Circulating tumour mutation detection in triple-negative breast cancer as an adjunct to tissue response assessment

Abstract

Circulating tumour DNA (ctDNA) detection via liquid biopsy is an emerging alternative to tissue biopsy, but its potential in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. Here we determined the prevalence of actionable mutations detectable in ctDNA using a clinically validated cancer gene panel assay in patients with TNBC, without recurrence at the time of study entry. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in neoadjuvant therapy protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

Fig. 1. Sample collection and cohort overview.

a Schematic of sample collection and sequencing summary for participants with a post-treatment sample collected within 7 months of treatment completion. b Clinical characteristics of NAT participants. c Clinical characteristics of ADJ participants. d Participant-specific concordance between somatic variants identified in FFPE tumour and plasma samples for participants with a detectable panel-targeted mutation.

Fig. 2. Recurrence-free survival and ctDNA in post-treatment plasma collected within 7 months of primary treatment completion in TNBC participants.

a Distribution of detected somatic ctDNA variants across target genes. (Left) Prevalence of somatic mutations in patients with post-treatment ctDNA; the number of mutations in each target gene is indicated. (Middle) Population prevalence of mutations in corresponding genes in breast cancer patients (METABRIC). (Right) Variant VAF (%) and predicted SnpEff functional impact. b Kaplan-Meier survival probability faceted by ctDNA detection in post-treatment samples. c Cox proportional hazards models are shown for clinical characteristics and post-treatment ctDNA status. Error bars indicate 95% confidence intervals. d Survival probability of NAT participants, faceted by ctDNA detection in post-treatment samples and whether pathologic complete response was achieved. e Intersections of pCR status, post-treatment ctDNA status and treatment with adjuvant Capecitabine in NAT participants. f Cox proportional hazards model for post-treatment ctDNA status in NAT participants who did not achieve pCR.