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  • 1.
    Wadsten, Charlotta
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    DCIS of the breast: aspects on treatment and prognosis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is the most common cancer form and a leading cause of death in women worldwide. Ductal breast carcinoma in situ (DCIS) is characterized by a proliferation of malignant cells confined within the mammary ducts and is a potential precursor of invasive breast cancer. The risk estimations of a DCIS to develop into invasive cancer over a 10 year period range from 30-50%. In the past 25 years, concomitant with the implementation of screening mammography, the incidence of DCIS has increased dramatically and presently almost 1 000 women are diagnosed with DCIS each year in Sweden. The increased incidence poses concerns of overtreatment and current research aim at identifying clinical or pathological markers that can reliably distinguish hazardous from harmless DCIS.                                        The overall aim of this thesis was to explore the prognostic significance of clinical and tumourbiological characteristics of DCIS and to assess the benefits and harms of adjuvant treatment.

    In a population-based cohort of 2 952 women with primary DCIS, we analysed trends in incidence, treatment and outcome over a 20-year period (paper I). Information was obtained from the regional breast cancer register in Uppsala-Örebro healthcare region between 1992 and 2012. A validation of 300 randomly selected women revealed high overall completeness and reliability of most key variables, whereas follow-up data were of moderate quality with only 65% of the recurrences reported to the register.

    The major finding of the study was a trend towards more intensified treatment over time. The frequency of mastectomy increased from 23.0% to 39.0% and the proportion of patients receiving adjuvant radiotherapy after breast-conserving surgery increased from 30.1% to 67.6%. This did not, however, translate into any noteable improvements in outcome. Relative survival was >97% after 10 years with no significant variation over time. In conclusion, these results may reflect adequate treatment selection, but may also indicate a significant overtreatment.

    In paper II and III, a nested case-control study was conducted from a cohort of 6 964 women with primary DCIS to identify clinical characteristics in DCIS associated with subsequent breast cancer death. Ninety-six women who later died from breast cancer were compared to 318 controls selected by incidence density sampling. Information was obtained from medial records and histopathology reports.

    Tumour size over 25 mm or multifocal DCIS (OR 2⋅55; 95%CI 1⋅53 to 4⋅25), a positive or uncertain margin status (OR 3⋅91; 95%CI 1⋅59 to 9⋅61) and detection outside the screening programme (OR 2⋅12; 95%CI 1⋅16 to 3⋅86) increased the risk of death from breast cancer. In the multivariable analysis, tumour size (OR 1⋅95; 95%CI 1⋅06 to 3⋅67) and margin status (OR 2⋅69; 95%CI 1⋅15 to 7⋅11) remained significant. More extensive treatment was not associated with lower risk, which may be due to confounding by indication, or indicate that some DCIS have an inherent potential for metastatic spread.                                    

    In paper III, to further explore the association of tumour biology and risk of breast cancer death, archival tumour blocks were collected. Freshly cut hematoxylin and eosin (H&E) stained sections of the primary DCIS were histopathologically evaluated for nuclear grade, presence of comedonecrosis and lymphocytic infiltration (LI). Tissue microarrays were constructed for immunohistochemical analysis (IHC) of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki67. Using the results of the IHC analyses, tumours were classified into surrogate molecular subtypes.

    Presence of intense periductal LI was associated with an increased risk of subsequent breast cancer death (OR 2.25; 95%CI 1.02 to 4.99). None of the other biomarkers were individually related to breast cancer death, nor were there any statistically significant differences in risk between the molecular subtypes. In multivariable analysis, stepwise adjusting for age, tumour size and treatment, PR negativity in combination with LI; PR negativity, LI and presence of comedonecrosis and the combination of PR negativity, LI, comedonecrosis and HER2 positivity were all independently associated with increased risk of breast cancer death. The significance of features in the peritumoral stroma need further investigation and may have implications for targeted treatments.

    In paper IV, we studied the risk of ischemic heart disease (IHD) after treatment for DCIS. Postoperative radiotherapy (RT) in DCIS reduces recurrence rates by half but confers no benefits in terms of survival. It is thus of major importance to consider long-term adverse effects. Left-sided breast irradiation may involve exposure of the heart to ionising radiation with an associated risk of subsequent cardiovascular disease. The cumulative incidence of IHD was analysed in a population-based cohort of 6270 women with DCIS compared 31 257 women without a history of breast cancer. Of the women with DCIS, 38.9% had received adjuvant RT.

