Efficacy And Safety Of Neoadjuvant Pyrotinib For HER2-positive Breast Cancer And Predictive Value Of PIK3CA Mutations For Efficacy

Human epidermal growth factor receptor 2（HER2）,also known as Erb B2,is a member of the HER family of receptor tyrosine kinases.Heterodimerization of HER2 with other members of the HER family,or homodimerization with each other,lead to activation of downstream signaling pathways,notably phosphatidylinositol 3-kinase/Protein kinase B/mammalian target of rapamycin（PI3K/Akt/m TOR）and mitogen activate protein kinase（MAPK）pathways,thus form a complex multilayer network that promote cell survival,proliferation,differentiation and migration.The overexpression of HER2 is considered to promote oncogenic processes via triggering dimer formation bias of the HER family of receptors and aberrantly activating downstream pathways.Breast cancer with overexpression of HER2 protein on the cell surface,commonly known as HER2-positive breast cancer,is considered as a risk factor associated with disease aggression and malignancy,which accounts for approximately 15%to 20%of all types of breast cancers.Trastuzumab,a HER2-directed humanized monoclonal antibody,when combined with chemotherapy,has remarkably improved outcomes of patients with HER2-positive breast cancer.However,a considerable number of HER2-positive patients with inherent and acquired resistance to trastuzumab will still suffer disease progression and relapse.Numerous attempts with novel approaches to target therapy have been performed to solve the above problems and improve outcomes for patients with HER2-positive breast cancer,e.g.,tyrosine kinase inhibitors（TKIs）.Pyrotinib is a small-molecule,irreversible pan-HER TKI that targets HER1,HER2 and HER4.In patients with HER2-positive metastatic breast cancer,pyrotinib has been approved by health authorities in China in combination with capecitabine as standard second-line therapy and alternative first-line in patients treated with prior trastuzumab and taxane based on the results of the phase III PHOEBE trial and the PHENIX trial.In the neoadjuvant setting,pyrotinib added to trastuzumab plus docetaxel was shown to significantly increase the rate of pathological complete response（p CR）based on the results from phase III PHEDRA study,which led to its approval as neoadjuvant therapy for patients with HER2-positive breast cancer in China.Although pyrotinib plus trastuzumab in combination with docetaxel has been approved in the field of neoadjuvant therapy,the optimal chemotherapy partner still needs exploration.Firstly,this study designed a multicenter single-arm trial,aiming to investigate the efficacy and safety of epirubicin,cyclophosphamide and pyrotinib followed by docetaxel,trastuzumab and pyrotinib（ECPy-THPy）as neoadjuvant therapy for patients with stage II-III HER2-positive breast cancer.Meanwhile,we developed a spectrum of somatic alterations and copy number variations（CNV）from the preoperative biopsy specimens of part of enrolled patients via the next-generation sequencing（NGS）of 425 genes,and conducted an exploration of the relationship between tumour biomarkers and the postoperative p CR.The exploration revealed that PIK3CA mutations were associated with a reduced treatment response to pyrotinib-containing dual anti-HER2 neoadjuvant chemotherapy.For now,the effect of PIK3CA mutations on the efficacy of HER2-targeted therapy remains controversial,so a robust meta-analysis was conducted on the association between PIK3CA mutation status and treatment response to anti-HER2 therapy with TKIs in early-stage and metastatic breast cancer,with the aim of providing evidence of evidence-based medicine addressing this controversial issue.Methods and Results1.A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for stage II-III HER2-positive breast cancerMethods:In this prospective,multicenter,single-arm study（Registration ID:Chi CTR1900022293）,patients with stage II-III HER2-positive breast cancer from 16hospitals in China were recruited for intravenous epirubicin and cyclophosphamide for four21-days cycles,followed by four cycles of intravenous docetaxel and trastuzumab.Pyrotinib was given orally once daily throughout the neoadjuvant therapy period.The primary endpoint was total pathological complete response（tp CR）rate,other endpoints included objective response rate（ORR）,survival outcomes and safety.Results:Between May 2020 and May 2022,a total of 175 patients were enrolled,among which 156 patients underwent surgery with evaluable pathological data.Overall,the tp CR rate was 68.6%（107/156;95%confidence interval[CI]:60.7%–75.8%）in the efficacy-evaluable set and the ORR was 89.1%（139/156;95%CI:83.1%–93.5%）.A post hoc subgroup analysis found no clinical characteristics that related to p CR.Of 175 patients with available safety data,the most common grade≥3 adverse events included diarrhea（54.3%）,white blood cell count decreased（5.1%）,and neutrophil count decreased（4.6%）.Conclusions:Patients with stage II-III HER2-positive