OP-JNCI210065 1274..1276

Cyclophosphamide is an important component of most adjuvant breast cancer chemotherapy regimens (1,2). However, research has repeatedly demonstrated that it also contributes substantially to the risk of gonadotoxicity in premenopausal women, an issue of great importance for young patients (3,4). The development of chemotherapy-induced premature ovarian insufficiency (POI) is associated with not only attendant infertility but also the additional negative health consequences of an early loss of ovarian function (5). Together with patient age, type, and dose of chemotherapy are the other crucial factors influencing gonadotoxicity risk, with alkylating agents such as cyclophosphamide being associated with the highest negative gonadal impact (3,4,6). Therefore, investigating the possibility of effective novel adjuvant chemotherapy regimens with lower risk of this long-term toxicity is a highly relevant clinical question. In this issue of the Journal, Yu and colleagues (7) report the results of Substitution of PaclitaxEl for Cyclophosphamide on survival ouTcomes and ResUmption of Menses in young women with ER-positive breast cancer (SPECTRUM), a phase III randomized trial designed to evaluate a cyclophosphamide-free adjuvant chemotherapy regimen to reduce ovarian toxicity in young women with hormone receptor–positive and HER2-negative breast cancer. Through 8 institutions in China, 521 women with a median age of 34 years were randomly assigned to receive adjuvant epirubicin and cyclophosphamidefollowed by weekly paclitaxel (EC-wP) or a cyclophosphamide-free regimen with epirubicin and paclitaxel followed by weekly paclitaxel (EP-wP). At 12 months following chemotherapy completion, a greater proportion of women in the cyclophosphamide-free group resumed ovarian function (63.1% vs 48.3%) and had a posttreatment pregnancy (9.6% vs 2.7%). At a median follow-up of 62 months, the cyclophosphamide-free group experienced better 5-year disease-free survival compared with those in the standard group (84.7% vs 78.3%) (7). The investigators of the SPECTRUM trial should be applauded for conducting the first prospective trial specifically designed to study a less ovarian toxic regimen in young women with breast cancer receiving adjuvant chemotherapy. They were able to succeed in a challenging setting where prior attempts, including the phase II TRIal evalUating the Menstrual and Ovarian Function of Young Breast Cancer Patients Treated With a cycloPHosphamide-free Regimen (TRIUMPH) study (NCT02053597), have failed. These findings have potential implications for the treatment of young women with breast cancer, providing a new alternative adjuvant chemotherapy regimen. However, these results should be considered in the context of potential study limitations and of other literature addressing this issue. First, defining chemotherapy-induced POI is challenging (3,4). Although most women who remain premenopausal after treatment will resume menstrual functioning during the first year after chemotherapy, longer-term ovarian function recovery occurs in a nonnegligible proportion of patients between year 1 and 2 or thereafter (8-10). Moreover, the gonadotoxicity of chemotherapy can induce damage to women’s ovarian reserve irrespective of the occurrence of perturbation in the menstrual cycle (11). Therefore, empirically defining POI with a composite endpoint including amenorrhea for at least 2 years following chemotherapy completion in conjunction with a postmenopausal hormonal profile and ultrasound evidence of nonfunctioning ovaries has been recommended (12). The antimullerian hormone is currently being investigated as a promising serum marker to more accurately measure the gonadal damage induced by anticancer therapies (3,4). In the SPECTRUM trial, recovery of ovarian function was defined as 2 consecutive menstrual cycles or 1 menstrual cycle ED IT O R IA L