Risk Of Early Events Research Articles

Abstract P5-08-27: Estrogen receptor beta expression is prognostic among chemotherapy-treated patients – Results from a population-based breast cancer cohort

Abstract Background and aim Estrogen receptor beta (ERβ) expression has been suggested to hold prognostic and predictive information, especially for endocrine treatment. The role of ERβ may depend on the expression of estrogen receptor alpha (ERα). The aim of this study was to evaluate ERβ expression in relation to tumor characteristics and risk for early events (disease-free survival, DFS) – overall and in different treatment groups, in a population-based cohort of primary breast cancer patients. Materials and methods Patients with primary breast cancer were invited at the preoperative visit between October 2002 and June 2012. After exclusion of patients who received preoperative treatment and patients with in situ carcinoma, the study population consisted of 1026 patients. Tumor specimens mounted in tissue microarrays were analyzed for ERβ expression using immunohistochemistry (antibody PPG5/10, Dako, dilution 1:20). Two cut-offs for positivity were evaluated (>10% and >75% of stained nuclei, respectively). Cox regression analyses yielding hazard ratios (HRs) with 95% confidence intervals (CIs) were adjusted for ERα status, tumor size, axillary lymph node involvement, histological grade, age at inclusion and body mass index. Events were defined as ipsi- or contralateral recurrences, regional or distant metastases. DFS was calculated from inclusion to event, non-breast cancer related death or last follow-up by June 30 2014, whichever came first. Patients were followed for up to 11 years (median follow-up 5.0 years for patients still at risk). Results ERβ expression was available for 911 patients (89%). ERβ positivity defined as >10% (ERβ10+, 92.1%) was positively associated with ERα (P<0.0001). ERβ10+ was not associated with DFS, overall or in patients who received tamoxifen and/or aromatase inhibitors. ERβ positivity defined as >75% (ERβ75+, 72.7%) was associated with ERα and PR positivity, lower histological grade, smaller invasive tumor size and no involvement of axillary nodes (all Ps≤0.03). In survival analyses among all patients, ERβ75+ was inversely associated with risk of early events (LogRank P=0.0005, adjHR 0.62: 95% CI 0.42-0.90; P=0.013). The magnitude of the association was larger in patients with ERα negative tumors (LogRankERα- P=0.011, adjHRERα- 0.42: 95% CI 0.17-1.02; P=0.05) compared to patients with ERα positive tumors (LogRankERα+ P=0.069, adjHRERα+ 0.74: 95% CI 0.48-1.14; P=0.18). In analyses stratified for chemotherapy, ERβ75+ expression was significantly associated with lower risk of early events among the 232 patients who had received chemotherapy (Log Rank P=0.0005, adjHR 0.31: 95% CI 0.15-0.63; P=0.001), but not among the 670 patients without chemotherapy (Log Rank P=0.14, adjHR 0.81: 95% CI 0.50-1.31; P=0.38). ERβ75+ was not associated with early events in patients with ERα+ tumors who received tamoxifen and/or aromatase inhibitors. Conclusion This study provides support for high tumor ERβ expression as a prognostic marker in breast cancer, for patients who received chemotherapy. Previous reports of ERβ as a predictor of endocrine therapy response could not be confirmed. Citation Format: Elebro K, Borgquist S, Rosendahl A, Markkula A, Simonsson M, Jirström K, Rose C, Ingvar C, Jernström H. Estrogen receptor beta expression is prognostic among chemotherapy-treated patients – Results from a population-based breast cancer cohort. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-27.

Abstract P5-08-29: Tamoxifen or aromatase inhibitors: Should smoking status impact on selection of endocrine therapy in breast cancer patients?

