Reducing the Long-term Effects of Chemotherapy in Young Women With Early-Stage Breast Cancer

Abstract

A LTHOUGH THE MEDIAN AGE OF WOMEN DIAGnosed with breast cancer is 61 years, about 35% of women newly diagnosed with breast cancer are 54 years or younger, and 12%-almost 25 000-are younger than 45 years.1 The majority of women with breast cancer will receive adjuvant therapy including chemotherapy, hormone therapy, or both, which has been documented to improve disease-free and overall survival. Treatment has a number of adverse effects that directly affect short-term and, in some cases, long-term quality of life. For young women of childbearing age, one of the most devastating adverse effects involves the prospect of loss of fertility, and this concern may influence choice of therapy and adherence to a prescribed treatment plan.2 For some women, concern about early menopause is paramount.Chemotherapy agents exert toxicity in the ovary by causing apoptotic oocyte death in primordial follicles, damaging ovarian reserve and interrupting follicle recruitment and maturation.3 Almost all women develop at least temporary chemotherapy-induced amenorrhea. Reports have suggested a wide range of permanent amenorrhea rates following adjuvant chemotherapy, with important variables including age, treatment regimen, and use of tamoxifen. Historically, the risk of permanent amenorrhea in women younger than 40 years with earlystage breast cancer following adjuvant chemotherapy was reported to be about 40%, compared with 76% in older women. 4 Alkylating agents, particularly the combination regimen of oral CMF (cyclophosphamide, methotrexate, and fluorouracil), are associated with the highest risk of ovarian failure, reaching 90% in women older than 40 years. 4 Current chemotherapy regimens generally have less ovarian toxicity, with significantly lower rates of permanent amenorrhea. Although recovery of menses is still closely related to the variables listed above, in one report 85% of women aged 40 years or younger treated with adjuvant anthracycline and taxane-based chemotherapy recovered menses within 1 year, 5 with docetaxel regimens resulting in higher rates of prolonged amenorrhea.

Chemotherapy-induced ovarian toxicity in patients affected by endocrine-responsive early breast cancer

“…Since GnRH receptors are expressed by a variety of cancers and mediate several effects (e.g., inhibition of proliferation, induction of cell-cycle arrest, and inhibition of apoptosis), it has been suggested that the concomitant administration of GnRH agonist therapy might antagonize CT, reducing its efficacy [84,85]. Therefore, ovarian suppression with GnRH agonists might be safer in women with estrogen receptor-negative BC [86]. Detrimental effects of GnRH agonists on patients under CT, however, were not shown in clinical trials.…”

Temporary amenorrhea predicts future infertility in young women treated with chemotherapy

“…An association between such biomarkers and important clinical outcomes like infertility has yet to be clearly established amongst a diverse group of cancers. An ability to better predict increased risk for reproductive difficulties after treatment could improve counseling for the 123,000 reproductive-age women diagnosed with cancer each year in the United States [2,[5][6][7][8][9].…”

“…However, subsequent studies have demonstrated that even women who continue to menstruate after treatment also remain at increased risk of infertility and early menopause [1,18,19]. Thus, at least in part due to treatment, some women lose their ability to conceive children naturally and others experience significant compromise from a shortened reproductive window [2,3,8,10].…”

“…However, much of this research has focused on women without a history of cancer treatment. When cancer is considered, breast cancer has been the most common focus [1,2,8,13,20,21]. Efforts are underway to broaden our assessment reproductive potential in young women who undergo various types of cancer treatment [1,[22][23][24][25].…”

Accelerating Ovarian Age: Cancer Treatment in the Premenopausal Woman

“…[12][13][14] In the past, when assessing the gonadotoxicity of cancer treatments, most studies used the presence or absence of normal menses as their primary outcome. 15,16 This approach had limitations in terms of improving our understanding of fertility and premature menopause as outcomes remote from treatment. Albright et al first described primary ovarian insufficiency (also known as premature ovarian failure) in 1942 17,18 ; since then an increased understanding has been gained regarding partial ovarian injury.…”