Association Between Breast Circulating Free DNA Levels To Tumor Size And Metabolic Parameters In Locally-Advanced Breast Cancer Patients Before Neoadjuvant Chemotherapy

Background:

Breast cancer is the most common malignancy in women, almost 1 in 9 women will be diagnosed during life-time. Circulating cell-free DNA (cfDNA) has been suggested to correlate to tumor burden and\or aggressiveness of disease. We have applied a novel method utilizing tissue-specific methylation patterns for detection of breast cfDNA. We examined the association between breast cfDNA levels on time of diagnosis to tumor size and metabolic parameters, as measured by MRI and ¹⁸F-fluoro-D-glucose positron emission tomography (¹⁸FDG PET).

Methods:

We prospectively enrolled locally advanced breast cancer patients who were assigned to neo-adjuvant therapy. Before treatment, total and breast cfDNA levels were examined. Local staging was done using breast MRI while systemic evaluation and assessment of tumor metabolic parameters were performed using ¹⁸FDG PET/CT.

Results:

A total of 30 women with invasive ductal carcinoma were enrolled at an average age 49.1 (range: 33-91). Axillary involvement was identified in 12 cases and 5 patients had multifocal\multicentric disease.

Receptor status was as following: 9 HR+\HER2-, 7 HR-\HER2+, 7 triple negative, 7 triple positive.

There was no correlation between total cfDNA and breast cfDNA in all subgroups, except for grade 3 tumors (R=0.76).

Average breast tumor size measured by MRI was 2.64 cm in the HR+\HER2- group, 4.9 in HR-\HER2+, 3.51 in triple negative and 2.94 in triple positive. As expected, in 11 cases the MRI overestimated the size as measured by PET\CT.

By PET, average SUVmax was 22.93 in the HR+\HER2- group, 10.28 in HR-\HER2+, 12.18 in triple negative and 4.85 in triple positive.

CfDNA total and breast average plasma levels (copies\ml) were 1290.8, 7.292 in the HR+\HER2- group, 2799.88, 87.79 in HR-\HER2+, 1662.62, 1659 in triple negative and 2820.16, 2.971 in triple positive, respectively. Axillary involvement per se did not raised significantly cfDNA levels.

Interestingly, in HR-\HER2+ patients we found inverse correlation between breast cfDNA to tumor size(R=-0.99) and ¹⁸FDG uptake (R=-0.99). In HR+\HER2- subgroup, a strong positive correlation was found between tumor size to cfDNA (R=0.74).

Conclusions:

In our small cohort, HER2 positive tumors have relatively higher levels of cfDNA. Triple negative and HER2 positive tumors` higher cfDNA levels may not be directly related to larger tumors or higher metabolic activity. Further research is required to elucidate the precise cellular and molecular mechanisms of cfDNA biology.