BackgroundThe mevalonate pathway synthetizes cholesterol, steroid hormones, and non-steriod isoprenoids necessary for cell survival. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) is the rate-limiting enzyme of the mevalonate pathway and the target for statin treatment. HMGCR expression in breast tumors has recently been proposed to hold prognostic and treatment-predictive information. This study aimed to investigate whether HMGCR expression in breast cancer patients was associated with patient and tumor characteristics and disease-free survival (DFS).MethodsA population-based cohort of primary breast cancer patients in Lund, Sweden was assembled between October 2002 and June 2012 enrolling 1,116 patients. Tumor tissue microarrays were constructed and stained with a polyclonal HMGCR antibody (Cat. No HPA008338, Atlas Antibodies AB, Stockholm, Sweden, diluted 1:100) to assess the HMGCR expression in tumor tissue from 885 patients. HMGCR expression was analyzed in relation to patient- and tumor characteristics and disease-free survival (DFS) with last follow-up June 30th 2014.ResultsModerate/strong HMGCR expression was associated with less axillary lymph node involvement, lower histological grade, estrogen and progesterone receptor positivity, HER2 negativity, and older patient age at diagnosis compared to weak or no HMGCR expression. Patients were followed for up to 11 years. The median follow-up time was 5.0 years for the 739 patients who were alive and still at risk at the last follow-up. HMGCR expression was not associated with DFS.ConclusionIn this study, HMGCR expression was associated with less aggressive tumor characteristics. However, no association between HMGCR expression and DFS was observed. Longer follow-up may be needed to evaluate HMGCR as prognostic or predictive marker in breast cancer.

Multiple clinical trials investigate statins' effects in breast cancer. The ABCB1 genotype appears to influence statin response and toxicity in the cardiovascular setting. This exploratory study aimed to investigate the interplay between preoperative statin use, ABCB1 genotype, and tumor-specific expression of the statin target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in breast cancer. Preoperative statin use, ABCB1 C3435T genotype, and HMGCR expression in relation to outcome were analyzed in 985 primary breast cancer patients from a population-based prospective cohort in Sweden from 2002 to 2012. Preoperative statin use (n = 80) was not associated with ABCB1 C3435T genotype (n = 576), HMGCR expression (n = 848), or clinical outcomes. ABCB1 C3435T TT-carriers had lower risk of breast cancer events than any C-carriers (adjusted hazard ratio (HRadj) 0.74; 95%CI 0.49, 1.12), but only in non-statin users (Pinteraction = 0.042). Statin users with TT genotype had higher risk of distant metastasis (HRadj 4.37; 95%CI 1.20, 15.91; Pinteraction = 0.009) and shorter overall survival than other patients (HRadj 3.77; 95%CI 1.37, 10.39; Pinteraction = 0.019). In conclusion, there were nominally significant interactions between ABCB1 genotype and preoperative statin use on clinical outcomes, while preoperative statin use was not associated with outcomes. Since this is an exploratory study of the impact of the ABCB1 genotype in relation to statin use and clinical outcomes in the breast cancer setting, the results should be interpreted with caution and warrant replication in an independent cohort, preferably in a randomized setting. Since statin use is common in breast cancer patients, it would be of interest to further elucidate the clinical impact of the ABCB1 genotype in breast cancer.

Breast-feeding is a known protective factor against breast cancer. Breast-feeding duration is influenced by hormone levels, milk production, and lifestyle factors. The aims were to investigate how breast-feeding duration and milk production affected tumor characteristics and risk for early breast cancer events in primary breast cancer patients. Between 2002 and 2008, 634 breast cancer patients in Lund, Sweden, took part in an ongoing prospective cohort study. Data were extracted from questionnaires, pathology reports, and patients’ charts from 592 patients without preoperative treatment. Breast-feeding duration ≤12 months of the first child was associated with higher frequency of ER+/PgR+ tumors (P=0.02). Median follow-up time was 4.9 years. Higher risk for early events was observed for breast-feeding duration of first child >12 months (LogRank P=0.001), total breast-feeding duration >12 months (LogRank P=0.008), as well as ‘excessive milk production’ during breast-feeding of the first child (LogRank P=0.001). Patients with ‘almost no milk production’ had no events. In a multivariable model including both ‘excessive milk production’ and breast-feeding duration of the first child >12 months, both were associated with a two-fold risk for early events, adjusted HRs 2.33 (95% CI: 1.25-4.36) and 2.39 (0.97-5.85), respectively, while total breast-feeding duration was not. ‘Excessive milk production’ was associated with a two-fold risk of early distant metastases, adjusted HR 2.59 (1.13-5.94), but not duration. In conclusion, ‘excessive milk production’ during breast-feeding was associated with higher risk for early events independent of tumor characteristics, stressing the need to consider host factors in the evaluation of prognostic markers.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-298) contains supplementary material, which is available to authorized users.

