The efficacy and safety of using pyrotinib combined with capecitabine as neoadjuvant therapy in elderly patients with HER2-positive breast cancer: a single-arm prospective clinical trial
Original Article

The efficacy and safety of using pyrotinib combined with capecitabine as neoadjuvant therapy in elderly patients with HER2-positive breast cancer: a single-arm prospective clinical trial

Wei Wang1,2#, Juan Zhang1#, Jin-Yi Chang1,2, De-Shun Yao1, Fen Hu3, Yong-Ping Liang4, Yan Shen1,2, Yu-Qi Liu1,2, Huai-Hua Qi1, Jian-Bin Tong5,6, Hai-Feng Cai1

1Department of Breast Surgery, Tangshan People’s Hospital, North China University of Science and Technology, Tangshan, China; 2School of Clinical Medicine, North China University of Science and Technology, Tangshan, China; 3College of Life Sciences, North China University of Science and Technology, Tangshan, China; 4Department of Medical Imaging (Ultrasound), Tangshan People’s Hospital, Tangshan, China; 5Department of Anesthesiology, The Third Xiangya Hospital of Central South University, Changsha, China; 6Hunan Province Key Laboratory of Brain Homeostasis, The Third Xiangya Hospital of Central South University, Changsha, China

Contributions: (I) Conception and design: HF Cai; (II) Administrative support: HF Cai; (III) Provision of study materials or patients: W Wang, J Zhang, DS Yao, F Hu, YP Liang, S Shen, YQ Liu, JY Chang, HH Qi, JB Tong; (IV) Collection and assembly of data: W Wang, J Zhang, DS Yao, F Hu, YP Liang; (V) Data analysis and interpretation: W Wang, J Zhang, DS Yao, F Hu, JY Chang, HH Qi, JB Tong, HH Qi, JB Tong; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Hai-Feng Cai. Department of Breast Surgery, Tangshan People’s Hospital, North China University of Science and Technology, Shengli Road 65, Tangshan 063000, China. Email: 13303050005@163.com.

Background: Pyrotinib combined with capecitabine has been approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in China. To date, the management of early-stage or locally advanced HER2-positive breast cancer in the clinic remains challenging. We conducted this trial to investigate the efficacy and safety of pyrotinib combined with capecitabine as neoadjuvant therapy (NAT) in elderly patients with HER2-positive breast cancer. Due to the stimulation of blood vessels by chemotherapy drugs, the elasticity of blood vessels in the elderly decreases, and then chemotherapy infusion is more likely to lead to phlebitis. Both pyrotinib and capecitabine can be taken to facilitate home treatment for elderly patients with HER2-positive breast cancer (BC).

Methods: From January 2020 to March 2021, patients aged between 70 and 81 years old with stage IIA–IIIB HER2-positive breast cancer were screened, enrolled, and assigned to receive six cycles of pyrotinib (320–400 mg, orally, once daily) plus capecitabine (1,250 mg/m2, orally, twice daily) on days 1–14 in every 21-day cycle. The primary endpoint was the objective response rate (ORR). Adverse events (AEs) were assessed in every neoadjuvant cycle. Surgery was performed after the last cycle, and the total pathological complete response (tpCR) was evaluated postoperatively.

Results: Of the 23 patients enrolled, the ORR was 100% (23/23; 95% confidence intervals: 85 to 100). All patients underwent surgery with a tpCR rate of 43.5% (10/23; 95% confidence intervals: 23 to 66). The most common AE was diarrhea, occurring in 19 of 23 patients (82.6%); most of these patients sustained mild diarrhea (Grade 1 or Grade 2) and only three had moderate diarrhea (Grade 3). The incidences of other AEs, including weakness, loss of appetite, leukopenia, nausea, vomiting, hand-foot syndrome, etc., were low and the symptoms were mild. No severe AEs (Grade 4 or 5) were observed throughout the treatment.

Conclusion: In our study, pyrotinib combined with capecitabine as neoadjuvant therapy in elderly women with HER2-positive breast cancer is safe and showed efficacy in this population, which may be widely used as a protocol for clinical neoadjuvant therapy.

Keywords: Breast cancer (BC); human epidermal growth factor receptor 2 (HER2); neoadjuvant therapy (NAT); pyrotinib; capecitabine

Submitted Dec 01, 2022. Accepted for publication Feb 10, 2023. Published online Feb 27, 2023.

doi: 10.21037/gs-23-11

Highlight box

Key findings

• In this study, pyrotinib combined with capecitabine as neoadjuvant therapy was safe and showed activity in elderly women with HER-2-positive breast cancer.

What is known and what is new?

• We already knew that pyrotinib plus capecitabine is effective in treating locally advanced HER-2-positive breast cancer.

