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Supplementary Table 3. Risk of death from breast cancer between diagnostic periods, for each molecular subtype 5 and 15 years after diagnosis (Cox regression analysis).

Supplementary Figure 2. Subtype-specific incidence rates according to age and year of birth. Blue lines: Women born before 1929. Red lines: Women born in 1929 or later. Dotted lines (red and blue) represent incidence rates of subtyped cases. Solid lines (red and blue) represent average incidence rates from 50 imputed datasets with corresponding 95% confidence intervals (CIs).

Supplementary Figure 3. Cumulative incidence of death from breast cancer according to breast cancer subtypes. A: Women diagnosed before 1995 (Gray's test: p=0.0002). B: Women diagnosed in 1995 or later (Gray's test: p

Supplementary Table 1. Characteristics of the study population used in estimations of breast cancer incidence.

Supplementary Table 2. Incidence rates and incidence rate ratios of breast cancer according to hormone and HER2 receptor status, age at diagnosis and year of birth. Observed and imputed estimates.

Supplementary Figure legends.

Supplementary Table 5. Risk of death from breast cancer between diagnostic periods, for each breast cancer subtype 5 and 15 years after diagnosis (Cox regression analysis).

Supplementary Figure legends.

Background: Secular trends in incidence and prognosis of molecular breast cancer subtypes are poorly described. We studied long-term trends in a population of Norwegian women born 1886–1977.Methods: A total of 52,949 women were followed for breast cancer incidence, and 1,423 tumors were reclassified into molecular subtypes using IHC and in situ hybridization. We compared incidence rates among women born 1886–1928 and 1929–1977, estimated age-specific incidence rate ratios (IRR), and performed multiple imputations to account for unknown subtype. Prognosis was compared for women diagnosed before 1995 and in 1995 or later, estimating cumulative risk of death and HRs.Results: Between 50 and 69 years of age, incidence rates of Luminal A and Luminal B (HER2−) were higher among women born in 1929 or later, compared with before 1929 [IRRs 50–54 years; after imputations: 3.5; 95% confidence interval (CI), 1.8–6.9 and 2.5; 95% CI, 1.2–5.2, respectively], with no clear differences for other subtypes. Rates of death were lower in women diagnosed in 1995 or later, compared to before 1995, for Luminal A (HR 0.4; 95% CI, 0.3–0.5), Luminal B (HER2−; HR 0.5; 95% CI, 0.3–0.7), and Basal phenotype (HR 0.4; 95% CI, 0.2–0.9).Conclusions: We found a strong secular incidence increase restricted to Luminal A and Luminal B (HER2−) subtypes, combined with a markedly improved prognosis for these subtypes and for the Basal phenotype.Impact: This study documents a clear secular increase in incidence and a concomitant improved prognosis for specific molecular breast cancer subtypes. Cancer Epidemiol Biomarkers Prev; 25(12); 1625–34. ©2016 AACR.

BACKGROUND: Preoperative predictors for the need of prophylactic lymph node dissection in the lateral neck have been studied in patients with medullary thyroid carcinoma (MTC). OBJECTIVES: To evaluate the ability of serum calcitonin to predict the extent of surgery needed in the lateral neck. METHODS: This retrospective population-based cohort study includes data from 94 of 139 patients with MTC surgically treated in Norway from 2003 to 2016. Patients were identified in the 4 regional centers treating MTC and by the Cancer Registry of Norway, and grouped according to calcitonin levels. In 58 patients without distant metastases or disease progression to the next tumor level (NPNL), data were compared in prognostic groups (N0-NPNL), (N1a-NPNL), and (N1b-NPNL). RESULTS: At calcitonin levels ≤500, 501–1,000, and >1,000 pmol/L, metastatic lymph nodes in the lateral neck were found in 16, 50, and 71% of the patients, respectively. In the prognostic groups, 19% of N0-NPNL patients had calcitonin >500 pmol/L and 17% of N1b-NPNL patients had calcitonin ≤500 pmol/L. In multivariate analysis, factors predicting biochemical cure and calcitonin level ≤500 pmol/L were no metastatic lymph nodes in the lateral neck (p = 0.030) and tumor diameter ≤20 mm (p < 0.001), respectively. Factors related to metastatic lymph nodes in the lateral neck were extrathyroidal extension (p = 0.007) and no biochemical cure (p = 0.028). CONCLUSIONS: Basal calcitonin cannot predict the need for prophylactic lateral lymph node dissection in patients with MTC. Further prospective, randomized studies are warranted.

