Skip to main content

Advertisement

Log in

Is transplantation of cryopreserved ovarian tissue from patients with advanced-stage breast cancer safe? A pilot study

  • Fertility Preservation
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To assess the safety of reimplantation of cryopreserved ovarian tissue from advanced-stage breast cancer patients.

Methods

Cryopreserved ovarian cortical fragments were obtained from 13 advanced-stage breast cancer patients aged 17–35 years. After thawing, part of the ovarian cortical tissue was grafted to severe combined immunodeficient mice for 6 months. The presence of malignant mammary cells in ovarian tissue was evaluated after thawing as well as after grafting by 1) histology and immunohistochemistry (epithelial membrane antigen, Her2/neu and gross cystic disease fluid protein 15 identification), and 2) detection of the MGB2 gene by qPCR.

Results

No malignant cells were evidenced by histology and immunohistochemistry. None of the mice died during the 6-month grafting period, nor developed macroscopically visible masses. MGB2 gene expression was detected by qPCR and confirmed by sequencing in frozen-thawed ovarian tissue in 4 cases and in grafts in 1 case.

Conclusions

This pilot study is the first to evaluate the risk of contamination of cryopreserved ovarian tissue from advanced-stage breast cancer patients by xenotransplantation for 6 months to immunodeficient mice, associated with more conventional screening methods. Our xenografting results are reassuring, but caution needs to be exercised, as MGB2 gene expression was detected in some cases. Larger numbers of ovarian tissue samples from patients with advanced-stage breast cancer are required to confirm our findings before ovarian tissue transplantation can be contemplated in these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Aihara T, Fujiwara Y, Ooka M, Sakita I, Tamaki Y, Monden M. Mammaglobin B as a novel marker for detection of breast cancer micrometastases in axillary lymph nodes by reverse transcription-polymerase chain reaction. Breast Cancer Res Treat. 1999;58:137–40.

    Article  PubMed  CAS  Google Scholar 

  2. Andersen CY, Rosendahl M, Byskov AG, Loft A, Ottosen C, Dueholm M, et al. Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue. Hum Reprod. 2008;23:2266–72.

    Article  PubMed  Google Scholar 

  3. Azem F, Hasson J, Ben-Yosef D, Kossoy N, Cohen T, Almog B, et al. Histologic evaluation of fresh human ovarian tissue before cryopreservation. Int J Gynecol Pathol. 2010;29:19–23.

    Article  PubMed  Google Scholar 

  4. Becker RM, Darrow C, Zimonjic DB, Popescu NC, Watson MA, Fleming TP. Identification of mammaglobin B, a novel member of the uteroglobin gene family. Genomics. 1998;54:70–8.

    Article  PubMed  CAS  Google Scholar 

  5. Braun S, Hepp F, Sommer HL, Pantel K. Tumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease. Int J Cancer. 1999;84:1–5.

    Article  PubMed  CAS  Google Scholar 

  6. Breast Cancer Facts & Figures 2011–2012, American Cancer Society 2011. Available at: http://www.cancer.org/research/cancerfactsfigures/breastcancerfactsfigures/breast-cancer-facts-and-figures-2011-2012.

  7. Choi M, Craft B, Geraci SA. Surveillance and monitoring of adult cancer survivors. Am J Med. 2011;124:598–601.

    Article  PubMed  Google Scholar 

  8. Colpaert C, Salgado R. Belgian guidelines for HER2/neu testing in breast cancer. Belg J Med Oncol. 2007;1:22–9.

    Google Scholar 

  9. Dolmans MM, Jadoul P, Gilliaux S, Amorim CA, Luyckx V, Squifflet J, et al. A review of 15 years of ovarian tissue bank activities. J Assist Reprod Genet. 2013;30:305–14.

