| 31. |
- Borgquist, Signe
(författare)
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Life Style, Molecular Pathology, and Breast Cancer Risk
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The breast cancer diagnosis covers a wide range of tumours with different geno- and phenotypic characteristics. The diversity among studies on life-style factors and their impact on breast cancer risk might be clarified by recognizing breast cancer as a heterogeneous disease. A major aim of this thesis was to investigate the association between several life-style factors and subsequent breast cancer risk according to pathological- and tumour biological characteristics. Further, we examined two novel tumour markers with respect to their relation to established tumour characteristics, estrogen-related-life-style-factors, and/or response to endocrine breast cancer treatment. The thesis is predominantly based on breast cancer cases from the Malmö Diet and Cancer Study, a prospective cohort study including 17 035 women with baseline examinations performed 1991-1996. The study cohort was followed by record-linkage with national cancer registries and at the end of follow-up in 2004, 622 women had been diagnosed with breast cancer. Additionally, we used a consecutive cohort of 512 women diagnosed with breast cancer at the Malmö University Hospital 1988 and 1992. Immunohistochemical assessments of different tumour markers were performed using the tissue microarray (TMA) technique. Analyses of dietary habits and tumour characteristics revealed an association between low energy intakes and a more aggressive histopathological phenotype as well as over-expression of the cell cycle regulating protein, cyclin D1. A low fat intake showed similar associations to tumour characteristics. The use of combined (estrogen-progestin) hormone replacement therapy was associated with an increased risk of breast cancer, although with comparatively favourable prognostics factors, such as lobular type, low grade, low proliferation, negative/low cyclin D1 expression and maintained expression of the tumour suppressor gene, p27. In a similar way obesity was associated with an increased risk of less aggressive breast cancer characterised by lobular type, grade II, low proliferation, HER2 negativity, ERα+, PgR+, but negative ERβ expression. The enzyme HMG-CoA reductase was differentially expressed in breast cancer and high expression was associated with a smaller tumour size, low grade, low proliferation, and expression of ERα and ERβ, but not PgR. Estrogen-related factors, such as obesity and use of hormonal replacement, were associated with an increased risk of tumours with high expression of HMG-CoA reductase. The novel estrogen receptor, ERβ, was associated with expression of ERα and PgR, but not with other established prognostic factors, such as tumour size, grade, and lymph node metastases. Co-expression of both estrogen receptors indicated an improved response to endocrine therapy.
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| 32. |
- Borgquist, Signe, et al.
(författare)
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Long-term exposure to insulin and volumetric mammographic density : Observational and genetic associations in the Karma study
- 2018
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long-term insulin exposure has been implicated in breast cancer etiology, but epidemiological evidence remains inconclusive. The aims of this study were to investigate the association of insulin therapy with mammographic density (MD) as an intermediate phenotype for breast cancer and to assess associations with long-term elevated circulating insulin levels using a genetic score comprising 18 insulin-associated variants. Methods: We used data from the KARolinska MAmmography (Karma) project, a Swedish mammography screening cohort. Insulin-treated patients with type 1 (T1D, n = 122) and type 2 (T2D, n = 237) diabetes were identified through linkage with the Prescribed Drug Register and age-matched to 1771 women without diabetes. We assessed associations with treatment duration and insulin glargine use, and we further examined MD differences using non-insulin-treated T2D patients as an active comparator. MD was measured using a fully automated volumetric method, and analyses were adjusted for multiple potential confounders. Associations with the insulin genetic score were assessed in 9437 study participants without diabetes. Results: Compared with age-matched women without diabetes, insulin-treated T1D patients had greater percent dense (8.7% vs. 11.4%) and absolute dense volumes (59.7 vs. 64.7 cm3), and a smaller absolute nondense volume (615 vs. 491 cm3). Similar associations were observed for insulin-treated T2D, and estimates were not materially different in analyses comparing insulin-treated T2D patients with T2D patients receiving noninsulin glucose-lowering medication. In both T1D and T2D, the magnitude of the association with the absolute dense volume was highest for long-term insulin therapy (≥ 5 years) and the long-acting insulin analog glargine. No consistent evidence of differential associations by insulin treatment duration or type was found for percent dense and absolute nondense volumes. Genetically predicted insulin levels were positively associated with percent dense and absolute dense volumes, but not with the absolute nondense volume (percentage difference [95% CI] per 1-SD increase in insulin genetic score = 0.8 [0.0; 1.6], 0.9 [0.1; 1.8], and 0.1 [- 0.8; 0.9], respectively). Conclusions: The consistency in direction of association for insulin treatment and the insulin genetic score with the absolute dense volume suggest a causal influence of long-term increased insulin exposure on mammographic dense breast tissue.