breast cancer showed favorable clinical and pathological response to this ECPy-THPy neoadjuvant regimen,with an acceptable safety profile.2.Biomarker Analysis of the efficacy to neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancerMethods:The genomic characteristics of 425 cancer-related genes from the archived tumour blocks of 50 patients enrolled in a prospective neoadjuvant pyrotinib and trastuzumab plus chemotherapy clinical trial and its pilot trail（Chi CTR1900022293）from February 2019to March 2021 were assessed by NGS.The relationship between tumour biomarkers and the postoperative p CR were explored,logistic regression models were built to predict p CR.Results:Forty-five patients completed neoadjuvant chemotherapy and final surgery,of which 26（58%）achieved a p CR.Among all driver gene mutations,PIK3CA mutation was screened out for having a significant relationship with the treatment response.The p CR rate of patients with wild-type PIK3CA was significantly higher than patients with mutated PIK3CA（80.8%vs.26.3%;P=0.00057）,and remained significant after a multiple comparison adjustment(P_adjusted=0.024).We further evaluated the predictive value with logistic regression model of clinical features（hormone receptor status,lymph node status,clinical stage,HER2 immunohistochemistry and tumor-infiltrating lymphocytes）,genetic biomarkers（PIK3CA mutations,MYC amplification）or both,an area under curve（AUC）of 0.912（95%CI:0.827-0.997）was achieved in the integrated model.By March 2023,the median follow-up time was 33.3 months,results of short-term survival analysis showed that patients with wild-type PIK3CA had a longer trend in event-free survival（EFS）compared to patients with mutated PIK3CA（HR=0.18;95%CI:0.02–1.62;log-rank P=0.085）,but did not reach statistical significance.Conclusions:This study suggest that HER2-positive breast cancers with activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy,survival differences remain to be supported by long-term follow-up.3.Predictive value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors:A meta-analysisMethods:This meta-analysis study investigates the predictive and prognostic value of PIK3CA mutations for HER2-positive breast cancer treated with TKIs.Eligible studies were identified by a systematic literature search in the Medline,Embase,and Cochrane Library databases.Studies that met the following inclusion criteria were selected:（i）phase II-III clinical study;（ii）evaluation of the efficacy of anti-HER2 treatment for early or advanced-stage HER2-positive breast cancer;（iii）inclusion of TKIs in at least one treatment arm（as monotherapy or in combination with anti-HER2 drugs）;（iv）data on the mutational status of PIK3CA of the tumor;（v）therapy response or outcome,including p CR,ORR,clinical benefit rate（CBR）,PFS,and overall survival（OS）,included as the primary or secondary endpoints;（vi）sufficient data reported to allow the estimation of odds ratio（OR）with 95%CI or hazard ratio（HR）with 95%CI;and（vii）comparison of endpoints between patients with wild-type and mutated PIK3CA in TKI-containing treatment arms.The pooled estimates for various endpoints of enrolled studies were calculated.Results:Seventeen studies,comprising 1706 patients,were assessed for eligibility.Ten neoadjuvant studies including 902 patients were selected.Overall,the p CR rate was significantly higher in wild-type PIK3CA patients than in mutated PIK3CA patients（OR=0.45;95%CI:0.31–0.65;P<0.001）.In subgroup analysis,in the lapatinib plus trastuzumab dual anti-HER2 regimen group,the wild-type PIK3CA patients had a significantly higher p CR rate than the mutated PIK3CA patients（OR=0.40;95%CI:0.24–0.66;P<0.001）;while in the lapatinib single-target regimen group,no difference was found according to PIK3CA mutation status（OR=0.74;95%CI:0.35–1.56;P=0.428）.Seven studies were conducted in the metastatic setting and included 804 patients.A pooled analysis of treatment responses found that the pooled ORR was significantly higher in wild-type patients than in mutated patients（OR=0.40;95%CI:0.23–0.70;P=0.001）,and CBR is also higher（OR=0.43;95%CI:0.19–0.98;P=0.045）.A pooled analysis of prognosis found that PIK3CA mutations had a marginally significant relationship with poor PFS（HR=0.82;95%CI:0.67–1.00;P=0.052）and OS（HR=0.63,95%CI:0.39–1.02;P=0.062）.Conclusions:This meta-analysis demonstrate that PIK3CA mutations are associated with a lower rate of p CR in neoadjuvant chemotherapy for early-stage HER2-positive breast cancer with TKI-containing regimens;in metastatic HER2-positive breast cancers,PIK3CA mutations were significantly associated with lower ORR and CBR in cases treated with TKI monotherapy,and had a marginally significant association with poor PFS and OS based on the evidence available at present.Full Text ConclusionsNeoadjuvant pyrotinib for HER2-positive breast cancer showed favorable efficacy and acceptable safety profile.PIK3CA mutation can be used as a genetic biomarker of clinical response to TKI therapy.