Background Topical administration of tranexamic acid (TXA) may be an alternative to intravenous administration to reduce bleeding with a lower risk of systemic adverse events. The aim of this study was to investigate whether moistening a surgical wound with TXA before closure, leaving a thin film of drug only, would reduce postoperative bleeding. Methods This was a two‐centre, stratified, parallel‐group, placebo‐controlled, double‐blind RCT. Patients undergoing mastectomy with or without axillary lymph node clearance were randomized 1 : 1 to moistening of wound surface before closure with either 25 mg/ml TXA or 0·9 per cent sodium chloride (placebo). The primary endpoint was postoperative bleeding as measured by drain production in the first 24 h. Secondary endpoints were early haematoma, total drain production, postoperative complications and late aspirations of seroma within 3 months. Results Between 1 January 2016 and 31 August 2018, 208 patients were randomized. Two patients were converted to a different surgical procedure at surgery, and four did not receive the intervention owing to technical error. Thus, 202 patients were included in the study (101 in the TXA and 101 in the placebo group). TXA reduced mean drain production at 24 h (110 versus 144 ml; mean difference 34 (95 per cent c.i. 8 to 60) ml, P = 0·011). One patient in the TXA group had early haematoma compared with seven in the placebo group (odds ratio (OR) 0·13 (95 per cent c.i. 0·02 to 1·07); P = 0·057). There was no significant difference in postoperative complications between TXA and placebo (13 versus 10; OR 1·11 (0·45 to 2·73), P = 0·824) or need for late seroma aspirations (79 versus 67 per cent; OR 1·83 (0·91 to 3·68), P = 0·089). Conclusion Moistening the wound with TXA 25 mg/ml before closure reduces postoperative bleeding within the first 24 h in patients undergoing mastectomy. Registration number: NCT02627560 (https://clinicaltrials.gov)., Moistening surgical wounds with tranexamic acid 25 mg/ml before closure is a simple, low‐cost intervention that reduces bleeding by one‐third and may reduce risk of rebleeding. The effect is comparable to intravenous administration, with a reduced risk of systemic adverse events. The authors propose this preventive measure for general reduction of postoperative bleeding. Local tranexamic acid reduces bleeding after mastectomy

Background: Medullary thyroid carcinoma (MTC) is rare. Nationwide population-based studies are important to evaluate its clinical course. Objectives: To describe all patients with MTC in Norway during 1994–2016 and compare time-related trends in diagnostics and surgical treatment, including prognostic factors for biochemical cure and disease-specific survival (DSS). Methods: This retrospective population-based cohort study includes data for 228 out of 237 patients (96%) with MTC; 201 patients were surgically treated. Patients were identified in the 4 regional centers treating MTC and by the Cancer Registry of Norway. Data were collected from patients’ files. Trends were compared over 2 study periods. Results: MTC accounted for 4.2% of thyroid carcinomas. During the study periods, the incidence increased from 0.18 to 0.25: 100,000 per year, preoperative diagnostics improved with increased use of calcitonin, ultrasound, and fine-needle cytology (p = 0.010, p < 0,001, and p = 0.001), patients were diagnosed at an earlier tumor stage (p = 0.004), and more patients were cured (p = 0.002). Via multivariate analysis of patients with metastatic lymph nodes, independent prognostic factors for cure were: a low ratio of metastatic and total number of dissected lymph nodes (p = 0.021) and no extrathyroidal extension (p = 0.030). Independent prognostic factors for DSS were: no distant metastasis, a younger age, and a low ratio of metastatic and dissected lymph nodes (p = 0.005, p = 0.020, p = 0.022). Conclusions: Preoperative diagnostics have improved over time with increased therapeutic control. A low ratio of metastatic and dissected lymph nodes predicts better outcomes in patients with metastatic lymph nodes.

The aim of this study was to evaluate the outcome of risk-reducing mastectomy in BRCA1/2 mutation carriers with and without breast cancer. Uptake, methods of operation and reconstruction, complications, patient satisfaction and histopathological findings were registered at all five departments of genetics in Norway. Data from 267 affected and unaffected BRCA1/2 mutation carriers were analyzed, including a study-specific questionnaire returned by 178 mutation carriers. There was a steady increase in the uptake of risk-reducing mastectomies during the study period. Complications were observed in 106/266 (39.7%) women. Patient satisfaction was high. The majority of women expressed great relief after risk-reducing mastectomy and would have chosen the same option again.

