Breast cancer mortality in Sweden is now in decline, thanks to early detection and the wide use of adjuvant endocrine therapy and chemotherapy. While hormone receptor status is predictive of response to endocrine treatment, there is no clinically useful predictive marker of a patient’s response to chemotherapy. Consequently, patients receive chemotherapy with considerable toxicity but minimal benefit. The aim of this thesis was to investigate a number of methods with the potential to predict response to chemotherapy and thus enhance treatment efficacy in breast cancer patients.We found that topo IIα, the key target enzyme of topo II inhibitors, is significantly expressed in nonproliferating breast cancer cells…
Contents
Introduction
Incidence and mortality
Diagnosis
Staging
Prognostic factors
Treatment
Surgery
Adjuvant loco-regional therapy
Adjuvant systemic therapy
Adjuvant trastuzumab
Predictive factors in clinical use
Hormone receptor status
HER2
Prediction of chemosensitivity
Topoisomerase IID
HER2
Proliferation rate
Hormone receptor status
Fluoropyrimidine biomarkers
p53
In vitro assays
Gene expression profiling
In vivo chemosensitivity testing
The problem of tumor heterogeneity
Aims of the study
Materials and methods
Paper I
Patients
Determination of S-phase fraction and ploidy
Flow cytometry topo IID analysis
Statistical methods
Paper II
Patients
Preparation of tissue arrays
CISH
Statistical methods
Paper III
Patients
FMCA
Clinical evaluation and in vitro/in vivo correlation
Paper IV
Patients
Immunohistochemical essays
Statistical methods
Paper V
Patients
Treatment and response evaluation
Analysis of predictive markers
Statistics
Results
Paper I
Expression of topo IID in the total cell population
Topo IID in relation to cell cycle phase in diploid tumors
Topo IID in relation to cell cycle phase in non-diploid tumors
Paper II
Paper III
Paper IV
Paper V
Treatment administered
Anti-tumor activity and survival
Safety
Predictive markers
General discussion
Papers
General conclusions
Acknowledgements
References
Author: Villman, Kenneth
Source: Uppsala University Library
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