Dataset Information

Plasma PIK3CA ctDNA specific mutation detected by next generation sequencing is associated with clinical outcome in advanced breast cancer.

ABSTRACT: Through next generation sequencing, this study evaluated the circulating tumor DNA (ctDNA) of advanced breast cancer patients to prospectively explore the relationship between specific DNA mutations and prognosis as well as therapeutic decision making. The target region covered 1021 gene totally. Clinical characteristics, treatment and outcome data were collected. We analyzed progression-free survival (PFS) from first-line therapy and overall survival (OS), and found that their endpoints were correlated with observed gene mutations. We enrolled 54 patients, with a median follow-up time of 8 years. Mutations were found in TP53, PIK3CA, and ERBB family, at 40.7%, 35.2%, and 25.9%, respectively. PIK3CA more frequently occurred in the site of 3140 A>G (p.H1047R) for 20.4% and HER2+ diseases, and it was associated with shorter median PFS and worse OS among HER2+ patients [mutant vs. wild type: 4 (range 2-9) vs. 8 (range 2-22) months, P=0.006], and [mutant vs. wild type: 29 (range 12-74) vs. 64 (range 20-96) months, P=0.043], respectively. The patients with mutations in TP53 had shorter OS (median 64 vs. 121 months, P=0.006). Multivariate analysis for HER2+ disease demonstrated that the PIK3CA p.H1047R mutation was the only factor associated with shorter PFS (P=0.025); while the receiver operating characteristic (ROC) analysis produces an area under the curve (AUC) of 0.789. The ctDNA analysis, found PIK3CA p.H1047R mutation was more frequent in HER2+ disease and associated with worse OS. It was also the only mutation associated with shorter PFS through a multivariate analysis of HER2+ patients who were treated with trastuzumab, suggesting trastuzumab had lower activity in these patients. The presence of a TP53 mutation was associated with worse OS.

SUBMITTER: Li H

PROVIDER: S-EPMC6176180 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Plasma PIK3CA ctDNA specific mutation detected by next generation sequencing is associated with clinical outcome in advanced breast cancer.

Li Huiping H Xu Yaping Y Zhao Fangyuan F Song Guohong G Rugo Hope S HS Zhang Yan Y Yang Ling L Liu Xiaoran X Shao Bin B Yang Liang L Liu Yaxin Y Ran Ran R Zhang Ruyan R Guan Yanfang Y Chang Lianpeng L Yi Xin X

American journal of cancer research 20180901 9

Through next generation sequencing, this study evaluated the circulating tumor DNA (ctDNA) of advanced breast cancer patients to prospectively explore the relationship between specific DNA mutations and prognosis as well as therapeutic decision making. The target region covered 1021 gene totally. Clinical characteristics, treatment and outcome data were collected. We analyzed progression-free survival (PFS) from first-line therapy and overall survival (OS), and found that their endpoints were co ...[more]

PMID: 30323979

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Project description:Genetic testing to detect somatic alterations is usually performed on formalin-fixed paraffin-embedded tumor samples. However, tumor molecular profiling through ctDNA analysis may be particularly interesting with the emergence of targeted therapies for ovarian cancer (OC), mainly when tumor is not available and biopsy is not viable, also allowing representation of multiple neoplastic subclones. Using a custom panel of 27 genes, next-generation sequencing (NGS) was performed on tumor and matched plasma samples from 96 OC patients, which were combined in two groups (treatment naive and post-treatment). Overall, at least one somatic variant present in the tumor sample was also detected in the matched plasma sample in 35.6% of the patients, a percentage that increased to 69.6% of the treatment naive patients and 83.3% of those with stage IV disease, showing the potential of ctDNA analysis as an alternative to identify somatic variants in these patients, namely those that have predictive value for targeted therapy. In fact, of the two treatment-naive patients with somatic BRCA1 variants identified in tumor samples, in one of them we detected in ctDNA a BRCA1 somatic variant that was present in the tumor with a VAF of 53%, but not in the one that had a VAF of 5.4%. We also showed that ctDNA analysis has a complementary role to molecular unraveling of inter- and intra-tumor heterogeneity, as exemplified by one patient diagnosed with bilateral OC in which different somatic variants from both tumors were detected in ctDNA. Interestingly, as these bilateral tumors shared a rare combination of two of the three variants identified in ctDNA, we could conclude that these morphologically different tumors were clonally related and not synchronous independent neoplasias. Moreover, in the post-treatment group of patients with plasma samples collected after surgery, those with detectable somatic variants had poor prognosis when compared with patients with no detectable somatic variants, highlighting the potential of ctDNA analysis to identify patients at higher risk of recurrence. Concluding, this study demonstrated that somatic variants can be detected in plasma samples of a significant proportion of OC patients, supporting the use of NGS-based ctDNA testing for noninvasive tumor molecular profiling and to stratify patients according to prognosis.

Project description:BackgroundCirculating tumor (ct) DNA assays performed in clinical laboratories provide tumor biomarker testing support for biopharmaceutical clinical trials. Yet it is neither practical nor economically feasible for many of these clinical laboratories to internally develop their own liquid biopsy assay. Commercially available ctDNA kits are a potential solution for laboratories seeking to incorporate liquid biopsy into their test menus. However, the scarcity of characterized patient samples and cost of purchasing validation reference standards creates a barrier to entry. In the current study, we evaluated the analytical performance of the AVENIO ctDNA liquid biopsy platform (Roche Sequencing Solutions) for use in our clinical laboratory.MethodIntra-laboratory performance evaluation of AVENIO ctDNA Targeted, Expanded, and Surveillance kits (Research Use Only) was performed according to College of American Pathologists (CAP) guidelines for the validation of targeted next generation sequencing assays using purchased reference standards, de-identified human plasma cell-free (cf) DNA samples, and contrived samples derived from commercially purchased normal and cancer human plasma. All samples were sequenced at read depths relevant to clinical settings using the NextSeq High Output kit (Illumina).ResultsAt the clinically relevant read depth, Avenio ctDNA kits demonstrated 100% sensitivity in detecting single nucleotide variants (SNVs) at ≥0.5% allele frequency (AF) and 50% sensitivity in detecting SNVs at 0.1% AF using 20-40 ng sample input amount. The assay integrated seamlessly into our laboratory's NGS workflow with input DNA mass, target allele frequency (TAF), multiplexing, and number of reads optimized to support a high-throughput assay appropriate for biopharmaceutical trials.ConclusionsOur study demonstrates that AVENIO ctDNA liquid biopsy platform provides a viable alternative for efficient incorporation of liquid biopsy assays into the clinical laboratory for detecting somatic alterations as low as 0.5%. Accurate detection of variants lower than 0.5% could potentially be achieved by deeper sequencing when clinically indicated and economically feasible.

Dataset Information

Plasma PIK3CA ctDNA specific mutation detected by next generation sequencing is associated with clinical outcome in advanced breast cancer.

Publications

Plasma PIK3CA ctDNA specific mutation detected by next generation sequencing is associated with clinical outcome in advanced breast cancer.

Similar Datasets

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