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

H A Parsons; T Blewett; X Chu; S Sridhar; K Santos; K Xiong; V G Abramson; A Patel; J Cheng; A Brufsky; J Rhoades; J Force; R Liu; T A Traina; L A Carey; M F Rimawi; K D Miller; V Stearns; J Specht; C Falkson; H J Burstein; A C Wolff; E P Winer; N Tayob; I E Krop; G M Makrigiorgos; T R Golub; E L Mayer; V A Adalsteinsson

doi:10.1016/j.annonc.2023.08.004

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

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

Authors

H A Parsons¹, T Blewett², X Chu³, S Sridhar², K Santos⁴, K Xiong², V G Abramson⁵, A Patel⁴, J Cheng², A Brufsky⁶, J Rhoades², J Force⁷, R Liu², T A Traina⁸, L A Carey⁹, M F Rimawi¹⁰, K D Miller¹¹, V Stearns¹², J Specht¹³, C Falkson¹⁴, H J Burstein¹⁵, A C Wolff¹², E P Winer¹⁵, N Tayob³, I E Krop¹⁵, G M Makrigiorgos¹⁶, T R Golub², E L Mayer¹⁷, V A Adalsteinsson¹⁸

Affiliations

¹ Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston; Harvard Medical School, Boston. Electronic address: Heather_Parsons@dfci.harvard.edu.
² Broad Institute of MIT and Harvard, Cambridge.
³ Data Science, Dana-Farber Cancer Institute, Boston.
⁴ Medical Oncology, Dana-Farber Cancer Institute, Boston.
⁵ Vanderbilt-Ingram Cancer Center, Nashville.
⁶ University of Pittsburgh School of Medicine, Pittsburgh.
⁷ Duke Cancer Center, Durham.
⁸ Memorial Sloan Kettering Cancer Center, New York.
⁹ The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.
¹⁰ Baylor College of Medicine Dan L. Duncan Comprehensive Cancer Center, Houston.
¹¹ Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis.
¹² Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.
¹³ Seattle Cancer Care Alliance, Seattle.
¹⁴ The University of Alabama at Birmingham, Birmingham.
¹⁵ Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston; Harvard Medical School, Boston.
¹⁶ Radiation Oncology, Dana-Farber Cancer Institute, Boston, USA.
¹⁷ Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston; Harvard Medical School, Boston. Electronic address: Erica_Mayer@dfci.harvard.edu.
¹⁸ Broad Institute of MIT and Harvard, Cambridge. Electronic address: viktor@broadinstitute.org.

PMID: 37597579
PMCID: PMC10898256 (available on 2024-10-01)
DOI: 10.1016/j.annonc.2023.08.004

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / etiology
Circulating Tumor DNA* / genetics
Female
Humans
Neoadjuvant Therapy / adverse effects
Neoplasm Recurrence, Local / drug therapy
Neoplasm Recurrence, Local / genetics
Neoplasm, Residual / genetics
Neoplasm, Residual / pathology
Prospective Studies
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / genetics

Substances

Circulating Tumor DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding