| Background:Human epidermal growth factor receptor 2（HER2）positive breast cancer accounts for about 20%of all breast cancers and is characterized by easy recurrence and metastasis,rapid progression and poor patient prognosis.Prior to pertuzumab,trastuzumab in combination with chemotherapy was the standard first-line treatment,but resistance was inevitable.For resistant patients,subsequent treatment is particularly critical to inhibit tumor development.Second-line treatments for HER2 positive advanced breast cancer treated with trastuzumab have been explored in a number of phase II/III randomized controlled trials（RCTs）,including trastuzumab combined with chemotherapy,anti-HER2 tyrosine kinase inhibitor（TKI）alone or combined with chemotherapy,trastuzumab combined with TKI,antibody-cytotoxic drug conjugate（ADC）alone or combined with immunotherapy,and other targeted drugs such as pertuzumab on the basis of trastuzumab plus chemotherapy.However,the relative efficacy between all these treatment regimens is unknown.Simultaneous comparison of multiple regimens in the real world has also rarely been reported.In addition,clinical trial results may differ from real-world studies.Objective:To compare the efficacy of different second-line treatments on the prognosis of patients with trastuzumab-resistant HER2 positive advanced breast cancer,and explore the optimal second-line regimen;compare the clinical trial results with the real-world data.Methods:The study is divided into 2 parts.Part 1 is to use the available data of phase II/III RCTs on the comparison of second-line treatments for HER2 positive advanced breast cancer,perform Bayesian network meta-analysis using R software,and compare the survival benefits between multiple second-line treatments.The primary endpoint is progression-free survival（PFS）,and the secondary endpoint is overall survival（OS）.In part 2,patients with trastuzumab-resistant HER2 positive advanced breast cancer who visited our hospital from June 2015 to November 2020 were included.According to the second-line anti-HER2 treatment regimen,efficacy and adverse events（AEs）,Medcalc 15.2.2 software and SPSS 26.0 software were used to compare the efficacy and safety of different regimens.Results:1.Network meta-analysis using RCT data1.1.Due to the lack of head-to-head comparisons between some interventions,the PFS analysis was divided into two parts.（1）PFS#1:（1）8 treatment regimens in 9RCTs were included:pyrotinib+capecitabine（Py+X）,T-DM1+atezolizumab（T-DM1+Atezo）,pertuzumab+trastuzumab+capecitabine（P+H+X）,trastuzumab+capecitabine（H+X）,lapatinib+capecitabine（L+X）,T-DM1,neratinib（Nera）and capecitabine（X）.The analysis showed that the PFS benefit of Py+X was greater than that of T-DM1,H+X,L+X,Nera and X;there was no difference between Py+X,T-DM1+Atezo and P+H+X;the PFS benefit of T-DM1+Atezo was better than that of Nera,X and L+X;P+H+X was better than Nera and X,and tended to be better than H+X;T-DM1 was superior to L+X,Nera and X;the regimens of L+X,H+X and Nera had consistent efficacy in PFS,and all were superior to X.Pairwise comparisons showed that there was no difference between Py+X,T-DM1+Atezo,and P+H+X;Py+X was superior to T-DM1,H+X,L+X,Nera,and X;T-DM1 was superior to L+X,Nera,and X;and H+X,L+X,and Nera had consistent efficacy and were all superior to X.Ranking probabilities showed that Py+X>T-DM1+Atezo>P+H+X>T-DM1>H+X>L+X>Nera>X.