Abstract Introduction: The association between smoking and breast cancer prognosis has been investigated in several studies but remains unclear. To our knowledge, no study has investigated whether the response to different endocrine treatments differs between smokers and non-smokers. Smoking can suppress aromatase activity, but also increase inflammation, which may lead to higher activity. The aim was to investigate whether preoperative smoking was associated with risk of breast cancer events in endocrine-treated patients. Patients and methods: This population based cohort consisted of 1026 female breast cancer patients with invasive tumors and no preoperative treatment who were enrolled in an ongoing prospective cohort study at Skåne University Hospital in Lund between October 2002 and June 2012. Pre- and postoperative questionnaires regarding lifestyle factors, including smoking status, and treatments were completed. Information on tumor characteristics, treatments, and dates for new breast cancer events or deaths was obtained from pathology reports, patients' charts and population registers. A breast cancer event was defined as local or regional recurrence, contralateral breast cancer, or distant metastasis. Results: For the survival analyses, two patients were excluded due to missing information on smoking and eight patients were excluded due to metastatic spread within 0.3 years of inclusion, leaving 1016 patients of which 206 (20.3%) reported preoperative smoking. Less than 1% of the 810 preoperative non-smokers reported smoking at either the 3-6-months or 1-year postoperative visits, while about 10% of the patients who smoked preoperatively reported not to smoke during the follow-up visits. Thus, the majority of the patients did not switch smoking status. Patients were followed for up to 11 years (median 5.1 years for patients still at risk). Overall, there was no significant association between smoking and risk of breast cancer events (adjusted hazard ratio (HR) 1.45: 95% CI 0.95-2.20; P=0.08) adjusted for patient and tumor characteristics. For the 408 tamoxifen-treated patients aged 50 years or older with estrogen receptor positive tumors, smoking was not significantly associated with risk for early events (adjusted HR 1.58: 95% CI 0.76-3.30; P=0.22). However, for the 309 aromatase inhibitor-treated patients aged 50 years or older with estrogen receptor positive tumors, smoking was significantly associated with a 3-fold increased risk of breast cancer events (adjusted HR 2.97: 95% CI 1.44-6.12; P=0.003). Some patients had been treated with sequential tamoxifen and aromatase inhibitor therapy. Conclusions: Preoperative smoking was associated with a significantly increased risk for breast cancer events among patients treated with aromatase inhibitors, but not among tamoxifen-treated patients. If confirmed, smoking status should be taken into consideration when selecting endocrine therapy. Citation Format: Jernström H, Persson M, Simonsson M, Markkula A, Rose C, Ingvar C. Tamoxifen or aromatase inhibitors: Should smoking status impact on selection of endocrine therapy in breast cancer patients?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-29.

Abstract P5-08-26: CYP1A2– A novel genetic marker for aromatase inhibitor response in the treatment of breast cancer patients

Abstract Background: Endocrine resistance is a major obstacle for optimal endocrine treatment in breast cancer (BC). Several genetic markers for tamoxifen response have been proposed. Although some genetic markers have been proposed for response to aromatase inhibitors (AI), data is insufficient. The aim of this study was 1) to perform an exploratory analysis of genes involved in Absorption, Distribution, Metabolism, and Elimination (ADME) to find new predictive markers in a subset of the cohort and 2) examine these potential markers in relation to risk for events in the extended cohort. Materials and methods: In Lund, Sweden, 190 AI-treated primary breast cancer patients with estrogen receptor positive tumors, who underwent breast cancer surgery between 2002 and 2008, were followed until December 31st 2012. Clinical data were obtained from medical records and population registries. The impact of single nucleotide polymorphisms (SNPs) on risk for breast cancer events was conducted on a subset of the cohort followed until December 31st 2011 (13 cases, 11 controls) and analyzed with data from a DMET (TM) chip including 1931 SNPs in 225 ADME-related genes. Secondly, four SNPs in CYP19A1 and the significant SNPs from the first analysis were reanalyzed concerning disease-free survival in the extended cohort of 190 patients. Results: A CYP1A2 SNP was significantly associated with risk for early events among the 24 AI-treated BC patients both in the subset of the cohort, (P=0.0007) and in the extended cohort, adjusted HR 3.83 (95% CI 1.40-10.42). SNPs in CYP19A1 alone were not significantly associated with disease-free survival in any of the analyses. The impact of the CYP1A2 SNP was modified by a SNP in CYP19A1, where patients with both SNPs had increased risk for early events, adjusted HR 5.21 (95% CI 2.05-13.23) compared to other patients. Conclusion: This study identified a potential and new predictive marker in BC patients: CYP1A2 alone and CYP1A2 in combination with CYP19A1. If confirmed, these results may provide a way to more personalized medicine. Citation Format: Simonsson M, Veerla S, Markkula A, Rose C, Ingvar C, Jernström H. CYP1A2– A novel genetic marker for aromatase inhibitor response in the treatment of breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-26.