We report the 5- and 10-year survival rate of women diagnosed with breast cancer in the context of an annual MRI-based surveillance program. In 2001, as part of a national initiative, women in Norway with a BRCA1 mutation were offered annual screening with breast MRI in addition to mammography. 802 women with a BRCA1 mutation were screened one or more times and followed for a mean of 4.2 years. As of December 2011, 68 of 802 women in the screening program were diagnosed with DCIS or invasive breast cancer (8.5 %), including eight prevalent, 50 incident screen-detected and eight interval cancers. Two latent cancers were detected at prophylactic mastectomy. Sixty-three of the cancers were invasive and five were in situ. The mean tumour size was 1.4 cm (range 0.2-4.5 cm), and 85 % of the patients were node-negative. Ten of the 68 patients died of cancer in the follow-up period. The 5-year breast cancer-specific survival for women with cancer was 75 % (95 % CI 56-86 %) and the 10-year survival was 69 % (95 % CI: 48-83 %). The 5-year survival for women with Stage 1 breast cancer was 82 % compared to 98 % in the population. The 5- and 10-year survival of women with a BRCA1-associated breast cancer detected in a national MRI-based screening program in BRCA1 mutation carriers Norway was less than anticipated. The benefit of annual MRI surveillance on reducing breast cancer mortality in BRCA1 mutation carriers remains to be proven.

Background The aim of the present study was to explore whether preoperative white blood cell (WBC) count may predict 30-day mortality and long-term survival following surgery for abdominal aortic aneurysm (AAA). Secondarily, we wanted to assess the potential sex differences in WBC in these patients. Methods The study was carried out as a retrospective cohort study. Patients undergoing surgery for intact and ruptured AAA (rAAA) at our institution consecutively in the time period 1994–2007 were included. Patients were either treated with open aneurysm repair or with endovascular aneurysm repair. Data were collected from the patients' medical records, including laboratory reports for WBC count prior to surgery. Mortality and long-term survival were extracted from The Patient Administrative System. Results A total of 988 patients were included, 712 (72%) patients were treated for intact AAA and 276 (28%) underwent surgery for rAAA. Patients with WBC ≥11 ×109/L had a 8.7-fold higher risk of 30-day mortality undergoing surgery for intact AAA compared to patients with WBC

Background: Secular trends in incidence and prognosis of molecular breast cancer subtypes are poorly described. We studied long-term trends in a population of Norwegian women born 1886–1977. Methods: A total of 52,949 women were followed for breast cancer incidence, and 1,423 tumors were reclassified into molecular subtypes using IHC and in situ hybridization. We compared incidence rates among women born 1886–1928 and 1929–1977, estimated age-specific incidence rate ratios (IRR), and performed multiple imputations to account for unknown subtype. Prognosis was compared for women diagnosed before 1995 and in 1995 or later, estimating cumulative risk of death and HRs. Results: Between 50 and 69 years of age, incidence rates of Luminal A and Luminal B (HER2−) were higher among women born in 1929 or later, compared with before 1929 [IRRs 50–54 years; after imputations: 3.5; 95% confidence interval (CI), 1.8–6.9 and 2.5; 95% CI, 1.2–5.2, respectively], with no clear differences for other subtypes. Rates of death were lower in women diagnosed in 1995 or later, compared to before 1995, for Luminal A (HR 0.4; 95% CI, 0.3–0.5), Luminal B (HER2−; HR 0.5; 95% CI, 0.3–0.7), and Basal phenotype (HR 0.4; 95% CI, 0.2–0.9). Conclusions: We found a strong secular incidence increase restricted to Luminal A and Luminal B (HER2−) subtypes, combined with a markedly improved prognosis for these subtypes and for the Basal phenotype. Impact: This study documents a clear secular increase in incidence and a concomitant improved prognosis for specific molecular breast cancer subtypes. Cancer Epidemiol Biomarkers Prev; 25(12); 1625–34. ©2016 AACR.