    Article  PubMed  Google Scholar 

  10. Dolmans MM, Luyckx V, Donnez J, Andersen CY, Greve T. Risk of transferring malignant cells with transplanted frozen-thawed ovarian tissue. Fertil Steril. 2013;99:1514–22.

    Article  PubMed  Google Scholar 

  11. Dolmans MM, Marinescu C, Saussoy P, Van Langendonckt A, Amorim C, Donnez J. Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe. Blood. 2010;116:2908–14.

    Article  PubMed  CAS  Google Scholar 

  12. Dolmans MM, Martinez-Madrid B, Gadisseux E, Guiot Y, Yuan WY, Torre A, et al. Short-term transplantation of isolated human ovarian follicles and cortical tissue into nude mice. Reproduction. 2007;134:253–62.

    Article  PubMed  CAS  Google Scholar 

  13. Dolmans MM, Yuan WY, Camboni A, Torre A, Van Langendonckt A, Martinez-Madrid B, et al. Development of antral follicles after xenografting of isolated small human preantral follicles. Reprod BioMed Online. 2008;16:705–11.

    Article  PubMed  Google Scholar 

  14. Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;364:1405–10.

    Article  PubMed  CAS  Google Scholar 

  15. Donnez J, Dolmans MM, Pellicer A, Diaz-Garcia C, Sanchez-Serrano M, Schmidt KT, et al. Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation. Fertil Steril. 2013;99:1503–13.

    Article  PubMed  Google Scholar 

  16. Donnez J, Jadoul P, Pirard C, Hutchings G, Demylle D, Squifflet J, et al. Live birth after transplantation of frozen-thawed ovarian tissue after bilateral oophorectomy for benign disease. Fertil Steril. 2012;98:720–5.

    Article  PubMed  Google Scholar 

  17. Donnez J, Martinez-Madrid B, Jadoul P, Van Langendonckt A, Demylle D, Dolmans MM. Ovarian tissue cryopreservation and transplantation: a review. Hum Reprod Update. 2006;12:519–5.

    Article  PubMed  Google Scholar 

  18. Durant JF, Fonteyne PA, Richez P, Marot L, Belkhir L, Tennstedt D, et al. Real-time PCR and DNA sequencing for detection and identification of Trichophyton rubrum as a cause of culture negative chronic granulomatous dermatophytosis. Med Mycol. 2009;47:508–14.

    Article  PubMed  CAS  Google Scholar 

  19. Gagnon Y, Têtu B. Ovarian metastases of breast carcinoma. A clinicopathologic study of 59 cases. Cancer. 1989;64:892–8.

    Article  PubMed  CAS  Google Scholar 

  20. Gillanders WE, Mikhitarian K, Hebert R, Mauldin PD, Palesch Y, Walters C, et al. Molecular detection of micrometastatic breast cancer in histopathology-negative axillary lymph nodes correlates with traditional predictors of prognosis: an interim analysis of a prospective multi-institutional cohort study. Ann Surg. 2004;239:828–37.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gosden RG, Baird DT, Wade JC, Webb R. Restoration of fertility to oophorectomized sheep by ovarian autografts stored at −196 degrees C. Hum Reprod. 1994;9:597–603.

    PubMed  CAS  Google Scholar 

  22. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17:1474–81.

    PubMed  CAS  Google Scholar 

  23. Kim SS, Lee WS, Chung MK, Lee HC, Lee HH, Hill D. Long-term ovarian function and fertility after heterotopic autotransplantation of cryobanked human ovarian tissue: 8-year experience in cancer patients. Fertil Steril. 2009;91:2349–54.

    Article  PubMed  Google Scholar 

  24. Kyono K, Doshida M, Toya M, Sato Y, Akahira J, Sasano H. Potential indications for ovarian autotransplantation based on the analysis of 5,571 autopsy findings of females under the age of 40 in Japan. Fertil Steril. 2010;93:2429–30.

    Article  PubMed  Google Scholar 

  25. Lacroix M. Significance, detection and markers of disseminated breast cancer cells. Endocr Relat Cancer. 2006;13:1033–67.

