The efficacy and safety of pyrotinib in treating HER2-positive metastatic breast cancer patients:A multi-center study

The efficacy and safety of pyrotinib in treating HER2-positive metastatic breast cancer patients:A multi-center study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The efficacy and safety of pyrotinib in treating HER2-positive metastatic breast cancer patients:A multi-center study Min Gao, Yuhui Li, Qingfen Dong, Fang Chen, Chao Fu, Shuaishuai Liu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3670277/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: To investigate the efficacy and safety of pyrotinib in treating patients with HER2-positive metastatic breast cancers (MBC). Patients and Methods: We performed a multi-center retrospective study, and the HER2-positive MBC patients were recruited. The progression-free survival (PFS), and overall survival (OS) were considered in the assessment of treatment outcomes. Results: 275 female patients were enrolled. The objective response rate (ORR) and disease control rate (DCR) , were found in 154 of 275 (56%) and in 205 of 275 (75%), respectively. The median effective time was 45 days. The median follow-up time was 41 months.The median time for progression and OS were 16 and 35 months. The PFS of survival general population at 1-year, 2-year and 3-year was 72.7% , 40.4%, and 33.1%, respectively, whle the OS was 91.6% , 78.2%, and 63.2%, respectively. The PFS of brain metastases patients at 1-3-year was 67.3%, 25% and 13.5%, while, the OS was 84.6%, 63.5% and 46.2%. Conclusion: Pyrotinib mono-therapy showed equivalent local control rates, PFS and OS, compared with the combined therapy of pyrotinib and chemotherapy in both the general population and patients with brain metastases, with manageable toxicity, highlighting the significance of mono-therapy of pyrotinib in treating HER-2 positive MBC. efficacy HER2 breast cancers brain metastasis pyrotinib safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 INTRODUCTION Breast cancer (BC) is the most common female cancer, and the primary cause of cancer-related deaths in women worldwide[ 1 – 2 ]. The human epidermal growth factor receptor type 2 (HER2) is activated through amplification and protein over-expression in 15–20% of BC populations[ 3 , 4 ] and the high recurrence of central nervous system with HER2 activation had been demonstrated[ 5 – 8 ], which is associated with a more aggressive phenotype, a shorter recurrence time leading to a poorer prognosis[ 3 – 7 ]. In recent years, the HER2-targeted therapies were studied and widely used in clinical practice, which definitely improved the treatment outcomes in patients with HER2-positive BC[ 9 – 12 ].However, there are few studies to guide the treatment of HER2-positive BC patients with brain metastasis, and the treatment resistance to anti-HER2 therapy as well as its occasional intolerable adverse reactions remained challenging,, highlighting a clear urgent demand for more novel therapies[ 13 ]. Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI) with activity against epidermal growth factor receptor (EGFR)/HER1, HER2, and HER4[ 14 ].The pre-clinical data confirmed the role of pyrotinib in irreversible inhibition of multiple ErbB receptors and the proliferation of HER2 over-expressing cells both in vivo and in vitro[ 15 ]. Multi-phase clinical trials on treatment of HER2-positive metastatic BC with pyrotinib have been performed lately. However, the effect of pyrotinib treatment on the final outcome of HER2-positive metastatic BC was not fully elucidated. We previously performed a multi-center study to investigate the efficacy and safety of pyrotinib in treating patients with HER2-positive BC with brain metastasis[ 16 ], and we found Pyrotinib combined with chemotherapy/radiotherapy or alone showed significantly greater local control rates and PFS, with manageable toxicity for patients with HER2-positive BC with brain metastases. However, due to the short time of follow-up, no mature OS data was obtained, and we only performed the statistics of brain metastasis BC patients, and the statistics of the whole population of HER-2 positive MBC patients were not carried out in that study. In this multi-center study, we aimed to further investigate the efficacy and safety of pyrotinib on patients with HER2-positive MBC. MATERIALS AND METHODS The study was done in accordance with the Declarations of Helsinki and Good Clinical Practice, which was approved by the ethics committee of Shandong Cancer Hospital and Institute, Shandong First Medical University. The MBC patients were recruited from 8 hospitals in Shandong Province, China, with written informed consent obtained. Based on our previous study16,the independent committee of radiologists from each participating unit was set up to retrospectively confirm the validity and the objective response rate (ORR) and disease control rate (DCR, ). 