Interval cancer is cancer detected between screening rounds among screening participants. In the Norwegian Breast Cancer Screening Programme, 19 per 10,000 screened women are diagnosed with interval cancer. We conducted semi-structured interviews with 26 such women. The women interpreted their interval breast cancer in two ways: that mammography can never be completely certain, or as an experience characterized by shock and doubts about the technology and the conduct of the medical experts. Being diagnosed with interval cancer thus influenced their trust in mammography, but not necessarily to the point of creating distrust. The women saw themselves as exceptions in an otherwise beneficial screening programme. Convinced that statistics had shown benefits from mammography screening and knowing others whose malignant tumours had been detected in the programme, the women bracketed their own experiences and continued trusting mammography screening. Facing a potentially lethal disease and a lack of alternatives to mammography screening left the women with few options but to trust the programme in order to maintain hope. In other words, trust may not only be a basis for hope, but also a consequence of it.

Background The aim of this retrospective matched cohort study was to evaluate the rate of recurrence among women with delayed large flap breast reconstruction after mastectomy for breast cancer. The recurrence rate among women treated at a single hospital was compared with that in an individually matched control group of women with breast cancer who did not have reconstruction after mastectomy. Methods Between 1982 and 2001, 125 women with previous invasive breast carcinoma underwent delayed large flap breast reconstruction with pedicled musculocutaneous or microvascular flaps (a median of 32 months after mastectomy). They were matched individually with 182 women with breast cancer who had a mastectomy but did not undergo breast reconstruction. Matching criteria were year of diagnosis, age at diagnosis and treating hospital. Medical records were evaluated until October 2007. Histopathological specimens for all included women were re-evaluated. The endpoint was locoregional or distant breast cancer recurrence. The risk of recurrent disease was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. Results Median follow-up for the entire cohort was 146 months. The reconstruction group had a 2·08 (95 per cent confidence interval 1·07 to 4·06) times higher risk of recurrent disease than the mastectomy only group. Conclusion Women with breast cancer who had delayed reconstruction with a large flap in this study had a higher risk of recurrent disease than those with mastectomy alone.

Ten BRCA mutations were demonstrated to be frequent in the Norwegian population. We present maps verifying the uneven distribution of prevalences according to municipality. We tested incident breast cancer cases treated in Mid-Norway from 1999 onwards for these mutations. Uptake of testing was 97% and 2.5% were demonstrated to be mutation carriers. Ten (77%) were outside families previously known to carry a mutation. Ten (77%) did not meet clinical criteria to be selected for mutation testing. We tested incident ovarian cancer cases in South-West Norway from 2001 onwards. Uptake of testing was 80% and 23% were mutation carriers. Twenty-one (88%) were outside families previously known. Twelve (67%) did not meet clinical criteria to be selected for testing. All patients with mutation collaborated actively to give our offer of predictive genetic testing to their relatives. No complaint on the activity was received.

BRCA1 associated tumours are found to express an oestrogen receptor negative "basal epithelial-like" phenotype. In contrast to ER negative tumours in general, such tumours rarely harbour amplification of the HER-2 gene. However, little is known about TOP2A gene amplification status in BRCA1-associated tumours. Such information may be of importance to therapy, as amplification of TOP2A has been associated with dose-dependent sensitivity to anthracycline therapy in breast cancer. We examined 40 breast carcinomas from BRCA1 mutation carriers and 40 sporadic breast carcinomas matched for age, tumour diameter and histological grade for HER-2 and TOP2A amplification status using fluorescence in situ hybridisation (FISH). Co-amplification of TOP2A and HER-2 was found in four of the mutation carriers and in three of the controls. While six tumours in the control group harboured HER-2 amplifications with normal TOP2A, this occurred in three of the BRCA1 associated tumours only. In contrast, three of the BRCA1-associated tumours but none of the controls harboured TOP2A amplification despite normal HER-2 status. Our findings have potential therapeutic implications. HER-2 assessment is routinely used to select breast cancer patients for trastuzumab but also dose-intensive anthracycline therapy. Our data suggest that BRCA1-associated breast cancers also need to be tested for TOP2A amplification.

