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Aspects of Progression in Breast Carcinoma: from ductal carcinoma in situ to invasive cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown.

In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.

In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade.

In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2012. , p. 38
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 735
Keyword [en]
progression, ductal carcinoma in situ, breast cancer
National Category
Cancer and Oncology
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-166745ISBN: 978-91-554-8256-5 (print)OAI: oai:DiVA.org:uu-166745DiVA, id: diva2:477361
Public defence
2012-02-25, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2012-02-06 Created: 2012-01-13 Last updated: 2012-02-15Bibliographically approved
List of papers
1. Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution
Open this publication in new window or tab >>Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution
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2009 (English)In: Molecular Oncology, ISSN 1574-7891, Vol. 3, no 3, p. 214-219Article in journal (Refereed) Published
Abstract [en]

In breast cancer, previous studies have suggested that somatic TP53 mutations are likely to be an early event. However, there are controversies regarding the cellular origin and linear course of breast cancer. The purpose of this study was to investigate tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. The entire coding sequence of TP53 was sequenced in a cohort of pure ductal carcinoma in situ (DCIS), pure invasive cancer (</=15mm) and mixed lesions (i.e. invasive cancer with an in situ component). Of 118 tumor samples, 19 were found to harbor a TP53 mutation; 5 (15.6%) of the pure DCIS, 4 (10.5%) of the pure invasive cancers and 10 (20.8%) of the mixed lesions. In the mixed lesions, both the invasive and the DCIS components showed the same mutation in all 5 cases where the two components were successfully microdissected. Presence of the same mutation in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.

Keyword
TP53 mutation, Breast cancer, DCIS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-113745 (URN)10.1016/j.molonc.2009.03.001 (DOI)000266853200004 ()19403344 (PubMedID)
Available from: 2010-02-03 Created: 2010-02-03 Last updated: 2012-02-15Bibliographically approved
2. Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study
Open this publication in new window or tab >>Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study
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2010 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 10, p. 653-Article in journal (Refereed) Published
Abstract [en]

Background: Microarray gene-profiling of invasive breast cancer has identified different subtypes including luminal A, luminal B, HER2-overexpressing and basal-like groups. Basal-like invasive breast cancer is associated with a worse prognosis. However, the prognosis of basal-like ductal carcinoma in situ (DCIS) is still unknown. Our aim was to study the prognosis of basal-like DCIS in a large population-based cohort. Methods: All 458 women with a primary DCIS diagnosed between 1986 and 2004, in Uppland and Vastmanland, Sweden were included. TMA blocks were constructed. To classify the DCIS tumors, we used immunohistochemical (IHC) markers (estrogen-, progesterone-, HER2, cytokeratin 5/6 and epidermal growth factor receptor) as a surrogate for the gene expression profiling. The association with prognosis was examined for basal-like DCIS and other subtypes using Kaplan-Meier survival analyses and Cox proportional hazards regression models. Results: IHC data were complete for 392 women. Thirty-two were basal-like (8.2%), 351 were luminal or HER2-positive (89.5%) and 9 unclassified (2.3%). Seventy-six women had a local recurrence of which 34 were invasive. Another 3 women had general metastases as first event. Basal-like DCIS showed a higher risk of local recurrence and invasive recurrence 1.8 (Confidence interval (CI) 95%, 0.8-4.2) and 1.9 (0.7-5.1), respectively. However, the difference was not statistically significant. Also, no statistically significant increased risk was seen for triple-negative or high grade DCIS. Conclusions: Basal-like DCIS showed about a doubled, however not statistically significant risk for local recurrence and developing invasive cancer compared with the other molecular subtypes. Molecular subtyping was a better prognostic parameter than histopathological grade.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-142827 (URN)10.1186/1471-2407-10-653 (DOI)000285299300001 ()21118480 (PubMedID)
Available from: 2011-01-17 Created: 2011-01-17 Last updated: 2017-12-11Bibliographically approved
3. Tumor Markers Predicting Type of Recurrence after a Primary Ductal Carcinoma In Situ
Open this publication in new window or tab >>Tumor Markers Predicting Type of Recurrence after a Primary Ductal Carcinoma In Situ
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2012 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542XArticle in journal (Other academic) Submitted
Abstract [en]

Introduction:

About half of all recurrences after a primary ductal carcinoma in situ (DCIS) are invasive. The determinants for type of recurrence, in situ or invasive, are not known. We studied markers in primary DCIS in relation to type of recurrence.

