Indiana University-Purdue University Indianapolis (IUPUI) / Triple-negative breast cancers (TNBCs) are pathologically defined by the absence
of estrogen, progesterone, and HER2 receptors. Compared to other breast cancers, TNBC
has a relatively high mortality. In addition, TNBC patients are more likely to relapse in
the first few years after treatment, and experiencing a shorter median time from
recurrence to death. Detecting the presence of tumor in patients who are technically
“disease-free” after neoadjuvant chemotherapy and surgery as early as possible might be
able to predict recurrence of patients, and then provide timely intervention for additional
therapy. To this end, I applied the analysis of “liquid biopsies” for early detection of
minimal residual disease (MRD) on early-stage TNBC patients using next-generation
sequencing. For the first part of this study, I focused on detecting circulating tumor DNA
(ctDNA) from TNBC patients after neoadjuvant chemotherapy and surgery. First, patient-specific
somatic mutations were identified by sequencing primary tumors. From these
data, 82% of the patients had at least one TP53 mutation, followed by 16% of the patients
having at least one PIK3CA mutation. Next, I sequenced matched plasma samples
collected after surgery to identify ctDNA with the same mutations. I observed that by
detecting corresponding ctDNA I was able to predict rapid recurrence, but not distant
recurrence. To increase the sensitivity of MRD detection, in the second part I developed a
strategy to co-detect ctDNA along with circulating tumor RNA (ctRNA). An advantage
of ctRNA is its active release into the circulation from living cancer cells. Preliminary
data showed that more mutant molecules were identified after incorporating ctRNA with ctDNA detection in a metastatic breast cancer setting. A validation study in early-stage
TNBC is in progress. In summary, my study suggests that co-detection of ctDNA and
ctRNA could be a potential solution for the early detection of disease recurrence. / 2021-08-05
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/20202 |
| Date | 07 1900 |
| Creators | Chen, Yu-Hsiang |
| Contributors | Radovich, Milan, Ivan, Mircea, Li, Lang, Liu, Yunlong, Schneider, Bryan P., Skaar, Todd C., Medical & Molecular Genetics |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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