Albanghali, Mohammad
(2016)
Biology and clinical outcomes of early primary breast cancer in older women: a study based on core needle biopsy.
PhD thesis, University of Nottingham.
Abstract
Background: Older women with breast cancer (BC) appear to have more favourable biology compared to their younger counterparts. However, most studies involving older women with BC used surgical excisions (SE) to profile the tumour biology. Given that (i) older women are more likely to have oestrogen receptor (ER) positive BC and (ii) treatment decisions are complex which often take into account patients’ choice and/or age associated comorbidities, there is expected bias towards having more ER-positive diseases in the group of patients receiving non-operative treatments, notably primary endocrine therapy (PET), and proportionally slightly more ER-negative diseases in the surgical group. Hence, simply characterising the tumour biology according to SE might result in significant bias.
Diagnostic core needle biopsy (CNB) is an alternative source of tumour tissue to SE. However, the limited amount of tissue available from the CNB requires optimisation of a laboratory technique for amplifying tissue obtained from CNB. Such technique presents an opportunity for researchers to profile tumours from all patients, including those receiving non-operative treatment.
Aims: This thesis aims to investigate the biology of BC in older women and correlate it with clinical outcomes, based on tumour tissue obtained from diagnostic CNB.
Patient, Materials and Methods: From a series of older (≥70 years) women (n=1758) with early primary BC treated in a single institution with long-term follow-up (up to 37 years), tumour biology profiling was conducted following the development of a technique to construct tissue microarrays (TMAs) from CNB samples. Immunohistochemistry technique was employed to measure a panel of biomarkers (ER, PgR, Ki67, p53, EGFR, HER2, HER3, HER4, BCL2, CK5/6, CK7/8, MUC1, VEGF, PTEN, AIB1, LKB1 and BRCA1). Furthermore, expressions of these biomarkers were used in clustering analysis. Correlation was then made between the biological data and clinical outcomes.
Result: A CNB TMA technique was successfully developed with capacity of 54 cores per block, and estimated number of obtainable sections >600. Based on tumour tissue availability from diagnostic CNB, TMA blocks were constructed from 639 cases with ER-positive tumour. For all patients, PgR, Ki67 and MUC1 were identified as independently prognostic factors in terms of breast cancer specific survival (BCSS). In addition, ER, PgR, BCL-2 and LKB1 were found to have independent prognostic value in terms of time to progression (TTP) among PET treated patients. Clustering analysis revealed three luminal clusters of ER-positive tumour, each of these clusters were shown a specific pattern of ER, PgR, CK7/8 and MUC1 expression. Furthermore, these clusters identified sub-groups (luminal A and low ER luminal) of older women with a high chance to benefit from PET and achieving a comparable BCSS to that of surgery. Considering PET treated patients, biological clustering showed great value in defining sup-group of patients (luminal A) with low risk of relapse and longer time to disease progression.
Conclusion: The developed CNB TMA technique demonstrates high reliability of CNB for the use in tumour biology profiling based on CNB. The biology of early operable primary BC in older women identified based on CNB appears to have great benefit in formulating an evidence-based approach to treatment in the presence of age associated co-morbidities. Moreover, further investigations are needed to identify additional biomarkers with significant value in predicting response to PET.
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