Breast cancer is the most common malignant tumor in women. Approximately 10%-13% of women will develop breast cancer during their lifetime (1). Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15%-20% of all breast cancers (2). HER2-targeted therapy dramatically improved outcomes in HER2-positive breast cancer. Chemotherapy combined with dual HER2-targeted blockade has become a standard neoadjuvant regimen (3–8). Actually, more than half of patients can achieve pathological complete response (pCR) with neoadjuvant chemotherapy plus dual HER2-targeted monoclonal antibodies (trastuzumab and pertuzumab) (9–11). A randomized, open-label phase 3 KRISTINE trial showed a pCR rate of 44.4% (99 of 223) with trastuzumab emtansine plus pertuzumab and 55.7% (123 of 221) with docetaxel, carboplatin, and trastuzumab plus pertuzumab (absolute difference, -11.3%; 95% confidence interval [CI], -20.5% to -2.0%; P=0.016) (9). Chemotherapy combined with trastuzumab and a small-molecule tyrosine kinase inhibitor (TKI, such as lapatinib and neratinib) could also result in favorable breast pCR (bpCR) rate (51.3%-62.0%) (12–16) with acceptable safety profile. A meta-analysis demonstrated that pCR was associated with substantially longer event-free survival and overall survival in HER2-positive breast cancer (17). Thus, the dual HER2-targeted blockade with a macromolecular monoclonal antibody and a small-molecule TKI as components of neoadjuvant therapy deserves further investigation.

Pyrotinib is a small-molecule, irreversible TKI, targeting HER1, HER2, and HER4 (18). The phase 3 PHOEBE study confirmed the superiority of pyrotinib over lapatinib when combined with capecitabine in the treatment of HER2-positive relapsed or metastatic breast cancer, with significantly better objective response rate (ORR, 67.2% vs. 51.5%) and progression-free survival (12.5 months vs. 6.8 months) (19). Pyrotinib as a component of HER2-targeted neoadjuvant therapy has been investigated in small phase 2 clinical trials (20–22). We did a multicenter retrospective analysis to assess effectiveness and safety of pyrotinib-containing regimens as neoadjuvant therapy for patients with HER2-positive breast cancer in the real-world setting.

To identify the effectiveness and safety of pyrotinib-containing regimens as neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer in the real-world setting, we here made a multicenter retrospective analysis. Lapatinib, neratinib, and pyrotinib are three TKIs investigated in the neoadjuvant setting for patients with HER2-positive breast cancer. Lapatinib is a reversible TKI blocking HER1 and HER2, while pyrotinib is an irreversible pan-ErbB receptor TKI targeting HER2, HER1 and HER4, with similar molecular structure to neratinib (23). In a phase 1 clinical trial, pyrotinib plus capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive metastatic breast cancer (24). Pyrotinib in combination with capecitabine had a significantly higher ORR (78.5% vs. 57.1%, P=0.01) and longer progression-free survival (18.1 months vs. 7.0 months, P<0.001) compared with lapatinib plus capecitabine in a phase 2 study (25). Results from the phase 3 PHOEBE study confirmed that pyrotinib plus capecitabine could lead to progression-free survival benefit compared with lapatinib plus capecitabine (12.5 months [95% CI, 9.7-not reached] vs. 6.8 months [95% CI, 5.4-8.1]; hazard ratio, 0.39 [95% CI, 0.27-0.56]; P<0.0001) in HER2-positive metastatic breast cancer who had previously received anthracycline or taxane chemotherapy (19). Pyrotinib has the advantages of stability, safety, and good tolerance, with encouraging antitumor effects observed in patients with HER2-positive metastatic breast cancer. However, data on its activity in the neoadjuvant setting are still lacking. We supplemented real-world evidence on the basis of previous phase 2 neoadjuvant trials (20–22). The bpCR rate in 97 patients was 54.6% (95% CI, 44.2%-64.7%), and the tpCR rate was 48.5% (95% CI, 38.2%-58.8%). Grade 3 and 4 TRAEs were observed in 35.1% of patients, with the most common events of diarrhea (15.5%), decreased hemoglobin (9.3%), and decreased neutrophil count (8.2%). The safety profile was acceptable.

Taxane/carboplatin/trastuzumab/pertuzumab (TCbHP) and taxane/trastuzumab/pertuzumab (THP) are two class I recommendations in the 2021 version of Chinese Society of Clinical Oncology breast cancer guideline, while other regimens based on anti-HER2 monoclonal antibody and taxane (such as anthracycline/cyclophosphamide followed by taxane/trastuzumab/pertuzumab [AC-THP]) are class II recommendations (3, 4). The National Comprehensive Cancer Network guideline recommended TCbHP as preferred dual anti-HER2 regimens, and recommended the use of AC-THP and taxane followed by anthracycline/cyclophosphamide/trastuzumab/pertuzumab (T-ACHP) in certain circumstances (6). In our study, 84.5% of patients received the common combinations with chemotherapy plus dual HER2-targeted blockade, including 30 patients with TCbH+Py, 29 with AC-TH+Py or T-ACH+Py, and 23 with TH+Py. The selection of neoadjuvant therapy regimens was in accordance with the guidelines (3, 4, 6). Sixty-nine (84.1%) of 82 patients with these common regimens completed the full course of neoadjuvant therapy, including 17 (73.9%) of 23 patients with TH+Py receiving more than standard 4 cycles. The appropriate selection of neoadjuvant therapy regimens and good compliance might contribute to the high pCR rate. This also reflects a standardized clinical practice environment in China.

