Trastuzumab and Chemotherapy Could Reduce Early-Stage HER2-Positive Breast Cancer Deaths by a Third

The addition of trastuzumab to chemotherapy for the treatment of early-stage, HER2-positive breast cancer helps to reduce disease recurrence and can potentially reduce the mortality from breast cancer by a third worldwide, according to a study published in the Lancet Oncology.

Trastuzumab is designed to target the extracellular domain of the HER2 protein. It is already known that adding trastuzumab to chemotherapy for this patient population help to reduce death and recurrence. However, trastuzumab is also associated with cardiac toxicity, warranting further investigation on the actual benefit of the agent as well as its effect on cause-specific mortality.

Investigators conducted a meta-analysis of individual patient data from randomized trials that assessed the efficacy of chemotherapy plus trastuzumab versus chemotherapy alone. Data was collected on baseline characteristics and first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. 

In total, 13,864 participants with early-stage, HER2-positive breast cancer who were randomized to receive either chemotherapy plus trastuzumab or chemotherapy alone were identified across 7 relevant trials between February 2000 and December 2005. Of those women, 26.6% had breast cancer recurrence, and 19.7% died. Of those deaths, 12.7% were from causes unrelated to breast cancer and without a record of disease recurrence. Across all trials, the mean of scheduled treatment duration was 14.4 months. No significant heterogeneity between the 7 trial results for recurrence or breast cancer mortality was found. 

The analysis found that there was a highly statistically significant connection between the use of trastuzumab and chemotherapy on the reduced risk of recurrence and mortality compared to chemotherapy alone (RR, 0.66, 95% CI 0.62-0.71; P <.0001). The average 10-year reduction in risk of recurrence for the combination was 9% (95% CI, 0.4 -10.7; P <.0001) with a 6.4% (range, 4.9% to 7.8%) reduction in 10-year breast cancer mortality. The all-cause mortality risk was reduced by 6.5% (range, 5.0%-8.0%). There was no increase in death without recurrence.

The addition of trastuzumab to chemotherapy reduced the risk of both distant and local recurrence. Distant recurrence was reduced from 0.57 to 0.70 (RR, 0.63; 99% CI), and local recurrence was reduced from 0.72, 0.59 to 0.89. However, contralateral breast cancer incidence rates did not reduce (0.93, 0.68 to 1.26). Little to no reduction was seen in the incidence of brain metastases as the first site of distant recurrence (RR 0.91; 95% CI, 0.73-1.13; P =.40).

The largest proportional reduction in recurrence occurred in years 0-1 (RR 0.53; 99% CI 0.46-0.61). Smaller reductions were seen in years 2-4 (0.73, 0.62-0.85) and years 5–9 (0.80, 0.64-1.01). The studies provided little follow-up beyond year 10. The proportional reduction in the risk of recurrence for ER-negative and ER-positive cancers followed a similar trend (RR, 0.62; 95% CI 0.56−0.69) versus (RR, 0.67; 95% CI, 0.60-0.74). Higher recurrence rates in the first 2 years were more common in ER-negative cancers than ER-positive cancer. However, the trend flipped in years 5-9. This led to a similar recurrence rate between the 2 cancer types.

Proportional recurrence did not vary by age, duration of trastuzumab treatment, traditional histopathological features, and body mass index. The absolute 5-year risk of recurrence was the greatest in patients with more involved nodes due to their higher risk of recurrence. Additionally, the reduction in recurrence did not differ significantly from studies that administered trastuzumab and chemotherapy concurrently or after the completion of chemotherapy. The risk of death unrelated to breast cancer in the first year after randomization appeared to be no greater when trastuzumab was given concurrently or sequentially.

Of the 7 trials included in the analysis, only 1 had available data on cardiac toxicity. In total, few fatal toxic events were reported with no excess deaths in the trastuzumab group. 

“We found no overall increase in mortality from causes unrelated to breast cancer. Nevertheless, there were more deaths without recurrence in the first year after randomization with trastuzumab than with control, which was not explained by administering trastuzumab concurrently with chemotherapy,” study authors wrote. “This finding could well be due to chance, as the difference is spread over several different causes. However, even if the apparent excess risk is real, the excess number of these deaths was 30 times smaller than the number of deaths from breast cancer prevented.”

_REFERENCE:

_{Early Breast Cancer Trialists’ Collaborative group. Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13864 women in seven randomised trials. Lancet Oncol. 2021;22(8):1139-1150. doi: 10.1016/S1470-2045(21)00288-6.}