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Characterizing therapeutic target antigen expression in anaplastic carcinoma of the ovary
Mackenzie W Sullivan1, M Herman Chui2, Alexa N Kanbergs3
1Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Objective:
Novel treatment strategies are needed for patients with anaplastic carcinoma of the ovary given the high incidence of chemoresistance to conventional systemic therapies. Here we sought to evaluate HER2, FOLR1, TROP2, and mismatch repair protein expression as well as the tumor mutational burden of anaplastic carcinoma of the ovary.
Methods:
We retrospectively identified a total of 9 anaplastic ovarian carcinomas in institutional databases from 2013 to 2023, including one case from a collaborating institution. Cases with adequate tissue available underwent immunohistochemical analysis for HER2, FOLR1, TROP2, and mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. Tumor mutational burden was obtained from tumor-normal panel sequencing.
Results:
Anaplastic carcinoma of the ovary demonstrated low or absent expression of FOLR1, HER2, and TROP2 protein. FOLR1 expression in the two cases was weak and below currently used clinical cutoffs for mirvetuximab soravtansine eligibility. HER2 expression was low in the two anaplastic carcinomas (1-2+). TROP2 expression was low in one case (H-score of 60) and negative in the other five. All cases were mismatch repair proficient by immunohistochemistry and had low tumor mutational burden (median, 3.3 mut/Mb; range, 0.8-6.9).
Conclusion:
Only a subset of anaplastic carcinomas of the ovary express targetable tumor antigens at low levels, suggesting that these may have limited benefit from antibody-drug conjugates. Likewise, due to mismatch repair proficiency and low tumor mutational burden, immunotherapy is unlikely to be effective in this rare disease.
Insights
Anaplastic ovarian carcinoma shows low expression of targetable antigens like FOLR1, HER2, and TROP2, limiting antibody-drug conjugate efficacy. Mismatch repair proficiency and low tumor mutational burden suggest immunotherapy will be ineffective for this rare cancer.
Area of Science:
- Gynecologic Oncology
- Translational Research
- Cancer Biomarkers
Background:
- Anaplastic carcinoma of the ovary (ACO) presents a significant challenge due to high chemoresistance to conventional therapies.
- Novel treatment strategies are urgently needed for patients with this rare ovarian cancer subtype.
Purpose of the Study:
- To evaluate the expression of HER2, FOLR1, TROP2, and mismatch repair proteins in ACO.
- To determine the tumor mutational burden (TMB) in anaplastic ovarian carcinomas.
Main Methods:
- Retrospective analysis of 9 anaplastic ovarian carcinoma cases (2013-2023).
- Immunohistochemical analysis for HER2, FOLR1, TROP2, and mismatch repair proteins (MLH1, MSH2, MSH6, PMS2).
- Tumor mutational burden assessment using tumor-normal panel sequencing.
Main Results:
- Anaplastic ovarian carcinomas exhibited low or absent expression of FOLR1, HER2, and TROP2.
- FOLR1 and HER2 expression levels were below clinical cutoffs for targeted therapies.
- All cases were mismatch repair proficient with low tumor mutational burden (median 3.3 mut/Mb).
Conclusions:
- Limited expression of targetable tumor antigens in ACO suggests potential for minimal benefit from antibody-drug conjugates.
- Mismatch repair proficiency and low TMB indicate that immunotherapy is unlikely to be effective in anaplastic ovarian carcinoma.
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