Dynamics of circulating tumor DNA during postoperative radiotherapy in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: a prospective observational study

Abstract

Background

This study was performed to evaluate circulating tumor DNA (ctDNA) kinetics during postoperative radiotherapy (PORT) in patients with residual triple-negative breast cancer (TNBC) at surgery following neoadjuvant chemotherapy (NAC).

Methods

Stage II/III patients with post-NAC residual TNBC who required PORT were prospectively included in this study between March 2019 and July 2020. For 11 TNBC patients, next-generation sequencing targeting 38 genes was conducted in 55 samples, including tumor tissue, three plasma samples, and leukocytes from each patient. The plasma samples were collected at three-time points; pre-PORT (T0), after 3 weeks of PORT (T1), and 1 month after PORT (T2). Serial changes in ctDNA variant allele frequency (VAF) were analyzed.

Results

Somatic variants were found in the tumor specimens in 9 out of 11 (81.8%) patients. Mutated genes included TP53 (n = 7); PIK3CA (n = 2); and AKT1, APC, CSMD3, MYC, PTEN, and RB1 (n = 1). These tumor mutations were not found in plasma samples. Plasma ctDNA variants were detected in three (27.3%) patients at T0. Mutations in EGFR (n = 1), CTNNB1 (n = 1), and MAP2K (n = 1) was identified with ctDNA analysis. In two (18.2%) patients, the ctDNA VAF decreased through T1 and T2 while increasing at T2 in one (9.1%) patient. After a median follow-up of 22 months, no patient showed cancer recurrence.

Conclusion

Among patients with post-NAC residual TNBC, more than a quarter exhibited a detectable amount of ctDNA after curative surgery. The ctDNA VAF changed variably during the course of PORT. Therefore, ctDNA kinetics can serve as a biomarker for optimizing adjuvant treatment.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

NAC:

Neoadjuvant chemotherapy

BCS:

Breast-conserving surgery

ALN:

Axillary lymph node

TNBC:

Triple-negative breast cancer

PORT:

Postoperative radiotherapy

HER2:

Human epidermal growth factor receptor 2

ER:

Estrogen-receptor

PR:

Progesterone-receptor

pCR:

Complete pathologic response

MRD:

Minimal residual disease

cfDNA:

Cell-free DNA

ctDNA:

Circulating tumor DNA

CTC:

Circulating tumor cells

DTC:

Disseminated tumor cells

NGS:

Next-generation sequencing

US:

Ultrasound

MRI:

Magnetic resonance imaging

CT:

Computed tomography

IMN:

Internal mammary lymph node

SCN:

Supraclavicular lymph node

CW:

Chest wall

PBLs:

Peripheral blood leukocytes

gDNA:

Genomic DNA

VAF:

Variant allele frequency

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Funding

This study was supported by grants from the Ministry of Science and ICT, Republic of Korea (NRF-2019R1F1A1062069) and Samsung Medical Center (SMO 1200821 and SMO 1200391). The funding sources had no involvement in the study design, data collection, data analysis, data interpretation, writing of this report, or the decision to submit this article for publication.

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Authors

Contributions

HK designed and directed the study. YJK, DP, and WYP analyzed and interpreted the mutational data. HK and YJK wrote the manuscript. DHC, WP, WKC, and NK aided in interpreting the results. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Haeyoung Kim.

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Conflict of interest

The authors declare that they have no competing interests.

Ethics approval and consent to participate

All patients provided consents to participate. This study was approved by the institutional review board of the Samsung Medical Center (approval number, SMC 2018-10-137-009).

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This study was presented as a poster at the 17th St. Gallen International Breast Cancer Conference on March 17, 2021.

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Kim, H., Kim, Y.J., Park, D. et al. Dynamics of circulating tumor DNA during postoperative radiotherapy in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: a prospective observational study. Breast Cancer Res Treat 189, 167–175 (2021). https://doi.org/10.1007/s10549-021-06296-3

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Keywords

  • Circulating tumor DNA
  • Breast neoplasms
  • Triple Negative Breast Neoplasms
  • Radiotherapy