Carolina Ellberg

Breast cancer patients with lobular cancer more commonly have a father than a mother diagnosed with cancer

BackgroundThe association between lobular breast cancer and family history is not clear. The aim of the study was to possibly identifying new hereditary patterns predisposing for cancer in the different histopathologic subtypes of breast cancer, with focus on patients with lobular breast cancer and cancer in their first degree relatives.MethodsIn 1676 consecutive breast cancer patients detailed family history of cancer was related to histopathologic subtype of breast cancer.ResultsPatients with lobular breast cancer were found to be significantly positively associated with having a father diagnosed with cancer, OR 2.17 (95% confidence interval (CI) 1.37-3.46). The finding persisted after excluding breast cancer in the family. Ductal breast cancer was associated with having a mother diagnosed with cancer. There was a significant association between lobular breast cancer and having a father with prostate cancer, OR 2.4 (CI 1.1-5.3). The occurrence of having a father with prostate cancer for lobular breast cancer patients was higher in the younger patient group, OR 2.9 (CI 1.1-7.8), and was still high but lost statistical significance in the older patient group, OR 1.9 (CI 0.5-7.4). The association between lobular breast cancer and a father remained significant after excluding fathers with prostate cancer, OR 1.94 (CI 1.20-3.14). Other commonly occurring tumor types in the father included sarcoma and leukemia.ConclusionWe propose that lobular breast cancer is associated with having a father diagnosed with cancer, most commonly prostate carcinoma. Since the association remained after excluding family history of breast cancer, the association seems independent of classical breast cancer heredity. The association with a father diagnosed with cancer also remained after removing prostate cancer, indicating an independence from prostate cancer as well. The reason for this association is genetically unclear, but could involve sex-specific imprinting.

Impact of a paternal origin of germline BRCA1/2 mutations on the age at breast and ovarian cancer diagnosis in a Southern Swedish cohort.

Three studies have reported that BRCA1/2 mutations of paternal origin confer an earlier age at breast cancer diagnosis compared with maternal origin. The primary aim of this study was to investigate the impact of parental origin of BRCA1/2 mutations on age at breast and ovarian cancer diagnosis. This study included 577 female BRCA1/2 mutation carriers. All BRCA1/2 mutation carriers belonged to families registered between 1993 and 2011 at the Oncogenetic Clinic at Skånes University Hospital, Lund, Sweden. Cox proportional hazard ratios were used to analyze time to breast or ovarian cancer diagnosis. A novel finding was that carriers of BRCA1 mutations of paternal origin were 4 years older at age of ovarian cancer (P = 0.009) compared with those carrying a BRCA1 mutation of maternal origin. BRCA1 carriers with mutations of paternal origin were 4 years younger at breast cancer diagnosis (P = 0.017) compared with those carrying a BRCA1 mutation of maternal origin, which is in agreement with three previous studies. Both findings were adjusted for of year of inclusion, birth date, and oral contraceptive pill use. No associations between parental origin of BRCA2 mutations and time to breast or ovarian cancer diagnosis were found. An attempt to handle a potential selection bias regarding use of oral contraceptives was made using multiple imputations by chained equations. The observed age difference may allow a greater understanding of mechanisms associated with the differences in cancer penetrance in BRCA1/2 mutation carriers, some of which may depend on paternal origin.

Autoimmune diseases and hypersensitivities improve the prognosis in ER-negative breast cancer.

IntroductionBreast cancer (BC) is one of the leading causes of death among women worldwide. Immunostimulatory treatment has increasingly been used as adjuvant therapy in the last few years, in patients with melanoma and other cancer forms, often with an induction of autoimmunity as a consequence of a successful treatment. We aimed at investigating if coexisting autoimmune diseases (AD) or hypersensitivities (HS) similarly to the side effects of immunostimulatory treatment resulted in a better overall survival, compared to patients without these disorders.Material and methodsThe patient material used was a consecutive clinical material consisting of 1705 patients diagnosed with BC between 1980 and 2010 in Sweden. The patients were stratified according to coexisting AD, HS or lack of both. Overall survival was calculated using Kaplan-Meier and the Cox proportional hazard model.ResultsOur main finding was that BC patients with estrogen receptor (ER) negative tumors together with preexisting AD or HS had a statistically significant better overall survival (HR=0.53; 95% CI= 0.30-0.96) compared to patients without. Premenopausal BC patients with a coexistence of AD or HS had a better overall survival, but this was not statistically significant.DiscussionFor patients with premenopausal or ER-negative BC, coexistence with AD or HS was associated with a better overall survival. Although these findings require validation, and the mechanisms responsible need to be found, they hint to possible new treatment strategies for BC, especially for those with ER-negative tumors and potentially for premenopausal patients.

