and specificity for diandric triploid gestation, the sensitivity is only 60% to 65%. Therefore, in the presence of triploidy, histological assessment is unable to precisely classify 35% to 40% of diandric triploid gestations or partial moles.

A pilot study of p53 immunohistochemistry in atypical squamous lesions, using a vulvar scoring system

AbstractBackgroundHistopathologic overlap between cutaneous squamous cell carcinoma (cSCC) and its indolent mimics likely leads to the overdiagnosis of cSCC.ObjectiveTo perform a pilot study of the p53 immunohistochemical scoring system developed on vulvar squamous lesions in cSCC.MethodsThe consistency and reliability of p53 immunostaining using a scoring system developed on vulvar cases, as compared with TP53 genomic sequencing, was studied in an initial cohort of 28 cutaneous cases. p53 labeling was further assessed in an additional 63 cases of atypical squamous lesions, including 20 atypical squamous lesions classified by the authors as benign, 22 cases diagnosed as cSCC without high‐risk features, and 21 cases of high‐risk cSCC (cSCC‐HR).ResultsThe concordance of p53 labeling and TP53 sequencing was 82.1%. Four positive patterns of p53 mutation were identified: basal, parabasal/diffuse, null, and cytoplasmic. p53 positivity in atypical, benign squamous lesions (10%) was significantly lower than that of low‐risk cSCC (63.6%, p = 0.0004) or cSCC‐HR (90.5%, p &lt; 0.0001). p53 positivity in low‐risk cSCC versus cSCC‐HR was not statistically significant (p = 0.07).Conclusionp53 Labeling may be a helpful biomarker to support the diagnosis of cSCC and distinguish cSCC from atypical but benign mimics.

Extrauterine epithelioid trophoblastic tumour and its somatic carcinoma mimics: short tandem repeat genotyping meets the diagnostic challenges

AimsWhile epithelioid trophoblastic tumour (ETT) primarily arises from the uterus, cases have been increasingly documented at extrauterine sites, originating from an ectopic gestation or presenting as a metastatic tumour, leading to the major differential diagnosis of somatic carcinoma with trophoblastic differentiation. The precise separation of a gestational trophoblastic tumour from its somatic carcinoma mimics is highly relevant and crucial for patient management and prognosis.Methods and resultsWe summarise the clinicopathological and molecular features of four challenging epithelioid malignancies presenting at extrauterine sites, with ETT as the main differential diagnosis. All four tumours demonstrated histological and immunohistochemical features overlapping between a somatic carcinoma and an ETT, combined with inconclusive clinical and imaging findings. Serum beta‐hCG elevation was documented in two cases. Short tandem repeat (STR) genotyping was performed and was informative in all cases. The presence of a unique paternal allelic pattern in the tumour tissue confirmed the diagnosis of ETT in two cases with an initial consideration of either somatic carcinoma or suspicion of a gestational trophoblastic tumour. The presence of matching genetic profile with the patient's paired normal tissue was seen in two other cases (both initially considered as ETT), confirming their somatic origin, including one metastatic triple‐negative breast carcinoma and one primary lung carcinoma.ConclusionsDiagnostic separation of ETT at an extrauterine site from its somatic carcinoma mimics can be difficult at the histological and immunohistochemical levels. STR genotyping offers a robust ancillary tool that precisely separates ETT from somatic carcinomas with trophoblastic differentiation.