| BackgroundHuman epidermal growth factor receptor 2(HER2)belongs to the family of HER.The activation of HER2 activates a complex series of signal transduction pathways downstream,further regulates the proliferation,survival and migration of tumor cells.It is thought to be associated with the aggressiveness and poor prognosis of the tumor.HER2 is overexpressed in about 15-20%of breast cancer patients.HER2 positive is an independent predictor of poor prognosis of breast cancer patients.Compared with negative breast cancer,HER2-positive breast cancer has a higher degree of malignancy,more recurrence and metastasis,shorter disease-free survival and overall survival,and worse overall prognosis.Since trastuzumab,the marketing of multiple anti-HER2 targeted drugs has significantly improved the treatment status and prognosis of HER2 positive breast cancer.On March 30,2019,pertuzumab was officially marketed in the Chinese mainland.Both pertuzumab and trastuzumab bind to the extracellular domain of HER2 and inhibit heterodimerization between HER2 and other HER2 receptors,but the binding sites are different,and the combination of the two has a synergistic effect.A number of clinical studies have shown that both for early breast cancer patients with positive HER2 after surgery with high recurrence risk(such as hormone receptor negative,lymph node positive,etc.),for patients with positive HER2 breast cancer who plan to undergo preoperative neoadjuvant therapy,and for patients with advanced breast cancer with positive HER2,dual target therapy of Trastuzumab and pertuzumab has shown good efficacy.At present,pertuzumab combined with trastuzumab and paclitaxel has become the first-line treatment for patients with advanced HER2-positive breast cancer.The common adverse reactions of pertuzumab include diarrhea,neutropenia and cardiotoxicity,etc,which can be controlled clinically.However,compared with single target therapy,dual target therapy may increase the risk of adverse reactions.The purpose of this study was to analyze the selection of targeted treatment options for patients receiving postoperative adjuvant therapy and preoperative neoadjuvant therapy with HER2-positive breast cancer after pertuzumab was marketed in China and the comparison of efficacy and adverse reactions between single target and double target therapy,and to analyze the current clinical application of pertuzumab combined with trastuzumab dual target therapy in HER2-positive breast cancer patients,in order to better guide the clinical work.MethodsThis study collected and included patients with non-advanced HER2-positive breast cancer who underwent postoperative adjuvant or preoperative neoadjuvant targeted therapy at Qilu Hospital of Shandong University between March 2019 and September 2020.The general data,clinicopathology,efficacy,prognosis and adverse reactions were collected and analyzed retrospectively.The end date of follow-up was February 28,2021.The inclusion criteria includes the patients of breast cancer confirmed by preoperative biopsy or postoperative pathology in the hospital,and which were HER2-positive confirmed by immunohistochemistry or FISH test,underwent preoperative or postoperative trastuzumab single target or trastuzumab and pertuzumab dual target therapy,regardless of the combination of other treatment regimen.SPSS 26.0 software was used for data statistics and analysis.The continuous variables of normal distribution were represented by mean value and standard deviation,and the data of classified variables were represented by frequency and percentage.Chi-square test or rank sum test was used for the difference analysis of the classification variables.Two independent sample t test was used for the difference analysis of the continuous variables among the classification variables.Univariate Logistic regression model was used to analyze the relationship between the clinicopathological factors and the observation indicators.P<0.05 was considered statistically significant.ResultsAs of February 28,2021,the end date of follow-up,134 patients with HER2-positive breast cancer who met the inclusion criteria and exclusion criteria and had relatively complete data were included in this study.Among them 1 10 patients received postoperative adjuvant therapy,with 58 patients received trastuzumab(H)single target therapy and 52 patients received trastuzumab+pertuzumab(HP)double target therapy.24 patients received preoperative neoadjuvant therapy,and all received HP dual target therapy.Among patients with postoperative adjuvant therapy,the younger,the larger the diameter of the primary lesion,the presence of vascular infiltration,the more lymph node metastases,the higher Ki67 level,and the later overall staging tended to choose dual-target therapy.(P=0.015,P=0.002,P=0.009,P<0.001,P=0.005,P<0.001,all P<0.05).Menstrual status,histological grade and hormone receptor status were not correlated with the choice of targeted therapy(P=0.059,P=0.065,P=0.376,P>0.05).16 patients(27.6%)who received monotherapy had positive axillary lymph nodes and were not given pertuzumab for economic reasons.Since January 2020,when pertuzumab was reduced in price and included in medicare,the proportion of patients with positive axillary lymph nodes choosing dual-target therapy increased significantly(P=0.001).By the end of follow-up,all the 24 patients who received neoadjuvant therapy had completed surgical treatment,with a total pCR rate of 54.2%and a total effective rate of 70.8%.There was no statistically significant difference in pCR rate among all clinicopathological factors subgroups(P values of chi-square test,rank sum test and univariate logistic regression model analysis were>0.05).The safety of targeted therapy was evaluated for all patients,and the results showed that there were no statistical differences in baseline LVEF level(P=0.274>0.05)or the maximum change in LVEF level before and after treatment(P=0.167>0.05)between the single target therapy group and the double target therapy group.In the monotherapy group,2 patients developed asymptomatic cardiotoxicity(LVEF level decreased≥10%),and 1 patient developed transient precardiac discomfort without LVEF level reduction.Three patients in the dual-target treatment group developed asymptomatic cardiotoxicity and one patient developed chest tightness without a decrease in LVEF.There was no significant difference in symptoms of cardiac discomfort and asymptomatic cardiotoxicity between two groups(all P>0.05).In addition to cardiotoxicity,the major adverse reactions in the dual-target treatment group were diarrhea(10.5%),neutropenia(7.9%),infusion reaction(2.6%),rash(3.9%)and fatigue(5.3%).The most common adverse reactions were diarrhea and neutropenia.Compared with monotherapy group,the incidence and severity of diarrhea were increased in dual therapy group.Conclusion1.Factors influencing the selection of targeted therapy after operation for HER2-positive breast cancer mainly include recurrence risk factors mainly based on lymph node status.Patients with older age,larger diameter of primary foci,presence of vascular infiltration,more lymph node metastases,higher Ki67 level and later overall staging are more likely to choose dual target therapy.2.Economic factor is one of the important factors that influence patients’ choice of dual target therapy.Since January 2020,pertuzumab has been greatly reduced in price and officially included in the medical insurance.After January 2020,the proportion of patients with positive axillary lymph nodes choosing dual-target therapy has significantly increased compared with that before January 2020.3.The total pCR rate of double target therapy in preoperative neoadjuvant therapy was 54.2%,the total effective rate was 70.8%,and all subgroups had benefits.4.The overall compliance of patients with dual target therapy was good.The most common adverse reactions were cardiotoxicity,diarrhea and neutropenia,and the reactions were mostly mild and clinically controllable.Dual-target therapy did not increase cardiotoxicity compared with single-target therapy,but increased the risk of diarrhea and the incidence of severe diarrhea. |
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