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. 2023 Oct;34(10):899-906.
doi: 10.1016/j.annonc.2023.08.004. Epub 2023 Aug 18.

Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030

H A Parsons  1 , T Blewett  2 , X Chu  3 , S Sridhar  2 , K Santos  4 , K Xiong  2 , V G Abramson  5 , A Patel  4 , J Cheng  2 , A Brufsky  6 , J Rhoades  2 , J Force  7 , R Liu  2 , T A Traina  8 , L A Carey  9 , M F Rimawi  10 , K D Miller  11 , V Stearns  12 , J Specht  13 , C Falkson  14 , H J Burstein  15 , A C Wolff  12 , E P Winer  15 , N Tayob  3 , I E Krop  15 , G M Makrigiorgos  16 , T R Golub  2 , E L Mayer  17 , V A Adalsteinsson  18
Affiliations

Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030

H A Parsons et al. Ann Oncol. 2023 Oct.

Abstract

Background: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy.

Patients and methods: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.

Results: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12.

Conclusions: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

Keywords: biomarkers; circulating tumor DNA; minimal residual disease; recurrence; triple-negative breast cancer.

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Figures

Figure 1:
Figure 1:. REMARK diagram and MAESTRO ctDNA assay.
Depicts (A) how the cohort of patients were selected from the 13–383 study population and organized into case control pairs and (B) how bespoke MAESTRO assays were designed for ctDNA detection. (C) MAESTRO results were validated against MRD.Tracker – a complementary MRD assay without mutation enrichment. The number of ctDNA positive and negative samples using each assay is denoted in the inset table. Abbreviations: ctDNA, circulating tumor DNA; MRD, minimal residual disease; RCB, residual cancer burden; W, week
Figure 2:
Figure 2:. ctDNA dynamics correlated with response status and RCB score.
TFxs observed during neoadjuvant therapy separated by (A) response status and (C) RCB score. Additionally, TFx fold change relative to baseline observed separated by (B) response status and (D) RCB score. Statistical significance was evaluated using the Wilcoxon signed-rank test (A & B) and the Mann-Whitney U test (C & D) (*: p < 0.05; **: p < 0.01; ***: p < 0.001). Abbreviations: ctDNA, circulating tumor DNA; RCB, residual cancer burden; TFx, tumor fraction; W, week
Figure 3:
Figure 3:. ctDNA TFx prior to surgery correlated with RCB score relative to imaging.
Patients RCB score at time of surgery compared against (A) ctDNA TFx, (B) ultrasound diameter, (C) and MRI diameter after completion of neoadjuvant therapy. Abbreviations: ctDNA, circulating tumor DNA; RCB, residual cancer burden; TFx, tumor fraction; W, week
Figure 4:
Figure 4:. Patients with known distant recurrence had detectable ctDNA prior to surgery unlike most patients without known distant recurrence.
16 patients – 8 with known distant recurrence and 8 without – were selected to analyze whether ctDNA presence after neoadjuvant therapy was associated with distant recurrence. Samples with LODs > 1 × 10−4 were considered underpowered, likely due to technical issues. Abbreviations: ctDNA, circulating tumor DNA; LOD, limit of detection; MRD, minimal residual disease; PPM, parts per million; RCB, residual cancer burden; W, week; Y, year
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