Gareth Evans et al. in a recent article in the journal [http://www.ncbi.nlm.nih.gov/pubmed/24687378] concluded that survival from breast cancer in very high risk women is better in screened versus unscreened women with or without a demonstrated genetic cause, and that BRCA2 mutation carriers may benefit from MRI screening in addition to mammography (Mx). However, this may not be the case for BRCA1 mutation carriers. Their dataset included no more than 27 and 24 BRCA1 breast cancer cases detected through Mx or MRI, respectively. We recently reported survival in BRCA1 mutation carriers diagnosed with breast cancer through annual Mx and MRI [http://www.ncbi.nlm.nih.gov/pubmed/23615785]. The main finding was that despite detecting tumours at an early stage, survival was inferior to what might have been expected according to Kurian et al. [http://www.ncbi.nlm.nih.gov/pubmed/22231042]. Referring to our results, Evans et al. state in their discussion that ‘.. formal evidence for a survival advantage (for MRI versus mammography alone) has not so far been published’. In order to make our data for patients followed at the outpatient clinic at Oslo University Hospital available to all, we here present updated survival analysis in the MRI series previously reported (MRI series), and compare that series to survival in BRCA1 breast cancer cases detected through annual screening with mammography without MRI (Mx series). Our selection, methods and ethics were described in our recent publication mentioned above. The Mx series were the prospectively detected breast cancer cases before MRI was added to the protocol for BRCA1 mutation carriers in 2001, and those subjected to annual Mx alone based on family history before their BRCA1 mutations were detected subsequently. In contrast to our previous report, only patients not having had any cancer before or at first planned examination were included in the present analysis. We diagnosed 6 carcinoma in situ in the Mx series and 3 in the MRI series. Kaplan–Meier survival analyses were performed in the 47 invasive cancer cases detected in the Mx series among whom 12 had died, and in the 45 invasive cancer cases in the MRI series among whom 8 had died. None of the deceased had any other cancers. 5- and 10-years survival was 0.81 (95 % CI 0.63–0.88) and 0.72 (95 % CI 0.60–0.86), respectively, in the Mx series, compared to 0.82 (95 % CI 0.63–0.92) and 0.73 (95 % CI 0.52–0.86) in the MRI series (Fig. 1). Fig. 1 Survival in the MRI and Mx series with 95 % CIs Age (grouped as = 50 years), tumour size ( 20 mm), nodal spread (yes/no), ER, PR and grade were compared with survival through Cox proportional hazard models in the combined series. None gave significant results for univariate analyses (p ≥ 0.18 for any), nor for multivariate analyses (p ≥ 0.24). The findings in this larger series than the one reported by Gareth Evans et al. support their notion that there may be no additional survival benefit from early diagnosis through MRI compared to Mx for BRCA1 mutation carriers: As previously reported, tumours did appear to be downstaged in the MRI series compared to the Mx series—but the expected improved survival was not observed, and there was no association with survival and stage at diagnosis, which would have been expected if the earlier stage at diagnosis in the MRI series were to be associated with better prognosis. Prevalence of carcinoma in situ was low in both series. Time-trends in treatment are potential confounders to survival studies recruiting patients over many years: The MRI cases were treated in more recent years than the Mx cases and would have been expected to have improved survival because of that, nonetheless this was not found. We had expected a right-shift in the survival curve for the MRI series reflecting the earlier diagnosis even in the absence of a ‘true’ improved survival; however, this was not found. Our population has specific founder BRCA1 mutations, and the female carriers may be subjected to different environment factors compared to carriers in other populations. We had no control group without screening, and our results are not in conflict with the conclusion by Gareth Evans et al. that early diagnosis and treatment may be associated with improved survival. Our results address the putative benefit of adding MRI to annual Mx, for which none was apparent. We look forward to reports from other groups on the observed survival related to early diagnosis with MRI in BRCA1 mutation carriers, because despite our series being the largest reported so far, we are still short of patients included to be sure that results are not caused by chance variation based on limited numbers.

