The Exploratory Study Of Clinical Therapeutic Scheme And Resistance Indexes After TKI Treatment In HER2-positive Advanced Breast Cancer

Part ?:The exploratory study of clinical therapeutic scheme after TKI treatment in HER2-positive advanced breast cancer.Objective: Approximately 15-25% of breast cancers overexpress the human epidermal growth factor receptor-2(HER2),which is associated with the high rate of recurrence and poor prognosis.With advances in awareness of anti-HER2 therapy and application of targeted drugs,the prognosis of patients with HER2-positive breast cancer has been greatly improved.For patients with advanced HER2-positive breast cancer,the first-line standard regimens recommended by the NCCN and CSCO BC guidelines are based on trastuzumab-based treatment.After trastuzumab resistance,the guidelines regard TKI as second-line treatment.Even so,there are still some patients clinically resistant to trastuzumab and lapatinib,and international guidelines often recommend T-DM1 or other anti-HER2 treatment options.Based on medical insurance policies and the availability of medicines,domestic guidelines only include the new generation of TKI pyrotinib as an optional recommendation.However,there is currently no head-to-head clinical study comparing the efficacy of the two drugs.Therefore,this study combined with the clinical data of patients in our hospital to compare the efficacy and safety of pyrotinib and T-DM1 after trastuzumab and lapatinib failed,in order to provide a reference for clinical diagnosis and treatment.Methods: This study included patients with HER2-positive advanced breast cancer who were admitted to the Breast Oncology Department of our hospital.They had received trastuzumab and lapatinib treatment and failed.The follow-up treatment plan was: pyrotinib monotherapy or combination therapy,T-DM1 monotherapy.The primary observation endpoint was Progression Free Survival(PFS),which was defined as the time interval from the start of treatment to the onset of disease progression or death from any cause.Secondary study endpoints included Objective Response Rate(ORR),Clinical Benefit Rate(CBR),and safety.The clinical efficacy of all patients was evaluated using the RECIST 1.1 solid tumor treatment efficacy evaluation standard,and the curative effect was evaluated every 2 cycles or when the disease was suspiciously judged clinically based on symptoms and signs.Safety assessment includes vital signs and clinical laboratory assessments.Adverse event assessment is based on Common Terminology Criteria for Adverse Events(CTCAE)version 4.0.All statistical tests were performed using SPSS 25.0,which were two-sided tests with a significance level of 0.05.For survival analysis,Kaplan-Meier curves were used to estimate progression-free survival and confidence intervals.Subgroup analysis was performed based on important clinical factors.Differences between groups were compared using chi-square or Fisher's exact test.Results: From January 1,2013 to November 30,2019,a total of 105 patients with HER2-positive advanced breast cancer were included.Among them,55 patients(52.4%)received pyrotinib,40 patients received monotherapy,and 15 patients received combination therapy.The main combination drugs were capecitabine,vinorelbine,and albumin paclitaxel;T-DM1 are all monotherapy.The median age was 46 years(23-73 years),the median PFS in the pyrotinib group was 6.0 months(4.7-7.3 months),ORR was 16.3%,and CBR was 45.5%,The median PFS in the T-DM1 group was 4.2 months(3.6-4.8 months),ORR was 20.0%,and CBR was 40.0%.The difference in median PFS between the two groups was statistically significant(p = 0.044).In addition,for patients who had benefited from previous lapatinib treatment,the median PFS was longer in the pyrotinib group(n = 31;8.1 months,95% CI 4.8-11.4 months)than in the T-DM1 group(n = 32;4.4 months,95% CI 3.8-5.0 months)(p = 0.013);Among patients without liver metastasis,the median PFS in the pyrotinib group(n = 34;6.9 months,95% CI 3.7-10.1 months)was longer than that in the T-DM1 group(n = 29;4.1 months,95% CI 3.1-5.1 Months)(p = 0.010).The most common adverse reaction in the pyrotinib group was diarrhea(98.2%),and the T-DM1 group was fatigue(42.0%)and thrombocytopenia(32.0%).19 and 14 patients had ? 