• In our study, we added neoadjuvant therapy, elderly patients (≥70 years old), and first-time diagnosis. Notably, the cohort in our study was primarily comprised of first-time treatment patients aged ≥70 years.

What is the implication, and what should change now?

• Our data suggest that pyrotinib combined with capecitabine as neoadjuvant therapy may provide promising clinical activity for elderly HER2-positive breast cancer patients, with a manageable safety profile. The treatment regimen of pyrotinib combined with capecitabine can benefit elderly patients with HER-2-positive breast cancer and should be more widely used in clinical patients.

Introduction

Breast cancer (BC) is the most common malignancy among females worldwide, and its incidence is increasing every year, seriously threatening women’s health (1). Human epidermal growth factor receptor 2 (HER2)-positive BC, which accounts for 20–25% of all BCs, remains a clinical challenge due to its aggressiveness and poor treatment response (2). For the treatment of patients with HER2-positive BC, guidelines recommend preoperative neoadjuvant targeted therapy plus chemotherapy (3). In current neoadjuvant therapy, the treatment standard for patients with positive HER-2 is HER-2 targeted therapy plus chemotherapy (4). However, during the coronavirus disease (COVID)-19 pandemic, cancer treatment for patients has become a hot issue that needs attention, especially for elderly patients. As is known to all, the elderly have poor resistance and are susceptible to infection with the novel coronavirus, and the risk of viral cross infection in hospitalized patients with neoadjuvant chemotherapy is increased. We hold that domiciliary neoadjuvant therapy, if available, is the preferred treatment of choice.

With the advantages of restricting multiple targets, oral administration, and reduced cardiac toxicity, tyrosine kinase inhibitors (TKIs) have become another option for HER2-targeted blockade (5). Pyrotinib is an irreversible pan-epidermal growth factorreceptor family, ErbB family (EGFR family, ErbB) receptor TKI that was independently developed in China, which targets erbB1 (HER1), erbB2 (HER2), and erbB4 (HER4) (6), and achieved its first global approval for the treatment of advanced HER2-positive BC in 2018 (7). Capecitabine is also effective as a maintenance treatment of advanced BC (8). Previous studies have demonstrated the efficacy and tolerability of pyrotinib combined with capecitabine for the treatment of HER2-positive metastatic BC (9-11). Because elderly patients have many underlying diseases, drug selection is particularly important for elderly BC patients with HER-2 positive. In our previous study, pyrotinibe combined with chemotherapy did not increase cardiotoxicity in patients (12), so we believe that pyrotinib combined with cap may also be safe. At the same time, py and cap are two oral drugs that can avoid the side effects of chemotherapy infusion in elderly patients.

Taken together, these findings suggest that pyrotinib combined with capecitabine may be a good option for the treatment of elderly patients with HER2-positive BC. Therefore, this clinical trial was carried out to investigate the efficacy and safety of pyrotinib combined with capecitabine as neoadjuvant therapy for elderly HER2-positive BC patients, especially during the COVID-19 pandemic. We present the following article in accordance with the TREND reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-23-11/rc).

Methods

Patients

This study was approved by the Ethics Committee of Tangshan People’s Hospital (No. RMYY-LLKS-2022-040). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from each participant before enrollment.

Elderly female patients with HER2-positive BC were screened and admitted to the Second Department of Mammary Gland of Tangshan People’s Hospital from January 2020 to March 2021. The inclusion criteria were as follows: (I) newly diagnosed operable BC (clinical stage T2-T3/N0-N3/M0, IIA–IIIB); (II) ≥70 years old; (III) HER2-positive (defined as immunochemistry 3+ or immunochemistry 2+ with HER2 gene amplification confirmed by fluorescence in situ hybridization). The exclusion criteria were as follows: (I) Eastern Cooperative Oncology Group (ECOG) score ≥2; (II) dysfunction of major organs (heart, liver, and kidney); (III) patients with metastatic BC or other malignant tumors; (IV) those with allergies or other diseases that affect drug taking and/or absorption; (V) patients with endocrine disease; (VI) those participating in other clinical trials; (VII) refusal or inability to cooperate.

Study design and treatment

This study was a single-arm, open-label, single-center, prospective study. Patients who met the eligibility criteria were enrolled and received preoperative pyrotinib combined with capecitabine at home. The dose of pyrotinib (Jiangsu Hengrui Pharmaceuticals Co., Ltd, Jiangsu, China) was 400 mg, which was administered orally once daily every 21-day cycle for a total of 6 treatment cycles, and could be adjusted to 320 mg for patients with poor tolerance. The dose of capecitabine (Jiangsu Hengrui Pharmaceuticals Co., Ltd, Jiangsu, China) was 1,250 mg/m2, which was administered orally twice daily on days 1–14 every 21-day cycle for a total of 6 treatment cycles. Adverse events (AEs) were assessed in every neoadjuvant cycle. Surgery was performed following the completion of the neoadjuvant therapy (Figure 1).

