Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer

Abstract

The identification of early-stage breast cancer patients at high risk of relapse would allow tailoring of adjuvant therapy approaches. We assessed whether analysis of circulating tumor DNA (ctDNA) in plasma can be used to monitor for minimal residual disease (MRD) in breast cancer. In a prospective cohort of 55 early breast cancer patients receiving neoadjuvant chemotherapy, detection of ctDNA in plasma after completion of apparently curative treatment-either at a single postsurgical time point or with serial follow-up plasma samples-predicted metastatic relapse with high accuracy [hazard ratio, 25.1 (confidence interval, 4.08 to 130.5; log-rank P < 0.0001) or 12.0 (confidence interval, 3.36 to 43.07; log-rank P < 0.0001), respectively]. Mutation tracking in serial samples increased sensitivity for the prediction of relapse, with a median lead time of 7.9 months over clinical relapse. We further demonstrated that targeted capture sequencing analysis of ctDNA could define the genetic events of MRD, and that MRD sequencing predicted the genetic events of the subsequent metastatic relapse more accurately than sequencing of the primary cancer. Mutation tracking can therefore identify early breast cancer patients at high risk of relapse. Subsequent adjuvant therapeutic interventions could be tailored to the genetic events present in the MRD, a therapeutic approach that could in part combat the challenge posed by intratumor genetic heterogeneity.

WITHDRAWN: Prognostic value of circulating tumor DNA in breast cancers

“…Specifically, patients with advanced-stage breast cancers had a higher level of ctDNA than patients with early-stage cancers [7], indicating that ctDNA could be significantly correlated with distant metastasis and prognosis. Additionally, ctDNA (PIK3CA mutation) could be used to monitor relapse status in relapsing and non-relapsing patients, resulting in a 10-month leadtime on the detection of relapse compared with the conventional follow-up strategy [24]. Therefore, ctDNA (TP53, PIK3CA and ESR1 mutations) can be an important indicator of worse outcome and can be used to monitor disease progression after primary treatment among breast cancer patients.…”

“…Although these results are promising, the clinical relevance of ctDNA with TP53 mutations in exons 5-8 and ESR1 mutations in amino acids 537 or 538 in breast cancer patients remains to be determined, especially since analyses of ctDNA with TP53 mutations in exons 5-8 and ESR1 mutations in amino acids 537 or 538 in patients with other cancers are lacking. In addition, ctDNA may have promising clinical applications in the early detection of breast tumors, as a predictor of minimal residual disease after curative resection, in monitoring disease progression after chemotherapy and in categorizing patients who are at high risk of recurrence so that low-risk patients can avoid unnecessary systemic therapies [24,46,47]. In the future, large prospective clinical trials are required to facilitate the implementation of ctDNA detection into daily practice.…”

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

“…It is hoped that sequencing of circulating tumor DNA that can easily be obtained from blood may provide a tool to monitor risk of recurrence after potentially curative therapy, detect early recurrence, and monitor response to therapy [120][121][122][123][124].…”

The tumour trail left in blood

“…Another study 7 of 55 people with breast cancer identified relapse about 8 months before symptoms appeared, also using dPCR to detect mutations. "Twenty per cent of women with breast cancer will go on to die of their cancer, " says Nicholas Turner of the Institute of Cancer Research in London, whose team published the results.…”