3 treatment-related grade adverse reactions(TRAEs)in the pyrotinib group and T-DM1 group,but no treatment-related deaths were observed.Conclusions: The results of this study show that patients with HER2-positive advanced breast cancer who have failed trastuzumab and lapatinib can benefit from subsequent pyrotinib treatment and are well tolerated,especially for patients who have benefited from previous lapatinib treatment or have no liver metastases.However,further clinical research is still needed.Part ?:The exploratory study of TKI-related biomarkers of HER2-positive advanced breast cancer based on circulating tumor DNAObjective: Although anti-HER2 targeted drugs have a significant effect in patients with HER2-positive metastatic breast cancer,drug resistance has always been a difficult clinical problem.Studies shown that genomic variation of tumor cells is the main cause of drug resistance.To this end,we need to explore the possible mechanism of TKI resistance at the genetic level in order to provide direction for subsequent clinical treatment.Methods: The clinical data of 36 patients with HER2-positive advanced breast cancer who were treated in the Breast Oncology Department of our hospital from June 1,2018 to January 20,2020 were collected.The next-generation sequencing technology was used to detect mutations in ct DNA in specific regions,to screen for tumor-associated somatic mutations,and to analyze the correlation between the mutant genes and the efficacy of TKI.All patients collected blood samples for anti-HER2 targeted therapy failure,followed by TKI therapy.Oral TKI was lapatinib combination therapy,or pyrotinib monotherapy or combination therapy,until the tumor progressed or serious side effects reaction.In this study,patients who benefited from TKI(CR,PR or SD ? 6 months)were defined as the sensitive group,and those who did not benefit from TKI(SD <6 months or PD)were defined as the drug resistance group.Results: All 36 patients with HER2-positive advanced breast cancer were women.The median age is 49 years old(27-73).Of the 36 patients,25 were hormone receptor negative(69.4%)and 11 were hormone receptor positive(30.6%).There were 22 patients(61.1%)in the sensitive group and 14 patients(38.9%)in the drug-resistant group.Eleven patients(30.6%)received trastuzumab,15 patients(41.7%)received trastuzumab and TKI,and 10 patients(27.7%)received trastuzumab,TKI,and T-DM1.Five patients(13.9%)received lapatinib in the follow-up treatment,and 31 patients(86.1%)received pyrotinib.Of the 36 patients,33(91.7%)detected gene copy number variations and/or point mutations.Among them,TP53 mutation was detected in 25 cases(69.4%),and PI3 KCA mutation was detected in 15 cases(41.7%).Thirteen patients(36.1%)had co-mutation of TP53 and PI3 KCA genes,and 10 patients(27.8%)detected ERBB2 mutation.Comparing the PFS differences of 40 tumor-related gene mutant and wild type and TKI efficacy detected in the sample,the results showed that the median PFS of PI3 KCA gene mutant and wild type patients were 5 months and 27 months(p = 0.02),The median PFS of PI3 KCA and TP53 co-mutant and non-co-mutant patients was 5.0 months and 16.0 months(p = 0.015).There was no statistical difference in PFS between TP53,ERBB2 mutant and wild-type patients(P values are greater than 0.05).After screening drug resistance genes,3 patients were found to have KDM5A gene mutations,and all were resistant during the subsequent TKI treatment.Conclusions: Through the exploration of the genomic mutation map of 36 HER2-positive advanced breast cancer patients,we found that TP53,PI3 KCA,ERBB2 are the most frequently mutated genes in HER2-positive advanced breast cancer patients,and different gene mutation frequencies reflect the differences in genome long tail effect.Among them,the changes of PI3 KCA and TP53 genes may be related to the therapeutic effect of TKI.KDM5 A gene mutation may be related to the resistance of TKI targeted therapy.The above conclusion confirms that ct DNA has potential application value in predicting biomarker changes during TKI treatment.