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| 33. |
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| 34. |
- Borgquist, Signe, et al.
(författare)
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Oestrogen receptors alpha and beta show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer.
- 2008
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 61:2, s. 197-202
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The majority of all breast cancers are hormone responsive, traditionally defined by the expression of oestrogen receptor (ER) alpha and/or progesterone receptors. In contrast to ERalpha, the clinical significance of the relatively recently identified ERbeta is still unclear. This study aimed to define the relationship between ERbeta and clinicopathological parameters in a mixed cohort of breast cancer and, furthermore, to investigate the impact of ERbeta expression on disease outcome. METHODS: The immunohistochemical expression of ERalpha and ERbeta was analysed in tissue microarrays containing a total number of 512 tumours with all incident breast cancers diagnosed at the Malmö University Hospital between 1988 and 1992. RESULTS: 78% of the tumours were ERalpha positive and 50% were ERbeta positive. ERbeta correlated positively with ERalpha (p = 0.001). In contrast to ERalpha, ERbeta was not associated with any important clinicopathological variables. Furthermore, no overall prognostic significance could be demonstrated for ERbeta. In the ERalpha-positive subgroup, however, a low expression of ERbeta correlated with a decreased disease-free survival in patients receiving endocrine treatment (p = 0.003). CONCLUSIONS: Although interrelated, ERalpha and ERbeta seem to be differentially associated to clinicopathological parameters, and this would support the fact that they might have different functions in vivo. Furthermore, ERbeta might be a predictive marker of response to endocrine therapy, although this needs to be confirmed in additional studies, preferably randomised trials.
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| 35. |
- Borgquist, Signe, et al.
(författare)
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Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:5, s. R79-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We have previously reported that tumour-specific expression of the rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR), in the mevalonate pathway is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up. METHODS: The expression of HMG-CoAR was assessed by immunohistochemistry on tissue microarrays with tumour specimens from 498 consecutive cases of breast cancer with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the rate of recurrence-free survival (RFS) and breast cancer specific survival (BCSS). RESULTS: In line with our previous findings, tumour-specific HMG-CoAR expression was associated with low grade (p < 0.001), small size (p = 0.007), oestrogen receptor (ER) positive (p = 0.01), low Ki-67 (p = 0.02) tumours. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS, even when adjusted for established prognostic factors (relative risk [RR] = 0.60, 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In ER-negative tumours, however, there was a trend, that was not significantly significant, towards a shorter RFS in HMG-CoAR expressing tumours. CONCLUSIONS: HMG-CoAR expression is an independent predictor of a prolonged RFS in primary breast cancer. This may, however, not be true for ER-negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status.
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| 36. |
- Borgquist, Signe, et al.
(författare)
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Statin Use and Breast Cancer Risk in the Nurses' Health Study.
- 2016
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 25:1, s. 201-206
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82-1.1; current users: HRadj, 1.1; 95% CI, 0.92-1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. Cancer Epidemiol Biomarkers Prev; 25(1); 201-6. ©2016 AACR.
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| 37. |
- Borgquist, Signe, et al.
(författare)
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Statin use and breast cancer survival - A Swedish nationwide study
- 2019
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: A sizeable body of evidence suggests that statins can cease breast cancer progression and prevent breast cancer recurrence. The latest studies have, however, not been supportive of such clinically beneficial effects. These discrepancies may be explained by insufficient power. This considerably sized study investigates the association between both pre- and post-diagnostic statin use and breast cancer outcome. Methods: A Swedish nation-wide retrospective cohort study of 20,559 Swedish women diagnosed with breast cancer (July 1st, 2005 through 2008). Dispensed statin medication was identified through the Swedish Prescription Registry. Breast cancer related death information was obtained from the national cause-of-death registry until December 31st, 2012. Cox regression models yielded hazard ratios (HR) and 95% confidence intervals (CI) regarding associations between statin use and breast cancer-specific and overall mortality. Results: During a median follow-up time of 61.6 months, a total of 4678 patients died, of which 2669 were considered breast cancer related deaths. Compared to non- or irregular use, regular pre-diagnostic statin use was associated with lower risk of breast cancer related deaths (HR = 0.77; 95% CI 0.63-0.95, P = 0.014). Similarly, post-diagnostic statin use compared to non-use was associated with lower risk of breast cancer related deaths (HR = 0.83; 95% CI 0.75-0.93, P = 0.001). Conclusion: This study supports the notion that statin use is protective regarding breast cancer related mortality in agreement with previous Scandinavian studies, although less so with studies in other populations. These disparities should be further investigated to pave the way for future randomized clinical trials investigating the role of statins in breast cancer.