Abstract 4291: Body constitution in young healthy women from breast cancer higher risk families in relation to smoking

Introduction: The purpose of this study was to investigate potential associations between body composition and current smoking in young healthy women from high-risk families. Cigarette smoke contains >7000 chemicals of which 69 are established carcinogens and smoke also acts as an aromatase inhibitor. Smoking is now recognized as a carcinogen for the breast and influences both risk and prognosis. However, the underlying mechanisms need to be better elucidated. One study showed that breast cancer patients who smoked were younger, had a lower body mass index (BMI), smaller breast volumes, but a higher waist-to-hip ratio (WHR) than non-smokers. However, smoking was also associated with a higher frequency of prior oral contraceptive (OC) use. Since breast cancer development starts long before the tumor is clinically detectable, we aimed to study the impact of cigarette smoke on anthropometric factors. Material and methods: Between 1996 and 2006, 269 healthy women were included in a study on the impact of lifestyle factors in women 0.18). However, current smokers had significantly larger standardized waist circumference (78 vs 74 cm;adjP=0.02), and higher standardized WHR (0.79 vs 0.76;adjP=0.003) compared with non-smokers. Conclusion: Current smokers had significantly larger waist circumference and higher WHR, but similar BMI and breast volume compared with non-smokers, although most women had anthropometric measures within WHOs recommended limits. The difference in fat distribution towards more abdominal fat, suggests that current smoking is associated with a more inflammatory and/or androgenic profile at the age when breast cancer is initiated. (Less)

Abstract 2747: Increasing age at first full-time pregnancy correlates to use of oral contraceptives before age 20 in women with a family history of breast cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background Women with a family history of breast cancer (BC) in first-degree female relatives have an increased risk of BC. The aim of this study was to determine the BC risk associated with exposure to endogenous and exogenous hormones in familial BC compared with non-familial BC. Materials and methods A population-based prospective questionnaire-based cohort was initiated in 1990 in the South Swedish Health Care Region. Forty thousand healthy women between ages 25 to 65 years were randomly selected, out of which 29,520 answered the first questionnaire. Data was subsequently collected from several registries and a second questionnaire. Familial BC was defined as having first-degree relatives (mother, sisters, and/or daughters) diagnosed with BC. Known mutation carriers in BRCA-related genes (n = 13) were excluded from all analyses. To determine whether there are any differences between familial and non-familial BC risk according to hormonal exposures, Cox proportional hazard models were used. Hazard ratios (HR) were estimated with 95% confidence intervals (CI), and all models were adjusted for birthdate. Results At the end of follow-up (10/31/2013), 1,500 (5%) of the women were diagnosed with BC. Out of the 1,500 BC cases, 192 women (13%) had a family history of BC. Having a family history of BC in first-degree relatives was twice as prevalent among BC cases compared with women without BC diagnosis (OR 1.9 (CI 1.63-2.23)). When adjusting for age at menarche and ever-use of oral contraceptives (OC), an increased age at first full-time pregnancy was associated with an increased risk of BC, both for BC cases with familial BC and non-familial BC, HR 1.02 (CI 1.00-1.03) and HR 1.01 (CI 1.00-1.02), respectively. Adjusted for age at menarche and parity, an increased risk of BC was associated with use of OC before age 20 (HR 1.7 (CI 0.99-2.80)) for BC cases with familial BC compared with non-BC cases with familial BC. This was not observed in women with non-familial BC. Conclusion The main findings in this study were that older age at first full-time pregnancy has a larger impact on BC risk in women with familial BC than in women without, and that use of OC before age 20 increases the risk of BC in women with familial BC, not observed in women without. Well known familial and/or hormonal risk factors for BC were observed in our study, implying the validity of the cohort. Our results indicate similarities in risk of BC between women with, and without, familial BC regarding age at first full-term pregnancy. However, the impact seems to be larger in familial BC. If confirmed in other studies, our findings could be of interest for women with familial BC, especially regarding the increased risk when using OC during adolescence, where other alternatives are available. Citation Format: Annelie Augustinsson, Carolina Ellberg, Ulf Kristoffersson, Hakan Olsson. Increasing age at first full-time pregnancy correlates to use of oral contraceptives before age 20 in women with a family history of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2747. doi:10.1158/1538-7445.AM2015-2747

