Simultaneous cutaneous melanoma and ipsilateral breast cancer with metastasis to the same axilla. A case report with a focus on a multidisciplinary approach.

INTRODUCTION AND IMPORTANCE: Treatment of simultaneously occurring primary malignancies with separate lymphatic drainage is a surgical and medical challenge. We present a patient in which multidisciplinary management of coexisting melanoma and breast cancer was mandatory for optimal results. CASE PRESENTATION: A 67-year-old female had a primary surgical resection for a skin lesion on the back. Histology revealed melanoma with a Breslow thickness of 4.8 mm. According to guidelines, a wide local excision was scheduled. Prior to the surgery, routine mammography revealed simultaneous ipsilateral breast cancer. A preoperative work-up revealed a pathological lymph node in the left axilla. Biopsies found metastasis from malignant melanoma. She had combined surgery with breast-conserving therapy, wide local excision of the skin on the back, and extended axillary clearance of levels I-III. Final histology revealed axillary metastases both from melanoma and breast cancer. Adjuvant therapy was decided based on a multidisciplinary approach. CLINICAL DISCUSSION: To our knowledge, cases of synchronous primary cutaneous melanoma with biopsy-verified axillary metastases and independent, ipsilateral primary breast carcinoma have not been described. The surgical approach was done according to guidelines. The breast cancer was re-staged based on the histology of the surgical specimen. Adjuvant treatment was a combination of treatment strategies for the two primary malignancies. CONCLUSION: This case highlights the need for a multidisciplinary approach in treating simultaneous breast cancer and melanoma both with axillary metastasis. The optimal treatment approach was based on close collaboration between surgeons, oncologists, radiologists, and pathologists. Multidisciplinary meetings are mandatory for optimal results.

Extensive clinical testing of Deep Learning Segmentation models for thorax and breast cancer radiotherapy planning.

BACKGROUND: The performance of deep learning segmentation (DLS) models for automatic organ extraction from CT images in the thorax and breast regions was investigated. Furthermore, the readiness and feasibility of integrating DLS into clinical practice were addressed by measuring the potential time savings and dosimetric impact. MATERIAL AND METHODS: Thirty patients referred to radiotherapy for breast cancer were prospectively included. A total of 23 clinically relevant left- and right-sided organs were contoured manually on CT images according to ESTRO guidelines. Next, auto-segmentation was executed, and the geometric agreement between the auto-segmented and manually contoured organs was qualitatively assessed applying a scale in the range [0-not acceptable, 3-no corrections]. A quantitative validation was carried out by calculating Dice coefficients (DSC) and the 95% percentile of Hausdorff distances (HD95). The dosimetric impact of optimizing the treatment plans on the uncorrected DLS contours, was investigated from a dose coverage analysis using DVH values of the manually delineated contours as references. RESULTS: The qualitative analysis showed that 93% of the DLS generated OAR contours did not need corrections, except for the heart where 67% of the contours needed corrections. The majority of DLS generated CTVs needed corrections, whereas a minority were deemed not acceptable. Still, using the DLS-model for CTV and heart delineation is on average 14 minutes faster. An average DSC=0.91 and H95=9.8 mm were found for the left and right breasts, respectively. Likewise, and average DSC in the range [0.66, 0.76]mm and HD95 in the range [7.04, 12.05]mm were found for the lymph nodes. CONCLUSION: The validation showed that the DLS generated OAR contours can be used clinically. Corrections were required to most of the DLS generated CTVs, and therefore warrants more attention before possibly implementing the DLS models clinically.

Surface-guided positioning eliminates the need for skin markers in radiotherapy of right sided breast cancer: A single center randomized crossover trial.

