Editor's Note: Circulating tumor DNA (ctDNA) testing allows for continuous dynamic monitoring of tumor genetic variations without relying on tissue samples. This liquid biopsy technology has been widely used in clinical breast cancer research for prognosis and treatment evaluation, but there are still no standards for ctDNA testing, including population selection, testing frequency, and testing methods. At the recent 5th Comprehensive Cancer Treatment Academic Conference of the Dalian Xinghai Medical Forum, Oncology Frontier invited Professor Pengfei Qiu from Shandong Cancer Hospital, and Professor Hao Wang from Sichuan Cancer Hospital to discuss the application of ctDNA monitoring in breast cancer.Oncology Frontier: Many primary resistant patients experience rapid recurrence during adjuvant therapy. At this conference, the Spanish Breast Cancer Research Group GEICAM reported a study analyzing potential driver genes in these patients using ctDNA testing. Professor Pengfei Qiu, what are your thoughts on these findings? Would early ctDNA testing before adjuvant therapy help in identifying resistance and taking targeted measures?
Professor Pengfei Qiu: The Spanish Breast Cancer Research Group reported this study at this year’s ASCO conference. They classified patients into primary or secondary endocrine therapy resistance and endocrine therapy-sensitive groups based on sensitivity to adjuvant endocrine therapy according to ABC5 criteria. The study collected clinical pathology data and pre-first-line treatment blood samples for ctDNA testing, providing valuable information in three main areas: Firstly, it emphasized that sensitivity to adjuvant endocrine therapy in late-stage HR-positive breast cancer patients is closely related to prognosis. Primary and secondary resistant patients often have poor prognosis. Secondly, the study confirmed the association between first-line progression-free survival (PFS) and overall survival (OS). Patients with first-line PFS less than 12 months, especially less than 6 months, belong to a subgroup with poor OS. Thirdly, through ctDNA testing, the study found that mutations in ESR1, EGFR, and PIK3CA are associated with poorer PFS and OS. Differences in these actionable gene alterations were also observed among patients with different sensitivities to endocrine therapy during the adjuvant phase.
This study has limitations, such as only collecting late-stage ctDNA results without continuous monitoring throughout the adjuvant therapy phase (including before and during treatment). Continuous monitoring is crucial for future research and clinical practice, helping to early identify patients developing resistance to endocrine therapy during the adjuvant phase, allowing timely treatment adjustments instead of waiting for actual recurrence. With the advancement of NGS technology, when selecting prognostic indicators for patients, we will lean towards combining clinical pathology factors with biomarkers. Compared to tissue samples, ctDNA testing has many advantages, including higher sample accessibility and the ability to continuously monitor dynamically. With in-depth ctDNA testing research, I believe it can provide more decision-making information for early adjuvant therapy.
Oncology Frontier: Professor Hao Wang, regarding advanced breast cancer, this ASCO conference reported on the correlation between ctDNA dynamic changes and survival prognosis in patients from the MONALEESA-3 study. Could you introduce the main study results and your views on the value of ctDNA in advanced breast cancer applications? Currently, ctDNA dynamic monitoring seems to be more applied to early or locally advanced breast cancer.
Professor Hao Wang: The MONALEESA-3 study confirmed that CDK4/6 inhibitor ribociclib combined with fulvestrant improves PFS compared to fulvestrant alone in first-line/second-line treatment of HR+/HER2- advanced breast cancer. In advanced breast cancer, ctDNA testing is also mainly used to assess prognosis and evaluate treatment efficacy. The exploratory analysis of the MONALEESA-3 study showed that ctDNA changes during treatment are associated with PFS and OS. Patients who remained ctDNA-negative from cycle 1 day 1 (C1D1) to cycle 4 day 1 (C4D1) had longer PFS and OS. Patients who remained positive (C1+/C4+) had the worst PFS and OS. Patients with ctDNA clearance (C1+/C4-) had better PFS and OS trends than those whose ctDNA turned positive (C1-/C4+).