    After a median follow-up of 8 years, there was no increased risk of IHD for women with DCIS versus the comparison cohort. The risk was lower for women with DCIS allocated to RT compared to non-irradiated women and to the comparison cohort, probably due to patient selection. Comparison of RT by laterality did not show any over-risk for irradiation of the left breast. These results are reassuring, but longer follow-up may be warranted considering the continuously increasing use of RT in DCIS management.

  • 2.
    Wadsten, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Garmo, H.
    Umeå University.
    Fredriksson, I.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Warnberg, F.
    DCIS and the risk of breast cancer death: a case control study2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77Article in journal (Refereed)
    Abstract [en]

    Introduction: The risk of breast cancer death after a primary ductal carcinoma in situ (DCIS) is less than 2 % after 10 years. Whereas in situ recurrences do not influence survival, a 17-fold elevated risk of breast cancer specific mortality has been shown for invasive recurrences. Adjuvant radiotherapy (RT) effectively reduces recurrences after breast conserving surgery (BCS) for DCIS, but no studies have been able to demonstrate a survival benefit from adjuvant RT treatment or from choosing mastectomy instead of BCS. Here patient and tumour related risk factors for breast cancer death in women with a pure primary DCIS were studied.

    Patients and methods: Women registered with a primary DCIS, between 1992-2012 in three of Sweden´s health care regions with a population of approximately 5.2 million, were enrolled in a nested case-control study. Out of 6,964 women with DCIS, 96 patients who later died from breast cancer were identified. Four controls per case (n=318) were randomly selected by incidence density sampling. We retrieved medical records and pathology reports and calculated OR with 95% CIs for various variables using conditional logistic regression.

    Results: Of the 96 cases, 10 patients developed distant metastasis without a known local recurrence. In 56 patients death was preceded by an invasive ipsilateral recurrence and in 3 patients by a recurrent ipsilateral DCIS. Seven patients had invasive breast events in both the ipsilateral and the contralateral breast. Seventeen patients had contralateral invasive breast cancer and 3 patients contralateral DCIS.

    Multifocality and tumour size over 25mm (OR 2.6 (1.6 to 4.2)), positive or uncertain margin status (OR 2.8 (1.6 to 4.9)) and detection outside screening (OR 2.1 (1.2 to 3.9)) increased the risk of breast cancer death in univariate analysis, when adjusted for age and year of diagnosis. Suspicion of micro-invasion and nuclear grade 3 was associated with a nonsignificant increased risk, OR 1.8 (0.6 to 5.0) and 2.6 (0.9-6.5), respectively. The risk was not affected by age or treatment. Tumour size and margin status remained significant in the multivariable analysis, when adjusted for treatment and for contralateral breast cancer (OR 2.0 (1.2 to 3.7)).

    Conclusion: In the present study, large tumours and positive or uncertain margin status were significant risk factors for later breast cancer death after a primary DCIS. More extensive treatment was not related to a lower risk. The significance of tumour biology and nuclear grade will be further examined and evaluated.

  • 3.
    Wadsten, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Department of Surgery, Sundsvall Hospital, Sundsvall ; Department of Surgical Sciences, Uppsala University.
    Garmo, H.
    Fredriksson, I.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Warnberg, F.
    Risk of death from breast cancer after treatment for ductal carcinoma in situ2017In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 104, no 11, p. 1506-1513Article in journal (Refereed)
    Abstract [en]

    Background Studies to date have failed to demonstrate any survival benefit from preventing local recurrence after treatment for ductal breast carcinoma in situ (DCIS). Patient- and tumour-related risk factors for death from breast cancer in women with a primary DCIS were analysed here in a large case-control study.

    Methods A nested case-control study was conducted in a population-based cohort of women with primary DCIS between 1992 and 2012. Women who later died from breast cancer were identified. Four controls per case were selected randomly by incidence density sampling. Medical records and pathology reports were retrieved. Conditional logistic regression was used to calculate odds ratios (ORs) and 95 per cent confidence intervals for risk of death from breast cancer.

    Results From a cohort of 6964 women, 96 who died from breast cancer were identified and these were compared with a group of 318 controls. Tumour size over 25mm or multifocal DCIS (OR 255, 95 per cent c.i. 153 to 425), a positive or uncertain margin status (OR 391, 159 to 961) and detection outside the screening programme (OR 212, 116 to 386) increased the risk of death from breast cancer. The risks were not affected by age or type of treatment. In the multivariable analysis, tumour size (OR 195, 106 to 367) and margin status (OR 269, 115 to 711) remained significant.

