The perioperative setting as a platform for breast cancer biomarker development

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dc.contributor.advisorConnolly, Roisin
dc.contributor.advisorDahly, Darren
dc.contributor.advisorexternalO'Reilly, Seamus
dc.contributor.authorHennessy, Maeveen
dc.contributor.funderBreast Cancer Research Foundation
dc.contributor.funderAmerican Society of Clinical Oncology
dc.contributor.funderConquer Cancer Foundation
dc.date.accessioned2024-09-19T09:12:48Z
dc.date.available2024-09-19T09:12:48Z
dc.date.issued2024
dc.date.submitted2024
dc.description.abstractBreast cancer is the most common cancer in women, with 2.3 million new cases globally in 2022 (1). ‘Neoadjuvant’ systemic therapy prior to surgery is the standard of care for stage II-III human epidermal growth factor receptor-2 (HER2) positive breast cancer. The identification of predictive biomarkers of response to systemic therapy is of great research interest, as this may allow treatment to be tailored to the individual. Pathologic complete response (pCR), the absence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of neoadjuvant systemic therapy, is an accepted surrogate marker for survival outcomes in clinical trials (2). An advantage of the neoadjuvant setting is that tumour response to treatment can be assessed through tissue-based, biochemical, or radiologic changes throughout administration of therapy; allowing valuable information to be obtained in a short time period. Ideally, these potential biomarkers would be used early in the treatment paradigm allowing ‘individualisation’ of treatment decision-making. Certain patients could avoid receiving futile therapies, while others could be directed towards a more intensive approach to maximise their outcome. The studies in this Thesis were undertaken to evaluate imaging and tissue-based biomarkers for oestrogen receptor (ER)-negative, HER2-positive early-stage breast cancer in the Translational Breast Cancer Research Consortium (TBCRC) 026 trial (NCT01937117). TBCRC026 was a phase II, multicentre clinical trial incorporating serial positron emission tomography–computed tomography (PET-CT) imaging [baseline and 15 days after trastuzumab/pertuzumab (HP) initiation (C1D15)] and tumour biopsy collection (3). The primary hypothesis was that early measurements of tumour maximum standardised uptake value corrected for lean body mass (SULmax) on PET/CT would predict pCR to HP. Results found that participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (3). Thus, the use of PET/CT as an imaging biomarker may provide a more individualised approach to treatment in early-stage HER2-positive breast cancer. This Thesis presents secondary analyses of the TBCRC026 clinical trial. Chapter 2 builds on the primary study analysis and evaluates the correlation between early metabolic changes on PET/CT and survival outcomes in this cohort. A potential association between SULmax parameters on PET/CT and recurrence free survival (RFS) and overall survival (OS) outcomes was identified. This imaging-based biomarker has not previously been assessed in patients receiving anti-HER2 therapy alone and therefore is novel and potentially practice changing if validated in future trials. Chapter 3 explores the relationship between HER2 and immune tissue-based biomarkers and pCR in this dataset, through analysis of baseline archived tumour samples. NanoString codesets BC360 and IO360 were used to compare gene expression in baseline tumours that underwent pCR versus no pCR. NanoString GeoMx digital spatial profiling (DSP) assessed immune protein abundance in intraepithelial and stromal segments. There was a significant association between intraepithelial HER2 protein abundance and pCR. Overall, the results demonstrated the unique molecular and immunological features of ER-negative, HER2-positive breast cancer, which warrant further exploration as potential predictive biomarkers. Chapter 4 investigates improving on the prediction power of the PET/CT imaging biomarker by combining it with a HER2-tissue based biomarker. Promising HER2-tissue biomarkers available from our analysis included high HER2 expression by immunohistochemistry (IHC), HER2-enriched (HER2-E) intrinsic subtype and high levels of HER2 protein abundance. While the composite HER2/PET biomarker comprising D15 SULmax, % reduction in SULmax and tumour HER2 protein abundance had high prediction power for pCR, it was not significantly superior to the prediction power of PET/CT parameters alone. The combined data from the above analyses suggest clinical trials informed by early PET/CT biomarkers and promising HER2-tissue based biomarkers should be further evaluated to personalise breast cancer care. If these potential biomarkers can be validated, results will be used to design clinical utility studies, facilitating early individualisation of therapy for patients.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationHennessy, M. 2024. The perioperative setting as a platform for breast cancer biomarker development. MD Thesis, University College Cork.
dc.identifier.endpage143
dc.identifier.urihttps://hdl.handle.net/10468/16400
dc.language.isoen
dc.publisherUniversity College Corken
dc.relation.projectConquer Cancer Foundation (Career Development Award)
dc.rights© 2024, Maeve Hennessy.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0/
dc.subjectBreast cancer
dc.subjectBiomarkers
dc.subjectHER2-positive
dc.subjectNeoadjuvant
dc.titleThe perioperative setting as a platform for breast cancer biomarker developmenten
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnameMD - Doctor of Medicineen
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