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Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer

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Abstract

Purpose

To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate.

Methods

One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI.

Results

Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery.

Conclusions

Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12 months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.

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References

  1. Héry C, Ferlay J, Boniol M, Autier P (2008) Changes in breast cancer incidence and mortality in middle-aged and elderly women in 28 countries with Caucasian majority populations. Ann Oncol 19:1009–1018

    Article  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  Google Scholar 

  3. Bedoschi G, Navarro PA, Oktay K (2016) Chemotherapy-induced damage to ovary: mechanisms and clinical impact. Future Oncol 12:2333–2344

    Article  CAS  Google Scholar 

  4. Oktem O, Oktay K (2007) Quantitative assessment of the impact of chemotherapy on ovarian follicle reserve and stromal function. Cancer 110:2222–2229

    Article  CAS  Google Scholar 

  5. Soleimani R, Heytens E, Darzynkiewicz Z, Oktay K (2011) Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise. Aging 3:782–793

    Article  Google Scholar 

  6. Tham Y-L, Sexton K, Weiss H, Elledge R, Friedman LC, Kramer R (2007) The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. Am J Clin Oncol 30:126–132

    Article  CAS  Google Scholar 

  7. Oktay KH, Bedoschi G, Goldfarb SB, Taylan E, Titus S, Palomaki GE et al (2020) Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency. Fertil Steril 113:1251–1260

    Article  CAS  Google Scholar 

  8. Turan V, Oktay K (2020) BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging. Hum Reprod Update 26:43–57

    Article  CAS  Google Scholar 

  9. Dunlop CE, Anderson RA (2015) Uses of anti-Mullerian hormone (AMH) measurement before and after cancer treatment in women. Maturitas 80:245–250

    Article  CAS  Google Scholar 

  10. Durlinger ALL, Visser JA, Themmen APN (2002) Regulation of ovarian function: the role of anti-Mullerian hormone. Reproduction 124:601–609

    Article  CAS  Google Scholar 

  11. Fleming R, Seifer DB, Frattarelli JL, Ruman J (2015) Assessing ovarian response: antral follicle count versus anti-Mullerian hormone. Reprod Biomed Online 31:486–496

    Article  CAS  Google Scholar 

  12. Hansen KR, Hodnett GM, Knowlton N, Craig LB (2011) Correlation of ovarian reserve tests with histologically determined primordial follicle number. Fertil Steril 95:170–175

    Article  Google Scholar 

  13. Iliodromiti S, Anderson RA, Nelson SM (2015) Technical and performance characteristics of anti-Mullerian hormone and antral follicle count as biomarkers of ovarian response. Hum Reprod Update 21:698–710

    Article  CAS  Google Scholar 

  14. Van Rooij IAJ, Broekmans FJM, Scheffer GJ, Looman CWN, Habbema JF, de Jong FH et al (2005) Serum antiMullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril 83:979–987

    Article  Google Scholar 

  15. Bentzen JG, Forman JL, Johannsen TH, Pinborg A, Larsen EC, Andersen AN et al (2013) Ovarian antral follicle subclasses and anti-Mullerian hormone during normal reproductive aging. J Clin Endocrinol Metab 98:1602–1611

    Article  CAS  Google Scholar 

  16. Jeppesen JV, Anderson RA, Kelsey TW, Christiansen SL, Kristensen SG, Jayaprakasan K et al (2013) Which follicles make the most anti-Müllerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection. Mol Hum Reprod 19:519–527

    Article  CAS  Google Scholar 

  17. Durlinger ALL, Gruijters MJG, Kramer P, Karels B, Kumar TR, Matzuk MM et al (2001) Anti-Mullerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. Endocrinology 142:4891–4899

    Article  CAS  Google Scholar 

  18. Durlinger ALL, Gruijters MJG, Kramer P, Karels B, Ingraham HA, Nachtigal MW et al (2002) Anti-Mullerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology 140:5789–5796

    Article  Google Scholar 

  19. Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R et al (2014) The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update 20:370–385

    Article  Google Scholar 

  20. Riggs R, Kimble T, Oehninger S, Bocca S, Zhao Y, Leader B et al (2011) Anti-Mullerian hormone serum levels predict response to controlled ovarian hyperstimulation but not embryo quality or pregnancy outcome in oocyte donation. Fertil Steril 95:410–412

    Article  CAS  Google Scholar 

  21. Riggs RM, Duran EH, Baker MW, Kimble TD, Hobeika E, Yin L et al (2008) Assessment of ovarian reserve with anti-Mullerian hormone: a comparison of the predictive value of anti-Mullerian hormone, follicle-stimulating hormone, inhibin B, and age. Am J Obstet Gynecol 199(202):e1–8

    Google Scholar 

  22. Broer SL, Eijkemans MJC, Scheffer GJ, van Rooij IA, de Vet A, Themmen AP et al (2011) Anti-Mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women. J Clin Endocrinol Metab 96:2532–2539

    Article  CAS  Google Scholar 

  23. Freeman EW, Sammel MD, Lin H, Gracia CR (2012) Anti-Mullerian hormone as a predictor of time to menopause in late reproductive age women. J Clin Endocrinol Metab 97:1673–1680

    Article  CAS  Google Scholar 

  24. Tehrani FR, Solaymani-Dodaran M, Tohidi M, Gohari MR, Azizi F (2013) Modeling age at menopause using serum concentration of anti-mullerian hormone. J Clin Endocrinol Metab 98:729–735