Publshed article Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. However, its clinical significance remains to be established. In this study, the main aims were to discover whether reclassification of breast cancer into molecular subtypes provides more precise information regarding outcome compared to conventional histopathological grading and to study breast cancer-specific survival in the different molecular subtypes. Cases of breast cancer occurring in a cohort of women born between 1886 and 1928 with long-term follow-up were included in the study. Tissue microarrays were constructed from archival formalin-fixed, paraffin-embedded tissue from 909 cases. Using immunohistochemistry and in situ hybridisation as surrogates for gene expression analyses, all cases were reclassified into the following molecular subtypes: Luminal A; Luminal B (HER2−); Luminal B (HER2+); HER2 subtype; Basal phenotype; and five negative phenotype. Kaplan–Meier survival curves and Cox proportional hazards models were used in the analyses. During the first 5 years after diagnosis, there were significant differences in prognosis according to molecular subtypes with the best survival for the Luminal A subtype and the worst for HER2 and five negative phenotype. In this historic cohort of women with breast cancer, differences in breast cancer-specific survival according to subtype occur almost exclusively amongst the histopathological grade 2 tumours. From 5 years after time of diagnosis until the end of follow-up, there appears to be no difference in survival according to molecular subtype or histopathological grade (c) The Author(s) 2013. This article is published with open access at Springerlink.com

Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers. One hundred and sixty-seven women with disease-associated germline BRCA1 mutations and breast cancer from 1980 to 2001 were identified. Tumour characteristics, treatment given and survival were recorded. A control group comprising three hundred and four women matched for age, time of diagnosis and stage were used to compare survival. BRCA1 mutation carriers were found to have a poorer prognosis, which could be explained by neither the mode of surgical treatment nor the use of adjuvant chemotherapy. BRCA1 mutation carriers with node negative breast cancer had worse overall survival than controls. Our findings confirm the serious prognosis of BRCA1-associated breast cancer even when diagnosed at an early stage, and that type of treatment does not influence prognosis.

Women with germline BRCA1 mutation have a significant risk of breast and/or ovarian cancer. Prophylactic bilateral mastectomy (PBM) and prophylactic bilateral salpingo-oophorectomy (PBSO) prevent cancer in mutation carriers. The cost-effectiveness of PBSO (age of 35 years) with or without PBM five years earlier was compared to a no intervention setting employing a marginal cost analysis. National data on cancer incidence, mortality rates and costs were implemented together with observed Norwegian BRCA1 data in a Markov model and PBSO was assumed to reduce the risk of ovarian cancer by 90%. A 3% discount rate was used. The additional health care cost per mutation carrier undergoing PBSO and PBM was €15,784, and 6.4 discounted life years gained (LYG) was indicated (PBSO alone with 100% acceptance 3.1 LYG). The additional cost per LYG was €1973 (PBSO alone €1749/LYG). Including all resource use, the figure was a cost of €496 and €1284 per LYG, respectively. PBSO with or without PBM in BRCA1 mutation carriers is cost-effective. A testing of all incident breast cancers to identify mutation carrying families should be explored.

We wanted to compare the sensitivities of breast magnetic resonance imaging (MRI) and the conventional screening programme consisting of mammography (XRM) +/- ultrasound for early diagnosis of breast cancer in BRCA1/2 mutation carriers. BRCA1/2 mutation carriers were examined prospectively by both breast MRI and XRM +/- ultrasound. Eight hundred and sixty-seven MRI examinations were carried out in 445 BRCA1 and 46 BRCA2 mutation carriers. A total of 25 cancers were observed, five (20%) as interval cancers. At the time of diagnosis, sensitivity to detect cancer was 19/22=86% for MRI and 12/24=50% for XRM. Twenty-one were examined by both methods at the time of diagnosis. In the19 BRCA1 mutation carriers among them, MRI had a sensitivity of 1/3(33%) to diagnose DCIS and 15/16 (94%) among the invasive cancers. For XRM the sensitivities were 1/3(33%) for DCIS, 3/7(42%) for pT1b, 3/6(50%) for pT1c, and 3/3/100%) for pT2. In the two BRCA2 mutation carriers, both were demonstrated by breast MRI, neither was detected by XRM. Breast MRI had increased sensitivity compared to XRM to diagnose all cancers staged less than pT2.