Abstract 4218: Combined effect of COX2 genotype, ER status, body constitution, and treatment on risk of early events in breast cancer patients

Abstract Aim: The aim of the present study was to investigate the impact of the COX2 rs5277 polymorphism on early events and treatment response in relation to tumor ER-status and to determine whether any effect is modified by body constitution. Background: The synonymous COX2 rs5277 polymorphism (306G>C, V102V) has been directly linked to several cancers associated with inflammation. Breast cancer patients with tumors expressing COX-2 have a shorter disease-free survival. It is currently unclear whether the rs5277 genotype is correlated with tumor COX-2 expression. Tumor COX-2 expression may have contrasting effects on breast cancer tumors depending on the tumor's estrogen receptor (ER) status. It has been associated with increased estrogen levels in ER-positive tumors and Akt-pathway activation in ER-negative tumors. Methods: The present study is based on data collected from 634 patients initiating treatment between October 2002 and October 2008. Risk of early events was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained at the pre-operative visit. Clinical data, patient-, and tumor-characteristics were obtained from questionnaires, patients' charts, population registries, and pathology reports. Results: Among all patients, 70.1% were GG-carriers, 27.5% were GC-carriers, and 2.4% were CC-carriers. Median follow-up was 5.1 years. Median age was 59.6 years (range 25-99 years). No association was seen between the G/G genotype and risk of early events in patients with ER-positive tumors, but this genotype conferred an over 4-fold increased risk in patients with ER-negative tumors (Pinteraction=0.015). G/G-carriers with a larger breast volume who had received chemotherapy had a 9-fold risk of early events irrespective of ER-status. C-allele carriers with ER-positive tumors who had a larger breast volume and had received endocrine-therapy had a 2-fold increased risk of early events. Conclusion: COX2 genotype, body constitution, and ER-status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may provide a tool for identifying patients in need of more personalized treatment. Citation Format: Andrea Markkula, Maria Simonsson, Christian Ingvar, Carsten Rose, Helena Jernström. Combined effect of COX2 genotype, ER status, body constitution, and treatment on risk of early events in breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4218. doi:10.1158/1538-7445.AM2014-4218

Abstract 2171: Weight change in relation to early breast cancer events in breast cancer patients

Abstract Background: Weight change may influence breast cancer prognosis. The aim was to investigate whether weight change between the preoperative and 1-year postoperative visit was associated with risk of early breast cancer events in a population-based cohort of breast cancer patients in Sweden. Methods: Weight was measured by research nurses at the preoperative and the 1-year follow-up visits from 849 primary breast cancer patients operated between 2002 and 2011 in Lund, Sweden. Tumor characteristics, clinical data, and date of death were obtained from pathology reports, patient charts, and population registries. Results: The median follow-up was three years and 79 early breast cancer events occurred during the follow-up period. In all patients, there was a non-significant tendency towards decreased risk of early events with weight loss (Ptrend = 0.11). Weight loss was significantly associated with lower risk of early events compared to stable weight or weight gain in patients with axillary nodal involvement (Ptrend = 0.012), but not in patients without axillary nodal involvement. Further analysis showed that weight loss was only significantly associated with lower risk of early events among patients younger than 70 years with axillary nodal involvement, while patients who had gained more than 5% of the preoperative weight had significantly earlier events compared to those with stable weight. The results remained significant after adjustment for age at diagnosis, natural logarithm of the preoperative weight, invasive tumor size, axillary nodal involvement, and ER status. Further adjustments for smoking and alcohol abstinence, ever use of hormone therapy, or for treatments did not materially change the result. Conclusion: Weight loss was associated with significantly lower risk for early breast cancer events in patients younger than 70 years with axillary nodal involvement compared to stable weight or weight gain. If these results are confirmed, weight management may be incorporated in post-diagnosis management of breast cancer patients with axillary nodal involvement and have a significant beneficial impact on short-term prognosis. Citation Format: Xuyian Kenéz, Andrea Markkula, Maria Simonsson, Christian Ingvar, Carsten Rose, Helena C. Jernström. Weight change in relation to early breast cancer events in breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2171. doi:10.1158/1538-7445.AM2014-2171

Abstract B115: Excessive milk production during breast feeding prior to breast cancer diagnosis is associated with increased risk for early events

Abstract 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.

Excessive milk production during breast-feeding prior to breast cancer diagnosis is associated with increased risk for early events

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.

Abstract 108: Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status.

