Intraoperative Imaging of Folate Receptor Alpha Positive Ovarian and Breast Cancer Using the Tumor Specific Agent EC17

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Mar 26

PMID 27014973

Citations 69

Authors

Quirijn R J G Tummers

Charlotte E S Hoogstins

Katja N Gaarenstroom

Cor D de Kroon

Mariette I E van Poelgeest

Jaap Vuyk

Tjalling Bosse

Vincent T H B M Smit

Cornelis J H van de Velde

Adam F Cohen

Philip S Low

Jacobus Burggraaf

Alexander L Vahrmeijer

Affiliations

Soon will be listed here.

Abstract

Introduction: Intraoperative fluorescence imaging of the folate-receptor alpha (FRα) could support completeness of resection in cancer surgery. Feasibility of EC17, a FRα-targeting agent that fluoresces at 500nm, was demonstrated in a limited series of ovarian cancer patients. Our objective was to evaluate EC17 in a larger group of ovarian cancer patients. In addition, we assessed the feasibility of EC17 in patients with breast cancer.

Methods: Two-to-three hours before surgery 0.1mg/kg EC17 was intravenously administered to 12 patients undergoing surgery for ovarian cancer and to 3 patients undergoing surgery for biopsy-proven FRα-positive breast cancer. The number of lesions/positive margins detected with fluorescence and concordance between fluorescence and tumor- and FRα-status was assessed in addition to safety and pharmacokinetics.

Results: Fluorescence imaging in ovarian cancer patients allowed detection of 57 lesions of which 44 (77%) appeared malignant on histopathology. Seven out of these 44 (16%) were not detected with inspection/palpation. Histopathology demonstrated concordance between fluorescence and FRα- and tumor status. Fluorescence imaging in breast cancer patients, allowed detection of tumor-specific fluorescence signal. At the 500nm wavelength, autofluorescence of normal breast tissue was present to such extent that it interfered with tumor identification.

Conclusions: FRα is a favorable target for fluorescence-guided surgery as EC17 produced a clear fluorescent signal in ovarian and breast cancer tissue. This resulted in resection of ovarian cancer lesions that were otherwise not detected. Notwithstanding, autofluorescence caused false-positive lesions in ovarian cancer and difficulty in discriminating breast cancer-specific fluorescence from background signal. Optimization of the 500nm fluorophore, will minimize autofluorescence and further improve intraoperative tumor detection.

Citing Articles

Novel GAL7-targeted fluorescent molecular imaging probe for high-grade squamous intraepithelial lesion and cervical cancer screening.

Teng X, Tang C, He K, Chen C, Tian J, Du Y EJNMMI Res. 2025; 15(1):22.

PMID: 40082314 PMC: 11906962. DOI: 10.1186/s13550-025-01218-6.

Fluorescence-Guided Surgery to Detect Microscopic Disease in Ovarian Cancer: A Systematic Review with Meta-Analysis.

Erdemoglu E, Langstraat C, Kumar A, Ostby S, Girardo M, Giannini A Cancers (Basel). 2025; 17(3).

PMID: 39941778 PMC: 11815761. DOI: 10.3390/cancers17030410.

Progression in Near-Infrared Fluorescence Imaging Technology for Lung Cancer Management.

Chen X, Li Y, Su J, Zhang L, Liu H Biosensors (Basel). 2024; 14(10).

PMID: 39451714 PMC: 11506746. DOI: 10.3390/bios14100501.

In Vivo Labeling and Detection of Circulating Tumor Cells in Mice Using OTL38.

Pace J, Lee J, Srinivasarao M, Kallepu S, Low P, Niedre M Mol Imaging Biol. 2024; 26(4):603-615.

PMID: 38594545 PMC: 11281960. DOI: 10.1007/s11307-024-01914-0.

Intraoperative Resection Guidance and Rapid Pathological Diagnosis of Osteosarcoma using B7H3 Targeted Probe under NIR-II Fluorescence Imaging.

Zeng F, Li C, Wang H, Wang Y, Ren T, He F Adv Sci (Weinh). 2024; 11(33):e2310167.

PMID: 38502871 PMC: 11434027. DOI: 10.1002/advs.202310167.