Methods:

Two hundred and sixty six primary DCIS with a known recurrence were included. One hundred were from a population based cohort with 458 women diagnosed 1986-2004 in Uppland/Västmanland region, Sweden, and all 166 women with a recurrence from the randomized nationwide SweDCIS Trial (1987-1999). The 358 women without a recurrence were used as a reference group. TMA-blocks were constructed and estrogen receptor- (ER), progesterone receptor- (PR), HER2, EGFR, cytokeratin 5/6, Ki67, FOXA1, FOXC1, GATA-3 and CD10 status were evaluated in the primary tumors. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses (adjusted for age, free margin, surgical method and molecular subtype).

Results:

One hundred and thirty of the recurrences were in situ and 136 invasive. In multivariate analyses, a recurrence was more often invasive if the primary was ER positive (OR 2.5, CI 95 1.2 – 5.1). Primaries being HER2 positive (OR 0.5, CI 95 0.3-0.9), EGFR positive (OR 0.4, CI 95 0.2-0.9) and ER-/HER2+ (OR 0.2, CI 95 0.1-0.6) had a lower risk of the recurrence being invasive. Primaries of the molecular subtype ER+/HER2+ had higher risk of any recurrence (OR 1.9, CI 95 1.1-3.4) as did primaries expressing FOXA1 (OR 3.1, CI 95 1.5-6.2) and FOXC1 (OR 2.9, CI 95 1.7-5.0).

Conclusions:

Surprisingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

Keyword
tumor markers, recurrence type, DCIS
National Category
Cancer and Oncology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-166365 (URN)
Available from: 2012-01-11 Created: 2012-01-11 Last updated: 2017-12-08Bibliographically approved
4. Breast carcinoma with neoductgenesis: a new subgroup of breast cancer
Open this publication in new window or tab >>Breast carcinoma with neoductgenesis: a new subgroup of breast cancer
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: A new subgroup of breast cancer has been proposed: breast carcinoma with neoductgenesis. Cases presenting with casting type calcifications on the mammogram, histologically high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction and lymphocyte infiltration has been suggested to represent a more aggressive form of breast cancer. Treatment decision based on traditional histopathology showing DCIS might be challenged if neoductgenesis is diagnosed. We evaluated a histological classification system proposed for neoductgenesis and studied tumor biology in cases with and without neoductgenesis.

 

Material and Method: Seventy-four tumors with DCIS grade 2-3, with or without an invasive component, were blocked in TMAs. A classification system based on a pathological evaluation and Tenascin-C (Tn-C) expression was used to categorize tumors as showing neoductgenesis or not. Immunohistochemical staining for known tumor markers and correlation with mammographic features was performed. Logistic regression model was use to evaluate the correlation between breast carcinoma with neoductgenesis and molecular- and mammographic features.

 

Results: Four pathologists could categorize cases as “possible neoductgenesis” with an overall correlation of 72% and a kappa value of 0.44. Adding Tn-C staining resulted in a group with neoductgenesis (n=37) and one without (n=31). Neoductgenesis correlated significantly with mammographic casting- and crushed stone microcalcifications and estrogen receptor status (p-values 0.04 and 0.03, respectively). High nuclear grade, HER2 positivity, progesterone receptor negativity and high proliferation were also more often seen in the group with neoductgenesis, but this was not statistically significant (0.10, 0.07, 0.20 and 0.29).

 

Discussion: We developed reproducible histologic criteria for a new entity: breast carcinoma with neoductgenesis. The system seemed to be useful in receiving reproducibility between pathologists making the diagnosis. Neoductgenesis was related to more aggressive tumor biology and to the mammographic features. Our findings have to be repeated and the relation to prognosis further studied. However, we can already predict a potential benefit for women earlier considered having a pure DCIS but now diagnosed as breast carcinoma with neoductgenesis and a need to develop appropriate treatment regiments.

Keyword
breast carcinoma, neoductgenesis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-166704 (URN)
Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2012-02-15

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