Search

Purpose: We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer., Materials and Methods: Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform., Results: One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1 , TP53 , and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations., Conclusion: We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1 , TP53 , and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs., Competing Interests: Daniel Fernandez-Garcia Employment: Almirall (I) Stock and Other Ownership Interests: Exonate Ltd (I) Travel, Accommodations, Expenses: Almirall (I) Carlo Palmieri Honoraria: Pfizer Consulting or Advisory Role: Pfizer, Daiichi-Sankyo, Lilly, Novartis, Seattle Genetics Research Funding: Pfizer, Daiichi-Sankyo Travel, Accommodations, Expenses: Roche Simak Ali Stock and Other Ownership Interests: Carrick Therapeutics Research Funding: Carrick Therapeutics, AstraZeneca Patents, Royalties, Other Intellectual Property: Royalty from Carrick Therapeutics Uncompensated Relationships: Carrick Therapeutics Justin Stebbing Leadership: BB Healthcare Trust, Xerion Healthcare, Springer Nature Consulting or Advisory Role: Vaccitech, Celltrion, TLC Biopharmaceuticals, Vor Biopharma, Lansdowne, Vitruvian, Singapore Biotech, Benevolent AI R. Charles Coombes Research Funding: DNAe, Pfizer, AstraZeneca Patents, Royalties, Other Intellectual Property: I have shares in Carrick ltd and I am also a patent holder in the drug CT7001 that Imperial College has licensed to them No other potential conflicts of interest were reported. Daniel Fernandez-Garcia Employment: Almirall (I) Stock and Other Ownership Interests: Exonate Ltd (I) Travel, Accommodations, Expenses: Almirall (I) Carlo Palmieri Honoraria: Pfizer Consulting or Advisory Role: Pfizer, Daiichi-Sankyo, Lilly, Novartis, Seattle Genetics Research Funding: Pfizer, Daiichi-Sankyo Travel, Accommodations, Expenses: Roche Simak Ali Stock and Other Ownership Interests: Carrick Therapeutics Research Funding: Carrick Therapeutics, AstraZeneca Patents, Royalties, Other Intellectual Property: Royalty from Carrick Therapeutics Uncompensated Relationships: Carrick Therapeutics Justin Stebbing Leadership: BB Healthcare Trust, Xerion Healthcare, Springer Nature Consulting or Advisory Role: Vaccitech, Celltrion, TLC Biopharmaceuticals, Vor Biopharma, Lansdowne, Vitruvian, Singapore Biotech, Benevolent AI R. Charles Coombes Research Funding: DNAe, Pfizer, AstraZeneca Patents, Royalties, Other Intellectual Property: I have shares in Carrick ltd and I am also a patent holder in the drug CT7001 that Imperial College has licensed to them No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer., Experimental Design: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples ( n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X)., Results: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5-24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling., Conclusions: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention., (©2019 American Association for Cancer Research.)