2.1 Patient population The HER2-positive MBC at the time of pyrotinib initiation was included in the study,whether with or with chemotherapy. The inclusion criteria: (1) The HER2-positive breast cancer patients accompany are confirmed by pathology and imaging studies; (2)HER2 is positive (3 + by Immuno-histochemistry (IHC), or if 2 + by IHC, then confirmed by fluorescent in situ hybridization (FISH) with both gene amplification; (3) ECOG scoring 0–2; (4) previously received anti-HER2 therapies or not. (5)with any organ metastasis confirmed by imaging. All included patients received an oral dose of 400 mg of pyrotinib once a day for 21 days as a cycle, and patients were evaluated every two cycles. All the medical history, diagnosis details,treatment results, and adverse reactions, were recorded for final evaluation. Patients treated with pyrotinib and other modalities were compared with patients treated with mono-therapy of pyrotinib. For those patients who use pyrotinib in combination with chemotherapy but stop due to intolerance or chemotherapy termination within 15 days or treatment for other reasons is defined as the mono-therapy of pyrotinib. In the intracranial radiotherapy group, individual radiotherapy plans were made in different centers according to the differences of patients’ conditions. 2.2 Study end points and assessments The primary end point was the ORR and DCR of general population which were investigated according to the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1, and are assessed by the independent committee. Complete, partial response, and stable disease could be claimed only if confirmed by the first imaging examination. The secondary end points included PFS and OS of general population and brain metastases patients. The PFS was defined as the time of inclusion to the date of event to disease progression as assessed by the investigator according to RECIST, version 1.1, terminated due to unacceptable toxicity, or death. Adverse events were compiled according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. 2.3 Statistical analyses Statistical analysis was performed using Medcalc version 19.5.6. All p values were two-sided, and those less than 0.05 were regarded as statistically significant. The survival data were estimated by the Kaplan–Meier method.The local control of brain metastasis was analyzed by the chi-squared test. RESULTS 3.1 Patient characteristics Two hundred and seventy-five female patients (median age, 57 years; range, 24–86 years) were enrolled from November 2018 to August 2019. The last patient has been enrolled for more than 25 months until the end of follow-up. The baseline characteristics of the 275 patients are presented in Table 1 . ECOG scoring of all Table 1 Patients’ demographic and baseline characteristics Characteristics NO. % Stage II/III/IV 1/7/267 0.3/2.5/96 Brain radiotherapy Yes/No 42/233 15.2/84.7 IHC ER(+)/PR༈+༉ 109/92 39.6/33.4 Ki-67 30% 13/109/153 4.7/39.6/55.6 Combined chemotherapy Yes/No 152/123 55.3/44.7 Chemotherapy lines 3 45/141/89 16.4/51.3/32.4 Prior to used Trastuzumab Yes/No 242/33 88/12 Used other anti her2 theraty Yes/No 38/237 13.8/86.2 patients was 0–2 point. 3.2 Efficacy The ORR and DCR of our group were observed in 154 of 275(56%) and in 205 of 275 (75%). (Tables 2 ;Figure 1 ). The median effective time of brain metastases and Table 2 Parameters of different assessment Parameters NO. % ORR CR(5) + PR(149) 56 DCR CR(5) + PR(149) + SD(51) 75 other metastases was 43 and 50 days. Effective time was defined as the first imaging evaluation and different image assessment methods may be applied in different centers. 3.3 Survival analysis The median follow-up time was 34 months (interquartile range, 32–39 months). The number of events for OS were 41%. The median time for PFS and OS in our group was 16 months 35 months and the survival curve was shown in Figs. 2 and 3 . There was no statistical significance (p = 0.25) for the PFS of patients received combined chemotherapy with pyrotinib and mono-therapy of pyrotinib, (Fig. 4 ), and no statistical significance (p = 0.37) for OS of patients received combined chemotherapy with pyrotinib and pyrotinib mono-therapy (Fig. 5 ). The PFS of survival general population at 1-year, 2-year and 3-year were 72.7% , 40.4%, and 33.1%, respectively (Fig. 2 ). The OS of general population at 1-year, 2-year and 3-year were 91.6%, 78.2%, and 63.2% respectively (Fig. 3 ). The PFS of brain metastases patients at 1-year, 2-year and 3-year were 67.3%, 25% and 13.5%, respectively (Fig. 6 ). The OS of brain metastases patients at 1-year, 2-year and 3-year were 84.6%, 63.5% and 46.2%, respectively(Fig. 7 ). Among those 275 patients, 112 patients died, and 65 of them died of pulmonary metastasis, 20 died of brain metastasis, 8 died of liver metastasis, and the rest of patient have causes of death unknown listed. 