Should a patient with a history of breast cancer and current metastatic disease consider checking circulating tumor DNA (ctDNA) to guide treatment decisions?

ctDNA Testing in Metastatic Breast Cancer

There are insufficient data to recommend routine use of ctDNA to monitor response to therapy in metastatic breast cancer, but ctDNA testing should be performed for specific treatment selection purposes—namely, to detect PIK3CA mutations when considering alpelisib plus fulvestrant therapy. 1

When ctDNA Testing IS Recommended

Treatment Selection for PIK3CA Mutations

• Patients with hormone receptor-positive, HER2-negative metastatic breast cancer who are candidates for PI3K inhibitor therapy should undergo ctDNA testing in plasma to detect PIK3CA mutations to determine eligibility for alpelisib plus fulvestrant. 1
• If no mutation is found in ctDNA, testing in tumor tissue should be performed as this will detect a small number of additional patients with PIK3CA mutations. 1
• This represents a strong recommendation with high-quality evidence from ASCO guidelines. 1

Additional Biomarker Testing Priorities

• Germline BRCA1/2 testing should be performed in HER2-negative metastatic breast cancer to determine PARP inhibitor eligibility. 1
• PD-L1 status should be assessed in triple-negative breast cancer for immune checkpoint inhibitor eligibility. 1

When ctDNA Testing Is NOT Recommended

Treatment Response Monitoring

• ASCO guidelines explicitly state there are insufficient data to recommend routine use of ctDNA to monitor response to therapy among patients with metastatic breast cancer. 1
• The evidence quality for this recommendation is low, with moderate strength of recommendation. 1
• No studies meeting inclusion criteria demonstrated that ctDNA monitoring improves patient outcomes over standard imaging-based detection of tumor progression. 1

Clinical Interpretation of the Monitoring Limitation

• While ctDNA technology holds promise for identifying targetable mutations, neither measurement of dynamic ctDNA changes as a treatment response marker nor identification of specific mutations to direct therapy has been prospectively shown to improve patient outcomes. 1
• Standard imaging remains the gold standard for monitoring disease progression. 1

Important Caveats and Pitfalls

Avoid Overinterpretation of Research Data

• Research studies show ctDNA can detect metastatic disease earlier than clinical detection (average lead time of 11 months) and predict outcomes, but these findings have not translated into clinical utility recommendations because improved detection timing has not been shown to improve survival or quality of life. 2
• Prospective studies demonstrate ctDNA testing is feasible and can guide clinical trial enrollment, but this differs from routine clinical monitoring. 3

ESR1 Mutation Testing Remains Investigational

• There are insufficient data to recommend routine testing for ESR1 mutations to guide therapy, though existing data suggest reduced efficacy of aromatase inhibitors compared with fulvestrant in patients with ESR1 mutations. 1
• ESMO guidelines list ESR1 as an optional assessment with potential to guide treatment (ESCAT II-A), but this is not a routine recommendation. 1

The Gap Between Technology and Clinical Utility

• Multiple ctDNA detection technologies exist (digital PCR, targeted panel sequencing, low-coverage whole-genome sequencing) with varying sensitivity, but lack of comparative data and prospective outcome studies limits their clinical application beyond PIK3CA testing. 1, 3
• Panel tests from various companies have no available data comparing their performance for different patient populations and tumor subtypes. 1

Practical Clinical Algorithm

1. At metastatic breast cancer diagnosis: Perform tissue biopsy to confirm histology and reassess ER, PgR, and HER2 status. 1

2. For HR-positive/HER2-negative disease considering PI3K inhibitor therapy: Order ctDNA testing for PIK3CA mutations; if negative, test tumor tissue if available. 1

3. For treatment monitoring: Use standard imaging (CT chest/abdomen, bone scan, or PET-CT) at regular intervals rather than ctDNA monitoring. 1

4. Consider ctDNA testing for clinical trial enrollment when specific genomic alterations are required for eligibility, but this is distinct from routine monitoring. 3