A cyclophosphamide-free chemotherapy regimen may be linked to a higher likelihood of menses resumption with minimal impact on disease-free survival (DFS) and overall survival (OS) in young women with early-stage breast cancer, according to findings published in the Journal of the National Cancer Institute.

The authors noted that although adjuvant chemotherapy with cyclophosphamide in combination with anthracycline and/or taxanes has proven to be an effective treatment for breast cancer, cyclophosphamide-containing chemotherapy may induce premature menopause leading to infertility in women.

In a randomized phase 3 trial (ClinicalTrials.gov Identifier: NCT01026116), the researchers sought to determine if the elimination of cyclophosphamide from a chemotherapy regimen would result in higher menstrual resumption rates, specifically in young women with estrogen receptor (ER)-positive breast cancer.

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The study enrolled 521 young women (median age 34 years; interquartile range, 31-38) who had operable, ER-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer following definitive surgery. The primary endpoints were the rate of menstrual resumption at 12 months after chemotherapy and 5-year DFS. Secondary endpoints included “distant” DFS, OS, and toxicity in the intention-to-treat population.

The participants were randomly assigned 1:1 to receive adjuvant epirubicin and cyclophosphamide every 3 weeks for 4 cycles followed by weekly paclitaxel for 12 weeks (EC-wP arm; 261 patients) or epirubicin and paclitaxel every 3 weeks for 4 cycles followed by weekly paclitaxel for 12 weeks (EP-wP arm; 260 patients).

At 12 months following EC-wP chemotherapy, 48.3% (95% CI, 42.2-54.3) of the participants were reported to have resumed their menstrual cycle compared with 63.1% (95% CI, 57.2-68.9) of the participants who received EP-wP chemotherapy, with an absolute difference of 14.8% (95% CI, 6.37-23.2; P <.001) and an estimated odds ratio of 1.83 (95% CI, 1.29-2.60).

The median follow-up duration of the study was 62 months (interquartile range, 45-82). At 5 years, DFS was 84.7% (95% CI, 79.3-88.8) for the women who received EP-wP (stratified log-rank P =.07) compared with 78.3% (95% CI, 72.2-83.3) for the women who received EC-wP chemotherapy.

Post hoc exploratory analysis of pregnancy outcomes assessed by patient-reported questionnaires revealed a higher rate of successful pregnancy among women in the EP-wP arm (9.6%) compared with those in the EC-wP arm (2.6%; P =.03).

Grade 3 to 4 leukopenia and neutropenia were the most common adverse events (AEs) observed in both treatment arms. Treatment-related grade 3 to 4 AEs were consistent with the known safety profiles of relevant drugs and were generally well-tolerated and resolved. There were no fatalities reported in the study.

“…[O]ur findings can be extrapolated to patients with other subtypes of breast cancer,

such as [triple-negative] or HER2 enriched, because the effect of paclitaxel and cyclophosphamide on menstrual resumption is not cancer subtype specific,” the authors reported.


Yu K-D, Ge J-Y, Liu X-Y, Mo M, He M, Shao Z-M; SPECTRUM Investigators. Cyclophosphamide-free adjuvant chemotherapy for ovarian protection in young women with breast cancer: a randomized phase 3 trial. J Natl Cancer Inst. Published April 2, 2021. doi:10.1093/jnci/djab065