3.4 Safety Ninety three patients (34%) with adverse effects were recorded in the study, six with vomiting, 67 with diarrhea (forty-seven with grade 1 diarrhea, ten with grade 2 diarrhea, seven with grade 3 diarrhea, three with grade 4 diarrhea), eleven with hand foot syndrome, nine with myelosuppression, Thirteen subjects discontinued the treatment due to adverse evetens.,among which, three with termination of medication usage due to severe diarrhea. Toxicity-related treatment discontinuations were recorded only in three patient. Reduced dose of pyrotinib in nine patients was due to diarrhea (Table 3 ). Table 3 Adverse reactions (AE) AE NO. % Nausea and vomiting 6 2.1 Diarrhea 67 24.3 Grade 1 47 17.1 Grade 2 10 3.9 Grade 3 7 2.5 Grade 4 3 1.1 Hand foot syndrome 11 4 Myelosuppression 9 3.3 DISCUSSION The over-expression of HER2 was historically associated with worse prognosis and higher mortality rates in breast cancer[ 17 – 19 ], due to higher rate of metastasis and availability of limited therapeutic options in the past. In recent years, various targeted therapies and clinical trials have been reported to improve the outcomes of HER2- positive breast cancers.And the anti-HER2 therapy had been demonstrated in delaying the occurrence of brain metastasis[ 12 , 13 ],among which, trastuzumab, the first HER2-targeted medication, had been used in MBC for more than 20 years, and the combined therapy of trastuzumab, pertuzumab, and taxane is now the gold standard for treating MBC with HER2, regardless of whether the patient has HER2 + or HER2-negative MBC[ 20 ]. However, the results with trastuzumab remained unsatisfactory for those HER-2 positive MBC[ 21 ],and the trastuzumab-resistance attracted the attention of the researchers, highlighting the demand of new anti-HER2 positive BC medications. As an novel irreversible dual pan-ErbB receptor tyrosine kinase inhibitor (TKI) that targets HER1, HER2, and HER4, pyrotinib was investigated in the evaluation of treatment of patients with HER2-positive MBC in the phase I study in 2017, which showed significant improvement in response rate and PFS with good tolerance[ 22 ]. In August 2018, pyrotinib was approved in combination with capecitabine for the treatment of HER2-positive, advanced or MBC in China. And in the latest phase II and multi-center study[ 23 ], the combined therapy of pyrotinib and capecitabine resulted significantly better overall response rate and PFS than lapatinib plus capecitabine in female HER2-positive MBC previously treated with other modalities. And the following trials also have shown encouraging results for trastuzumab- resistant MBC patients[ 24 ]. Although a series of studies were performed in the treatment of HER2-positive BC21, the real-world data, and the efficacy and safety of pyrotinib in the MBC are not yet clearly elucidated. In our previous multi-center study[ 16 ], we found Pyrotinib combined with chemotherapy/radiotherapy or alone showed significantly greater local control rates and PFS, with manageable toxicity for patients with HER2-positive BC with brain metastases,which revealed that the ORR and DCR of CNS were 47.6% and 92.8%, respectively,while the ORR and DCR of extra-CNS were 23.6% and 94.7%, Respectively[ 16 ]. In this study, we retrospectively analyzed a series of 275 HER2-positive MBC treated with pyrotinib. The study revealed that the ORR and DCR of our group were 56% and 75%, respectively. The median time for PFS and OS in our group was 16 months 35 months.And our treatment outcomes were consistent with another latest study, .In that prospective trial of 113 patients with HER-2 positive MBC, the median PFS was 14.1 months with an ORR of 66.4%[ 25 ].There was no statistical significance for the PFS and OS of patients received combined chemotherapy with pyrotinib and pyrotinib mono-therapy, which indicated the significant role of pyrotinib mono-therapy in the treatment of HER-2 positive MBC to reduce the financial burden of those patients. Diarrhea is the most common adverse effect observed with tyrosine kinase inhibitors targeting epidermal growth factor receptor/HER2. In this study group, 34% patients with adverse effects were recorded, 72% with diarrhea, but three case dropped out the study due to grade 4 diarrhea, the other side effects were all grade 1. No cases of toxic death were recorded. The incidence of adverse events we followed was lower than that reported in Ma et al. study,21 though slightly different, it is all manageable and safe. Although we reported a big sample size, the study still had limitations. As a multi-center retrospective study,inevitable deviation may occur. and we did not assess the quality of life of the involved cases, and the pyrotinib concentrations in the cerebrospinal fluid were not measured,due to different experimental conditions of the units CONCLUSIONS Currently, there is less data of pyrotinib in treatment HER2-positive breast cancer patients, and the efficacy and safety are unknown in the real world. This study show that pyrotinib alone led to significantly greater local control rates, PFS and OS, with manageable toxicity for patients with HER2-positive MBC. Declarations ACKNOWLEDGMENTS The authors thank the patients who participated in this study, their families, and all the staff involved in this study. FUNDING INFORMATION The study was supported by supported by National Natural Science Foundation of China (62273329), Medical Science and Technology Project of Shandong Province(202209030779), and Wu Jieping Medical Foundation(320.6750.2022-09-54,and 320.6750.2022-18-41) Disclosure of potential conflicts of interest None Research involving Human Participants and/or Animals All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.” Informed consent Informed consent was obtained from all individual participants included in the study. References Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. 