Aromatase inhibitors improve relapse-free survival in early breast cancer, but there is concern about possible detrimental effects on bone mineral density (BMD) and plasma lipids. This paper presents the results of a 2-year study evaluating the effects of exemestane versus placebo on BMD, bone markers, plasma lipids and coagulation factors, including a 1-year follow-up after termination of treatment in 147 patients. During treatment, the mean annual rate of loss of BMD in the lumbar spine was 2.17% in the exemestane group versus 1.84% in the placebo group (n.s.) and 2.72% versus 1.48%, respectively, in the femoral neck (P=0.024). A loss of BMD above that expected in both arms of this study could be due to low vitamin D status (88% of all patients had vitamin D levels

Purpose To evaluate potential detrimental effects of exemestane on bone and lipid metabolism. Patients and Methods Postmenopausal women with early breast cancer were randomly assigned to exemestane 25 mg daily or placebo for 2 years in a double-blind setting. Primary objective was to evaluate the effect of exemestane on bone mineral density. Secondary objectives were effects on bone biomarkers, plasma lipids, coagulation factors, and homocysteine. Planned size was 128 patients. Results One hundred forty-seven patients were enrolled. All patients completed their 24-month visit except for those discontinuing treatment at an earlier stage. The mean annual rate of bone mineral density loss was 2.17% v 1.84% in the lumbar spine (P = .568) and 2.72% v 1.48% in the femoral neck (P = .024) in the exemestane and placebo arm, respectively. The mean change in T-score after 2 years was −0.21 for exemestane and −0.11 on placebo in the hip, and −0.30 and −0.21, respectively, in the lumbar spine. Exemestane significantly increased serum level and urinary excretion of bone resorption, but also bone formation markers. Except for a modest reduction in high-density lipoprotein cholesterol (P < .001) and apolipoprotein A1 (P = .004), exemestane had no major effect on lipid profile, homocysteine levels, or coagulation parameters. Conclusion Exemestane modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss. Except for a 6% to 9% drop in plasma high-density lipoprotein cholesterol, no major effects on serum lipids, coagulation factors, or homocysteine were recorded. Bone mineral density should be assessed according to the US Preventive Services Task Force guidelines.

Familial breast-ovarian cancer has been demonstrated to be frequent but unevenly distributed in Norway. This was assumed to be caused by the reduced population size created by the medieval Bubonic plagues 25 generations ago, and by the following rapid expansion. We have previously reported that four mutations account for 68% of the BRCA1 mutation carriers. Subsequent analysis has resulted in a total of 100 separate families carrying one of these founder mutations. The four mutations occurred on one specific BRCA1 haplotype each. The 1675delA, 816delGT and 3347delAG families originated from the South-West coast of Norway with a few families in the north, while the traceable ancestors of the 1135insA families clustered along the historical inland road from the South-East to mid-Norway. The carriers of each of the four mutations today are descendants of one or a few individuals surviving the plagues. We may identify the majority of BRCA1 mutation carriers in Norway by screening for local founder mutations.

Objectives: To explore how women with negative mammography screening results, but who were later diagnosed with interval breast cancer, reacted when they observed breast symptoms that could indicate malignancy in-between screening rounds. Design: Semistructured individual interviews with women who have been diagnosed with breast cancer during mammography screening intervals. Setting: Two breast diagnostic units covering two counties in Norway. Participants: 26 women diagnosed with interval breast cancer. Results: Women with a screening negative result react in two ways when experiencing a possible symptom of breast cancer. Among 24 women with a self-detected palpable lesion, 14 sought medical advice immediately. Their argument was to dispose of potential cancer as soon as possible. Ten women delayed seeking medical advice, explaining their delay as a result of practical difficulties such as holidays, uncertainty about the symptom, and previous experiences of healthcare services’ ability to handle diffuse symptoms. Also, a recent negative mammography scan led some women to assume that the palpable lesion was benign and wait for the next screening round. Conclusions: Participating in mammography screening may contribute to a postponed reaction to breast cancer symptoms, although most women acted rapidly when detecting a palpable breast lesion. Furthermore, screening participation does not necessarily increase awareness of breast cancer symptoms. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