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| 38. |
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| 39. |
- Borgquist, Signe, et al.
(författare)
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The prognostic role of HER2 expression in ductal breast carcinoma in situ (DCIS); a population-based cohort study
- 2015
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Ingår i: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: HER2 is a well-established prognostic and predictive factor in invasive breast cancer. The role of HER2 in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that HER2 is mainly related to in situ recurrences. Our aim was to study HER2 as a prognostic factor in a large population based cohort of DCIS with long-term follow-up. Methods: All 458 patients diagnosed with a primary DCIS 1986-2004 in two Swedish counties were included. Silver-enhanced in situ hybridisation (SISH) was used for detection of HER2 gene amplification and protein expression was assessed by immunohistochemistry (IHC) in tissue microarrays. HER2 positivity was defined as amplified HER2 gene and/or HER2 3+ by IHC. HER2 status in relation to new ipsilateral events (IBE) and Invasive Breast Cancer Recurrences, local or distant (IBCR) was assessed by Kaplan-Meier survival analyses and Cox proportional hazards regression models. Results: Primary DCIS was screening-detected in 75.5 % of cases. Breast conserving surgery (BCS) was performed in 78.6 % of whom 44.0 % received postoperative radiotherapy. No patients received adjuvant endocrine-or chemotherapy. The majority of DCIS could be HER2 classified (N = 420 (91.7 %)); 132 HER2 positive (31 %) and 288 HER2 negative (69 %)). HER2 positivity was related to large tumor size (P = 0.002), high grade (P < 0.001) and ER-and PR negativity (P < 0.001 for both). During follow-up (mean 184 months), 106 IBCRs and 105 IBEs were identified among all 458 cases corresponding to 54 in situ and 51 invasive recurrences. Eighteen women died from breast cancer and another 114 had died from other causes. The risk of IBCR was statistically significantly lower subsequent to a HER2 positive DCIS compared to a HER2 negative DCIS, (Log-Rank P = 0.03, (HR) 0.60 (95 % CI 0.38-0.94)). Remarkably, the curves did not separate until after 10 years. In ER-stratified analyses, HER2 positive DCIS was associated with lower risk of IBCR among women with ER negative DCIS (Log-Rank P = 0.003), but not for women with ER positive DCIS. Conclusions: Improved prognostic tools for DCIS patients are warranted to tailor adjuvant therapy. Here, we demonstrate that HER2 positive disease in the primary DCIS is associated with lower risk of recurrent invasive breast cancer.
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| 40. |
- Borgquist, Signe, et al.
(författare)
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Towards prevention of breast cancer : What are the clinical challenges?
- 2018
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Ingår i: Cancer Prevention Research. - 1940-6207. ; 11:5, s. 255-264
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Forskningsöversikt (refereegranskat)abstract
- The dramatic increase in breast cancer incidence compels a paradigm shift in our preventive efforts. There are several barriers to overcome before prevention becomes an established part of breast cancer management. The objective of this review is to identify the clinical challenges for improved breast cancer prevention and discuss current knowledge on breast cancer risk assessment methods, risk communication, ethics, and interventional efforts with the aim of covering the aspects relevant for a breast cancer prevention trial. Herein, the following five areas are discussed: (i) Adequate tools for identification of women at high risk of breast cancer suggestively entitled Prevent! Online. (ii) Consensus on the definition of high risk, which is regarded as mandatory for all risk communication and potential prophylactic interventions. (iii) Risk perception and communication regarding risk information. (iv) Potential ethical concerns relevant for future breast cancer prevention programs. (v) Risk-reducing programs involving multileveled prevention depending on identified risk. Taken together, devoted efforts from both policy makers and health care providers are warranted to improve risk assessment and risk counseling in women at risk for breast cancer to optimize the prevention of breast cancer.
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