Pyrotinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (PERSIST): A multicenter phase II trial

Reviewer #1 (Public review):

Summary:

This study introduces a novel therapeutic strategy for patients with high-risk HER2-positive breast cancer and demonstrates that the incorporation of pyrotinib into adjuvant trastuzumab therapy can improve invasive disease-free survival.

Strengths:

The study features robust logic and high-quality data. Data from 141 patients across 23 centers were analyzed, thereby effectively mitigating regional biases and endowing the research findings with high applicability.

Weaknesses:

(1) Introduction and Discussion: Update the literature regarding the efficacy of pyrotinib combined with trastuzumab in treating HER2-positive advanced breast cancer.

(2) Did all the data have a normal distribution? Expand the description of statistical analysis.

(3) The novelty and innovative potential of your manuscript compared to the published literature should be described in more detail in the abstract and discussion section.

(4) Figure legend should provide a bit more detail about what readers should focus on.

(5) P-values should be clarified for the analysis.

(6) The order (A, B, and C) in Figure 3 should be labeled in the upper left corner of the Figure.

Reviewer #2 (Public review):

In this manuscript, Cao et al. evaluated the efficacy and safety of 12 months pyrotinib after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer. Notably, the 2-year iDFS rate reached 94.59% (95% CI: 88.97-97.38) in all patients, and 94.90% (95% CI: 86.97-98.06) in patients who completed 1-year treatment of pyrotinib. This is an interesting and uplifting results, given that in ExteNET study, the 2-year iDFS rate was 93.9% (95% CI 92·4-95·2) in the 1-year neratinib group, and the 5-year iDFS survival was 90.2%, and 1-year treatment of neratinib in ExteNET study did not translate into OS benefit after 8-year follow-up. In this case, readers will be eagerly anticipating the long-term follow-up results of the current PERSIST study, as well as the results of the phase III clinical trial (NCT03980054).

I have the following comments:

(1) The introduction of the differences between pyrotinib and neratinib in terms of mechanism, efficacy, resistance, etc. is supposed to be included in the text so that authors could better highlight the clinical significance of the current trial.

(2) Please make sure that a total of 141 patients were enrolled in the study, 38 patients had a treatment duration of less than or equal to 6 months, and a total of 92 and 31 patients completed 1-year and 6-month treatment of extended adjuvant pyrotinib, respectively, which means 7 patients had a treatment duration of fewer than 6 months.

(3) The previous surgery history should be provided, and how many patients received lumpectomy, and mastectomy.