Abstract 5047: Impact of parental origin of BRCA1/ 2 mutation on age at breast and ovarian cancer diagnosis

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Parental origin of the mutation may be associated with the age of breast cancer (BC) onset in BRCA1 mutation carriers, three studies have reported that paternal origin of mutation confers an earlier BC diagnosis compared to a maternal origin. The primary aim of the study was to investigate the effect of parental origin of the BRCA1/2 mutation on age at BC and ovarian cancer (OvC) diagnosis. Material and methods: The present study consist of 400 women with a BRCA1 mutation; 92 with paternal and 241 with maternal origin of mutation, and 177 women with BRCA2 mutation; 50 with paternal and 102 with maternal origin of mutation. All carriers belongs to families registered in the OnkGen register at the Oncogenetic Clinic at Skanes University Hospital, Lund, Sweden between 1993 and 2011. All multivariate Cox Proportional Hazard models were adjusted for year of inclusion into the OnkGen register, and year of birth. All p-values were two sided and p-values less than 0.05 were regarded statistically significant. Results: The median age at diagnosis for BRCA1 mutation carriers was; BC 40 and OvC 54 years for paternal origin, and BC 42 and OvC 54 years for maternal origin. For BRCA2 mutation carriers it was; BC 41 and OvC 57 years for paternal origin, and BC 47 and OvC 54 years for maternal origin. BRCA1 mutation carriers with a paternal origin of the mutation were diagnosed with breast cancer at an earlier age compared with maternal origin of mutation, HR 1.53 (95% CI 1.08-2.17) adjusted for year of inclusion and birth date. On the other hand, BRCA1 mutation carriers with a paternal origin of the mutation were older at age of ovarian cancer diagnosis compared with maternal origin of the mutation, HR 0.44 (95% CI 0.23-0.81) adjusted for year of inclusion and birth date. Conclusions: We have confirmed earlier reported findings that BRCA1 mutation carriers with a paternal origin of BRCA1 are diagnosed with BC earlier than BRCA1 mutation carriers with a maternal origin of the BRCA1 mutation, regardless of adjustment of year of inclusion and birth date. A novel finding is that BRCA1 mutation carriers with a paternal origin of mutation are older at age of ovarian cancer than BRCA1 mutation carriers with a maternal origin of mutation, regardless of adjustment of year of inclusion and birth date. There were no associations between age at BC or OvC diagnosis and parental origin in BRCA2 mutation carriers, but the number of carriers in our material was small. The difference might be due to co-inherited modifiers, either gene or parent specific. The clinical relevance of these finding is small, we see no need of a change in the screening programs available for BRCA1/2 mutation carriers at the moment. However, the parental difference is interesting from a biological stand point. Citation Format: Carolina Ellberg, Helena Jernstrom, Per Broberg, Ake Borg, Hakan Olsson. Impact of parental origin of BRCA1/ 2 mutation on age at breast and ovarian cancer diagnosis. [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 5047. doi:10.1158/1538-7445.AM2014-5047

Abstract A127: Parental influence on breast cancer penetrance in BRCA1/2 mutation carriers: Impact of oral contraceptive use before age 20 years

