Efficacy Analysis Of Trastuzumab Combined With Pertuzumab In The Third-Line Treatment Of HER2-Positive Breast Cancer And The Value Of SOX11 In Predicting Its Efficacy

Efficacy Analysis of Trastuzumab Combined with Pertuzumab in the Third-Line Treatment of HER2-Positive Breast CancerBackground: Breast cancer is the most common malignant tumor in Chinese women,among which,about 15% ～ 20% are human epidermal growth factor receptor 2(HER2)positive breast cancer.HER2-positive breast cancer is aggressive and has poor prognosis.The introduction of trastuzumab(H)has significantly prolonged and changed the survival of patients with HER2-positive breast cancer.However,treatment options after trastuzumab resistance remain a major challenge for patients with advanced HER2-positive breast cancer.In March 2013,China Food and Drug Administration(CFDA)approved the marketing of Lapatinib,a small molecule tyrosine kinase inhibitor(TKI),as a second-line treatment for HER2-positive advanced breast cancer in China.In August 2018,CFDA approved pyrotinib,a Chinese original TKI,for second-line treatment after trastuzumab resistance,and then pyrotinib gradually replaced lapatinib as a second-line treatment option for HER2-positive advanced breast cancer patients.However,after the failure of second-line treatment with TKI like pyrotinib or lapatinib,there is no unified standard for the selection of third-line treatment.The Chinese Society of Clinical Oncology(CSCO)guidelines and Chinese anti-Cancer Association(CACA)guidelines encourage patients to participate in clinical studies.In domestic clinical practice,due to economic and drug availability reasons,most patients with resistance to TKI for second-line treatment still have to choose trastuzumab and pertuzumab(P)combination chemotherapy or switch to another small molecule TKI regimen for thirdline treatment.Within the scope of economy and drug accessibility,whether to use another small-molecule TKI therapy with different mechanism of action,or to use trastuzumab combined with pertuzumab(HP)is very scarce at home and abroad,so it is worth further discussion.Based on the above reasons,we conducted a retrospective analysis of the efficacy and safety of HP and pyrotinib in the third-line treatment of advanced HER2-positive breast cancer,hoping to provide a basis for the selection of the regimen for patients with trastuzumab resistance after multi-line treatment.Objective: To observe the efficacy and safety of trastuzumab combined with pertuzumab in third-line treatment of patients with HER2-positive advanced breast cancer after trastuzumab resistance,and to compare with patients receiving pyrotinib regimen,so as to explore the feasibility of HP in third-line treatment of patients with HER2-positive advanced breast cancer.Methods: This study retrospectively collected the clinical data of patients with HER2-positive advanced breast cancer admitted to the Department of Oncology Chemotherapy of Anhui Provincial Hospital from January 1,2020 to January 1,2022.After resistance to first-line Herceptin and second-line small molecule TKI treatment,all the patients received HP or pyrotinib in the third-line treatment.The efficacy and safety of HP were compared with those treated with pyrotinib,and the value of HP in the third-line treatment of HER2-positive advanced breast cancer was discussed.Descriptive statistics was used for baseline characteristics,and the Chi-square test or Fisher’s exact test was used to assess the heterogeneity of variables between HP and pyrotinib group.Univariate analysis and multivariate analysis were performed using COX proportional hazard regression models and hazard ratios(HR)and 95% confidence intervals(CI)were estimated.Kaplan-Meier method was used for survival analysis and Log-rank test was used to compare the progression-free survival time(PFS)between the two groups.COX proportional hazard regression model was used for subgroup analysis and the results were displayed by forest plots.SPSS 22.0 was used for statistical analysis.Survival curve and forest plot were completed by Graphpad Prism 9.0 version.P < 0.05 was considered statistically significant.Results:A total of 84 patients were enrolled in this study,including 44 patients in the HP group and 40 patients in the pyrotinib group.The median age of the HP group was48 years(26-68 years),and the median age of the pyrotinib group was 50 years(32-75years).The objective response rate(ORR),disease control rate(DCR)and clinical benefit rate(CBR)in HP group were 15.9%,81.8% and 54.5%,respectively,while those in pyrotinib group were 15.0%,82.5% and 30.0%,respectively.The subgroup analysis showed that the ORR,DCR and CBR of patients treated with HP were better than those of patients treated with pyrotinib in most subgroups.Only in the subgroup of brain metastases,the ORR,DCR and CBR of patients treated with pyrotinib were better than those of patients treated with HP.According to Kaplan-Meier survival analysis,the m PFS of all patients treated with HP was 6.4 months(95% CI,3.9-8.9 months),which was significantly better than patients receiving pyrotinib(5.1 months,95% CI,4.1-6.1months)(P = 0.042).Univariate COX analysis showed that in most subgroups,there was no significant difference in m PFS between the HP treatment group and the pyrotinib treatment