The updated network meta-analysis of neoadjuvant therapy for HER2-positive breast cancer

Highlights

• We firmly establish that two anti-HER2 agents with chemotherapy is most effective.

• The updated analysis improved data by reducing confidence/credibility intervals.

• New pzmb related trials are most required to determine the best regimen.

Abstract

Background

We previously described a systematic assessment of the neoadjuvant therapies for human epidermal growth factor receptor-2 (HER2) positive breast cancer, using network meta-analysis. Accumulation of new clinical data has compelled us to update the analysis.

Methods

Randomized trials comparing different anti-HER2 regimens in the neoadjuvant setting were included, and odds ratio for pathologic complete response (pCR) in seven treatment arms were assessed by pooling effect sizes. Direct and indirect comparisons using a Bayesian statistical model were performed. All statistical tests were two-sided.

Results

A database search identified 993 articles with 13 studies meeting the eligibility criteria, including three new studies with lapatinib (lpnb). In an indirect comparison, dual anti-HER2 agents with CT achieved a better pCR rate than other arms. The credibility intervals of CT + tzmb + lpnb arm were largely reduced compared to our former report, which we added sufficient clinical evidence by this update. Values of surface under the cumulative ranking (SUCRA) suggested that CT + tzmb + pzmb had the highest probability of being the best treatment arm for pCR, widening the difference between the top two dual-HER2 blockade arms compared to our former report. The overall consistency with our first report enhanced the credibility of the results.

Conclusion

Network meta-analysis using new clinical data firmly establish that combining two anti-HER2 agents with CT is most effective against HER2-positive breast cancer in the neoadjuvant setting. New pzmb related trials are required to fully determine the best neoadjuvant dual-HER2 blockade regimen.

Introduction

The characterization of the human epidermal growth factor receptor 2 (HER2), as a proto-oncogene, a poor prognostic marker, and finally as a therapeutic target has dramatically changed the categorization, risk assessment, and treatment of breast cancer. Overexpression or amplification of HER2 occurs in approximately 20% of human breast cancers, and trastuzumab (tzmb), an anti-HER2 agent, has demonstrated clinically significant efficacy against HER2-positive breast cancer [1].

As neoadjuvant systemic therapies are now routinely delivered in primary operable breast cancer [2], it is becoming increasingly popular to use neoadjuvant chemotherapy including anti-HER2 agents in patients with operable HER2-positive breast cancers. National Comprehensive Cancer Network (NCCN) Guidelines Version 2. 2017 recommend treating HER2-positive patients with systemic therapy incorporating tzmb for at least 9 weeks in the neoadjuvant setting. They also add that pertuzumab (pzmb) containing regimen may be administered preoperatively to patients with ≥ T2 or ≥ N1, HER2-positive early-stage breast cancer [3].

Increasing options for HER2-targeted agents prompts us to define the best neoadjuvant therapy for HER2-positive breast cancer. The agents include tyrosine kinase inhibitor lapatinib (lpnb) or monoclonal antibody pzmb, antibody-drug conjugate trastuzumab-DM1 (T-DM1), and neratinib, an HER2, HER4, and EGFR tyrosine kinase inhibitor. Lpnb is a small molecule tyrosine kinase inhibitor of the HER1 and HER2 receptors that suppresses the downstream signaling involving MAPK/Erk1/2 and P13K/Akt pathways [4]. Pzmb is a humanized monoclonal antibody that inhibits dimerization of HER2 with other HER receptors [5]. Based on the results of the CLEOPATRA trial, the combination of tzmb and pzmb with taxane has become a new first-line standard treatment for HER2-positive advanced breast cancer patients with good performance status [6].

Although trials have been conducted to compare various treatment regimens, it remains difficult to integrate information on their relative efficacies since each trial has compared only a few treatments at one time. In 2014, we reported the results of a systematic assessment of the efficacy and safety of neoadjuvant therapies for HER2-positive breast cancer, using a network meta-analysis based on the Bayesian model, conducting direct and indirect comparisons from multiple randomized clinical trials [7]. After collecting information from a network of trials, the network meta-analysis combines both the direct and indirect evidence for the relative effectiveness of treatments and ranks them thereafter [8], [9], [10]. By indirect comparison, we can compare treatment arms which are not directly compared in clinical trials. As the complexity of the analysis supporting the clinical guidelines increase, it helps to make sound clinical decisions [11].

In our previous study, we reported that the patients receiving dual-HER2 blockade treatments presented significantly better pathologic complete response (pCR) rates than those in other treatment arms, and recommended the combination of two anti-HER2 agents with chemotherapy (CT) to be the most effective treatment modality in the neoadjuvant setting for HER2-positive breast cancer [7]. Though there was no significant difference between the two dual targeting treatment arms of CT + tzmb + lpnb and CT + tzmb + pzmb, the latter was slightly more likely to be the best treatment arm in terms of pCR considering the values of ranking probability curve.

As mentioned before, NCCN Guidelines now recommend using two anti-HER2 antibodies preoperatively in selected HER2-positive breast cancer patients. Dual-HER2 blockade in a neoadjuvant setting is, therefore, getting to be more popular than it was at the time of our previous report [12]. Since our primary report, several important network meta-analysis were reported in the area of breast cancer therapy [13], [14], [15]. However, whether if dual neoadjuvant anti-HER2 antibody inhibition produce clinically significant improvements has still remained in controversy [2].

Five years after our first article search, we decided to update our analysis based on the new clinical evidence available and further verify the effectiveness of dual-HER2 blockade. We also aimed to determine if more clinical studies of neoadjuvant HER2-positive breast cancer are required, and if so, which treatment regimens require additional studies the most.