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04:17:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3670277/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3670277/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":48909247,"identity":"46ac9c73-24cc-4456-88f3-0f12f1115602","added_by":"auto","created_at":"2023-12-28 12:23:01","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":253371,"visible":true,"origin":"","legend":"\u003cp\u003eThe figure of local control\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3670277/v1/368e850ab323faa132503295.jpeg"},{"id":48910689,"identity":"f042b9d8-3b6c-4824-99c7-594bda574b7c","added_by":"auto","created_at":"2023-12-28 12:31:01","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":97442,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curve of PFS of our group\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3670277/v1/2692b0629bc781a2f87eb02f.jpeg"},{"id":48910688,"identity":"0284d802-80a2-4019-bbf2-9508d38cd2f7","added_by":"auto","created_at":"2023-12-28 12:31:00","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":82779,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curve of OS of our group\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3670277/v1/9915e72187313e5403ef883a.jpeg"},{"id":48909246,"identity":"d0aac5c8-6607-4e27-8f02-77536df3e325","added_by":"auto","created_at":"2023-12-28 12:23:00","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":34281,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curve of PFS combined and not combined chemotherapy with pyrotinib\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3670277/v1/2725aeea296b820255dff206.jpeg"},{"id":48909249,"identity":"341986df-e9df-417f-bc31-ee7b13dcd26f","added_by":"auto","created_at":"2023-12-28 12:23:01","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":135014,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curve of OS combined and not combined chemotherapy with pyrotinib\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3670277/v1/b47edb59cf0dbaa2230c759c.jpeg"},{"id":48910690,"identity":"7882a2ae-dd56-4ff3-87ef-54f2c9158d97","added_by":"auto","created_at":"2023-12-28 12:31:01","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":25193,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curve of PFS of brain metastases\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3670277/v1/39c919772c723d3ade068269.jpeg"},{"id":48909250,"identity":"adc529e5-359f-4157-a266-33358099b0ab","added_by":"auto","created_at":"2023-12-28 12:23:01","extension":"jpeg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":92247,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curve of OS of brain metastases\u003c/p\u003e","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3670277/v1/b78e0cee9e1b4ae02ca11b02.jpeg"},{"id":50276140,"identity":"4c60c94c-8602-4913-b612-db61c20ac821","added_by":"auto","created_at":"2024-01-29 01:40:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":527719,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3670277/v1/8cb0aaf9-cb1e-43ff-99c2-f14a273be814.pdf"}],"financialInterests":"","formattedTitle":"The efficacy and safety of pyrotinib in treating HER2-positive metastatic breast cancer patients:A multi-center study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eBreast cancer (BC) is the most common female cancer, and the primary cause of cancer-related deaths in women worldwide[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The human epidermal growth factor\u003c/p\u003e \u003cp\u003ereceptor type 2 (HER2) is activated through amplification and protein over-expression\u003c/p\u003e \u003cp\u003ein 15\u0026ndash;20% of BC populations[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and the high recurrence of central nervous system with HER2 activation had been demonstrated[\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which is associated with a more\u003c/p\u003e \u003cp\u003eaggressive phenotype, a shorter recurrence time leading to a poorer prognosis[\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, the HER2-targeted therapies were studied and widely used in clinical practice, which definitely improved the treatment outcomes in patients with\u003c/p\u003e \u003cp\u003eHER2-positive BC[\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].However, there are few studies to guide the treatment of\u003c/p\u003e \u003cp\u003eHER2-positive BC patients with brain metastasis, and the treatment resistance to\u003c/p\u003e \u003cp\u003eanti-HER2 therapy as well as its occasional intolerable adverse reactions remained\u003c/p\u003e \u003cp\u003echallenging,, highlighting a clear urgent demand for more novel therapies[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI)\u003c/p\u003e \u003cp\u003ewith activity against epidermal growth factor receptor (EGFR)/HER1, HER2, and\u003c/p\u003e \u003cp\u003eHER4[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].The pre-clinical data confirmed the role of pyrotinib in irreversible inhibition of multiple ErbB receptors and the proliferation of HER2 over-expressing cells both in vivo and in vitro[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Multi-phase clinical trials on treatment of HER2-positive metastatic BC with pyrotinib have been performed lately. However, the effect of pyrotinib treatment on the final outcome of HER2-positive metastatic BC was not fully elucidated.