Introduction: Recent data indicate that paternal inheritance may be associated with an earlier age a breast cancer (BC) diagnosis in BRCA1 mutation carriers. OC use prior to age 20 increases the risk for early onset BC ( Material and Methods: Data on 587 BRCA1/2 carriers from the OnkGen registry was retrieved; an additional 170 were added after pedigree review. Out of 757 BRCA1/2 carriers, 598 were eligible for analysis after excluding men, BRCA1/2 double carriers, and carriers screened for mutation after 01/12/2011. There were 414 BRCA1 carriers: 70 and 147 with a known paternal and maternal origin of mutation respectively. There were 184 BRCA2 carriers: 34 and 57 with a known paternal and maternal origin of mutation respectively. Information regarding OC use was obtained from questionnaires that were answered by registered carriers in the OnkGen registry. There was information regarding OC use before age 20 for 179 BRCA1 carriers and 76 BRCA2 carriers. Results: Paternal inheritance in BRCA1 carriers was associated with a lower age at BC diagnosis; crude HR 1.38 (0.98-1.94). A similar risk was observed in BRCA2 carriers but was not statistically significant crude HR 1.28 (0.81-2.00). Early OC use was more common in BRCA1 carriers with a maternal inheritance, OR 2.58 (1.30-5.11) compared to BRCA1 carriers with paternal inheritance. This was not observed in BRCA2 carriers; OR 0.81 (0.29-2.26). Paternal inheritance in BRCA1 carriers was not associated with paternal inheritance after adjustment for early OC use; HR 1.07 (0.63-1.81). For BRCA2 carriers, the risk remained similar after adjustment for early OC use, HR 1.33 (0.65-2.73). Conclusion: A borderline significant tendency towards younger age at BC diagnosis was observed in BRCA1 carriers with paternal inheritance, which is in line with previous findings. The tendency was lost after adjustment for early OC use. Since it has been previously shown that early OC use influences the risk of very early onset BC before and BRCA1 carriers with maternal inheritance were more than twice as likely to have used OCs prior to age 20 compared to those with paternal inheritance, we had expected a higher rate of early OC use in women with paternal inheritance. Citation Format: Carolina Ellberg, Helena Jernstrom, Hakan Olsson. Parental influence on breast cancer penetrance in BRCA1/2 mutation carriers: Impact of oral contraceptive use before age 20 years. [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 A127.

Abstract 3727: Telangiectasias in the skin of patients: Indicator of angiogenic status of tumors?

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: The angiogenic status of a tumor is related to the prognosis of the patient, and to the possibility of treatment with angiogenesis inhibitors. Patients who express telangiectasias (spiders) in the skin have an increased ability to form vessels, due to, for example, hormonal influences. We hypothesized that tumor tissue to some extent resembles the normal tissue in a patient, which could mean that is if a patient is prone to form spiders in the skin, the same would be true in their tumors. Spiders are associated with hormonal influence, and therefore telangiectasias in patients could be a reflection of hormonal influence and angiogenic status of their tumor. Materials and methods: A clinical series of 1682 consecutive breast cancer patients diagnosed between 1980 and June 2009 were studied. One physician scored the presence/absence of spiders on the upper part of the body at the time of breast cancer diagnosis. The aim was to further study the association between telangiectasias and classical histopathologic subtypes of breast cancer, HRT-ever use, life time number of menstrual cycles and ever use of oral contraceptive pills (OCP). All analyses were performed using multivariate logistic regression, a confidence interval (CI) of 95% was used. Results: The occurrence of telangiectasias of the upper thorax, neck and face was positively associated with HRT-ever use (OR = 3.24 (CI 2.02 – 5.19)), OCP-ever use (OR = 2.08 (CI 1.30 – 3.32)) and high number of menstrual cycles, above 550 – the upper quartile OR = 4.57 (CI 1.49-13.95). Weight was also associated with spiders, p = 0.006. Contrary to the other histopathologic subtypes no telangiectasias in the skin were observed in patients with comedo carcinoma, p = 0.0002 (Fishers exact test). No significant difference in spiders was seen between the other patients with the other subtypes. The results above were adjusted for age at diagnosis and for each studied variable simultaneously. Conclusion: The occurrence of spiders was associated with several hormonal factors indicating the importance of hormones in the induction of telangiectasias. Our theory that the tendency to form vessels is similar in normal tissue as well as in tumor tissue could explain the necrotic core in comedo carcinoma. It has been hypothesized that the necrotic core is due to the high growth rate of the tumor, but it might be due to a lesser ability to form vessels. Are comedo carcinoma patients a group who benefit less from anti-angiogenic therapy while patients with strong endogenous or exogenous hormonal exposures would benefit more from anti-angiogenic therapy? Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3727. doi:10.1158/1538-7445.AM2011-3727

