Shortened Trastuzumab Administration Does Not Improve DFS in ERBB2+ Breast Cancer

Heikki Joensuu, MD

Treatment with adjuvant trastuzumab (Herceptin) plus concurrent chemotherapy led to inferior disease-free survival (DFS) outcomes when administered for 9 weeks vs the standard 1-year duration in patients with ERBB2-positive breast cancer, according to long-term findings from a secondary analysis of the phase 3 SOLD trial (NCT00593697), which were published in JAMA Network Open.¹

At a median follow-up of 8.1 years (interquartile range [IQR], 8.0-8.9), among the 2174 patients analyzed, the 9-week administration of trastuzumab (n = 1085) was associated with a shorter DFS compared with the 1-year administration (n = 1089; HR, 1.36; 90% CI, 1.14-1.62; exploratory 2-sided log-rank superiority-testing P = .004). The 5-year DFS rates were 87.7% and 90.7% in the 9-week and 1-year groups, respectively; the 10-year DFS rates were 78.6% and 80.3% in these respective groups. Among the 357 total DFS events reported, 56.6% and 43.4% occurred in the 9-week and 1-year groups, respectively.

“Potential advantages of the 9-week regimen include little need for cardiac monitoring, fewer visits required for treatment administration, and lower cost,” lead study author Heikki Joensuu, MD, and colleagues, wrote in the paper. “Access to trastuzumab is still a major barrier to care, particularly in low-income and lower-middle–income countries. The 9-week regimen may be an option for patients who may not tolerate 1 year of trastuzumab or who cannot afford it.”

Joensuu is a research director in the Department of Oncology at Helsinki University Hospital and the University of Helsinki in Finland.

The 1-year duration of adjuvant trastuzumab administration has been compared with durations of 6 months and 9 weeks across 5 randomized, noninferiority clinical trials in patients with HER2-positive breast cancer. Only 1 of the trials, the phase 3 PERSEPHONE trial (NCT00712140), demonstrated noninferiority with 6 months vs 1 year of adjuvant trastuzumab.² However, all 5 trials reported improved cardiac safety with the shorter regimens.¹

In the primary analysis of SOLD, after a median follow-up of 5.2 years (IQR, 3.8-6.7), the 9-week regimen was deemed not noninferior to the 1-year regimen for DFS (HR, 1.39; 2-sided 90% CI, 1.12-1.72).³

This post-hoc secondary analysis of the open-label, multicenter, noninferiority-design, randomized SOLD trial enrolled patients aged 18 years or older with histologically confirmed, localized early ERBB2-positive breast cancer between January 3, 2008, and December 16, 2014, across 65 centers in 7 European countries.¹ Patients were excluded if they had a history of neoadjuvant therapy or distant metastases.

Patients received 3 cycles of intravenous (IV) docetaxel at 80 mg/m2 or 100 mg/m2 in 3-week intervals concomitantly with IV or subcutaneous trastuzumab followed by 3 cycles of fluorouracil at 600 mg/m2, epirubicin at 75 mg/m2, and cyclophosphamide at 600 mg/m2 in 3-week intervals. Trastuzumab was administered IV either weekly (first dose, 4 mg/kg; subsequent doses, 2 mg/kg) or in 3-week intervals (600 mg regardless of body weight), or subcutaneously in 3-week intervals (600 mg regardless of body weight). Patients in the 1-year group received trastuzumab in 3-week intervals 14 times after stopping chemotherapy. Patients in the 9-week group received no further trastuzumab after chemotherapy.

Patients received endocrine therapy and radiotherapy according to each center’s practice, but adjuvant endocrine therapy was given for 5 years or more after completing chemotherapy when a patient’s cancer was considered estrogen receptor (ER) positive and/or progesterone receptor positive.

The median patient age was 56 years (IQR, 48-64), and most had node-negative cancer (9-week group, 59.6%; 1-year group, 59.6%).

Subgroup analyses showed a significant interaction between docetaxel starting dose and DFS differences by treatment group (P = .007). A multivariable Cox proportional hazards regression model demonstrated that 4 or more positive axillary nodes (HR, 2.28; 95% CI, 1.65-3.15; P < .001), a disease stage of II or III vs I (HR, 1.53; 95% CI, 1.13-2.08; P = .006), and receiving 9 weeks of trastuzumab vs 1 year (HR, 1.36; 95% CI, 1.10-1.68; P = .005) were associated with shorter DFS, but age, ER status, and docetaxel starting dose were not.

Distant DFS was not significantly different between the 2 treatment groups (HR, 1.28; 90% CI, 1.00-1.65; exploratory 2-sided log-rank superiority-testing P = .10).

The 5-year overall survival (OS) rates were comparable between the 9-week and 1-year groups, at 95.0% and 95.9%, respectively. The 10-year OS rates were also comparable between these groups, at 89.1% and 88.2%, respectively (HR for all time points, 1.20; 90% CI, 0.94-1.54; exploratory 2-sided log-rank superiority-testing P = .22). Subgroup analyses for OS showed no interactions between treatment group and the factors tested, including docetaxel dose, ER status, positive axillary lymph nodes, disease stage, and age.

A multivariable analysis showed that 9 weeks of treatment was associated with a shorter DFS compared with 1 year of treatment (HR, 1.36; 95% CI, 1.10-1.68; P = .005) but that there was no OS difference between patients with different ER statuses, those who received different docetaxel starting doses, or those randomly assigned to the 2 treatment groups (HR, 1.22; 95% CI, 0.90-1.64; P = .20). This analysis also showed that the number of positive axillary nodes (HR, 2.77; 95% CI, 1.79-4.30; P < .001), age at study entry (HR, 1.03; 95% CI, 1.01-1.05; P < .001), and disease stage (HR, 1.93; 95% CI, 1.22-3.03; P = .005) were independently associated with the risk of death.

Four patients died of a cardiac cause, including myocardial infarction and/or coronary artery thrombosis (n = 3) and heart failure (n = 1). Three of these patients had received trastuzumab for a duration of 9 weeks. Among the 176 total deaths, 54.0% and 46.0% occurred in the 9-week and 1-year groups, respectively.

“This observation is consistent with findings in other trials in which death from cardiac failure was uncommon in patients treated with trastuzumab,” the authors concluded.

The authors noted that limitations of this research included the follow-up time, which may have been too short to capture all recurrences and breast cancer–related deaths; as well as the proportion of patients with node-negative cancer, which was slightly larger than that in other randomized clinical trials that have evaluated durations of adjuvant trastuzumab that were shorter than 1 year.

References

1. Joensuu H, Fraser J, Wildiers H, et al. Long-term outcomes of adjuvant trastuzumab for 9 weeks or 1 year for ERBB2-positive breast cancer: a secondary analysis of the SOLD randomized clinical trial. JAMA Netw Open. 2024;7(8):e2429772. doi:10.1001/jamanetworkopen.2024.29772
2. Earl HM, Hiller L, Vallier AL, et al. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019;393(10191):2599-2612. doi:10.1016/S0140-6736(19)30650-6
3. Joensuu H, Fraser J, Wildiers H, et al. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018;4(9):1199-1206. doi:10.1001/jamaoncol.2018.1380