\u003c/p\u003e \u003cp\u003eWe previously performed a multi-center study to investigate the efficacy and safety\u003c/p\u003e \u003cp\u003eof pyrotinib in treating patients with HER2-positive BC with brain metastasis[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and\u003c/p\u003e \u003cp\u003ewe found Pyrotinib combined with chemotherapy/radiotherapy or alone showed\u003c/p\u003e \u003cp\u003esignificantly greater local control rates and PFS, with manageable toxicity for patients\u003c/p\u003e \u003cp\u003ewith HER2-positive BC with brain metastases. However, due to the short time of\u003c/p\u003e \u003cp\u003efollow-up, no mature OS data was obtained, and we only performed the statistics of\u003c/p\u003e \u003cp\u003ebrain metastasis BC patients, and the statistics of the whole population of HER-2\u003c/p\u003e \u003cp\u003epositive MBC patients were not carried out in that study.\u003c/p\u003e \u003cp\u003eIn this multi-center study, we aimed to further investigate the efficacy and safety of\u003c/p\u003e \u003cp\u003epyrotinib on patients with HER2-positive MBC.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e The study was done in accordance with the Declarations of Helsinki and Good\u003c/p\u003e \u003cp\u003e Clinical Practice, which was approved by the ethics committee of Shandong Cancer\u003c/p\u003e \u003cp\u003eHospital and Institute, Shandong First Medical University. The MBC patients were\u003c/p\u003e \u003cp\u003e recruited from 8 hospitals in Shandong Province, China, with written informed\u003c/p\u003e \u003cp\u003econsent obtained. Based on our previous study16,the independent committee of\u003c/p\u003e \u003cp\u003e radiologists from each participating unit was set up to retrospectively confirm the\u003c/p\u003e \u003cp\u003evalidity and the objective response rate (ORR) and disease control rate (DCR, ).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patient population\u003c/h2\u003e \u003cp\u003eThe HER2-positive MBC at the time of pyrotinib initiation was included in the study,whether with or with chemotherapy. The inclusion criteria: (1) The HER2-positive breast cancer patients accompany are confirmed by pathology and imaging studies; (2)HER2 is positive (3\u0026thinsp;+\u0026thinsp;by Immuno-histochemistry (IHC), or if 2\u0026thinsp;+\u0026thinsp;by IHC, then confirmed by fluorescent in situ hybridization (FISH) with both gene amplification; (3) ECOG scoring 0\u0026ndash;2; (4) previously received anti-HER2 therapies or not. (5)with any organ metastasis confirmed by imaging.\u003c/p\u003e \u003cp\u003eAll included patients received an oral dose of 400 mg of pyrotinib once a day for 21\u003c/p\u003e \u003cp\u003edays as a cycle, and patients were evaluated every two cycles. All the medical history,\u003c/p\u003e \u003cp\u003ediagnosis details,treatment results, and adverse reactions, were recorded for final\u003c/p\u003e \u003cp\u003eevaluation. Patients treated with pyrotinib and other modalities were compared with\u003c/p\u003e \u003cp\u003epatients treated with mono-therapy of pyrotinib. For those patients who use pyrotinib\u003c/p\u003e \u003cp\u003ein combination with chemotherapy but stop due to intolerance or chemotherapy termination within 15 days or treatment for other reasons is defined as the mono-therapy of pyrotinib.\u003c/p\u003e \u003cp\u003eIn the intracranial radiotherapy group, individual radiotherapy plans were made in\u003c/p\u003e \u003cp\u003edifferent centers according to the differences of patients\u0026rsquo; conditions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study end points and assessments\u003c/h2\u003e \u003cp\u003eThe primary end point was the ORR and DCR of general population which were\u003c/p\u003e \u003cp\u003einvestigated according to the Response Evaluation Criteria in Solid Tumors RECIST\u003c/p\u003e \u003cp\u003eVersion 1.1, and are assessed by the independent committee. Complete, partial\u003c/p\u003e \u003cp\u003eresponse, and stable disease could be claimed only if confirmed by the first imaging\u003c/p\u003e \u003cp\u003eexamination.\u003c/p\u003e \u003cp\u003eThe secondary end points included PFS and OS of general population and brain\u003c/p\u003e \u003cp\u003emetastases patients. The PFS was defined as the time of inclusion to the date of event\u003c/p\u003e \u003cp\u003eto disease progression as assessed by the investigator according to RECIST, version\u003c/p\u003e \u003cp\u003e1.1, terminated due to unacceptable toxicity, or death.\u003c/p\u003e \u003cp\u003eAdverse events were compiled according to the National Cancer Institute Common\u003c/p\u003e \u003cp\u003eTerminology Criteria for Adverse Events, version 4.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analyses\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using Medcalc version 19.5.6. All p values were\u003c/p\u003e \u003cp\u003etwo-sided, and those less than 0.05 were regarded as statistically significant. The\u003c/p\u003e \u003cp\u003esurvival data were estimated by the Kaplan\u0026ndash;Meier method.The local control of brain\u003c/p\u003e \u003cp\u003emetastasis was analyzed by the chi-squared test.