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Title: Tumour evolution over time : treatment and progression : exploring the molecular heterogeneity of oestrogen receptor positive breast cancer
Author: Arthur, Laura Margaret
ISNI:       0000 0004 7229 0617
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2017
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Introduction Recent advances in microarray technology have allowed more understanding of the complex molecular biology of breast cancer. The traditional prognostic information afforded by hormone receptor status and pathology variables is being supplemented and superseded by gene signatures predictive of risk of recurrence and response to treatments. Approximately 75% of breast cancers are oestrogen receptor positive (ER+) and can be treated by drugs that block oestrogen production such as letrozole. However not all ER+ tumours respond and even those that initially respond can develop resistance. Treating patients with neoadjuvant letrozole affords a unique opportunity to sample the same tumour in vivo at different time points reducing any potential inter-patient and inter-tumour variability. The molecular effects of drugs can be assessed long before clinical outcome is apparent. Underlying genetic differences or characteristics of the patient, tumour or sample may affect the molecular response to treatment. This project set out to use sequential patient-matched samples to evaluate molecular changes in breast tumours in the presence or absence of endocrine treatment in different subtypes, defined by histology or mutation status and to assess molecular variation between primary tumour and nodal metastasis. Methods RNA was extracted and processed to generate whole transcriptome Illumina Beadarray gene expression data from four unique cohorts of patients. Clinical data on treatments, recurrence and survival was collected from medical records. The first cohort compared 25 breast cancer patients with matched samples at diagnosis and at surgery, 14-35 (median 23) days later, with no intervening treatment; with 36 patients treated with neoadjuvant letrozole. A PCR assay to detect 8 known PIK3CA mutations and assessment of PTEN status was performed at both the primary and secondary event in a second cohort of 120 patients with endocrine treated disease who relapsed with either recurrence, lymph node metastases, a new second primary or progression of disease on primary endocrine therapy. The third cohort compared the molecular response to neoadjuvant letrozole in 14 patients with invasive lobular cancer (ILC) and 14 patients with invasive ductal cancer (IDC). A fourth cohort of women with node positive disease at diagnosis were assessed for variations in gene expression profiles between primary tumour and synchronous metastatic axillary lymph nodes (68 samples from 31 patients). Results The genomic profile of the no intervening treatment cohort did not differ significantly. Some changes in inflammatory genes were evident. This reassures us that changes seen during treatment are truly due to drug effect. This validates the use of a second biopsy to explore prediction of response. PIK3CA mutation status is maintained in the majority of patients with endocrine resistant disease and changed in only 15.7%. Where there was a change in PIK3CA this was significantly more likely to be a second primary breast cancer rather than a recurrence or progression of the primary cancer. PTEN status was also maintained in most patients. This does not support the theory that acquisition of a PIK3CA mutation is responsible for developing endocrine resistance. Novel PI3K inhibitor drugs may still be suitable in endocrine-resistant disease if activation of the pathway develops by other mechanisms. Consistent with previous studies, significant molecular differences were observed between ILC and IDC pre-treatment. Over half of these molecular differences were maintained after 3 months of letrozole. However, changes over time in individual tumours in response to letrozole were highly consistent in both ILC and IDC. When comparing primary with synchronous metastatic nodes only 39% of tumours clustered together with their matched primary or node. The molecular subtype of the node was often a poorer prognosis than the primary. There were also differences in subtype between nodes in a small cohort of patients with 2 involved nodes. Conclusions We have demonstrated that neoadjuvant window studies are a valid model for assessment of drug effects and evaluated differences in histology and mutation status. Endocrine resistance in breast cancer is rarely related to acquisition of PIK3CA mutations. Synchronous lymph node metastases can differ greatly from their matched primary. These findings are highly relevant when considering prescribing (neo)/adjuvant therapy and have significantly improved our understanding of breast cancer as we strive towards personalised medicine.
Supervisor: Dixon, Mike ; Sims, Andrew Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: breast cancer ; endocrine therapy ; aromatase inhibitors ; neoadjuvant ; molecular subtypes ; endocrine resistance