554 Background: To evaluate potential detrimental effects of the aromatase inactivator exemestane on bone, 147 postmenopausal women with early breast cancer were randomised to receive either exemestane for 2 years or placebo (J. Clin. Oncol. 23 [22], 5126–5137, 2005). Exemestane increased the annual bone loss from the femoral neck (2.72%) compared to placebo (1.48%; P = 0.024) with a non-significant increase in the lumbar spine (exemestane 2.17% versus placebo 1.84%). The annual bone loss was higher than expected in the placebo arm. Methods: Various biomarkers involved in bone metabolism (25-hydroxyvitamin D, parathormone, calcium, estrogens, androgens) were analysed to elucidate their influence on bone status at baseline and BMD loss during treatment with exemestane compared to placebo. Results: Using a cut-off value of 30 ng/ml for 25-hydroxyvitamin D (J. Clin. Endocrinol. Metab. 90 [6], 3800–3801, 2005), the majority of study participants suffered from vitamin D deficiency (56 of 62 patients in the placebo group and 52 of 59 in the exemestane group). The mean levels (95% confidence interval) of vitamin D were 22.6 ng/ml (21.2 - 24.1) in the placebo group and 21.6 ng/ml (20.0 - 23.3) in the treatment group, revealing no differences between these groups. Low serum calcium levels at baseline were found to be significantly correlated to low BMD in the femoral neck in the exemestane group. However, individual levels of vitamin D, parathormone and estradiol at baseline were not correlated significantly to BMD. Conclusions: Considering an annual bone loss of 0.5% to be representative for postmenopausal women (Osteoporos. Int. 15, 881–886, 2004), our data indicate that vitamin D deficiency could be the most important factor elevating bone loss among patients treated with exemestane as well as in the placebo group. These findings, together with the observation of a moderate additional effect of exemestane on bone loss, underlines the need for proper vitamin D substitution of postmenopausal women in general and in breast cancer patients during treatment with aromatase inhibitors in particular. [Table: see text]

531 Background: Aromatase inhibitors may increase bone loss. We reported (Proc Am Soc Clin Oncol 2004; 23:6, Abs 518) that a 2-year treatment with E (Aromasin), a steroidal aromatase inactivator, h...

Women from breast cancer families without a demonstrable BRCA1/2 mutation were subjected to annual mammography from age 30 years onwards. One-hundred and ninety-eight patients were diagnosed prospectively with invasive breast cancer and followed for a total of 1513 years. Overall 10-year survival was 88 %. Together with our previous report that women in such kindreds had about twice the population risk of breast cancer, the combined conclusion was that the overall chances of developing breast cancer causing death within 10 years before 50 years of age was 1 % or less when subjected to annual mammography and current treatment. These are empirical prospective observations which may be used for genetic counselling. The majority (160/194 = 84 %) of patients had ER+ and/or low grade tumours with 92 % 10-year survival. One minor group of the patients had ER- tumours, another small group had high grade tumours with nodal spread, both groups were associated with worse prognosis, but the two groups were not mutually associated.

We report prospectively observed risk for breast cancer in breast cancer kindreds without a demonstrable BRCA1/2 mutation. According to family history, the optimal available member(s) of each breast cancer kindred attending our clinic was tested for BRCA mutations. Women in families without a demonstrable BRCA mutation were subjected to annual mammography. BRCA mutations were demonstrated in 496/2,118 (23 %) breast cancer kindreds. In families without a demonstrable BRCA mutation, a total of 3,161 healthy women aged 25–59 years were prospectively followed for 24,808 observation years. Sixty-four cancers were observed, compared to 34.0 expected (p 0.05). Excluding these, cumulative risk at 60 years was 8.8 % (RR = 2.2). The highest cumulative risk at 60 years was 11.4 %, found in families with two cases ≤55 years (RR = 2.8). In breast cancer kindreds without a demonstrable BRCA mutation, the risk for breast cancer in female first degree relatives was about twice the risk in the general population. Women with one early affected relative only did not have increased risk for early onset breast cancer, while those with more than one young affected relative had close to three times population risk.

Background The addition of annual MRI screening to mammography has heightened optimism that intensive screening along with improved treatments may substantially improve life expectancy of women at high risk of breast cancer. However, survival data from BRCA2 mutation carriers undergoing intensive combined breast screening are scarce. Methods We have collated the results of screening with either annual mammography or mammography with MRI in female BRCA2 mutation carriers in Manchester and Oslo and use a Manchester control group of BRCA2 mutation carriers who had their first breast cancer diagnosed without intensive screening. Results Eighty-seven BRCA2 mutation carriers had undergone combined (n = 34) or mammography (n = 53) screening compared to 274 without such intensive screening. Ten year breast cancer specific survival was 100 % in the combined group (95 % CI 82.5–100 %) and 85.5 % (95 % CI 72.6–98.4 %) in the mammography group compared to 74.6 % (95 % CI 66.6–82.6 %) in the control group. Better survival was driven by lymph node status (negative in 67 % of screened vs 39 % of unscreened women; p