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Detection of cancer DNA in plasma of patients with early-stage breast cancer.

ABSTRACT: Detecting circulating plasma tumor DNA (ptDNA) in patients with early-stage cancer has the potential to change how oncologists recommend systemic therapies for solid tumors after surgery. Droplet digital polymerase chain reaction (ddPCR) is a novel sensitive and specific platform for mutation detection.In this prospective study, primary breast tumors and matched pre- and postsurgery blood samples were collected from patients with early-stage breast cancer (n = 29). Tumors (n = 30) were analyzed by Sanger sequencing for common PIK3CA mutations, and DNA from these tumors and matched plasma were then analyzed for PIK3CA mutations using ddPCR.Sequencing of tumors identified seven PIK3CA exon 20 mutations (H1047R) and three exon 9 mutations (E545K). Analysis of tumors by ddPCR confirmed these mutations and identified five additional mutations. Presurgery plasma samples (n = 29) were then analyzed for PIK3CA mutations using ddPCR. Of the 15 PIK3CA mutations detected in tumors by ddPCR, 14 of the corresponding mutations were detected in presurgical ptDNA, whereas no mutations were found in plasma from patients with PIK3CA wild-type tumors (sensitivity 93.3%, specificity 100%). Ten patients with mutation-positive ptDNA presurgery had ddPCR analysis of postsurgery plasma, with five patients having detectable ptDNA postsurgery.This prospective study demonstrates accurate mutation detection in tumor tissues using ddPCR, and that ptDNA can be detected in blood before and after surgery in patients with early-stage breast cancer. Future studies can now address whether ptDNA detected after surgery identifies patients at risk for recurrence, which could guide chemotherapy decisions for individual patients.

SUBMITTER: Beaver JA

PROVIDER: S-EPMC4024333 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Detection of cancer DNA in plasma of patients with early-stage breast cancer.

Beaver Julia A JA Jelovac Danijela D Balukrishna Sasidharan S Cochran Rory R Croessmann Sarah S Zabransky Daniel J DJ Wong Hong Yuen HY Toro Patricia Valda PV Cidado Justin J Blair Brian G BG Chu David D Burns Timothy T Higgins Michaela J MJ Stearns Vered V Jacobs Lisa L Habibi Mehran M Lange Julie J Hurley Paula J PJ Lauring Josh J VanDenBerg Dustin D Kessler Jill J Jeter Stacie S Samuels Michael L ML Maar Dianna D Cope Leslie L Cimino-Mathews Ashley A Argani Pedram P Wolff Antonio C AC Park Ben H BH

Clinical cancer research : an official journal of the American Association for Cancer Research 20140206 10

<h4>Purpose</h4>Detecting circulating plasma tumor DNA (ptDNA) in patients with early-stage cancer has the potential to change how oncologists recommend systemic therapies for solid tumors after surgery. Droplet digital polymerase chain reaction (ddPCR) is a novel sensitive and specific platform for mutation detection.<h4>Experimental design</h4>In this prospective study, primary breast tumors and matched pre- and postsurgery blood samples were collected from patients with early-stage breast can ...[more]

PMID: 24504125

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Project description:ImportanceCurrent treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse.ObjectiveTo assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer.Design, setting, and participantsThis prospective, multicenter, sample collection, validation study conducted at 5 United Kingdom medical centers from November 24, 2011, to October 18, 2016, assessed patients with early-stage breast cancer irrespective of hormone receptor and ERBB2 (formerly HER2 or HER2/neu) status who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. The study recruited 170 women, with mutations identified in 101 patients forming the main cohort. Secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study.InterventionsPrimary tumor was sequenced to identify somatic mutations, and personalized tumor-specific digital polymerase chain reaction assays were used to monitor these mutations in serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months.Main outcomes and measuresThe primary end point was relapse-free survival analyzed with Cox proportional hazards regression models.ResultsIn the main cohort of 101 female patients (mean [SD] age, 54 [11] years) with a median follow-up of 35.5 months (interquartile range, 27.9-43.0 months), detection of ctDNA during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7-95.6; P < .001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2-27.1; P = .01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1-19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%). Brain-only metastasis was less commonly detected by ctDNA (1 of 6 patients [17%]), suggesting relapse sites less readily detectable by ctDNA analysis.Conclusions and relevanceThe findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.

Dataset Information

Detection of cancer DNA in plasma of patients with early-stage breast cancer.

Publications

Detection of cancer DNA in plasma of patients with early-stage breast cancer.

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