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Brief Report
August 1, 2019

Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer

Author Affiliations
  • 1Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom
  • 2Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom
  • 3Ralph Lauren Centre for Breast Cancer Research, London, United Kingdom
  • 4Breast Unit, Royal Marsden Hospital, London, United Kingdom
  • 5Hinchingbrooke Hospital, Huntingdon, United Kingdom
  • 6Poole General Hospital, Dorset, United Kingdom
  • 7Royal Bournemouth Hospital, Bournemouth, United Kingdom
  • 8Department of Oncology, Royal Cornwall Hospitals National Health Service Trust, Truro, United Kingdom
JAMA Oncol. 2019;5(10):1473-1478. doi:10.1001/jamaoncol.2019.1838
Key Points

Question  What is the clinical validity of molecular relapse detection with circulating tumor DNA analysis in early-stage breast cancer?

Findings  This independent, prospective, multicenter, validation study of 101 women early-stage breast cancer assessed circulating tumor DNA mutation tracking and found that detection of circulating tumor DNA during follow-up had a median lead time of 10.7 months compared with clinical relapse, anticipating relapse in all major breast cancer subtypes. Brain-only metastasis was detected less frequently by circulating tumor DNA analysis, potentially requiring alternative surveillance.

Meaning  The findings suggest that molecular relapse detection has high levels of clinical validity, and clinical trials of treatment initiated at molecular relapse without waiting for incurable metastatic disease to develop are needed.


Importance  Current treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse.

Objective  To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer.

Design, Setting, and Participants  This 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.

Interventions  Primary 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 Measures  The primary end point was relapse-free survival analyzed with Cox proportional hazards regression models.

Results  In 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 Relevance  The 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.