（2）PFS#2:3 treatments in 2 RCTs were included:trastuzumab+vinorelbine（H+N）,afatinib+vinorelbine（A+N）,and everolimus+trastuzumab+vinorelbine（E+H+N）.Pairwise comparisons revealed that E+H+N was superior to H+N and A+N;there was no difference between H+N and A+N.The ranking probability showed that E+H+N>H+N>A+N.1.2.OS:OS data were reported in 7 studies involving a total of 7 regimens:T-DM1+Atezo,P+H+X,H+X,L+X,T-DM1,Nera and X.Pairwise comparisons yielded that T-DM1+Atezo,P+H+X,and T-DM1 were not significantly different,T-DM1+Atezo and T-DM1 were both superior to L+X,Nera,and X,and P+H+X was superior to H+X and X.There was no significant difference between H+X,L+X,X and Nera.Ranking probability showed that T-DM1+Atezo>P+H+X>T-DM1>H+X>L+X>X>Nera.2.Retrospective analysis using clinical data of our hospitalThe aforementioned network meta-analysis found that Py+X was superior to T-DM1 in terms of PFS,and both were superior to L+X.T-DM1 was superior to L+X in terms of OS.Additional consideration of the current guideline recommendations in China for second-line treatment of trastuzumab-resistant patients,we used the clinical data of our hospital to compare the efficacy and adverse events（AEs）of T-DM1,Py+X and L+X as the second-line treatment.The median follow-up time was 33 months in the T-DM1 group（n=42）,13 months in the Py+X group（n=33）,and 27 months in the L+X group（n=28）.2.1.Survival and response evaluation in overall population:T-DM1 group,Py+X group L+X group:（1）PFS:PFS was 13 months,11 months and 8 months,respectively（P=0.09）;（2）OS:OS was not reached,20 months and 26 months,respectively（P=0.48）;（3）overall response rate（ORR）:ORR was 42.9%,66.7%and 35.7%,respectively（P=0.04）,and pairwise comparison（Bonferroni adjusted P value significance level was 0.017）showed that Py+X was superior to L+X（P=0.016）;（4）disease control rate（DCR）:DCR was 88.1%,97.0%and 85.7%,respectively（P=0.26）.Exploratory analysis revealed that metastatic sites≥3 and trastuzumab primary resistance were independent prognostic factors for poor PFS.2.2.Subgroup analysis of primary and secondary resistance:In the overall population,PFS was 8 months vs 12 months（hazard ratio[HR]=0.60,95%confidence interval[CI]:0.35～1.02,P=0.04）and OS was 20 months vs 44 months（HR=0.47,95%CI:0.25～0.88,P=0.01）in patients with primary and secondary resistance.（1）For patients with primary resistance,PFS in the 3 groups was 8 months,9 months and 8months,respectively（P=0.84）;ORR was 50.0%,61.5%and 33.3%,respectively（P=0.45）;DCR was 75.0%,92.3%and 77.8%,respectively（P=0.46）.（2）For patients with secondary resistance,PFS in the 3 groups was 13 months,28 months and 8 months,respectively（P=0.04）,and there was no significant difference in PFS in pairwise comparisons;ORR was 30.0%,70.0%and 36.8%,respectively（P=0.03）,and Py+X was superior to T-DM1（P=0.011）;DCR was 100%,100%and 89.5%,respectively（P=0.19）.2.3.Incidence of adverse events:（1）T-DM1 group:38.1%patients had grade 3or higher AEs,16.7%,33.3%and 11.9%patients had dose interruption,permanent discontinuation and dose reduction due to AEs,respectively,and 9.5%patients had serious AEs.（2）Py+X group:30.3%of patients had grade≥3 AEs,and the proportions of patients with dose interruption,permanent discontinuation,and dose reduction due to AEs were 12.5%,6.1%,and 6.1%,respectively.（3）L+X group:grade≥3 AEs occurred in 46.4%of patients,and the proportions of patients with dose interruption,permanent discontinuation,and dose reduction due to AEs were 25.9%,7.4%,and 11.1%,respectively.Conclusion:1.In the second-line treatment of trastuzumab-resistant HER2 positive advanced breast cancer,the efficacy of chemotherapy or TKI alone is poor,and the efficacy of chemotherapy combined with targeted therapy is better.2.In the network meta-analysis,Py+X,T-DM1+Atezo,P+H+X and T-DM1 had better efficacy in terms of PFS benefit,and Py+X may be the optimal regimen;T-DM1+Atezo,P+H+X and T-DM1 had better efficacy in terms of OS benefit,and T-DM1+Atezo may have the greatest OS benefit.3.In the retrospective analysis,in terms of PFS,Py+X and T-DM1 tended to be superior to L+X;in terms of ORR,DCR and safety,Py+X is better than T-DM1 and L+X.4.Compared with patients with trastuzumab primary resistance,patients with secondary resistance to trastuzumab have longer OS. |
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