Figure 1 Treatment profile. Surgery included modified radical mastectomy and breast-conserving surgery. ECOG, Eastern Cooperative Oncology Group.

Outcomes

The primary endpoint was the objective response rate (ORR), which was defined as the proportion of patients who had an overall complete or partial response over the treatment cycle by ultrasonography according to the investigator-assessed Solid Tumor Response Assessment Criteria (RECIST, version 1.1). The secondary endpoints included the total pathological complete response (tpCR), which was defined as the absence of invasive cancer in the breast and axillary nodes, regardless of ductal carcinoma in situ, and AEs graded according to the National Cancer Institue Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE v 4.03).

Statistical analysis

This single-arm exploratory study enrolled 23 patients. According to the literature, it is estimated that the ORR rate is 68%, and the pretest ORR is 93%. It is assumed that two-sided α =0.05, β =0.2, and the loss of follow-up rate was 10%, N=23. Continuous variables were expressed as the median (range). Categorical variables were expressed as frequencies (percentage). The clinical responses, including ORR, complete response (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) were evaluated in the intention-to-treat population, which included all enrolled patients and was reported with the 95% confidence intervals (CIs) calculated using the Clopper-Pearson method. The tpCR was assessed in patients who underwent surgery. Safety was evaluated in the population of patients who had received at least one dose of study medication. All statistical data were analyzed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) with a two-sided test (α =0.05).

Results

Characteristics of the included patients

From January 2020 to March 2021, 23 eligible patients [median age: 73 years (range: 70–81 years)] were enrolled. All enrolled patients received and completed the study treatment. The characteristics of the included patients are listed in Table 1. All patients had HER2-positive breast invasive ductal carcinoma. The majority had T2 disease (82.6%), and positive hormone receptor status (91.3%). Seven patients (30.4%) had coronary heart disease, 3 (13.0%) had hypertension, 1 (4.3%) had diabetes, 1 (4.3%) had cerebral insufficiency, and 2 (8.7%) had cerebral thrombosis.

Table 1

Baseline characteristics of the included patients

Characteristics Patients (n=23)
Age (years), median [range] 73 [70–81]
ECOG, n (%)
   0 18 (78.3)
   1 5 (21.7)
Pathological type, n (%)
   Invasive ductal carcinoma 23 (100.0)
Tumor size at diagnosis, n (%)
   T1 2 (8.7)
   T2 17 (73.9)
   T3-T4 4 (17.4)
Hormone receptor status, n (%)
   Negative ER and PR 2 (8.7)
   Positive ER or positive PR 21 (91.3)

ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PR, progesterone receptor.

Efficacy

After six cycles of neoadjuvant therapy, among the 23 patients enrolled, 10 patients achieved CR (43.5%; 95% CI: 23% to 66%), 13 patients achieved PR (56.5%; 95% CI: 34% to 77%), and none of the patients achieved SD (0%; 95% CI: 0% to 15%) or PD (0%; 95% CI: 0% to 15%). The ORR was 100% (Table 2). All patients successfully underwent surgery after 6 cycles of neoadjuvant therapy; 16 patients underwent modified radical mastectomy (69.6%), and 7 patients received breast-conserving surgery (30.4%). The pathological examination showed that 10 patients achieved pathological CR (43.5%; 95% CI: 23% to 66%).

Table 2

Curative effect

Response Patients (n=23)
Pathological complete response rate 10 (43.5%; 95% CI: 23 to 66)
Total objective response rate 23 (100%; 95% CI: 85 to 100)
Complete response 10 (43.5%; 95% CI: 23 to 66)
Partial remission 13 (56.5%; 95% CI: 34 to 77)
Stable disease 0 (0%; 95% CI: 0 to 15)
Progressive disease 0 (0%; 95% CI: 0 to 15)

CI, confidence intervals.

Safety

During the neoadjuvant follow-up period, the incidence of any grade AEs (regardless of causality) was 95.6%, most of which were grades 1–2. The most common AE of any grade was diarrhea (73.9%), followed by weakness (17.4%), loss of appetite (17.4%), leukopenia (8.7%), nausea (8.7%), vomiting (8.7%), and hand-foot syndrome (8.7%). The only grade 3 AE was diarrhea, reported in three (13.0%) patients (Table 3). All AEs were reversible after symptomatic treatment. No treatment-related deaths occurred.

