The prognostic utility of perioperative blood-based liquid biopsy, inflammatory and tumour biomarkers in patients with non-metastatic breast cancer

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dc.check.date2029-12-31
dc.contributor.advisorRedmond, Henry Paul
dc.contributor.advisorWang, Jianghuai
dc.contributor.authorHassan, Faraen
dc.contributor.funderHigher Education Authority
dc.date.accessioned2024-09-16T08:42:49Z
dc.date.available2024-09-16T08:42:49Z
dc.date.issued2022
dc.date.submitted2022
dc.description.abstractBackground: The analysis of tumour components in blood including systemic mediators of inflammation, tumour marker CA 15-3 and more recently liquid biopsy such as cell free DNA (cfDNA) and circulating tumour DNA (ctDNA) represents an easily accessible, minimally invasive, and cost- effective tool for both the monitoring of breast cancer and assessment of tumour response. These biomarkers in blood of patients with breast cancer have been well documented but largely underexplored in the perioperative period especially in patients with non-metastatic breast cancer. The analysis of circulating nucleic acids in blood, otherwise known as liquid biopsy, has gained significant consideration in the field of breast cancer. Dynamic changes in cfDNA and ctDNA usually correlates with disease status in breast cancer. This thesis investigated the role of blood-based biomarkers including cfDNA and ctDNA, inflammatory biomarkers (IL6, TNF α and VEGF) and tumour marker (CA 15-3) in the preoperative (Preop) and postoperative (Postop) period in patients with non-metastatic breast cancer. Furthermore, the relationship of these biomarkers with tumour characteristics and oncological outcomes in breast cancer was investigated. Methods: A cohort of 62 patients undergoing curative surgery for breast cancer were screened for inclusion. All patients had paired blood samples, preoperatively and post operatively. Post- operative (PO) samples were analysed in either of the following time periods, Postop week 1- 2 (PO week 1-2), Postop week 3-4 (PO week 3-4) and Postop week 5-12 (PO week 5-12). Cell free DNA (cfDNA) was extracted and quantified. Circulating tumour DNA (ctDNA) with PIK3CA gene mutation was detected using HRM PCR and Allele specific fluorescence probe-based PCR. Systemic inflammatory mediators and the tumour marker CA 15-3 were detected using ELISA kit. Results: In the cohort of 62 patients (age, median (IQR), 51.5(45.0-65.0) years), with a median follow- up of 90 months (interquartile range (IQR),60-120 months), significant association was observed between cfDNA concentrations and oncological outcomes in patients with breast cancer. The group of patients who had disease recurrence during the follow up period had significantly higher cfDNA concentrations (cutoff:400 ng/ml) during the perioperative period compared to disease-free patients (Preop and Postop period: p<0.0001). Furthermore, detection of PIK3CA gene mutation in ctDNA in the perioperative period had significant association with oncological outcomes in patients with breast cancer (p<0.0001). In total, 25 (40.3%) and 22 (35%) patients with breast cancer had detectable PIK3CA mutations in ctDNA in Preop and Postop period, respectively. Cox hazard model analysis revealed that PIK3CA mutations in Postop period (hazard ratio (H.R: 18.05, p=0.001) were negative prognostic factor for recurrence free survival (RFS) and overall survival (O.S) (H.R: 11.9, p=0.01) in patients with breast cancer. Postop higher cfDNA concentrations and Postop detection of PIK3CA in ctDNA preceded clinical detection of breast cancer recurrence with an average lead time of 12.00 months (IQR:20-28.5 months) compared to 72.00 (96-120) months; (p<0.0001) for patients who remain disease free on follow up. Univariate and multivariate cox regression analysis indicated that Postop cfDNA concentration and post op detection of PIK3CA (p<0.0001) were negative prognostic factor for RFS and O.S in patients with breast cancer. Serum IL6, TNF α, VEGF and CA15-3 correlated with certain breast tumour characteristics but no =significant effect on survival outcomes except Preop VEGF with significant effect on O.S in breast cancer (p=0.03). Conclusion Research efforts from this thesis have demonstrated potential clinical applications of liquid biopsy with cfDNA concentrations and ctDNA with PIK3CA gene mutation and inflammatory cytokines and CA 15-3 in patients with non-metastatic breast cancer.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationHassan, F. 2022. The prognostic utility of perioperative blood-based liquid biopsy, inflammatory and tumour biomarkers in patients with non-metastatic breast cancer. MD Thesis, University College Cork.
dc.identifier.endpage150
dc.identifier.urihttps://hdl.handle.net/10468/16362
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.projectHigher Education Authority (Call three, Cost Centre 3450, Project R20458)
dc.rights© 2022, Fara Hassan.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectBreast cancer
dc.subjectBiomarkers
dc.subjectPerioperative period
dc.subjectPreop period
dc.subjectPostop period
dc.subjectCell free DNA (cfDNA)
dc.subjectCirculating tumour DNA (ctDNA)
dc.subjectIL6
dc.subjectTNF alpha
dc.subjectVEGF
dc.subjectCA 15-3
dc.subjectRecurrence free survival (RFS)
dc.subjectOverall survival (O.S)
dc.titleThe prognostic utility of perioperative blood-based liquid biopsy, inflammatory and tumour biomarkers in patients with non-metastatic breast cancer
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnameMD - Doctor of Medicineen
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