Precision Medicine in Breast Cancer: A Molecular Genomics and Diagnostics Approach
Dalal, Hina LU
(2024)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Breast cancer is one of the most prevalent and diverse malignancies affecting women worldwide, with an estimated 2.3 million new cases globally in 2020 alone. In Sweden, breast cancer is a major societal issue with over 8600 new diagnoses and 1300 deaths per year. It presents significant challenges in diagnosis, treatment, and prognostication due to its complex biological, molecular, and clinical heterogeneity. The advent of molecular markers and advanced genomic technologies has opened new avenues for understanding and managing this disease more effectively. This thesis compiles five studies that underscore the importance of these advancements in refining breast cancer classification and contribute to new biomarker assessment which may... (More)
- Breast cancer is one of the most prevalent and diverse malignancies affecting women worldwide, with an estimated 2.3 million new cases globally in 2020 alone. In Sweden, breast cancer is a major societal issue with over 8600 new diagnoses and 1300 deaths per year. It presents significant challenges in diagnosis, treatment, and prognostication due to its complex biological, molecular, and clinical heterogeneity. The advent of molecular markers and advanced genomic technologies has opened new avenues for understanding and managing this disease more effectively. This thesis compiles five studies that underscore the importance of these advancements in refining breast cancer classification and contribute to new biomarker assessment which may ultimately improve patient outcomes. Study I explores the implications of estrogen receptor β (ERβ; ESR2) mRNA expression in breast cancer through a comprehensive transcriptomic analysis of a large cohort, SCAN-B. The findings indicate that higher ESR2 expression correlates with improved overall survival, especially in cases receiving endocrine therapy and in triple-negative breast cancer, suggesting ESR2's potential as a valuable prognostic marker and its potential role in immune modulation. Study II introduces a novel multiplex droplet digital PCR (ddPCR) assay for the accurate determination of HER2/ERBB2 DNA copy number, and demonstrated high accuracy compared to traditional clinical methods. This study revealed an “ultrahigh” ERBB2 copy number subgroup, as quantified by ddPCR, found to be associated with worse survival outcomes in patients treated with trastuzumab, emphasizing the assay’s potential utility in refining treatment decision-making and its implications for tailored therapeutic strategies. Study III examined CITED1 as a predictive marker for anti-endocrine treatment efficacy, particularly in the context of tamoxifen therapy. The association between higher CITED1 expression and favorable treatment outcomes in ER+ patients position CITED1 as a promising biomarker for tailoring endocrine therapy. Study IV details the first 10-years of achievements of the Sweden Cancerome Analysis Network - Breast (SCAN-B) project, a population-based initiative that integrates genomic profiling and RNA-sequencing into clinical practice. By analyzing a large and diverse group of patients, SCAN-B aims to enhance personalized breast cancer care through detailed molecular analysis, demonstrating the project's contribution to advancing the field of personalized medicine in breast cancer. Study V addresses the classification and treatment implications of the “HER2-low” breast cancer subclass. By developing a refined ddPCR assay for ERBB2 mRNA expression, this study provides a more nuanced understanding of ERBB2 expression levels, offering insights into the potential benefits of emerging targeted therapies such as trastuzumab deruxtecan for this distinct group.
In conclusion, the research projects presented in this thesis demonstrate the critical role of molecular markers and genomic technologies in advancing our understanding and management of breast cancer. By enabling a more precise approach to diagnosis, treatment, and prognosis, these studies contribute to the ongoing advancement towards more individualized and effective breast cancer care.
(Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/d4d85288-a681-4dce-b1db-ae5a7f464da6
- author
- Dalal, Hina
LU
- supervisor
-
- Lao H. Saal LU
- Niklas Loman LU
- opponent
-
- Professor Grigoriadis, Anita, Molecular and Digital Pathology, Head of Comprehensive Cancer Centre, School of Life Sciences and Medicine, King’s College London, UK
- organization
- publishing date
- 2024
- type
- Thesis
- publication status
- published
- subject
- keywords
- Breast Cancer, Precision Medicine, Genomics, Precision diagnostics, SCAN-B, Digital PCR, Estrogen receptors, HER2, CITED1, HER2 amplification, HER2 expression
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2024:90
- pages
- 142 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
- defense date
- 2024-06-17 14:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-585-5
- language
- English
- LU publication?
