Cyclophosphamide-free adjuvant chemo works against ERBB2-negative breast cancer

The adjuvant chemotherapy regimen epirubicin plus paclitaxel (EP) appears to be as good as the regimen that consists of epirubicin and cyclophosphamide followed by paclitaxel (EC-P) in the treatment of Asian women with operable ERBB2-negative breast cancer, according to the results of an open-label phase III trial.

In the intention-to-treat population, 89 patients who received EP and 100 who received EC-P remained disease-free during a median follow-up period of 93.6 months. The 5-year disease-free survival (DFS) rates were 86.0 percent with EP and 80.6 percent with EC-P (hazard ratio [HR], 0.82, 95 percent confidence interval [CI], 0.62–1.10; p=0.001 for noninferiority). [JAMA Netw Open  2023;6:e230122]

As for the secondary outcomes, the 5-year rates in the respective EP vs EC-P arms were 94.7 percent vs 95.0 percent for overall survival (OS; HR, 0.95, 95 percent CI, 0.61–1.49) and 88.4 percent vs 84.5 percent for distant DFS (HR, 0.77, 95 percent CI, 0.57–1.05).

Adverse events occurred more frequently with EP than with EC-P. Recorded events included any-grade leukopenia, neutropenia, anaemia, thrombocytopenia, gastrointestinal tract toxic effects, neurotoxic effects, hepatotoxic effects, cardiotoxic effects, alopecia, and fatigue. Among premenopausal patients, those who received EC-P more often experienced chemical menopause. There were no treatment-related deaths that occurred during the follow-up period.

“This trial was designed to determine whether the EP regimen is noninferior to the standard EC-P regimen in both efficacy and safety for ERBB2-negative breast cancer. The results demonstrate that EP regimen reaches the noninferior standard to the EC-P regimen mainly in operable hormone receptor–positive, ERBB2-negative, node-positive breast cancer,” the investigators said.

“To the best of our knowledge, this is the first phase III clinical trial to compare the long-term outcomes of two adjuvant chemotherapy regimens, specifically in Asian patients with operable breast cancer,” they added.

The trial involved 813 patients (median age 48 years) with operable hormone receptor–positive, ERBB2 (formerly HER2)-negative, lymph node–positive breast cancer treated at the Cancer Hospital, Chinese Academy of Medical Sciences in Beijing, China. They had been randomly assigned to receive either EP (n=407) or EC-P (n=406) after the surgical procedure.

Epirubicin (75 mg/m²) and paclitaxel (175 mg/m²) were administered every 3 weeks for six cycles, while epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) were given every 3 weeks for four cycles followed by paclitaxel (175 mg/m²) every 3 weeks for four cycles.

“Cyclophosphamide is an important component of most adjuvant chemotherapy regimens in breast cancer. However, research has repeatedly demonstrated that it also contributes substantially to the risk of gonadotoxic effects, especially in premenopausal women,” the investigators pointed out. [Lancet 2012;379:432-444; Breast Cancer Res Treat 2019;174:27-37; Ann Oncol 2020;31:1664-1678; Hum Reprod Open 2020;2020:hoaa052]

Indeed, in the SPECTRUM* trial that included young women with breast cancer, the rate of menstrual resumption at 12 months after chemotherapy was 48.3 percent among those who received the standard adjuvant epirubicin plus cyclophosphamide followed by weekly paclitaxel (EC-wP) and 63.1 percent among those who received epirubicin plus paclitaxel followed by weekly paclitaxel (EP-wP; p<0.001). Furthermore, data from the patient-reported questionnaires indicated that pregnancy might occur in fewer women in the EC-wP group than in the EP-wP group. [J Natl Cancer Inst 2021;113:1352-1359]

“In the present study, subgroup analysis showed that the EP group had a better DFS than the EC-P group among postmenopausal women and patients without radiotherapy. These results indicate that the EP regimen may be more suitable for postmenopausal women and patients who are unable to receive radiotherapy,” they said, acknowledging that such a difference may have resulted from the higher dose of epirubicin and paclitaxel used in the EP regimen.

The current findings, combined with reports from former studies, underscore the feasibility of cyclophosphamide-free regimens in ERBB2-negative breast cancer, according to the investigators. [J Clin Oncol 2003;21:1431-1439; J Natl Cancer Inst 2021;113:1352-1359] 

“However, it is essential for clinicians to pay more attention to adverse effects of EP regimen to promote medication safety,” they added.