    Article  PubMed  CAS  Google Scholar 

  26. Lau SK, Weiss LM, Chu PG. Differential expression of MUC1, MUC2, and MUC5AC in carcinomas of various sites: an immunohistochemical study. Am J Clin Pathol. 2004;122:61–9.

    Article  PubMed  Google Scholar 

  27. Li CI, Anderson BO, Daling JR, Moe RE. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003;289:1421–4.

    Article  PubMed  Google Scholar 

  28. Moreno-Bueno G, Sánchez-Estévez C, Cassia R, Rodríguez-Perales S, Díaz-Uriarte R, Domínguez O, et al. Differential gene expression profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed and amplified in nonendometrioid carcinomas. Cancer Res. 2003;63:5697–702.

    PubMed  CAS  Google Scholar 

  29. Müller-Schöttle F, Classen-Linke I, Beier-Hellwig K, Sterzik K, Beier HM. Uteroglobin expression and release in the human endometrium. Ann N Y Acad Sci. 2000;923:332–5.

    Article  PubMed  Google Scholar 

  30. Nissan A, Jager D, Roystacher M, Prus D, Peretz T, Eisenberg I, et al. Multimarker RT-PCR assay for the detection of minimal residual disease in sentinel lymph nodes of breast cancer patients. Br J Cancer. 2006;94:681–5.

    PubMed  CAS  PubMed Central  Google Scholar 

  31. Oktay K. Ovarian tissue cryopreservation and transplantation: preliminary findings and implications for cancer patients. Hum Reprod Update. 2001;7:526–34.

    Article  PubMed  CAS  Google Scholar 

  32. Oktay K. Further evidence on the safety and success of ovarian stimulation with letrozole and tamoxifen in breast cancer patients undergoing in vitro fertilization to cryopreserve their embryos for fertility preservation. J Clin Oncol. 2005;23:3858–9.

    Article  PubMed  Google Scholar 

  33. Oktay K, Buyuk E, Veeck L, Zaninovic N, Xu K, Takeuchi T, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;363:837–40.

    Article  PubMed  Google Scholar 

  34. Ouellette RJ, Richard D, Maïcas E. RT-PCR for mammaglobin genes, MGB1 and MGB2, identifies breast cancer micrometastases in sentinel lymph nodes. Am J Clin Pathol. 2004;121:637–43.

    Article  PubMed  CAS  Google Scholar 

  35. Perrotin F, Marret H, Bouquin R, Fischer-Perrotin N, Lansac J, Body G. Incidence, diagnosis and prognosis of ovarian metastasis in breast cancer. Gynecol Obstet Fertil. 2001;29:308–15.

    Article  PubMed  CAS  Google Scholar 

  36. Rosendahl M, Timmermans Wielenga V, Nedergaard L, Kristensen SG, Ernst E, Rasmussen PE, et al. Cryopreservation of ovarian tissue for fertility preservation: no evidence of malignant cell contamination in ovarian tissue from patients with breast cancer. Fertil Steril. 2011;95:2158–61.

    Article  PubMed  Google Scholar 

  37. Sánchez-Serrano M, Crespo J, Mirabet V, Cobo AC, Escribá MJ, Simón C, et al. Twins born after transplantation of ovarian cortical tissue and oocyte vitrification. Fertil Steril. 2010;93:268.

    Article  PubMed  Google Scholar 

  38. Sánchez-Serrano M, Novella-Maestre E, Roselló-Sastre E, Camarasa N, Teruel J, Pellicer A. Malignant cells are not found in ovarian cortex from breast cancer patients undergoing ovarian cortex cryopreservation. Hum Reprod. 2009;24:2238–43.