group,except for the subgroup with lung metastasis and the subgroup with aged 50 years or older(P < 0.05).Univariate COX analysis of all patients treated with HP showed that brain metastasis and the number of metastatic organs were risk factors related to disease progression.Further multivariate COX regression analysis showed that brain metastasis was an independent risk factor for disease progression.In the survival analysis of each subgroup,the m PFS of patients with brain metastasis was 4.1 months,which was significantly shorter than 9.2 months of patients without brain metastasis(P = 0.002).The m PFS of patients with no more than 2 metastatic organs was significantly better than that of patients with more than 2metastatic organs(16.0 months vs.6.2 months,P = 0.033).There were 24 adverse events of grade 3 or above in the HP group,and the most common adverse event was anemia(84.1%).There were 21 adverse events of grade 3 or above in the pyrotinib group,and the most common adverse event was gastrointestinal reaction(80%).Conclusions: Trastuzumab combined with pertuzumab remains an option in third-line treatment of HER2-positive advanced breast cancer,and is safe and effective,especially in patients without prior brain metastases and no more than 2 metastatic organs.In patients who have already received TKI treatment,HP still has some advantages,and small-molecule TKI cross-line therapy is not recommended.For patients with brain metastases,cross-line treatment of pyrotinib may have some therapeutic value.The Value of SOX11 in Predicting the Efficacy of Trastuzumab Combined with PertuzumabBackground: At present,breast cancer has become the most common malignant tumor in Chinese women,and the incidence rate is increasing year by year.Early detection,diagnosis and treatment of breast cancer can significantly reduce the mortality of breast cancer patients.Neoadjuvant therapy for early breast cancer is very important to improve disease-free survival and overall survival of breast cancer patients.Objective: The aim of this study is to investigate the correlation between SOX11 and the efficacy of trastuzumab combined with pertuzumab in patients with HER2-positive breast cancer,and to explore the value of SOX11 in predicting the efficacy of trastuzumab combined with pertuzumab.Methods: In this study,the transcriptome data of patients treated with taxanes +trastuzumab + pertuzumab as neoadjuvant therapy in the GEO database were obtained,and the differentially expressed genes in all patients who achieved pCR and Non-pCR were analyzed,and the genes with the most significant expression differences were selected for subsequent analysis.According to the inclusion and exclusion criteria,the medical records of patients with HER2-positive breast cancer who received HP as neoadjuvant targeted therapy in Anhui Provincial Hospital from January 1,2020 to December 31,2020 were collected.The data included histological type,histological grade,tumor size,surgical margin,vascular or lymphatic invasion,lymph node metastasis,hormone receptor status,Ki-67 and response evaluation(pCR or Non-pCR).The corresponding tissue samples were collected from the pathology department and stained with immunohistochemistry.The results of immunohistochemistry were analyzed.Descriptive statistical analysis was used to analyze the clinicopathological parameters and SOX11 expression of patients with HER2-positive breast cancer who received HP as neoadjuvant therapy.Chi-square test and Fisher exact test were used to analyze the correlation between clinicopathological parameters,SOX11 expression level and neoadjuvant efficacy of neoadjuvant therapy in HER2-positive breast cancer patients.Logistic regression model was used for multivariate regression analysis,and SPSS 22.0 was used for statistical analysis.Differences were considered significant if P value was less than 0.05.Results: In this study,44 patients treated with taxanes + trastuzumab + pertuzumab neoadjuvant therapy from the GEO database were obtained.In the differential gene analysis of pCR and Non-pCR patients,SOX11 was the most significant.According to the inclusion and exclusion criteria,a total of 33 patients receiving HP as neoadjuvant treatment in our hospital were enrolled.Among them,13 patients(39.4%)achieved pCR and 20 patients(60.6%)did not achieve pCR.7 patients had high expression of SOX11 and 26 patients had low expression of SOX11.In addition,among the patients with high SOX11 expression,2 achieved pCR and 5 did not achieve pCR,while among the patients with low SOX11 expression,11 achieved pCR and 15 did not achieve pCR.No significant correlation was found between the clinicopathological parameters and the neoadjuvant response or SOX11 expression level in all patients receiving HP as neoadjuvant therapy by chi-square test and Fisher’s exact test.However,multivariate Logistic regression analysis of all patients who achieved pCR after neoadjuvant targeted therapy suggested that SOX11 expression level was significantly correlated with pCR(P< 0.05).Conclusion: Low SOX11 expression is closely related to pCR in patients with HER2-positive breast cancer receiving HP as neoadjuvant therapy,and it is an effective indicator for predicting the efficacy of neoadjuvant targeted therapy in patients with early breast cancer.