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CtDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy.

ABSTRACT: BACKGROUND:Most studies utilizing circulating tumor DNA (ctDNA) to monitor disease interrogated only one or a few genes and failed to develop workable criteria to inform clinical practice. We evaluated the feasibility of detecting resistance to anti-HER2 therapy by serial gene-panel ctDNA sequencing. RESULTS:Primary therapeutic resistance was identified in 6 out of 14 patients with events of progressive disease. For this subset comparison of pre- and post-treatment ctDNA assay results revealed that HER2 amplification concurred with disease progression (4/6, 66.7%). Mutations in TP53 (3/6, 50.0%) and genes implicated in the PI3K/mTOR pathway (3/6, 50.0%) were also dominant markers of resistance. Together, resistance to HER2 blockade should be indicated during treatment if any of the following situations applies: 1) recurrence or persistence of HER2 amplification in the blood; 2) emergence or ?20% increase in the fraction of mutations in any of these resistance-related genes including TP53/PIK3CA/MTOR/PTEN. Compared with CT scans, dynamic ctDNA profiling utilizing pre-defined criteria was sensitive in identifying drug resistance (sensitivity 85.7%, specificity 55.0%), with a concordance rate up to 82.1%. Besides, the ctDNA criteria had a discriminating role in the prognosis of HER2-positive metastatic breast cancer. METHODS:52 plasma samples were prospectively collected from 18 patients with HER2-positive metastatic breast cancer who were treated with an oral anti-HER1/HER2 tyrosine kinase inhibitor (ClinicalTrials.gov NCT01937689). ctDNA was assayed by gene-panel target-capture next-generation sequencing. CONCLUSIONS:Longitudinal gene-panel ctDNA sequencing could be exploited to determine resistance and guide the precise administration of anti-HER2 targeted therapy in the metastatic setting.

SUBMITTER: Ma F

PROVIDER: S-EPMC5323211 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy.

Ma Fei F Zhu Wenjie W Guan Yanfang Y Yang Ling L Xia Xuefeng X Chen Shanshan S Li Qiao Q Guan Xiuwen X Yi Zongbi Z Qian Haili H Yi Xin X Xu Binghe B

Oncotarget 20161001 40

<h4>Background</h4>Most studies utilizing circulating tumor DNA (ctDNA) to monitor disease interrogated only one or a few genes and failed to develop workable criteria to inform clinical practice. We evaluated the feasibility of detecting resistance to anti-HER2 therapy by serial gene-panel ctDNA sequencing.<h4>Results</h4>Primary therapeutic resistance was identified in 6 out of 14 patients with events of progressive disease. For this subset comparison of pre- and post-treatment ctDNA assay res ...[more]

PMID: 27602761

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Project description:PurposePrognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy.Experimental designCorrelative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model.Results201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms.ConclusionsWe show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor-positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.

Project description:IntroductionThe clinical prognosis of the HER2-overexpressing (HER2-OE) subtype of breast cancer (BC) is influenced by the immune infiltrate of the tumor. Specifically, monocytic cells, which are promoters of pro-tumoral immunosuppression, and NK cells, whose basal cytotoxic function may be enhanced with therapeutic antibodies. One of the standards of care for HER2+ BC patients includes the combination of the anti-HER2 antibodies trastuzumab and pertuzumab. This dual combination was a breakthrough against trastuzumab resistance; however, this regimen does not yield complete clinical benefit for a large fraction of patients. Further therapy refinement is still hampered by the lack of knowledge on the immune mechanism of action of this antibody-based dual HER2 blockade.MethodsTo explore how the dual antibody challenge influences the phenotype and function of immune cells infiltrating the HER2-OE BC microenvironment, we developed in vitro 3D heterotypic cell models of this subtype. The models comprised aggregates of HER2+ BC cell lines and human peripheral blood mononuclear cells. Cells were co-encapsulated in a chemically inert alginate hydrogel and maintained in agitation-based culture system for up to 7 days.ResultsThe 3D models of the HER2-OE immune microenvironment retained original BC molecular features; the preservation of the NK cell compartment was achieved upon optimization of culture time and cytokine supplementation. Challenging the models with the standard-of-care combination of trastuzumab and pertuzumab resulted in enhanced immune cytotoxicity compared with trastuzumab alone. Features of the response to therapy within the immune tumor microenvironment were recapitulated, including induction of an immune effector state with NK cell activation, enhanced cell apoptosis and decline of immunosuppressive PD-L1+ immune cells.ConclusionsThis work presents a unique human 3D model for the study of immune effects of anti-HER2 biologicals, which can be used to test novel therapy regimens and improve anti-tumor immune function.

Dataset Information

CtDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy.

Publications

ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy.

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