Table 3

Adverse events

Adverse events Patients (n=23)
Any grade, n (%) Grade 1, n (%) Grade 2, n (%) Grade ≥3, n (%)
Diarrhea 19 (82.6) 7 (30.4) 9 (39.1) 3 (13.0)
Weak 4 (17.4) 4 (17.4) 0 0
Loss of appetite 4 (17.4) 4 (17.4) 0 0
WBC count decreased 2 (8.7) 2 (8.7) 0 0
Nausea 2 (8.7) 2 (8.7) 0 0
Vomiting 2 (8.7) 2 (8.7) 0 0
Hand-foot syndrome 2 (8.7) 2 (8.7) 0 0
Rash 1 (4.3) 1 (4.3) 0 0
Abnormal creatinine 1 (4.3) 1 (4.3) 0 0
AST, ALT increased 1 (4.3) 1 (4.3) 0 0

WBC, white blood cell; AST, aspartate transaminase; ALT, alanine aminotransferase.

The dose of pyrotinib was reduced in all patients with diarrhea and was subsequently restored when diarrhea disappeared. No patients discontinued pyrotinib due to any AEs throughout the treatment.

Discussion

In our study, 23 elderly patients with HER2-positive BC accepted neoadjuvant therapy with pyrotinib combined with capecitabine. Among these patients, 10 (43.5%) achieved tpCR, 10 (43.5%) achieved CR, and 13 (56.5%) achieved PR. Thus, the ORR was 100%. No severe AEs were observed during the treatment. Our data suggested that pyrotinib combined with capecitabine as neoadjuvant therapy may provide promising clinical activity for elderly HER2-positive BC patients, with a manageable safety profile.

Increasing evidence supports the idea that neoadjuvant therapy can provide an opportunity for patients who are not eligible for surgery, and facilitate breast-conserving surgery rather than mastectomy (13). The ErbB-2 gene, also known as the neu or HER2 gene, is a known proto-oncogene located on the long arm of human chromosome 17 (14), which is positively expressed in various cancers (15). HER2 overexpression is an indicator of poor prognosis in BC. HER2-targeted therapy is important in the treatment of patients with HER2-positive BC (16).

A previous study demonstrated that pyrotinib combined with capecitabine yields an overall response rate of 78.5% in patients with HER2-positive BC. Pyrotinib has also exhibited efficacy in BC with brain metastases (17). Pyrotinib and capecitabine were recommended as second-line anti-HER2 therapy in BC by the 2021 Chinese Society of Clinical Oncology (CSCO) guidelines (18). Several small sample clinical trials have also revealed the effectiveness of pyrotinib combined with capecitabine as neoadjuvant therapy for patients with HER2-positive BC. Strikingly, the ORR in our study was 100%, which may be because the patients enrolled in our study were all newly diagnosed and did not develop drug resistance or metastasis.

The outbreak of COVID-19 has seriously impacted hospitalization for the treatment of cancer patients. Elderly patients are often plagued by physical weakness and inconvenient mobility, leading to more obvious difficulties during hospitalization. Also, this population is more susceptible to COVID-19 and tends to have a worse prognosis. Unlike other therapeutic agents, both pyrotinib and capecitabine can be administered orally, allowing patients to receive treatment at home, thereby facilitating elderly patients with HER2-positive BC during the COVID-19 pandemic. Moreover, in our study, pyrotinib combined with capecitabine was safe and no severe AEs were observed.

The limitations of our study are as follows: firstly, the sample size was too small to represent the total relevant patient population; secondly, home-based treatment made it difficult for us to monitor the patients’ medication; finally, a follow-up assessment of the patients was not performed, and thus, the long-term benefits to patients remain unknown.

Conclusions

Pyrotinib combined with capecitabine as neoadjuvant therapy was safe and showed efficacy in the elderly HER-2-positive BC population. Since both of these medicines are taken orally, pyrotinib combined with capecitabine may provide a home-based treatment option for elderly HER-2-positive BC patients as neoadjuvant therapy, especially during the COVID-19 pandemic.

Acknowledgments

Funding: This work was supported by the Project of Hebei Provincial Health Commission (No. 20181231).

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-23-11/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-23-11/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-11/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committee of Tangshan People’s Hospital (No. RMYY-LLKS-2022-040). Informed consent was obtained from all patients before enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: A. Kassem)

Cite this article as: Wang W, Zhang J, Chang JY, Yao DS, Hu F, Liang YP, Shen Y, Liu YQ, Qi HH, Tong JB, Cai HF. The efficacy and safety of using pyrotinib combined with capecitabine as neoadjuvant therapy in elderly patients with HER2-positive breast cancer: a single-arm prospective clinical trial. Gland Surg 2023;12(2):208-214. doi: 10.21037/gs-23-11

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