    Article  PubMed  Google Scholar 

  39. Taback B, Chan AD, Kuo CT, Bostick PJ, Wang HJ, Giuliano AE, et al. Detection of occult metastatic breast cancer cells in blood by a multimolecular marker assay: correlation with clinical stage of disease. Cancer Res. 2001;61:8845–50.

    PubMed  CAS  Google Scholar 

  40. Tassi RA, Bignotti E, Rossi E, Falchetti M, Donzelli C, Calza S, et al. Overexpression of mammaglobin B in epithelial ovarian carcinomas. Gynecol Oncol. 2007;105:578–85.

    Article  PubMed  CAS  Google Scholar 

  41. Telfer EE, McLaughlin M. In vitro development of ovarian follicles. Semin Reprod Med. 2011;29:15–23.

    Article  PubMed  CAS  Google Scholar 

  42. Telfer EE, McLaughlin M, Ding C, Thong KJ. A two-step serum-free culture system supports development of human oocytes from primordial follicles in the presence of activin. Hum Reprod. 2008;23:1151–8.

    Article  PubMed  CAS  Google Scholar 

  43. Tornos C, Soslow R, Chen S, Akram M, Hummer AJ, Abu-Rustum N, et al. Expression of WT1, CA 125, and GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary. Am J Surg Pathol. 2005;29:1482–9.

    Article  PubMed  Google Scholar 

  44. Van Eyck AS, Bouzin C, Feron O, Romeu L, Van Langendonckt A, Donnez J, et al. Both host and graft vessels contribute to revascularization of xenografted human ovarian tissue in a murine model. Fertil Steril. 2010;93:1676–85.

    Article  PubMed  Google Scholar 

  45. Vanacker J, Camboni A, Dath C, Van Langendonckt A, Dolmans MM, Donnez J, et al. Enzymatic isolation of human primordial and primary ovarian follicles with Liberase DH: protocol for application in a clinical setting. Fertil Steril. 2011;96:379–83.

    Article  PubMed  CAS  Google Scholar 

  46. Wallwiener CW, Wallwiener M, Kurth RR, Röhm C, Neubauer H, Banys MJ, et al. Molecular detection of breast cancer metastasis in sentinel lymph nodes by reverse transcriptase polymerase chain reaction (RT-PCR): identifying, evaluating and establishing multi-marker panels. Breast Cancer Res Treat. 2011;130:833–44.

    Article  PubMed  CAS  Google Scholar 

  47. Watson MA, Dintzis S, Darrow CM, Voss LE, DiPersio J, Jensen R, et al. Mammaglobin expression in primary, metastatic, and occult breast cancer. Cancer Res. 1999;59:3028–31.

    PubMed  CAS  Google Scholar 

  48. Watson MA, Fleming TP. Mammaglobin, a mammary-specific member of the uteroglobin gene family, is overexpressed in human breast cancer. Cancer Res. 1996;56:860–5.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The present study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (Grant Télévie n°7.4507.10, grant 3.4.590.08), the Fondation St Luc, the Foundation Against Cancer, and the Centre du Cancer, and donations from Mr Pietro Ferrero, Baron Albert Frère and Viscount Philippe de Spoelberch.

The authors thank Mira Hryniuk for reviewing the English language of the manuscript and Dolores Gonzalez for her technical assistance. They also thank the biobank for providing samples of breast tumors and normal ovarian fragments.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. M. Dolmans.

Additional information

Capsule Cryopreserved ovarian tissue from advance-stage breast cancer patients is potentially unsafe for transplantation.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental Table 1

(DOC 32 kb)

Supplemental Fig. 1

(PPT 40 kb)

Supplemental Fig. 2

(DOC 37 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luyckx, V., Durant, J.F., Camboni, A. et al. Is transplantation of cryopreserved ovarian tissue from patients with advanced-stage breast cancer safe? A pilot study. J Assist Reprod Genet 30, 1289–1299 (2013). https://doi.org/10.1007/s10815-013-0065-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-013-0065-3

Keywords

Navigation