Scientific Research Report

Background Introduction

Breast cancer is the most commonly diagnosed cancer worldwide among both men and women, and it is the leading cause of cancer-related deaths in women. The standard treatment for early-stage breast cancer usually involves surgery and (neo)adjuvant chemotherapy and/or endocrine therapy, aiming to eliminate minimal residual disease (MRD). However, up to 30% of breast cancer patients eventually relapse with life-threatening metastasis after primary treatment. Therefore, there is an urgent need to develop more sensitive techniques to detect MRD and follow up with patients after primary breast cancer treatment. The goal is to identify whether interventions in MRD patients may help improve prognosis.

Personalized circulating tumor DNA (ctDNA) detection is considered a promising technique for predicting relapse in lung and colorectal cancers. In breast cancer patients, several studies have shown that ctDNA detection can predict metastatic relapse before clinical or imaging recurrence. This study aims to evaluate the prognostic value of personalized, tumor-informed ctDNA detection in breast cancer patients during long-term follow-up.

Paper Source

This research paper was written by Dr. Jacqueline A. Shaw and her team and was published by the American Society of Clinical Oncology in the journal JCO Precision Oncology on May 1, 2024. The DOI of the paper is: https://doi.org/10.1200/po.23.00456.

Research Process and Methodology

Study Subjects and Samples

This study is a multicenter, prospective cohort study funded by Cancer Research UK and NIHR. The subjects were primary breast cancer patients who had undergone surgery and adjuvant chemotherapy, totaling 188 patients. The patients were 18 years or older, pathologically diagnosed with breast cancer, and had completed all surgeries and chemotherapy at the time of entry into the study. The final study cohort included 156 patients, providing 1,136 plasma samples for ctDNA detection.

Experimental Design and Analysis

The personalized Signatera ctDNA test was developed from whole-exome sequencing (WES) data of primary tumors, targeting 16 highly clonal somatic single nucleotide variants (SNVs) to detect ctDNA in the plasma. All tests were conducted in CLIA-certified laboratories.

Clinical Follow-Up and ctDNA Detection

During up to 12 years of follow-up, these patients provided blood samples every six months. These samples were then analyzed using ultra-deep sequencing technology to detect residual lesions. The personalized Signatera ctDNA test identified 30 cases of lesion recurrence (88.2% sensitivity) before clinical or imaging recurrence, with the longest prediction time being 38 months (median time 10.5 months).

Main Results

Association Between Molecular Recurrence Detection and Clinical Recurrence

In 34 recurrent patients, the Signatera ctDNA test detected ctDNA in 30 patients, achieving 88.2% sensitivity. The prediction time for recurrence ranged from 0 to 38 months, with a median of 10.5 months. All recurrent triple-negative breast cancer patients (n = ⁷⁄₂₃) tested ctDNA positive 8 months prior to recurrence (range 0-19 months), while 16 non-recurrent triple-negative breast cancer patients remained ctDNA negative during a median follow-up of 58 months (range 8-99 months).

Relationship Between ctDNA Positivity and Recurrence Time

The study showed that ctDNA positivity was significantly associated with shorter relapse-free survival and overall survival (p < .0001). Moreover, patients whose first postoperative plasma sample tested ctDNA positive had significantly shorter relapse-free survival and overall survival, with hazard ratios of 30.15 and 19.32, respectively (p < .0001).

Interpretation and Value of Results

The personalized, tumor-informed ctDNA detection method could detect breast cancer recurrence early, providing a potential window for early therapeutic intervention. This method may be more effective than existing clinical tests such as cancer antigen 15-3 (CA15-3) in monitoring patient prognosis.

Research Conclusion

Research Significance

This study provides evidence that serial postoperative ctDNA testing not only has strong prognostic value but also can predict relapse in breast cancer patients. This creates potential opportunities for early therapeutic intervention and may improve clinical outcomes, especially in the triple-negative breast cancer subtype. Additionally, for patients with hormone receptor-positive (HR1) disease, although long-term follow-up positive results need to be cautiously interpreted, multiple tests can provide diagnostic reliability.

Highlights

• Key Findings: This study is the largest to date with the longest follow-up period for a breast cancer cohort, demonstrating the strong prognostic value of ctDNA detection in predicting breast cancer recurrence.
• Innovative Method: Using a personalized, tumor-informed Signatera ctDNA detection method can predict recurrence up to three years in advance, offering new inspection and monitoring means for clinical practice.
• Practical Application Value: These findings can provide a basis for potential early treatment for breast cancer patients and improve patient psychological comfort during the treatment process.

Final Summary

This study demonstrates the significant value and potential of personalized, tumor-informed ctDNA detection in postoperative monitoring and predicting recurrence in breast cancer patients. Serial postoperative ctDNA testing not only provides prognostic information for patients but also offers clinical doctors the possibility for early intervention. This study provides an essential basis for future breast cancer monitoring and treatment strategies, particularly for more aggressive subtypes such as triple-negative breast cancer.