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Patient characteristics\u003c/h2\u003e \u003cp\u003eTwo hundred and seventy-five female patients (median age, 57 years; range,\u003c/p\u003e \u003cp\u003e24\u0026ndash;86 years) were enrolled from November 2018 to August 2019. The last patient has\u003c/p\u003e \u003cp\u003ebeen enrolled for more than 25 months until the end of follow-up. The baseline\u003c/p\u003e \u003cp\u003echaracteristics of the 275 patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. ECOG scoring of all\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients\u0026rsquo; demographic and baseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNO.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII/III/IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/7/267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3/2.5/96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes/No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42/233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.2/84.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER(+)/PR༈+༉\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109/92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.6/33.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;15%/15%-30%/\u0026gt;30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13/109/153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.7/39.6/55.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombined chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes/No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e152/123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.3/44.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy lines\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2/2\u0026ndash;3\u0026thinsp;\u0026gt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45/141/89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.4/51.3/32.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior to used Trastuzumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes/No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e242/33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88/12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUsed other anti her2 theraty\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes/No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38/237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.8/86.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003epatients was 0\u0026ndash;2 point.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Efficacy\u003c/h2\u003e \u003cp\u003eThe ORR and DCR of our group were observed in 154 of 275(56%) and in 205 of\u003c/p\u003e \u003cp\u003e275 (75%). (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e;Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median effective time of brain metastases and\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eParameters of different assessment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNO.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCR(5)\u0026thinsp;+\u0026thinsp;PR(149)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCR(5)\u0026thinsp;+\u0026thinsp;PR(149)\u0026thinsp;+\u0026thinsp;SD(51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eother metastases was 43 and 50 days. Effective time was defined as the first imaging\u003c/p\u003e \u003cp\u003eevaluation and different image assessment methods may be applied in different centers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Survival analysis\u003c/h2\u003e \u003cp\u003eThe median follow-up time was 34 months (interquartile range, 32\u0026ndash;39 months).\u003c/p\u003e \u003cp\u003eThe number of events for OS were 41%. The median time for PFS and OS in our group was 16 months 35 months and the survival curve was shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere was no statistical significance (p\u0026thinsp;=\u0026thinsp;0.25) for the PFS of patients received\u003c/p\u003e \u003cp\u003ecombined chemotherapy with pyrotinib and mono-therapy of pyrotinib, (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e),\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eand no statistical significance (p\u0026thinsp;=\u0026thinsp;0.37) for OS of patients received combined\u003c/p\u003e \u003cp\u003echemotherapy with pyrotinib and pyrotinib mono-therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe PFS of survival general population at 1-year, 2-year and 3-year were 72.7% ,\u003c/p\u003e \u003cp\u003e40.4%, and 33.1%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The OS of general population at 1-year,\u003c/p\u003e \u003cp\u003e2-year and 3-year were 91.6%, 78.2%, and 63.2% respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The PFS of\u003c/p\u003e \u003cp\u003ebrain metastases patients at 1-year, 2-year and 3-year were 67.3%, 25% and 13.5%,\u003c/p\u003e \u003cp\u003erespectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). The OS of brain metastases patients at 1-year, 2-year