References

Soucy G, Belanger J, Leblanc G, Sideris L, Drolet P, Mitchell A . Surgical margins in breast-conservation operations for invasive carcinoma: does neoadjuvant chemotherapy have an impact?. J Am Coll Surg. 2008; 206(6):1116-21. DOI: 10.1016/j.jamcollsurg.2007.12.025. View

De Jesus E, Keating J, Kularatne S, Jiang J, Judy R, Predina J . Comparison of Folate Receptor Targeted Optical Contrast Agents for Intraoperative Molecular Imaging. Int J Mol Imaging. 2015; 2015:469047. PMC: 4600912. DOI: 10.1155/2015/469047. View

Matsumura Y, Maeda H . A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986; 46(12 Pt 1):6387-92. View

Weissleder R, Pittet M . Imaging in the era of molecular oncology. Nature. 2008; 452(7187):580-9. PMC: 2708079. DOI: 10.1038/nature06917. View

Monici M, Basile V, Romano G, Evangelisti L, Lucarini L, Attanasio M . Fibroblast autofluorescence in connective tissue disorders: a future tool for clinical and differential diagnosis?. J Biomed Opt. 2008; 13(5):054025. DOI: 10.1117/1.2982533. View

Handgraaf H, Verbeek F, Tummers Q, Boogerd L, van de Velde C, Vahrmeijer A . Real-time near-infrared fluorescence guided surgery in gynecologic oncology: a review of the current state of the art. Gynecol Oncol. 2014; 135(3):606-13. DOI: 10.1016/j.ygyno.2014.08.005. View

Weissleder R, Ntziachristos V . Shedding light onto live molecular targets. Nat Med. 2003; 9(1):123-8. DOI: 10.1038/nm0103-123. View

OShannessy D, Yu G, Smale R, Fu Y, Singhal S, Thiel R . Folate receptor alpha expression in lung cancer: diagnostic and prognostic significance. Oncotarget. 2012; 3(4):414-425. PMC: 3380576. DOI: 10.18632/oncotarget.519. View

Parker N, Turk M, Westrick E, Lewis J, Low P, Leamon C . Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem. 2005; 338(2):284-93. DOI: 10.1016/j.ab.2004.12.026. View

10.

Hyun H, Park M, Owens E, Wada H, Henary M, Handgraaf H . Structure-inherent targeting of near-infrared fluorophores for parathyroid and thyroid gland imaging. Nat Med. 2015; 21(2):192-7. PMC: 4319985. DOI: 10.1038/nm.3728. View

11.

Stummer W, Pichlmeier U, Meinel T, Wiestler O, Zanella F, Reulen H . Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006; 7(5):392-401. DOI: 10.1016/S1470-2045(06)70665-9. View

12.

Crane L, Arts H, van Oosten M, Low P, van der Zee A, van Dam G . The effect of chemotherapy on expression of folate receptor-alpha in ovarian cancer. Cell Oncol (Dordr). 2011; 35(1):9-18. PMC: 3268989. DOI: 10.1007/s13402-011-0052-6. View

13.

Kalli K, Oberg A, Keeney G, Christianson T, Low P, Knutson K . Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008; 108(3):619-26. PMC: 2707764. DOI: 10.1016/j.ygyno.2007.11.020. View

14.

Maeda H, Wu J, Sawa T, Matsumura Y, Hori K . Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000; 65(1-2):271-84. DOI: 10.1016/s0168-3659(99)00248-5. View

15.

Vahrmeijer A, Hutteman M, van der Vorst J, van de Velde C, Frangioni J . Image-guided cancer surgery using near-infrared fluorescence. Nat Rev Clin Oncol. 2013; 10(9):507-18. PMC: 3755013. DOI: 10.1038/nrclinonc.2013.123. View

16.

Tummers Q, Hoogstins C, Peters A, de Kroon C, Trimbos J, van de Velde C . The Value of Intraoperative Near-Infrared Fluorescence Imaging Based on Enhanced Permeability and Retention of Indocyanine Green: Feasibility and False-Positives in Ovarian Cancer. PLoS One. 2015; 10(6):e0129766. PMC: 4482512. DOI: 10.1371/journal.pone.0129766. View

17.

Pleijhuis R, Graafland M, De Vries J, Bart J, de Jong J, van Dam G . Obtaining adequate surgical margins in breast-conserving therapy for patients with early-stage breast cancer: current modalities and future directions. Ann Surg Oncol. 2009; 16(10):2717-30. PMC: 2749177. DOI: 10.1245/s10434-009-0609-z. View

18.

Choi H, Gibbs S, Lee J, Kim S, Ashitate Y, Liu F . Targeted zwitterionic near-infrared fluorophores for improved optical imaging. Nat Biotechnol. 2013; 31(2):148-53. PMC: 3568187. DOI: 10.1038/nbt.2468. View

19.

Low P, Henne W, Doorneweerd D . Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc Chem Res. 2007; 41(1):120-9. DOI: 10.1021/ar7000815. View

20.

Vergote I, Marth C, Coleman R . Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications. Cancer Metastasis Rev. 2015; 34(1):41-52. DOI: 10.1007/s10555-014-9539-8. View