    Article  CAS  Google Scholar 

  25. Anderson RA, Cameron DA (2011) Pretreatment serum anti-Mullerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab 96:1336–1343

    Article  CAS  Google Scholar 

  26. Henry NL, Xia R, Schott AF, McConnell D, Banerjee M, Hayes DF (2014) Prediction of postchemotherapy ovarian function using markers of ovarian reserve. Oncologist 19:68–74

    Article  CAS  Google Scholar 

  27. Anderson RA, Themmen APN, Al-Qahtani A, Groome NP, Cameron DA (2006) The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod 21:2583–2592

    Article  CAS  Google Scholar 

  28. Lee S, Ozkavukcu S, Heytens E, Moy F, Oktay K (2010) Value of early referral to fertility preservation in young women with breast cancer. J Clin Oncol 28:4683–4686

    Article  Google Scholar 

  29. Su HI, Sammel MD, Green J, Velders L, Stankiewicz C, Matro J et al (2010) Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer 116:592–599

    Article  CAS  Google Scholar 

  30. Oktay K, Harvey BE, Partridge AH, Quinn GP, Reinecke J, Taylor HS et al (2018) Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 36:1994–2001

    Article  Google Scholar 

  31. Lambertini M, Anserini P, Levaggi A, Poggio F, Del Mastro L (2013) Fertility counseling of young breast cancer patients. J Thorac Dis 5:68–80

    Google Scholar 

  32. Fitzmaurice G, Laird N, Ware J (2011) Longitudinal analysis. 2nd edn, Wiley, Hoboken. https://content.sph.harvard.edu/fitzmaur/ala2e/

  33. Partridge AH, Ruddy KJ, Gelber S, Schapira L, Abusief M, Meyer M et al (2010) Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer. Fertil Steril 94:638–644

    Article  Google Scholar 

  34. Shandley LM, Spencer JB, Fothergill A, Mertens AC, Manatunga A, Paplomata E et al (2017) Impact of tamoxifen therapy on fertility in breast cancer survivors. Fertil Steril 107:243–252.e5

    Article  CAS  Google Scholar 

  35. Oktay K, Buyuk E, Davis O, Yermakova I, Veeck L, Rosenwaks Z (2003) Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 18:90–95

    Article  CAS  Google Scholar 

  36. Yu B, Douglas N, Ferin MJ, Nakhuda GS, Crew K, Lobo RA et al (2010) Changes in markers of ovarian reserve and endocrine function in young women with breast cancer undergoing adjuvant chemotherapy. Cancer 116:2099–2105

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Trapp E, Steidl J, Rack B, Kupka MS, Andergassen U, Jückstock J et al (2017) Anti-Müllerian hormone (AMH) levels in premenopausal breast cancer patients treated with taxane-based adjuvant chemotherapy: a translational research project of the SUCCESS A study. Breast 35:130–135

    Article  Google Scholar 

  38. Oktay K, Newton H, Mullan J, Gosden RG (1998) Development of human primordial follicles to antral stages in SCID/hpg mice stimulated with follicle stimulating hormone. Hum Reprod 13:1133–1138

    Article  CAS  Google Scholar 

  39. Bines J, Oleske DM, Cobleigh MA (1996) Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 14:1718–1729

    Article  CAS  Google Scholar 

  40. Li F, Turan V, Lierman S, Cuvelier C, De Sutter P, Oktay K (2014) Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death. Hum Reprod 29:107–113

    Article  CAS  Google Scholar 

  41. Plante BJ, Cooper GS, Baird DD, Steiner AZ (2010) The impact of smoking on anti-Mullerian hormone levels in women aged 38 to 50 years. Menopause 17:571–576

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Ansh Laboratories for their assistance in the analysis of serum AMH levels and Angelena Crown, MD for help with data extraction.

Funding

This study was supported by RO1 HD053112 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and National Cancer Institute. H. Bang is partly supported by the National Institutes of Health through Grant UL1 TR001860.

Author information

Author notes

  1. Shari B. Goldfarb, Volkan Turan, and Giuliano Bedoschi have contributed equally to this work.

Authors and Affiliations

  1. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Shari B. Goldfarb, Nadia Abdo, Sujita Patil & Maura N. Dickler

  2. Weill Cornell Medical Center, New York, NY, USA

    Shari B. Goldfarb & Tessa Cigler

  3. Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA

    Volkan Turan, Giuliano Bedoschi, Enes Taylan & Kutluk H. Oktay

  4. Department of Obstetrics and Gynecology, Health and Technology University School of Medicine, Istanbul, Turkey

    Volkan Turan

  5. Department of Obstetrics and Gynecology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil

    Giuliano Bedoschi

  6. Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, USA

    Heejung Bang

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  1. Shari B. Goldfarb
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Contributions

Conception of the idea: KO; Design: KO, MD, SG, SP; Study execution: SG, MD, KO, GB, VT, ET; Provision of study materials: KO, MD, SG, TC; Manuscript writing: KO, VT, SG, GB, HB; Statistical Analysis: VT, HB; Final approval: All authors.

Corresponding author

Correspondence to Kutluk H. Oktay.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Goldfarb, S.B., Turan, V., Bedoschi, G. et al. Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer. Breast Cancer Res Treat 185, 165–173 (2021). https://doi.org/10.1007/s10549-020-05933-7

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