Abstract Whether coffee modulates response to endocrine therapy in breast cancer patients is currently unknown. The CYP1A2 and CYP2C8 enzymes contribute to tamoxifen and caffeine metabolism. The aim was to investigate the impact of coffee consumption on tumor characteristics and disease-free survival in relation to breast cancer treatment and CYP1A2 and CYP2C8 genotypes. Questionnaires regarding lifestyle were completed preoperatively by 592 patients in Southern Sweden. CYP1A2*1F and CYP2C8*3 were genotyped. Clinical data and tumor characteristics were obtained from patients’ charts, population registries, and pathology reports. Coffee consumption was categorized as low (0-1 cups/day), moderate (2-4 cups/day), or high (5+cups/day). The proportion of estrogen receptor negative (ER-) tumors increased with increasing coffee consumption (Ptrend=0.042). Low consumption was associated with higher frequency of discordant receptor status (ER+PgR-) OR 2.61 (1.59-4.29) compared to higher consumption. Median follow-up time was 4.92 years. Tamoxifen-treated patients with low consumption had significantly increased risk for early events compared to patients who consumed two or more cups/day, adjusted HR 2.50 (1.20-5.26). Low coffee consumption was also associated with higher risk for distant metastases in tamoxifen-treated patients with ER+ tumors, adjusted HR 2.43 (1.00-5.88). Low consumption combined with at least one CYP1A2*1F C-allele or CYP2C8*3 was associated with a high risk for early events in tamoxifen-treated patients, adjusted HRs 3.49 (1.54-7.90) and 6.14 (2.46-15.34), respectively. In conclusion, a moderate to high coffee consumption of caffeinated coffee was associated with significantly lower risk for early breast cancer events in tamoxifen-treated patients. This may be due to modification of the hormone receptor status or altered CYP enzyme activity. If confirmed, new recommendations regarding coffee consumption during tamoxifen-treatment may be warranted. Citation Format: Maria Simonsson, Viktoria Söderlind, Maria Henningson, Maria Hietala, Carsten Rose, Christian Ingvar, Helena C. Jernström. Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 108. doi:10.1158/1538-7445.AM2013-108

Abstract 2869: Interaction between a COX2 polymorphism and ER status in relation to risk for early events in breast cancer patients.

Abstract Background. Cyclooxygenase-2 (COX2) polymorphisms are associated with cancer in the lung, colorectum, and breast. In several studies, the COX2 rs5277 variant has been implicated in cancers associated with inflammation. COX-2 is the rate-limiting enzyme in the production of the pro-inflammatory prostaglandin, which activates CYP19 transcription and increases CYP19 (aromatase) levels, the key enzyme in androgen to estrogen conversion. The aim of this study was to investigate whether associations between the COX2 rs5277 polymorphism and early breast cancer events vary according to ER-status. Methods. COX2 rs5277 (306G>C, V102V) was genotyped with PCR based methods in 634 breast cancer patients in a population-based ongoing cohort from southern Sweden. Clinical data were obtained from patient charts and pathology reports. Rs5277 was examined in relation to patient, tumor characteristics and early events. Results. Minor allele frequency was 16.1%. Rs5277 was not associated with patient or tumor characteristics. Median follow-up was 4.92 years in patients with invasive tumors. Overall, increasing number of C-alleles was not associated with early events (Log Rank 1df; p=0.35). However, after stratification according to ER status, increasing number of C-alleles was associated with a fewer early events in the 73 patients with ER-negative tumors (Log Rank 1df; p=0.029) and borderline associated with more early events among the among the 497 patients with ER-positive tumors (Log Rank 1df; p=0.081). The interaction between ER-status and COX2 rs5277 on early events was significant (pinteraction=0.010). In a multivariate model among patients with ER-positive tumors, a CC genotype predicted an increased risk for early events (HR 4.25; 95 %CI 1.18-15.29; p=0.027), adjusted for tumor size (pT), nodal involvement, age, and histological grade. None of the patients with a CC genotype and an ER-negative tumor had a breast cancer event during the follow-up. Conclusion. The results indicate that the association between the COX2 rs5277 polymorphism and early breast cancer events varies according to ER-status. Information on rs5277 genotype may provide additional prognostic information for individual breast cancer patients. Citation Format: Andrea Markkula, Maria Simonsson, Christian Ingvar, Carsten Rose, Helena C. Jernström. Interaction between a COX2 polymorphism and ER status in relation to risk for early events in breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2869. doi:10.1158/1538-7445.AM2013-2869