and\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e3-year were 84.6%, 63.5% and 46.2%, respectively(Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong those 275 patients, 112 patients died, and 65 of them died of pulmonary\u003c/p\u003e \u003cp\u003emetastasis, 20 died of brain metastasis, 8 died of liver metastasis, and the rest of\u003c/p\u003e \u003cp\u003epatient have causes of death unknown listed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Safety\u003c/h2\u003e \u003cp\u003eNinety three patients (34%) with adverse effects were recorded in the study, six\u003c/p\u003e \u003cp\u003ewith vomiting, 67 with diarrhea (forty-seven with grade 1 diarrhea, ten with grade 2\u003c/p\u003e \u003cp\u003ediarrhea, seven with grade 3 diarrhea, three with grade 4 diarrhea), eleven with hand\u003c/p\u003e \u003cp\u003efoot syndrome, nine with myelosuppression, Thirteen subjects discontinued the treatment due to adverse evetens.,among which, three with termination of medication usage due to severe diarrhea. Toxicity-related treatment discontinuations were recorded only in three patient. Reduced dose of pyrotinib in nine patients was due to diarrhea (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse reactions (AE)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNO.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea and vomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand foot syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyelosuppression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe over-expression of HER2 was historically associated with worse prognosis and higher mortality rates in breast cancer[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], due to higher rate of metastasis and\u003c/p\u003e \u003cp\u003eavailability of limited therapeutic options in the past. In recent years, various targeted\u003c/p\u003e \u003cp\u003etherapies and clinical trials have been reported to improve the outcomes of HER2- positive breast cancers.And the anti-HER2 therapy had been demonstrated in\u003c/p\u003e \u003cp\u003edelaying the occurrence of brain metastasis[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e],among which, trastuzumab, the first HER2-targeted medication, had been used in MBC for more than 20 years, and the combined therapy of trastuzumab, pertuzumab, and taxane is now the gold standard for treating MBC with HER2, regardless of whether the patient has HER2\u0026thinsp;+\u0026thinsp;or HER2-negative MBC[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, the results with trastuzumab remained\u003c/p\u003e \u003cp\u003eunsatisfactory for those HER-2 positive MBC[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e],and the trastuzumab-resistance\u003c/p\u003e \u003cp\u003eattracted the attention of the researchers, highlighting the demand of new anti-HER2\u003c/p\u003e \u003cp\u003epositive BC medications.\u003c/p\u003e \u003cp\u003eAs an novel irreversible dual pan-ErbB receptor tyrosine kinase inhibitor (TKI) that\u003c/p\u003e \u003cp\u003etargets HER1, HER2, and HER4, pyrotinib was investigated in the evaluation of\u003c/p\u003e \u003cp\u003etreatment of patients with HER2-positive MBC in the phase I study in 2017, which\u003c/p\u003e \u003cp\u003eshowed significant improvement in response rate and PFS with good tolerance[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In\u003c/p\u003e \u003cp\u003eAugust 2018, pyrotinib was approved in combination with capecitabine for the\u003c/p\u003e \u003cp\u003etreatment of HER2-positive, advanced or MBC in China. And in the latest phase II\u003c/p\u003e \u003cp\u003eand multi-center study[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], the combined therapy of pyrotinib and capecitabine resulted significantly better overall response rate and PFS than lapatinib plus capecitabine in female HER2-positive MBC previously treated with other modalities. And the following trials also have shown encouraging results for trastuzumab- resistant MBC patients[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough a series of studies were performed in the treatment of HER2-positive BC21, the real-world data, and the efficacy and safety of pyrotinib in the MBC are not yet clearly elucidated. In our previous multi-center study[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], we found Pyrotinib combined with chemotherapy/radiotherapy or alone showed significantly greater local control rates and PFS, with manageable toxicity for patients with HER2-positive BC with brain metastases,which revealed that the ORR and DCR of CNS were 47.6% and 92.8%, respectively,while the ORR and DCR of extra-CNS were 23.6% and 94.7%,\u003c/p\u003e \u003cp\u003eRespectively[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we retrospectively analyzed a series of 275 HER2-positive MBC treated with pyrotinib. The study revealed that the ORR and DCR of our group were 56% and 75%, respectively. The median time for PFS and OS in our group was 16 months 35 months.And our treatment outcomes were consistent with another latest study, .In that prospective trial of 113 patients with HER-2 positive MBC, the median PFS was 14.1 months with an ORR of 66.4%[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].There was no statistical significance for the PFS and OS of patients received combined chemotherapy with pyrotinib and pyrotinib mono-therapy, which indicated the significant role of pyrotinib mono-therapy in the treatment of HER-2 positive MBC to reduce the financial burden of those patients.