In the present study, the tpCR rate in patients with TCbH+Py was 73.3%, higher than docetaxel/carboplatin/trastuzumab/pertuzumab (55.7%) in the KRISTINE study (9) and docetaxel/carboplatin/trastuzumab/lapatinib (51.7%) in the TRIO-US B07 study (15). Patients who received TH+Py had a consistent tpCR rate with paclitaxel/trastuzumab/lapatinib in the NeoALTTO study (43.5% vs. 46.8%) (12). The tpCR rate in patients with AC-TH+Py or T-ACH+Py was 44.8%, similar with paclitaxel/trastuzumab/neratinib followed by doxorubicin/cyclophosphamide (50.0%) in the NSABP FB-7 study (16), and paclitaxel followed by fluorouracil/epirubicin/cyclophosphamide/trastuzumab/lapatinib (46.7%) in the CHER-LOB study (26). A previous phase 2 neoadjuvant trial of pyrotinib also showed a high tpCR rate with epirubicin/cyclophosphamide/pyrotinib followed by docetaxel/trastuzumab/pyrotinib (73.7%) (20), but the efficacy might be exaggerated due to the limited sample size (n=19; Table 5 ). Although the cross-study comparisons need to be interpreted in cautions, and the number of patients with different neoadjuvant regimens was small, these results indirectly suggest that trastuzumab plus pyrotinib as dual HER2-targeted blockade is feasible when combined with chemotherapy as neoadjuvant therapy in the real-world setting.

Patients with HR-negative disease accounted for 53.6% of the total population. The bpCR and tpCR rates were 65.4% and 63.5%, respectively, numerically higher than those of patients with HR-positive disease (42.2% and 31.1%). This trend was consistent with previous studies (12–16). Actually, we found that ER status just correlated with tPCR, not bPCR. PR status correlated with both bPCR and tPCR. Compared with PR-positive subgroup, PR-negative patients showed higher bpCR (61.5% vs. 40.6%) and tpCR (58.5% vs. 28.1%) rates with pyrotinib-containing neoadjuvant therapy. PR synthesis requires estrogen and ER, and PR expression is upregulated by ER; thus, ER-positive/PR-positive breast cancer is common (29). PR is also a biomarker used routinely at diagnosis to characterize breast cancer. It participates in molecular subtyping and plays a determining factor in treatment decisions. The absence of PR reflects a nonfunctional ER pathway, which is less responsive to selective ER modulators (30). Our findings suggest that both ER and PR status are potential prognostic factors for tpCR in HER2-positive breast cancer with pyrotinib-containing neoadjuvant therapy. Further investigation is needed.

The incidence of TRAEs in our study was 92.8%, and the most common TRAEs were diarrhea (63.9%), decreased hemoglobin (58.8%), increased alanine transaminase (37.1%), nausea (35.1%), decreased neutrophil count (32.0%), and decreased white blood cell count (30.9%). The AE profile was consistent with previous neoadjuvant trials of pyrotinib (20–22) and the phase 3 results of pyrotinib in advanced breast cancer (19, 31). The incidence of hand-foot syndrome was 7.2%, and only grade 1 events occurred. Capecitabine is a partner of pyrotinib when used in advanced breast cancer, and one of its frequently reported AEs is hand-foot syndrome. However, capecitabine is not a common component of standard neoadjuvant regimens, with only two (2.1%) patients receiving capecitabine in our study. This might explain the low incidence and severity of hand-foot syndrome. In addition, only 35.1% of patients had grade ≥3 TRAEs, mainly grade 3 diarrhea (15.5%). The incidence of serious TRAEs was 5.2%. The overall safety of pyrotinib-containing neoadjuvant therapy was manageable, without new safety signals. Of patients with available data of initial dose for pyrotinib, 70.4% received 400 mg pyrotinib without dose reductions throughout the neoadjuvant therapy period, indicating a good tolerability.

There are some limitations in this multicenter real-world study. First, bias is inevitable due to the retrospective nature. Second, the judgement of AEs needs incorporation of medical records, laboratory test reports, and medical advice. There could be recall bias and missing reports in the real-world setting. Thus, the AE data might be underestimated. Third, some patients could not complete the full course of neoadjuvant therapy due to the impact of coronavirus disease 2019 (COVID-19), leading to reduced effectiveness. Fourth, this study only reported pathological response. The long-term outcomes in patients with HER2-positive breast cancer who received pyrotinib-containing neoadjuvant regimens needs further investigation. Finally, although all patients were treated with pyrotinib, the effectiveness and safety might be attributed to other components as many combination regimens were included.

Small-molecule TKI pyrotinib as a component of neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer shows effectivenesswith manageable toxicity in the real-world setting. Trastuzumab plus pyrotinib may be a novel option of dual HER2-targeted blockade when combined withchemotherapy as neoadjuvant therapy. Our study suggests a trend PR-negative was a significant prognostic factor for tPCR or bPCR in HER2+ breast cancer with pyrotinib-containing neoadjuvant therapy.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by The ethics committee of the First Hospital of China Medical University (No. [2021]308). The patients/participants provided their written informed consent to participate in this study.

FJ and JL contributed to the study conception and design. FJ, JL, XM, PL, YG, XW, PT, SW, DZ, WY, OW, and JZ contributed to the acquisition of data. XM analyzed and interpreted the data. XM drafted the manuscript. FJ and JL contributed to the critical review and revision of the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (No. 81972791). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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