Liquid Biopsies, What We Do Not Know (Yet)

Cancer Cell, Journal Year: 2017, Volume and Issue: 31(2), P. 172 - 179

Published: Feb. 1, 2017

Language: Английский

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Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer

JAMA Oncology, Journal Year: 2016, Volume and Issue: 2(10), P. 1310 - 1310

Published: Aug. 17, 2016

Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent activation and resistance to estrogen-deprivation therapy laboratory models. The prevalence of these their potential impact on clinical outcomes has not been established.To determine the ESR1 (Y537S D538G) estrogen (ER)-positive MBC whether mutation is associated with inferior outcomes.From December 16, 2014, August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples participants BOLERO-2 double-blind phase 3 study that randomized patients 189 centers 24 countries exemestane plus placebo or everolimus. enrolled postmenopausal women a diagnosis prior exposure an aromatase inhibitor. Baseline were available 541 724 (74.7%). We assessed effect overall survival population progression-free (PFS) by treatment arm.Patients (25 mg oral daily) together everolimus (10 placebo.The 2 most frequent cfDNA using droplet digital polymerase chain reaction scored as wild-type, D538G, Y537S, double mutant. Cox-proportional hazards model was used assess PFS patient subgroups defined mutations, each survival.Of evaluable patients, 156 (28.8%) had D538G (21.1%) and/or Y537S (13.3%), 30 both. These shorter (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; 25.99 19.19-32.36 19.98 [13.01-29.31 both 15.15 10.87-27.43 months]). group (hazard ratio, 0.34 0.02-0.57]) derived similar benefit wild type addition exemestane.ESR1 are prevalent ER-positive inhibitor-treated MBC. Both more aggressive disease biology.clinicaltrials.gov Identifier: NCT00863655.

Language: Английский

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Liquid Biopsy: From Discovery to Clinical Application

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(4), P. 858 - 873

Published: April 1, 2021

Over the past 10 years, circulating tumor cells (CTC) and DNA (ctDNA) have received enormous attention as new biomarkers subjects of translational research. Although both are already used in numerous clinical trials, their utility is still under investigation with promising first results. Clinical applications include early cancer detection, improved staging, detection relapse, real-time monitoring therapeutic efficacy, targets resistance mechanisms. Here, we propose a conceptual framework CTC ctDNA assays point out current challenges research, which might structure this dynamic field SIGNIFICANCE: The analysis blood for CTCs or cell-free nucleic acids called "liquid biopsy" has opened avenues diagnostics, including tumors, risk assessment well relapse evolution context therapies.

Language: Английский

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Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: Feb. 23, 2018

Abstract CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of heterogeneity is unknown. Here we use plasma samples from patients randomized phase III PALOMA-3 study inhibitor palbociclib and fulvestrant cancer show that relative change PIK3CA ctDNA after 15 days treatment strongly predicts PFS on (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy shown to be frequently sub clonal, dynamics offering limited prediction clinical outcome. These results suggest a robust biomarker inhibitors, demonstrating divergent clones treatment.

Language: Английский

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Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer

Annals of Oncology, Journal Year: 2017, Volume and Issue: 29(3), P. 640 - 645

Published: Dec. 8, 2017

Language: Английский

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Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival

Annals of Oncology, Journal Year: 2020, Volume and Issue: 32(2), P. 229 - 239

Published: Nov. 21, 2020

Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk metastatic recurrence.Cell-free (cfDNA) was isolated from 291 plasma samples 84 high-risk early breast cancer patients treated in I-SPY 2 TRIAL standard NAC alone or combined MK-2206 (AKT inhibitor) treatment. Blood collected at pretreatment (T0), 3 weeks after initiation paclitaxel (T1), between anthracycline regimens (T2), prior surgery (T3). A personalized ctDNA test designed detect up 16 patient-specific mutations (from whole-exome sequencing tumor) cfDNA by ultra-deep sequencing. The median follow-up time survival analysis 4.8 years.At T0, 61 (73%) were positive, which decreased over (T1: 35%; T2: 14%; T3: 9%). Patients who remained positive T1 significantly more likely have residual disease (83% non-pCR) compared those cleared (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all achieved negative (n 17, 100%). For did not achieve 43), ctDNA-positive (14%) had a increased recurrence [hazard (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, but (86%) excellent outcome, similar (HR 1.4; CI 0.15-13.5).Lack clearance significant predictor poor recurrence, while improved even pCR. Personalized monitoring during may aid real-time assessment treatment help fine-tune as surrogate endpoint survival.

Language: Английский

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Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies

Lab on a Chip, Journal Year: 2018, Volume and Issue: 18(8), P. 1174 - 1196

Published: Jan. 1, 2018

Opportunities and challenges in translational application of ctDNA along with recent developments chip-based detection technologies have been reviewed.

Language: Английский

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Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

Nature Communications, Journal Year: 2016, Volume and Issue: 7(1)

Published: May 13, 2016

Abstract Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy patients ER+ metastatic breast cancer. Little is known of the impact these mutations receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot and PIK3CA from ctDNA were assayed clinical trial samples cancer randomized either SERD fulvestrant or plus a pan-PI3K inhibitor. are present 37% baseline enriched luminal A -mutated tumours. often polyclonal longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. mutation allele frequency does not show consistent pattern increases during treatment, progression-free survival different compared wild-type patients. study.

Language: Английский

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The current state of molecular testing in the treatment of patients with solid tumors, 2019

CA A Cancer Journal for Clinicians, Journal Year: 2019, Volume and Issue: 69(4), P. 305 - 343

Published: May 22, 2019

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad is now nearly essential for all patients with metastatic solid tumors. New agents been approved based on testing instead tumor site origin. Molecular methodologies likewise changed such that tests were performed a ago are no longer complete possibly inaccurate today. As rapid change, medical providers can quickly fall behind or struggle to find up-to-date sources ensure he she provides optimum care. In this review, authors provide current state art profiling/precision medicine, standards, view into future ahead.

Language: Английский

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ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

Breast Cancer Research, Journal Year: 2021, Volume and Issue: 23(1)

Published: Aug. 15, 2021

In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone therapy, estrogen deprivation by aromatase inhibition. How these affect tumor sensitivity established and novel therapies active areas research. These include receptor-targeting agents, such as selective receptor modulators, covalent antagonists, degraders (including tamoxifen, fulvestrant, agents), combination therapies, endocrine therapy plus CDK4/6, PI3K, or mTORC1 this review, we summarize existing knowledge surrounding mechanisms action roles in We then analyze recent literature on how outcomes therapies. For tamoxifen relative vitro but do not clearly lead patients, making agents category promising. Regarding nullify any inhibitor component combination. Thus, combinations using alternatives inhibition, where non-endocrine is efficacious monotherapy, still effective against mutations. results emphasize importance investigating combinatorial resistance, challenging efforts are. also discuss future directions open questions, studying differences among distinct mutations, asking adjust clinical decisions based molecular surveillance testing, developing that

Language: Английский

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