The Optimization Of Maintenance Treatment And A Exploratory Research Of HER2 Positive Metastatic Breast Cancer With Detection By CtDNA

ObjectiveMetastatic breast cancer(MBC) is incurable. Maintenance therapy is a management measure of advanced breast cancer. It’s a measure to prolong the time of progression and improve the quality of life. It has extensive studied in hematologic malignancies, but still explore a best way in breast cancer. There is no common view of maintenance therapy for breast cancer. In clinical practice, doctors can choose maintenance therapy by initial regimens, keep single-agent chemo or switch drug after combination chemotherapy in MBC. At present there is no such international comparative study. Our study part one compare capecitabine with endocrine therapy as maintenance regimens in patients with HR positive HER-2 negative metastatic breast cancer(MBC) who achieved diseas e control with capecitabine-based chemotherapy. Now breast cancer diagnosis and treatment from population to classification then individuals. Today’s medical science has entered the era of precision medicine based on big data. Combined with the current international development of medicine and based on our group’s previous studies in traditional tumor markers, ECD, CTC and so on, part two of the study detected ct DNA to monitor HER2 positive metastatic breast cancer(MBC) patients to explore the relationship between gene mutation and targeted therapy resistance by found the mutant gene related in plasma.Part OneMethods118 patients with HR positive HER-2 negative MBC were enrolled during 2009.2-2013.7. All patients achieved disease control(CR,PR or SD) with capecitabine-based chemotherapy were divided into capecitabine arm(n=65) and endoc rine therapy arm(n=53). Response Evaluation Criteria in Solid Tumors(RECIST1.1) was used to evaluate the efficacy. The follow-up work was done through out-patients in-patients and telephone to record the survival and therapy circumstances. The primary endpoint is progression-free survival(PFS).Results1、The ages, DFS, menopausal status, number of metastases and treatment line numbers had no significant differences between two arms. The median PFS time from capecitabine-based chemotherapy was longer in the endocrine arm than in the capecitabine arm(13.6 vs 9.4 months, respectively; P=0.02). The median PFS time after assignment was longer in the endocrine arm than in the capecitabine arm(8.1 vs 4.7months, respectively; P=0.03).2、The PFS benefits of endocrine maintenance therapy were observed in patients younger than 50 years of age(P =0.004), premenopausal women(P=0.03), patients without visceral metastasis(P=0.04) and patients with ER PR both positive disease(P=0.02).Conclusion1、In clinical practice, single-agent capecitabine or switch to endoc rine therapy is a choice as maintenance therapy after combination chemotherapy in HR positive MBC.2、In patients with HR positive HER-2 negative MBC who achieved disease control with capecitabine-based chemotherapy, maintenance endocrine therapy resulted in better PFS compared with maintenance single-agent chemotherapy. T he PFS benefits were observed in premenopausal, visceral metastases, ER PR both positive patients. 3、HR positive patients who should chosen endoc rine therapy as the first-line therapy can get better PFS by switch to endocrine therapy, Even though they treated with combination chemotherapy first.Part TwoMethods42 patients with HER-2 positive MBC were enrolled in 2014.3-2014.12. Enrolled patients were treated with 1 to 3 lines anti-HER2 targeted therapy(with or without chemotherapy) according to NCCN guidelines. Blood tested before treatment and every two cycle’s treatment until progression of disease. Response Evaluation Criteria in Solid Tumors(RECIST1.1) was used to evaluate the efficacy. 34 cases circulating cell free DNA was detected in blood cell and plasma by amplicon next-generation deep sequencing(NGS). 10 of them finished detection and analysis, then screened cancer-related gene mutation.Results1、11 mutant genes were detected in enrolled patients by 50 gene test in 10 cases, include PTEN, AKT, KRAS, BRAF, TP53, EGFR, HRAS, NRAS, ERBB2, ERBB4 and PIK3 CA. All of 10 patients have PIK3 CA and ERBB4 mutation, AKT and TP53 mutati on detection rate were 90%, EGFR, ERBB2 and PTEN mutation detection rate were 80%, BRAF mutation detec tion rate was 50%, NRAS and HRAS mutation detec tion rate ware 40%, KRAS mutation detection rate was 30%.2、Resistant group that include 8 cases detected 11 mutant genes and sensitive group that include 2 cases detected 8 mutant genes. Average mutant SNPs of each gene in resistant group are as follows: AKT=3.8, PTEN=2.5, ERBB4=4, NRAS=1, PIK3CA=5, KRAS=1.4, HRAS=0.6, ERBB2=2.6, BRAF=0.8, TP53=6.4, EGFR=5.3.Average mutant SNPs of each gene in s ensitive group are as follows: AKT=1.5, PTEN=2, ERBB4=2.5, PIK3CA=1.5, KRAS=2.5, ERBB2=1.5, TP53=1, EGFR=3.Conclusion1、Covering property and depth was performed followed by size selection and Quality Control, 11 genes have SNPs mutation, and all of 11 mutant genes related to PI3K-AKT-m TOR pathway and Ras-Raf-MEK-ERK pathway.2、Resistant group has more SNPs supposed a monitor increased number from the time before treatment to the time of res istant.