- yes
- id
- d4d85288-a681-4dce-b1db-ae5a7f464da6
- date added to LUP
- 2024-05-23 17:28:53
- date last changed
- 2024-05-24 12:53:57
@phdthesis{d4d85288-a681-4dce-b1db-ae5a7f464da6,
abstract = {{Breast cancer is one of the most prevalent and diverse malignancies affecting women worldwide, with an estimated 2.3 million new cases globally in 2020 alone. In Sweden, breast cancer is a major societal issue with over 8600 new diagnoses and 1300 deaths per year. It presents significant challenges in diagnosis, treatment, and prognostication due to its complex biological, molecular, and clinical heterogeneity. The advent of molecular markers and advanced genomic technologies has opened new avenues for understanding and managing this disease more effectively. This thesis compiles five studies that underscore the importance of these advancements in refining breast cancer classification and contribute to new biomarker assessment which may ultimately improve patient outcomes. Study I explores the implications of estrogen receptor β (ERβ; ESR2) mRNA expression in breast cancer through a comprehensive transcriptomic analysis of a large cohort, SCAN-B. The findings indicate that higher ESR2 expression correlates with improved overall survival, especially in cases receiving endocrine therapy and in triple-negative breast cancer, suggesting ESR2's potential as a valuable prognostic marker and its potential role in immune modulation. Study II introduces a novel multiplex droplet digital PCR (ddPCR) assay for the accurate determination of HER2/ERBB2 DNA copy number, and demonstrated high accuracy compared to traditional clinical methods. This study revealed an “ultrahigh” ERBB2 copy number subgroup, as quantified by ddPCR, found to be associated with worse survival outcomes in patients treated with trastuzumab, emphasizing the assay’s potential utility in refining treatment decision-making and its implications for tailored therapeutic strategies. Study III examined CITED1 as a predictive marker for anti-endocrine treatment efficacy, particularly in the context of tamoxifen therapy. The association between higher CITED1 expression and favorable treatment outcomes in ER+ patients position CITED1 as a promising biomarker for tailoring endocrine therapy. Study IV details the first 10-years of achievements of the Sweden Cancerome Analysis Network - Breast (SCAN-B) project, a population-based initiative that integrates genomic profiling and RNA-sequencing into clinical practice. By analyzing a large and diverse group of patients, SCAN-B aims to enhance personalized breast cancer care through detailed molecular analysis, demonstrating the project's contribution to advancing the field of personalized medicine in breast cancer. Study V addresses the classification and treatment implications of the “HER2-low” breast cancer subclass. By developing a refined ddPCR assay for ERBB2 mRNA expression, this study provides a more nuanced understanding of ERBB2 expression levels, offering insights into the potential benefits of emerging targeted therapies such as trastuzumab deruxtecan for this distinct group. <br/>In conclusion, the research projects presented in this thesis demonstrate the critical role of molecular markers and genomic technologies in advancing our understanding and management of breast cancer. By enabling a more precise approach to diagnosis, treatment, and prognosis, these studies contribute to the ongoing advancement towards more individualized and effective breast cancer care.<br/>}},
author = {{Dalal, Hina}},
isbn = {{978-91-8021-585-5}},
issn = {{1652-8220}},
keywords = {{Breast Cancer; Precision Medicine; Genomics; Precision diagnostics; SCAN-B; Digital PCR; Estrogen receptors; HER2; CITED1; HER2 amplification; HER2 expression}},
language = {{eng}},
number = {{2024:90}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Precision Medicine in Breast Cancer: A Molecular Genomics and Diagnostics Approach}},
url = {{https://lup.lub.lu.se/search/files/184721005/Heena_Dalal_-_WEBB.pdf}},
year = {{2024}},
}