Large Meta-Analysis of Additional Trastuzumab for Early HER2+ Breast Cancer Confirms Large Treatment Benefit Regardless of Baseline Characteristics

A meta-analysis of trials examining the addition of adjuvant or neoadjuvant trastuzumab (Herceptin) to therapy for operable HER2-positive early breast cancer confirmed benefit of therapy across a range of baseline patient and tumor characteristics, according to a study published in The Lancet Oncology.

Pooled analysis for breast cancer recurrence (rate ratios [RR], 0.66; 95% CI, 0.62-0.71; P < .0001) and the risk of death (RR, 0.67; 95% CI, 0.61-0.73; P < .0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Risk of recurrence at 10 years was reduced by 9.0% (95% CI, 7.4%-10.7%; P < .0001), while the 10-year mortality risk was reduced by 6.4% (95% CI, 4.9%-7.8%; P < .0001). In addition, there was a 6.5% reduction in all-cause mortality (95% CI, 5.0-8.0; P < .0001) and no increase in death without recurrence (0.4%, 95% CI, -0.3 to 1.1; P = .35).

“This meta-analysis substantiates that—for patients with operable HER2-positive breast cancer—the addition of trastuzumab to chemotherapy further reduces recurrence of, and mortality from, breast cancer during the first decade of follow-up by about a third,” investigators of the study wrote.

This meta-analysis used data from 7 identified trials, which included 13,864 women with early-stage HER2-positive breast cancer. Within this group, 26.6% (n = 3685) had recurrence and 19.7% (n = 2738) had died, of whom 12.7% (n = 347) had died from causes unrelated to breast cancer and did not have disease recurrence.

The median follow-up was 10.7 years with most trial’s inclusion criteria allowing patients who had either lymph node–positive or high-risk node-negative disease. In order to determine the HER2 status, local immunohistochemistry or fluorescence in-situ hybridization testing was used.

Most patients received anthracyclines, taxane chemotherapy, and endocrine therapy that was recommended for their disease. Trials included were the NSABP trial B-31 (NCT00004067), the NCCTG trial N9831 (NCT00005970), the BCIRG 006 trial (NCT00021255), the FinHER trial (ISRCTN76560285), the PACS 04 trial (NCT00054587), and the the HERA study NCT00045032).

In all the studies except for NOAH, trastuzumab plus chemotherapy was administered after surgery. For patients in the HERA, PACS 04, and 1 group of the NCTG trial N9831, trastuzumab was commenced after completion of chemotherapy. The duration of the treatment was 12 months except in FinHER that tested 9 weeks of trastuzumab. The HERA trial also included a 24-month trastuzumab treatment group that had the primary analysis of trastuzumab vs no trastuzumab. The mean treatment duration across all trials was 14.4 months

It was found that trastuzumab reduced distant recurrence (RR, 0.63, 99% CI, 0.57-0.70) and local recurrence (RR, 0.72; 99% CI, 0.59-0.89), but not contralateral breast cancer incidence (RR, 0.93; 99% CI, 0.68-1.26).

For patients with distance recurrence, there was little or no reduction in the incidence of brain metastases as the first site of distance recurrence (RR, 0.91; 95% CI, 0.73-1.13; P = .40) which was significantly less than the effects of trastuzumab on other sites of distant recurrence (RR, 0.60; 95% CI, 0.55-0.65; P <.0001).

Throughout the 10 years, the largest proportional reduction in recurrence was in years 0 to 1 (RR, 0.53; 99% CI, 0.46-0.61), then there were smaller proportional reductions in years 2 to 4 (RR, 0.73; 99% CI, 0.62-0.85), and years 5 to 9 (RR, 0.80; 99% CI, 0.64-1.01). Little follow-up occurred beyond year 10.

Patient characteristics such as age, body mass index, duration of treatment, or traditional histopathological features did not vary with this proportional reduction in recurrence.

The 5-year risk for absolute reduction was greatest in patients with involved nodes, at 5.7% (95% CI, 3.1%-8.3%) for N0 , 6.8% (95% CI, 4.7%-9.0%) for N1 to N3, and 10.7% (95% CI, 7.7%-13.6%) for N4 and up .

In patients receiving trastuzumab plus chemotherapy, there were no significant increases in death without breast cancer recurrence (RR, 0.90; 95% CI, 0.72-1.12; P = .35), including mortality from cardiovascular effects (RR, 1.23; 95% CI, 0.73-2.06; P = .44) or cancers at sites other than the breast (RR, 0.79; 95% CI, 0.54-1.17; P = .24).

Investigators did find that there were more deaths unrelated to breast cancer in the first year of chemotherapy plus trastuzumab therapy at 0.37% (n = 31) vs 0.16% (n = 13) in the chemotherapy group (RR, 2.15; 95% CI, 1.11-4.14; P = .023).

There were 414 patients who died without recorded recurrence, of whom and 17% (n = 72) died from unknown causes. They were unrelated to treatment allocation or TNM stage, so they were included with the deaths unrelated to breast cancer.

Congestive heart failure and left ventricular ejection fraction was higher in the trastuzumab group compared with the control. This usually resulted in treatment discontinuation, but the number of patients this affected was low. There were few fatal toxic events reported and no excess in the trastuzumab group.

Reference

Early Breast Cancer Trialists’ Collaborative group (EBCTCG). Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol. 2021;22(8):1139-1150. doi:10.1016/S1470-2045(21)00288-6