\u003c/p\u003e \u003cp\u003eDiarrhea is the most common adverse effect observed with tyrosine kinase\u003c/p\u003e \u003cp\u003einhibitors targeting epidermal growth factor receptor/HER2. In this study group, 34%\u003c/p\u003e \u003cp\u003epatients with adverse effects were recorded, 72% with diarrhea, but three case\u003c/p\u003e \u003cp\u003edropped out the study due to grade 4 diarrhea, the other side effects were all grade 1.\u003c/p\u003e \u003cp\u003eNo cases of toxic death were recorded. The incidence of adverse events we followed\u003c/p\u003e \u003cp\u003ewas lower than that reported in Ma et al. study,21 though slightly different, it is all\u003c/p\u003e \u003cp\u003emanageable and safe.\u003c/p\u003e \u003cp\u003eAlthough we reported a big sample size, the study still had limitations. As a\u003c/p\u003e \u003cp\u003emulti-center retrospective study,inevitable deviation may occur. and we did not assess\u003c/p\u003e \u003cp\u003ethe quality of life of the involved cases, and the pyrotinib concentrations in the cerebrospinal fluid were not measured,due to different experimental conditions of the units\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eCurrently, there is less data of pyrotinib in treatment HER2-positive breast cancer\u003c/p\u003e \u003cp\u003epatients, and the efficacy and safety are unknown in the real world. This study show\u003c/p\u003e \u003cp\u003ethat pyrotinib alone led to significantly greater local control rates, PFS and OS, with\u003c/p\u003e \u003cp\u003emanageable toxicity for patients with HER2-positive MBC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eACKNOWLEDGMENTS\u003c/h2\u003e\n\u003cp\u003eThe authors thank the patients who participated in this study, their families, and all the staff involved in this study.\u003c/p\u003e\n\u003ch2\u003eFUNDING INFORMATION\u003c/h2\u003e\n\u003cp\u003eThe study was supported by supported by National Natural Science Foundation of China (62273329), Medical Science and Technology Project of Shandong Province(202209030779), and Wu Jieping Medical Foundation(320.6750.2022-09-54,and 320.6750.2022-18-41)\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003eResearch involving Human Participants and/or Animals\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u0026rdquo;\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFerlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. 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Front Pharmacol. 2023;14:110055.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"efficacy, HER2, breast cancers, brain metastasis, pyrotinib, safety","lastPublishedDoi":"10.21203/rs.3.rs-3670277/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3670277/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTo investigate the efficacy and safety of pyrotinib in treating patients with HER2-positive metastatic breast cancers (MBC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and Methods: \u003c/strong\u003eWe performed a multi-center retrospective study, and the HER2-positive MBC patients were recruited. The progression-free survival (PFS), and overall survival (OS) were considered in the assessment of treatment outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e275 female patients were enrolled. The objective response rate (ORR) and disease control rate (DCR) , were found in 154 of 275 (56%) and in 205 of 275 (75%), respectively. The median effective time was 45 days. The median follow-up time was 41 months.The median time for progression and OS were 16 and 35 months. The PFS of survival general population at 1-year, 2-year and 3-year was 72.7% , 40.4%, and 33.1%, respectively, whle the OS was 91.6% , 78.2%, and 63.2%, respectively. The PFS of brain metastases patients at 1-3-year was 67.3%, 25% and 13.5%, while, the OS was 84.6%, 63.5% and 46.2%.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003ePyrotinib mono-therapy showed equivalent local control rates, PFS and OS, compared with the combined therapy of pyrotinib and chemotherapy in both the general population and patients with brain metastases, with manageable toxicity, highlighting the significance of mono-therapy of pyrotinib in treating HER-2 positive MBC.\u003c/p\u003e","manuscriptTitle":"The efficacy and safety of pyrotinib in treating HER2-positive metastatic breast cancer patients:A multi-center study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-12-28 12:22:56","doi":"10.21203/rs.3.rs-3670277/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"af1f5e25-4672-4b4d-9f7f-67155888da41","owner":[],"postedDate":"December 28th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-01-29T01:32:10+00:00","versionOfRecord":[],"versionCreatedAt":"2023-12-28 12:22:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3670277","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3670277","identity":"rs-3670277","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}