Background: The purpose of this study was to investigate whether pre-diagnostic statin use was associated with tumor expression of HMG-CoA reductase (HMGCR) and disease-free survival (DFS) in breast cancer. Previous studies have shown anti-carcinogenic properties of statins and a significantly longer survival among breast cancer patients using statins. We recently showed, that the target of statins, HMGCR, was up-regulated in breast cancer among patients preoperatively treated with statins in a window-of-opportunity trial. Methods: A population-based cohort of primary breast cancer patients in Lund, Sweden was assembled between October 2002 and June 2012. Patients completed a questionnaire including information on medication use. Statin use in relation to DFS was analyzed in 985 patients. Tumor tissue microarrays were constructed and stained with a polyclonal HMGCR antibody to assess HMGCR expression (n=848). Results: Patients were followed for up to 11 years (median follow-up time 5.0 years). In the present study, pre-diagnostic statin use was neither associated with HMGCR expression (P=0.53) nor with DFS (P=0.92), overall or separately in any of the HMGCR expression groups (negative, weak, moderate/strong). Moreover, statin use was not associated with clinical tumor characteristics (tumor size, axillary lymph node involvement, histological grade, hormone receptor status or HER-2 amplification). Conclusion: In contrast to previous studies, the present study did not show any significant association between pre-diagnostic statin use and DFS. It is possible that patients who already used statins have developed tumors that are less dependent on cholesterol metabolism and consequently less influenced by statin treatment. The timing of statin use in relation to breast cancer diagnosis and prognosis should be evaluated in another cohort with preferably longer follow-up time. Citation Format: Helga Tryggvadottir, Emma Gustbée, Andrea Markkula, Maria Simonsson, Björn Nodin, Karin Jirström, Carsten Rose, Christian Ingvar, Signe Borgquist, Helena Jernström. Pre-diagnostic statin use among breast cancer patients - the relation to HMG-CoA reductase expression and disease-free survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3805. doi:10.1158/1538-7445.AM2017-3805

Background: Breast feeding is a known protective factor against breast cancer. Breast feeding duration is influenced by hormone levels, milk production, and lifestyle factors. We aimed to investigate how breast feeding duration and milk production affect tumor characteristics and risk for early breast cancer events in women who subsequently developed breast cancer. Methods: Between 2002 and 2008, 634 primary breast cancer patients in Lund, Sweden, took part in an ongoing prospective cohort study. Data were extracted from preoperative questionnaires, pathology reports, patients' charts and Swedish registries from 592 patients without preoperative treatment. Results: Breast feeding duration ≥12 months of the first child was associated with higher frequency of ER+/PgR+ tumors (P=0.02). Median follow-up time was 4.9 years. Higher risk for early events was observed for breast feeding duration of first child >12 months (LogRank P=0.001), total breast feeding duration >12 months (LogRank P=0.004), as well as ‘excessive milk production’ during breast feeding of the first child (LogRank P=0.003). Patients with ‘almost no milk production’ had no events. In a multivariable model including both ‘excessive milk production’ and breast feeding duration of the first child >12 months, both were significantly associated with a two-fold risk for early events, adjusted HRs 2.19 (95% CI: 1.17-4.11) and 2.61 (1.06-6.38), respectively, adjusted for age, invasive tumor size, axillary lymph node involvement, ER and PgR status, age at first birth, time since last birth, smoking status, and BMI, while total breast feeding duration was not. ‘Excessive milk production’ was associated with a two-fold risk of early distant metastases, adjusted HR 2.41 (1.09-5.32), but not breast feeding duration. Conclusion: ‘Excessive milk production’ during breast feeding was associated with higher risk for early events independent of tumor characteristics, while patients who reported ‘almost no milk production’ had no events. This finding stresses the need to consider host factors in the evaluation of prognostic markers. Citation Format: Emma Gustbée, Charlotte Anesten, Andrea Markkula, Maria Simonsson, Carsten Rose, Christian Ingvar, Helena Jernstrom. Excessive milk production during breast feeding prior to breast cancer diagnosis is associated with increased risk for early events. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B115.