    Conclusion In the present study, large tumour size and positive or uncertain margin status were associated with a higher risk of death from breast cancer after treatment for primary DCIS. More extensive treatment was not associated with lower risk, which may be due to confounding by indication, or indicate that some DCIS has an inherent potential for metastatic spread. Rare, but worse for large tumours and uncertain margins.

  • 4.
    Wadsten, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Heyman, Hanna
    Holmqvist, Marit
    Ahlgren, Johan
    Lambe, Mats
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Warnberg, Fredrik
    A validation of DCIS registration in a population-based breast cancer quality register and a study of treatment and prognosis for DCIS during 20 years: Two decades of DCIS in Sweden2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 11, p. 1338-1343Article in journal (Refereed)
    Abstract [en]

    Aims: Sweden has a long history of population-based cancer registration. The aim of our study was to assess the validity of DCIS registration in a regional Breast Cancer Quality Register (BCQR) and to analyze trends in incidence, treatment and outcome of DCIS, over a 20-year period.Material and methods: All patients with a diagnosis of primary DCIS reported in the BCQR of the Uppsala-orebro healthcare region in Sweden 1992-2012 were included. Three hundred women were randomly selected and their medical records were compared to register data. The study period was divided into four time periods.Results: A total of 2952 women were registered with a DCIS diagnosis. In the final validation cohort of 295 patients, 23 were found to have either recurrent DCIS or invasive breast cancer and eight had LCIS. The completeness and validity of key variables were 91-99%. Twenty of 31 local recurrences were registered (65%).The proportion of DCIS to all breast cancers was 9.5%. Tumor size increased over time. The frequency of mastectomy increased from 23.0% to 39.0%. The proportion of patients receiving radiotherapy after breast conserving surgery increased from 30.1% to 67.6%. The reported local recurrence rate was 9.7% after 10 years. Reported recurrences after BCS and mastectomy were 12.0 and 7.0%, respectively. The recurrence rate did not differ between women undergoing BCS with or without radiotherapy.Conclusion: Only 89.5% of reported DCIS was a primary pure DCIS. The completeness of primary treatment and tumor data was high. The proportion of reported local recurrences was disappointingly low, 65%. The proportion of DCIS was stable over time with a trend towards more intensified treatment. The reported recurrence rate was low independent of treatment and can reflect adequate patient selection, but also over treatment. Our results address the necessity to validate register data on a regular basis.

  • 5.
    Wadsten, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wennstig, A. K.
    Garmo, H.
    Nilsson, G.
    Blomqvist, C.
    Holmberg, L.
    Fredriksson, I.
    Wärnberg, Fredrik
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Biomarkers in DCIS associated with breast cancer related deathManuscript (preprint) (Other (popular science, discussion, etc.))
  • 6.
    Wadsten, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Surgery, Sundsvall Hospital, Sundsvall, Sweden.
    Wennstig, A.-K
    Garmo, H.
    Nilsson, Greger
    Blomqvist, Carl
    Holmberg, Lars
    Fredriksson, Irma
    Wärnberg, F.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Risk of ischemic heart disease after radiotherapy for ductal carcinoma in situ2018In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 171, no 1, p. 95-101Article in journal (Refereed)
    Abstract [en]

    Purpose: The use of adjuvant radiotherapy (RT) in the management of ductal carcinoma in situ (DCIS) is increasing. Left-sided breast irradiation may involve exposure of the heart to ionising radiation, increasing the risk of ischemic heart disease (IHD). We examined the incidence of IHD in a population-based cohort of women with DCIS.

    Methods: The Breast Cancer DataBase Sweden (BCBase) cohort includes women registered with invasive and in situ breast cancers 1992-2012 and age-matched women without a history of breast cancer. In this analysis, 6270 women with DCIS and a comparison cohort of 31,257 women were included. Through linkage with population-based registers, data on comorbidity, socioeconomic status and incidence of IHD was obtained. Hazard ratios (HR) for IHD with 95% confidence intervals (CI) were analysed.

    Results: Median follow-up time was 8.8 years. The risk of IHD was not increased for women with DCIS versus women in the comparison cohort (HR 0.93; 95% CI 0.82-1.06), after treatment with radiotherapy versus surgery alone (HR 0.77; 95% CI 0.60-0.98) or when analysing RT by laterality (HR 0.85; 95% CI 0.53-1.37 for left-sided versus right-sided RT).

    Conclusions: The risk of IHD was lower for women with DCIS allocated to RT compared to non-irradiated women and to the comparison cohort, probably due to patient selection. Comparison of RT by laterality did not show any over-risk for irradiation of the left breast.

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