보이지 않는 암을 빠르고 정확하게 발견할 수 있습니다.
2024-05-02
Abstract
Background
Metastatic breast cancer can be classified
into different subtypes depending on hormone receptor (HR) and HER2 status. The
subtype can change during tumor progression, and repeated biopsy is needed to
deliver the most appropriate treatment every time a new lesion is found. It is
not always possible to get a new biopsy from metastatic sites, and therefore
liquid biopsy using circulating tumor DNA (ctDNA) is suggested as an
alternative method to replace conventional biopsy.
Methods
We performed a prospective serial
collection of 65 ctDNA samples from 17 patients with metastatic breast cancer
(mBC) at Seoul National University Hospital from October 2020 to March 2022. We
used IMBdx AlphaLiquid®100 method to detect the genetic changes and analyzed
the correlation with clinical outcomes.
Results
Median age was 45 (range 32 – 62). Fifteen
patients (88.2%) were relapsed mBC and most of the patients (14/17: 82.4%) were
HR-positive and HER2-negative. Most of the patients had their ctDNA examined at
baseline and at the time of maximal response and/or at progression. Fifteen
patients (88.2%) received systemic therapy including hormone therapy, anti-HER2
therapy, and cytotoxic chemotherapy. Eight patients (47.1%) were on the
first-line treatment for mBC, and 7 patients (41.2%) were on the second or later
lines for mBC at the time of baseline sampling. The concentration of ctDNA and
the sum of mutated allelic frequency was calculated for each sample. The ctDNA
concentration ranged from 0.71 to 1386.00 ng/mL, and the median value was 5.37
ng/mL. We dichotomized these samples into two groups, with ctDNA concentration
either higher or lower than the median value. Then we analyzed progression free
survival (PFS) of each group. Patients with higher ctDNA concentration showed
shorter PFS (7 mo. vs. not reached, p< 0.001). The sum of mutated allelic
frequency ranged from 0.00% to 223.46% and the median value was 6.36%. Patients
with higher mutated allelic frequency showed shorter PFS (6 mo. vs. 22 mo.,
p< 0.001). In addition, the PFS was significantly worse in patients who had
mutated PIK3CA (5 mo vs. 22 mo, p< 0.001). The patients with mutated TP53
also showed shorter PFS (6 mo vs. 17 mo, p< 0.001) in univariate analysis.
High estrogen receptor positivity in immunohistochemistry was correlated with
lower mutated allelic frequency in ctDNA (p=0.003) but had no impact on the
concentration of ctDNA (p=0.165). The concentration of ctDNA differed by
metastatic sites. Patients with metastases to bones (p=0.007), liver (p<
0.001), soft tissue or lymph nodes (p=0.002) were more likely to have higher
concentrations of ctDNA, while patients with brain metastases had significantly
lower ctDNA concentration (p=0.006). When the sum of mutated allelic frequency
of ctDNA and metastatic sites was analyzed, bone (p=0.001), liver (p< 0.001),
and soft tissue or lymph node (p< 0.001) metastases had a positive
correlation, while brain had negative correlation (p=0.017). Lung or pleural
metastases had no significant correlation with ctDNA, neither concentration
(p=0.271) nor mutated allelic frequency (p=0.965).
Conclusion
Patients with mBC with higher
concentrations of ctDNA or higher mutated allelic frequency of ctDNA at
baseline showed significantly shorter PFS. PIK3CAmt and TP53mt detected by
liquid biopsy could be used as a poor prognostic biomarkers for mBC patients.