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Journal of Clinical Oncology, Vol 26, No 16 (June 1), 2008: pp. 2612-2613 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.1976
Fertility Preservation: A Vital Survivorship Issue for Young Women With Breast CancerDana-Farber Cancer Institute, Boston, MA Improvements in the diagnosis and treatment of early breast cancer have led to an increased number of women living with a history of the disease. There are now more than 2.4 million breast cancer survivors in the US alone, and an estimated 10% of these women are of childbearing age.1,2 In a landmark essay on cancer survivorship, Fitzhugh Mullen wrote: "The challenge in overcoming cancer is not only to find therapies that will prevent or arrest the disease quickly, but also to map the middle ground of survivorship and minimize medical and social hazards."3 For young adults with cancer, the threat or experience of infertility may be a particularly distressing consequence of a cancer diagnosis. In recognition of this concern, and with an awareness of the recent advances in the reproductive sciences, the American Society of Clinical Oncology (ASCO) has published guidelines recommending that oncologists discuss with patients the possibility of infertility when treated during their reproductive years.4 Furthermore, ASCO suggests that oncologists be prepared to discuss possible fertility preservation options or to refer appropriately. However, many of the available strategies for fertility preservation have not been fully evaluated in terms of both efficacy and safety. These limitations likely hamper discussion of fertility concerns, referrals to reproductive specialists, and the enthusiasm for patients and providers to embrace some of the available options.4-7 For young women with breast cancer, in particular, fertility preservation is associated with a number of unique concerns. Because the initiation of systemic breast cancer treatment is rarely a medical emergency, newly diagnosed women with breast cancer usually have the opportunity to weigh pros and cons of treatment recommendations, seek consultation regarding fertility preservation, and consider available options. Traditionally, however, the strategies for fertility preservation in young women with breast cancer have been limited both by safety concerns and limited data regarding efficacy. For these reasons, such approaches have been considered experimental.8,9 Ovarian stimulation and oocyte harvesting followed by in vitro fertilization (IVF) is the only widely available, effective procedure for fertility preservation, with an excellent track record among infertile couples. In women with newly diagnosed breast cancer, however, it has been hypothesized that the supraphysiologic estradiol levels arising from conventional ovarian stimulation might increase a woman's risk of recurrence, particularly for women with hormone receptor–positive disease. Given this uncertainty, only a small proportion of young breast cancer patients utilize this option, and investigators have sought to identify strategies that would avoid the possible risks associated with high levels of circulating estrogens.4,10,11 In this issue of Journal of Clinical Oncology, Azim et al report on continued research with young breast cancer patients evaluating alternative ovarian stimulation strategies to mitigate concern about high hormonal levels in women at risk for recurrent disease.12-14 In previous work, Oktay et al found that ovarian stimulation using low-dose follicle-stimulating hormone (FSH) with letrozole resulted in higher embryo yields and lower peak estradiol levels than was observed with either tamoxifen alone or tamoxifen with FSH ovarian stimulation.13 In the present study, Azim et al expand on this experience and have prospectively followed young women with early breast cancer seeking consultation for fertility preservation at their center.14 They have compared outcomes of 79 women who underwent ovarian stimulation using an aromatase inhibitor (letrozole) followed by oocyte collection with a control population of 136 young breast cancer patients who did not undergo ovarian stimulation before systemic therapy. After median follow-up of 23 months for the ovarian stimulation group and 33 months for the control group, they found no statistically significant survival difference between the two groups. In an effort to compare the two groups, they calculated mortality and relapse risks using Adjuvant! online (www.adjuvantonline.com) and found the groups had remarkably similar baseline risks.15 These findings provide further reassurance that the administration of letrozole and FSH to induce ovulation does not, at least with short follow-up, lead to a dramatic increase in the risk of recurrence or death. However, legitimate concern remains that the ovarian stimulation could have a negative impact on outcome. The Azim et al study is relatively small, the follow-up is limited, and—most importantly—the data are not from a randomized controlled trial. Adjuvant therapy for breast cancer is routinely recommended when the anticipated survival benefit is less than 10%, and