Aggressive breast cancer : epidemiological studies addressing disease heterogeneity
Author: Holm, Johanna
Date: 2018-02-23
Location: Lecture Hall Hillarp, Retzius Väg 8, Karolinska Institutet, Solna
Time: 09.00
Department: Inst för medicinsk epidemiologi och biostatistik / Dept of Medical Epidemiology and Biostatistics
View/ Open:
Thesis (5.095Mb)
Abstract
Breast cancer is either the number one or the second most common cause of cancer
death in women in the world, depending on region¹. It is a cancer heterogeneous
in many aspects related to the aggressiveness, such as proliferation rate, metastatic
capacity and survival. This thesis is seeking to increase our understanding of aggressive
breast cancer, and how risk factors may be related to it.
In study I, we compared interval cancers (IC) to cancers detected at screening (SC) and found the group of IC to be characterized by higher frequency of BRCA mutations, family history of breast cancer and use of hormonal therapy (HRT) as compared to SC. IC in non-dense breasts were enriched for aggressive tumour features, and in this group the estimates for family history and BRCA mutations were increased.
In study II, we studied if predictors intended to identify healthy women’s risk of breast cancer in future prevention efforts were skewed towards certain tumour characteristics. A 77-SNP breast cancer polygenic risk score appeared to underestimate risk in women with high grade and Oestrogen receptor (ER) negative tumours, as it was on average higher in women with low grade, ER positive tumours. The TyrerCuzic model of breast cancer risk also appeared to underestimate risk in ER negative, high grade tumours but this was restricted to early onset cases. Only mammographic density appeared to be a general risk factor/predictor for all tumours independent of prognosticators.
Study III was a case-control study where we estimated odds ratios for each of four breast cancer molecular subtypes separately in multinomial logistic regression. We found subtype heterogeneity in the odds ratios for genetic risk factors and for breastfeeding. The 77-SNP polygenic risk score was associated with all subtypes except for the basal-like subtype, which showed no association with the score. Although breastfeeding was protective for both luminal and basal-like subtypes, the magnitude and underlying mechanism appeared to differ across subtypes.
In Study IV we assessed the concordance between PAM50 gene expression-based and immunohistochemistry-based molecular subtypes. No proxy showed more than moderate concordance with PAM50, however if luminal A and B subtypes were collapsed into one category, substantial concordance was achieved. Sensitivity for HER2-enriched breast cancer as defined by PAM50 was low, at 0.36 for all proxies investigated, whereas sensitivity and specificity was high for classifying basal-like breast cancer.
¹ According to Cancer facts sheets, GLOBOCAN 2012, [IARC]
In study I, we compared interval cancers (IC) to cancers detected at screening (SC) and found the group of IC to be characterized by higher frequency of BRCA mutations, family history of breast cancer and use of hormonal therapy (HRT) as compared to SC. IC in non-dense breasts were enriched for aggressive tumour features, and in this group the estimates for family history and BRCA mutations were increased.
In study II, we studied if predictors intended to identify healthy women’s risk of breast cancer in future prevention efforts were skewed towards certain tumour characteristics. A 77-SNP breast cancer polygenic risk score appeared to underestimate risk in women with high grade and Oestrogen receptor (ER) negative tumours, as it was on average higher in women with low grade, ER positive tumours. The TyrerCuzic model of breast cancer risk also appeared to underestimate risk in ER negative, high grade tumours but this was restricted to early onset cases. Only mammographic density appeared to be a general risk factor/predictor for all tumours independent of prognosticators.
Study III was a case-control study where we estimated odds ratios for each of four breast cancer molecular subtypes separately in multinomial logistic regression. We found subtype heterogeneity in the odds ratios for genetic risk factors and for breastfeeding. The 77-SNP polygenic risk score was associated with all subtypes except for the basal-like subtype, which showed no association with the score. Although breastfeeding was protective for both luminal and basal-like subtypes, the magnitude and underlying mechanism appeared to differ across subtypes.