ctDNA may represent an inherent tumor attribute, similar to PAM50 testing. Fluctuations in ctDNA levels before and after treatment can indicate efficacy and patient prognosis. In terms of short-term efficacy, ctDNA fluctuations moderately correlate with imaging assessments and can detect disease progression approximately 8.2 months earlier than imaging. However, whether ctDNA status can be used for long-term efficacy assessment needs further prospective studies. The PADA-1 study included ctDNA assessment in its design. The study enrolled first-line AI-sensitive patients, giving palbociclib plus AI first-line treatment. If ctDNA monitoring detected an increase in ESR1 mutations, AI was switched to fulvestrant. The results showed that patients guided by this strategy to switch endocrine therapy had better PFS (HR 0.63, P=0.007) compared to those who continued the original regimen.
Whether ctDNA can be used for treatment monitoring in advanced breast cancer needs to address three main issues. First, it is necessary to clarify which populations are more suitable for ctDNA monitoring. Given the current high cost of ctDNA testing, we want patients to “spend money where it counts.” Therefore, ctDNA should be used in truly high-risk populations, such as baseline ctDNA-positive patients or those with significant, high-risk mutations detected at baseline. Second, the timing or frequency of ctDNA monitoring needs to be defined. The MONALEESA-3 study monitored from C1D1 to C4D1, with a 3-cycle interval. High-risk patients may need increased monitoring frequency, while lower-risk patients might reduce frequency or extend intervals. These aspects require further exploration. Third, the testing method needs to be determined. As the previous professors mentioned, we have large NGS panels and hotspot mutation PCR testing. While large-panel, high-throughput deep testing improves detection sensitivity, whether increased sensitivity translates to improved clinical prognosis requires further research. I believe there is still a long way to go for ctDNA to be applied in treatment monitoring for breast cancer.
Professor Pengfei Qiu
- Deputy Chief of the Breast Surgery Department, Shandong Cancer Hospital
- Director of the Day Treatment Center
- Chief Physician, Medical Doctor, Doctoral Supervisor
- Visiting Scholar at the University of Cambridge, UK Cancer Research Center
- Young Expert of Taishan Scholars in Shandong Province
- Outstanding Young Talent in Health and Hygiene in Shandong Province
- Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
- Member of the International Medical Exchange Branch of the Chinese Anti-Cancer Association
- Member of the Youth Group of the Breast Tumor Professional Committee of the Oncology Branch of the Chinese Medical Association
- Standing Member of the Youth Council of the Shandong Clinical Oncology Association
- Youth Editorial Board Member of Cancer Biology & Medicine
- Hosting two National Natural Science Foundation projects and publishing over 30 papers as the first or corresponding author
Professor Hao Wang
- Doctor, Associate Chief Physician, Master’s Supervisor
- Deputy Chief of the Breast Department, Sichuan Cancer Hospital
- Visiting Scholar at McGill University, Canada
- Member of the Breast Tumor Group of the Oncology Branch of the Chinese Medical Association
- Standing Member of the Professional Committee of Integrated Prevention and Screening of Breast Cancer of the Chinese Anti-Cancer Association
- Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
- Member of the Professional Committee of Integrated Chinese and Western Breast Cancer of the Chinese Anti-Cancer Association
- Vice Chairman of the Breast Disease Prevention and Control Branch of the Sichuan Preventive Medicine Association
- Vice Chairman of the Breast Cancer Professional Committee of the Sichuan Anti-Cancer Association
- Vice Chairman of the Breast Disease Professional Committee of the Sichuan Medical Association
- Vice President of the Second Breast Professional Branch of the Sichuan Medical Doctor Association
- Secretary of the Breast Professional Group of the Sichuan Tumor Disease Quality Control Center
- Chairman of the Clinical Research and Translational Medicine Professional Committee of the Chengdu Anti-Cancer Association