studies suggest that this is consonant with patient preferences.16,17 Indeed, available data, and the experience of clinicians, would suggest that women opt for a course of adjuvant chemotherapy for survival benefits of 1% to 5%. Thus, a nonrandomized experience that provides an 80% power to detect a 10% difference in survival lacks the ability to detect potentially meaningful clinical differences in outcome and provides marginal reassurance. As noted, more extended follow-up is critical, particularly for women with hormone receptor–positive disease who have a risk of disease recurrence that extends for many years.18 Indeed, Azim et al plan ongoing follow-up, and the investigators’ continued research effort in this area of great importance to many young breast cancer survivors is commendable. Although it is important that investigators, physicians, and young breast cancer patients approach decisions about fertility preservation with caution, decisions in the clinic cannot always wait until more solid data are available. For some young women with breast cancer, having a future biologic child and the threat to this possibility has major psychosocial and developmental consequences. Infertility can be a devastating experience for some individuals and relationships, and limited research in cancer survivors suggests that infertility in this population is also quite distressing.19,20 Many young women with breast cancer struggle with the competing interests of optimizing personal survival, and the powerful desire to have a future biologic child. For some women, modifications of treatment, or intervention aimed at fertility preservation may be appropriate. Many other women and their loved ones may choose to avoid any potential personal risk, and ultimately modify expectations regarding future biologic children. In such challenging situations, the oncology community can strive to provide accurate, unbiased information and psychosocial assistance, and to support continued research focused on rigorous evaluation of fertility preservation strategies, as well as tailored treatments to optimize both survival and quality of life of survivors. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Ann H. Partridge, Novartis (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None ACKNOWLEDGMENTS I thank Eric Winer, MD, for thoughtful insights regarding the issues discussed in this manuscript. REFERENCES 1. Ries LAG, Melbert D, Krapcho M, et al: SEER Cancer Statistics Review, 1975-2004. Bethesda, MD, National Cancer Institute. http://seer.cancer.gov/csr/1975_2004 2. American Cancer Society: Breast Cancer Facts and Figures 2007-2008. Atlanta, GA, American Cancer Society Inc, 2007 3. Mullan F: Seasons of survival: Reflections of a physician with cancer. N Engl J Med 313:270-273, 1985[Medline] 4. Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 24:2917-2931, 2006 5. Thewes B, Meiser B, Taylor A, et al: Fertility- and menopause-related information needs of younger women with a diagnosis of early breast cancer. J Clin Oncol 23:5155-5165, 2005 6. Duffy CM, Allen SM, Clark MA: Discussions regarding reproductive health for young women with breast cancer undergoing chemotherapy. J Clin Oncol 23:766-773, 2005 7. Partridge AH, Gelber S, Peppercorn J, et al: Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 22:4174-4183, 2004 8. Gerber B, Dieterich M, Muller H, et al: Controversies in preservation of ovary function and fertility in patients with breast cancer. Breast Cancer Res Treat 108:1-7, 2008[CrossRef][Medline] 9. Partridge AH, Ruddy KJ: Fertility and adjuvant treatment in young women with breast cancer. Breast 16:S175-S181, 2007 (suppl)[CrossRef][Medline] 10. Partridge AH, Winer EP: Fertility after breast cancer: Questions abound. J Clin Oncol 23:4259-4261, 2005 11. Partridge AH, Gelber S, Peppercorn J, et al: Fertility outcomes in young women with breast cancer. Clin Breast Cancer (in press) 12. Oktay K, Buyuk E, Davis O, et al: Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 18:90-95, 2003 13. 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 23:3858-3859, 2005 14. Azim AA, Costantini-Ferrando M, Oktay K: Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: A prospective controlled study. J Clin Oncol 26:2630-2635, 2008 15. Olivotto IA, Bajdik CD, Ravdin PM, et al: Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 23:2716-2725, 2005 16. Ravdin PM, Siminoff IA, Harvey JA: Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 16:515-521, 1998[Abstract] 17. Simes RJ, Coates AS: Patient preferences for adjuvant chemotherapy of early breast cancer: How much benefit is needed? J Natl Cancer Inst Monogr 146-152, 2001 18. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738-2746, 1996 19. Schover LR: Psychosocial aspects of infertility and decisions about reproduction in young cancer survivors: A review. Med Pediatr Oncol 33:53-59, 1999[CrossRef][Medline] 20. Canada AL, Schover LR: Research promoting better patient education on reproductive health after cancer. J Natl Cancer Inst Monogr 98-100, 2005 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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