In Study IV we assessed the concordance between PAM50 gene expression-based and immunohistochemistry-based molecular subtypes. No proxy showed more than moderate concordance with PAM50, however if luminal A and B subtypes were collapsed into one category, substantial concordance was achieved. Sensitivity for HER2-enriched breast cancer as defined by PAM50 was low, at 0.36 for all proxies investigated, whereas sensitivity and specificity was high for classifying basal-like breast cancer.
¹ According to Cancer facts sheets, GLOBOCAN 2012, [IARC]
List of papers:
I. Johanna Holm, Keith Humphreys, Jingmei Li, Alexander Ploner, Abbas Cheddad, Mikael Eriksson, Sven Törnberg, Per Hall, Kamila Czene. Risk Factors and Tumor Characteristics of Interval Cancers by mammographic density. Journal of Clinical Oncology 2015 Mar 20;33(9):1030-7.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Johanna Holm, Jingmei Li, Hatef Darabi, Martin Eklund, Mikael Eriksson, Keith Humphreys, Per Hall, Kamila Czene. Associations of Breast Cancer Risk Prediction Tools With Tumor Characteristics and Metastasis. Journal of Clinical Oncology 2016 Jan 20;34(3):251-8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Johanna Holm, Louise Eriksson, Alexander Ploner, Mikael Eriksson, Mattias Rantalainen, Jingmei Li, Per Hall, Kamila Czene. Assessment of Breast Cancer Risk Factors Reveals Subtype Heterogeneity. Cancer Research 2017 Jul 1;77(13):3708-3717.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Johanna Holm, Nancy Yu, Alexander Ploner, Linda Lindström, Kamila Czene. Concordance of immunohistochemistry based and PAM50 molecular subtypes of breast cancer. [Manuscript]
I. Johanna Holm, Keith Humphreys, Jingmei Li, Alexander Ploner, Abbas Cheddad, Mikael Eriksson, Sven Törnberg, Per Hall, Kamila Czene. Risk Factors and Tumor Characteristics of Interval Cancers by mammographic density. Journal of Clinical Oncology 2015 Mar 20;33(9):1030-7.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Johanna Holm, Jingmei Li, Hatef Darabi, Martin Eklund, Mikael Eriksson, Keith Humphreys, Per Hall, Kamila Czene. Associations of Breast Cancer Risk Prediction Tools With Tumor Characteristics and Metastasis. Journal of Clinical Oncology 2016 Jan 20;34(3):251-8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Johanna Holm, Louise Eriksson, Alexander Ploner, Mikael Eriksson, Mattias Rantalainen, Jingmei Li, Per Hall, Kamila Czene. Assessment of Breast Cancer Risk Factors Reveals Subtype Heterogeneity. Cancer Research 2017 Jul 1;77(13):3708-3717.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Johanna Holm, Nancy Yu, Alexander Ploner, Linda Lindström, Kamila Czene. Concordance of immunohistochemistry based and PAM50 molecular subtypes of breast cancer. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Czene, Kamila
Co-supervisor: Humphreys, Keith; Hall, Per
Issue date: 2018-01-25
Rights:
Publication year: 2018
ISBN: 978-91-7676-876-1
Statistics
Total Visits
Views | |
---|---|
Aggressive ...(legacy) | 781 |
Aggressive ... | 712 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Aggressive ... | 12 | 26 | 19 | 22 | 18 | 17 | 18 |
File Visits
Views | |
---|---|
Thesis_Johanna_Holm.pdf | 1445 |
Thesis_Johanna_Holm.pdf(legacy) | 358 |
Top country views
Views | |
---|---|
Sweden | 329 |
United States | 275 |
Denmark | 134 |
United Kingdom | 79 |
Australia | 76 |
Germany | 76 |
Vietnam | 74 |
Ireland | 71 |
China | 59 |
Finland | 17 |
Top cities views
Views | |
---|---|
Stockholm | 96 |
Copenhagen | 71 |
Dublin | 69 |
Ashburn | 67 |
Sydney | 64 |
Hanoi | 45 |
Woodbridge | 31 |
Houston | 29 |
Beijing | 26 |
Wilmington | 26 |