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Meta-Analysis
. 2024 Mar;9(3):102390.
doi: 10.1016/j.esmoop.2024.102390. Epub 2024 Mar 10.

Circulating tumor DNA for predicting recurrence in patients with operable breast cancer: a systematic review and meta-analysis

G Nader-Marta  1 , M Monteforte  2 , E Agostinetto  3 , M Cinquini  2 , D Martins-Branco  4 , M Langouo  5 , A Llombart-Cusac  6 , J Cortés  7 , M Ignatiadis  8 , V Torri  9 , G Apolone  10 , V Cappelletti  11 , G Pruneri  12 , E de Azambuja  13 , S Di Cosimo  14
Affiliations
Meta-Analysis

Circulating tumor DNA for predicting recurrence in patients with operable breast cancer: a systematic review and meta-analysis

G Nader-Marta et al. ESMO Open. 2024 Mar.

Abstract

Background: The incorporation of circulating tumor DNA (ctDNA) into the management of operable breast cancer (BC) has been hampered by the heterogeneous results from different studies. We aimed to assess the prognostic value of ctDNA in patients with operable (non metastatic) BC.

Materials and methods: A systematic search of databases (PubMed/Medline, Embase, and CENTRAL) and conference proceedings was conducted to identify studies reporting the association of ctDNA detection with disease-free survival (DFS) and overall survival (OS) in patients with stage I-III BC. Log-hazard ratios (HRs) were pooled at each timepoint of ctDNA assessment (baseline, after neoadjuvant therapy, and follow-up). ctDNA assays were classified as primary tumor-informed and non tumor-informed.

Results: Of the 3174 records identified, 57 studies including 5779 patients were eligible. In univariate analyses, ctDNA detection was associated with worse DFS at baseline [HR 2.98, 95% confidence interval (CI) 1.92-4.63], after neoadjuvant therapy (HR 7.69, 95% CI 4.83-12.24), and during follow-up (HR 14.04, 95% CI 7.55-26.11). Similarly, ctDNA detection at all timepoints was associated with worse OS (at baseline: HR 2.76, 95% CI 1.60-4.77; after neoadjuvant therapy: HR 2.72, 95% CI 1.44-5.14; and during follow-up: HR 9.19, 95% CI 3.26-25.90). Similar DFS and OS results were observed in multivariate analyses. Pooled HRs were numerically higher when ctDNA was detected at the end of neoadjuvant therapy or during follow-up and for primary tumor-informed assays. ctDNA detection sensitivity and specificity for BC recurrence ranged from 0.31 to 1.0 and 0.7 to 1.0, respectively. The mean lead time from ctDNA detection to overt recurrence was 10.81 months (range 0-58.9 months).

Conclusions: ctDNA detection was associated with worse DFS and OS in patients with operable BC, particularly when detected after treatment and using primary tumor-informed assays. ctDNA detection has a high specificity for anticipating BC relapse.

Keywords: breast neoplasms; circulating tumor DNA; disease-free survival; liquid biopsy; prognosis; sensitivity and specificity; tumor biomarker.

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Conflict of interest statement

Disclosure GNM reports meeting/travel grants from AstraZeneca. EA reports consultancy fees/honoraria from Eli Lilly, Sandoz, and AstraZeneca; research grant to the institution from Gilead; meeting/travel grants from Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo, and AstraZeneca (all outside the submitted work). DMB reports full time employment at European Society for Medical Oncology since September 1, 2023; speaker’s engagement from Daiichi Sankyo/AstraZeneca; participation as medical research fellow in research studies with institutionally funded by Eli Lilly, Novartis, and F. Hoffmann-La Roche Ltd to Institut Jules Bordet; non-financial interest as member of the board of directors for Associaҫão de Investigaҫão e Ciudados de Suporte em Oncologia; non-remunerated prior leadership role as Portuguese Young Oncologists Committee Chair from Sociedade Portuguesa de Oncologia (all outside the submitted work). ALC reports leadership role at Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD; intellectual property for MEDSIR; a consulting role for Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, Exact Sciences, Seagen, and GSK; to be part of the speaker bureau for Lilly, AstraZeneca, and MSD; to receive research funding from Pfizer, Roche, Foundation Medicine, Exact Sciences, Pierre-Fabre, and Agendia; and travel compensation from Roche, Lilly, Novartis, Pfizer, and AstraZeneca. JC reports consulting/advisor role for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, HiberCell, BioInvent, GEMoaB, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, and AbbVie; honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca; research funding to the institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, PIQUR Therapeutics, IQVIA, and Queen Mary University of London; stocks from MAJ3 Capital and Leuko (relative); travel, accommodation, and other expenses covered by Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead, and Merck Sharp & Dohme; patents ‘Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent’—Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde, WO 2014/199294 A (issued) and ‘Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy’—Aleix Prat, Antonio Llombart, Javier Cortés, US 2019/ 0338368 A1 (licensed). MI reports honoraria from Novartis and Seattle Genetics; research support to the institution from Natera Inc, Inivata, Roche, and Pfizer; and travel grants from Roche and Gilead. GP reports being part of the advisory board/speaker bureau for Roche, Bayer, AstraZeneca, Novartis, Illumina, and ADS Biotech; and grants from Candriam and Thermo Fisher. EA reports honoraria and/or being part of the advisory board for Roche/GNE, Novartis, Seagen, Zodiac, Libbs, Pierre Fabre, Lilly, and Astra-Zeneca; travel grants from Roche/GNE and AstraZeneca; research grant to the institution from Roche/GNE, Astra-Zeneca, and GSK/Novartis. SDC reports being on the speaker’s bureau for AstraZeneca; and on the advisory board for Pierre-Fabre, IQVIA, and MEDSIR. All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Association of circulating tumor DNA detection at baseline with disease-free survival., , , , , , , , , , , , , , , , , (A) Univariate and (B) multivariate analyses, and overall survival, (C) univariate and (D) multivariate analyses, using tumor-informed and non tumor-informed assays. CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 1
Figure 1
Association of circulating tumor DNA detection at baseline with disease-free survival., , , , , , , , , , , , , , , , , (A) Univariate and (B) multivariate analyses, and overall survival, (C) univariate and (D) multivariate analyses, using tumor-informed and non tumor-informed assays. CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 2
Figure 2
Association of circulating tumor DNA detection after neoadjuvant therapy with disease-free survival., , , , , , , , , , , , , , (A) Univariate and (B) multivariate analyses, and overall survival, (C) univariate and (D) multivariate analyses, using tumor-informed and non tumor-informed assays. CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 2
Figure 2
Association of circulating tumor DNA detection after neoadjuvant therapy with disease-free survival., , , , , , , , , , , , , , (A) Univariate and (B) multivariate analyses, and overall survival, (C) univariate and (D) multivariate analyses, using tumor-informed and non tumor-informed assays. CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 3
Figure 3
Association of circulating tumor DNA detection during follow-up with disease-free survival., , , , (A) Univariate and (B) multivariate analyses, and overall survival, (C) univariate and (D) multivariate analyses, using tumor-informed and non tumor-informed assays. CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 3
Figure 3
Association of circulating tumor DNA detection during follow-up with disease-free survival., , , , (A) Univariate and (B) multivariate analyses, and overall survival, (C) univariate and (D) multivariate analyses, using tumor-informed and non tumor-informed assays. CI, confidence interval; IV, inverse variance; SE, standard error.
Figure 4
Figure 4
Sensitivity and specificity of circulating tumor DNA (ctDNA) detection for the diagnosis of overt recurrent disease., , , CI, confidence interval; FN, false negative; FP, false positive; TN, true negative; TP, true positive.
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