Is lobular breast cancer mainly inherited from the father

1544 Background: The association between invasive lobular carcinoma (ILC) and family history is not clear, some studies show no association; however, a few studies made on younger women show an association to family history, especially in BRCA2 carriers. Therefore, we thought it would be interesting to investigate the relationship between histopathological subtype of breast cancer, focusing on lobular breast cancer, and cancer other than breast cancer in first degree relatives to possibly find new hereditary patterns predisposing for cancer. We also excluded male breast cancer. Methods: In 1677 consecutive breast cancer patients the following risk factors were related to histopathology; parity, HRT use and detailed family history of breast cancer. All analyses were age adjusted and factors were simultaneously adjusted for. Results: In binary regression logistic models adjusted for age at diagnosis, type of breast cancer inheritance, HRT use and number of children, the patients with ILC were found to be si...

Abstract 5745: Hormonal risk factors in breast cancer in relation to histopathology: A clue to tissue of origin of the tumor

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background. The association between breast cancer (bc) and hormonal influence is well known. Associations to certain hormonal risk factors in the different histopathological bc types could indicate that exposure to hormones during different stages of breast development could give rise to different types of bc. We wanted to get an overview of several risk factors with a known or a possible hormonal effect in relation to the classical histopathological groups of breast cancer to explore our hypothesis. Materials and method. A clinical series of 1676 patients diagnosed with bc were investigated. In the present study we investigated possible associations between classical histopathological bc and possible risk factors such as occurrences of spider telangiectasias, varicose veins, HRT-ever use, number of childbirths and combined oral contraceptive pill (COCP) before first child. Analyses were performed using a binary logistic regression model, and were adjusted for age at diagnosis and for each factor simultaneously. A confidence interval (CI) of 95% was used. Results. COCP use before first child was significantly positively associated with pure invasive ductal bc and invasive ductal bc combined with ductal carcinoma in situ (ductal/DCIS), odds ratio (OR) 1.5 (CI 1.2-2.1) and 3.3 (CI 1.6-7.0) respectively. Comedo bc was associated with a large number of childbirths (p-value 0.004), whereas mucinous bc (ductal bc was borderline significant p-value 0.006), on the other hand, was associated with a low number of childbirths (p-value 0.004). HRT-ever use was associated with an increased risk for pure lobular, mixed lobular, mixed ductal bc, OR 1.5 (CI 1.0-2.3), 1.9 (1.2-3.1) and 1.7 (1.2-2.5) respectively. The occurrence of spider telangiectasias was nonexistent in comedo breast cancer, but increased the risk of ductal cancer/DCIS (OR 4.7 (CI 2.2-10.1)). Varicose veins were significantly associated with pure comedo (OR 2.8(CI 1.2-6.8) and tubular bc (OR 4.4(CI 1.3-15.4)). Conclusions. Before first pregnancy the lobules are not completely developed, therefore COCP use before first pregnancy possibly affects the duct system to a larger extent then the lobules, in line with our findings. However, HRT is used by women in menopause, and could therefore have a greater influence on the lobules. The association between HRT use and lobular bc has been shown in other studies. Varicose veins are thought to be induced by an increased hormonal level, either during pregnancy or menopause, and could be used as an indicator of large hormonal exposures or specific phenotypes regarding the estrogen receptor. Different histopathological groups respond differently to the hormonal risk factors in the present study, which could indicate that there is a slight difference in the biology between them. We propose that based on risk factors it might be possible to locate the origin of different tumors within the breast. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5745.