Multi-Modality Plasma-Based Detection of Minimal Residual Disease in Triple-Negative Breast Cancer

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dc.contributor.advisorRadovich, Milan
dc.contributor.authorChen, Yu-Hsiang
dc.contributor.departmentMedical & Molecular Genetics
dc.contributor.otherIvan, Mircea
dc.contributor.otherLi, Lang
dc.contributor.otherLiu, Yunlong
dc.contributor.otherSchneider, Bryan P.
dc.contributor.otherSkaar, Todd C.
dc.date.accessioned2019-08-06T16:17:14Z
dc.date.available2021-08-08T09:30:11Z
dc.date.issued2019-07
dc.degree.date2019en_US
dc.degree.disciplineMedical & Molecular Genetics
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractTriple-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.en_US
dc.description.embargo2021-08-05
dc.identifier.urihttps://hdl.handle.net/1805/20202
dc.identifier.urihttp://dx.doi.org/10.7912/C2/1979
dc.language.isoen_USen_US
dc.subjectcirculating tumor DNA/RNAen_US
dc.subjectearly cancer detectionen_US
dc.subjectliquid biopsiesen_US
dc.subjectminimal residual diseaseen_US
dc.subjectnext-generation sequencingen_US
dc.subjecttriple-negative breast canceren_US
dc.titleMulti-Modality Plasma-Based Detection of Minimal Residual Disease in Triple-Negative Breast Canceren_US
dc.typeDissertation
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