BACKGROUND AND PURPOSE: To prospectively investigate whether surface guided setup of right sided breast cancer patients can increase efficiency and accuracy compared to traditional skin marker/tattoo based setup. MATERIAL AND METHODS: Twenty-five patients were included in this study. Each patient was positioned using skin marks and tattoos (procedure A) for half of the fractions and surface guidance using AlignRT (procedure B) for the other half of the fractions. The order of the two procedures was randomized. Pretreatment CBCT was acquired at every fraction for both setup procedures. A total of ten time points were recorded during every treatment session. Applied couch shifts after CBCT match were recorded and used for potential error calculations if no CBCT had been used. RESULTS: In the vertical direction procedure B showed significant smaller population based systematic (Æ©) and random (σ) errors. However, a significant larger systematic error on the individual patient level (M) was also shown. This was found to be due to patient relaxation between setup and CBCT matching. Procedure B also showed a significant smaller random error in the lateral direction, while no significant differences were seen in the longitudinal direction. No significant difference in setup time was found between the two procedures. CONCLUSION: Setup of right sided breast cancer patients using surface guidance yields higher accuracy than setup using skin marks/tattoos and lasers with the same setup time. Patient alignment for this patient group can safely be done without the use of permanent tattoos and skin marks when utilizing surface-guided patient positioning. However, CBCT should still be used as final setup verification.

Normal and unusual days for dietary intake during the 12 months after a breast cancer diagnosis in women.

PURPOSE: There are several reasons to report days as being unusual with regard to dietary intake, including special occasions and celebrations. For breast cancer patients during the 12 month post-surgery period, unusual days may also include days that are affected by being a cancer patient. The aim of this study was to study dietary intake on "normal" and "unusual" days, and to study what is reported in "free text fields" of a food diary. METHODS: Women (n = 456), mean age 55.5 years newly diagnosed with invasive breast cancer (stage I/II) were included in this clinical study. "Normal" and "unusual" days in general, over time and during the week and weekends were studied using repeated administration of a 7-day pre-coded food diary. RESULTS: The breast cancer patients reported 26% of all days as unusual. The intake of energy, most nutrients, especially alcohol and sugar, red and processed meat, and sweets, cakes, and snacks was 5-126% higher, whereas intake of fiber, fruit and berries, vegetables, and dairy products was 7-17% lower on unusual than on normal days (P < 0.001). The same pattern was seen for normal/unusual days during the weekdays, weekends and over time. Finally, 99% of the breast cancer patients used the free text fields to report additional intake with a mean energy of 1.1 MJ/day. CONCLUSION: For breast cancer patients during the 12-month post-surgery period, unusual days are important drivers of total intake, especially for alcohol. The free text fields in the pre-coded food diary contributed substantially to the total intake.

Do Breast Cancer Patients Manage to Participate in an Outdoor, Tailored, Physical Activity Program during Adjuvant Breast Cancer Treatment, Independent of Health and Socio-Demographic Characteristics?

Exercise could reduce the side-effects of adjuvant breast cancer treatment; however, socio-demographic, health, and intervention conditions may affect patients' adherence to interventions. This study aimed to examine adherence to a 12-month outdoor post-surgery exercise program among newly diagnosed breast cancer patients during adjuvant treatment, and to identify socio-demographic and health-related predictors. In total, 47 women with invasive breast cancer stage I-II or ductal/lobular carcinoma grade 3 were included pre-surgery and randomized two weeks post-surgery to exercise (2 × 60 min/week). Patient characteristics (body-mass index (BMI), socioeconomic status, comorbidity, physical activity, and maximal oxygen uptake (VO2max)) were recorded pre-surgery. Correlations between adherence and patient characteristics and statistics for between-group differences were performed. The mean age was 54.2 years, mean BMI 27.8 kg/m2, and 54.2% received chemotherapy. Completers had a mean adherence of 81%, independent of season. Withdrawals (23%) occurred after a mean of 6.5 weeks (0-24 weeks), they were suggestively older, had lower socioeconomic status and pre-surgery VO2max, and higher BMI. Household income was significantly lower among withdrawals. There were insignificant correlations between adherence and health conditions. High adherence is achievable in a Nordic outdoor physical exercise program in breast cancer patients during adjuvant treatment, including chemotherapy. Additional studies are needed to clarify follow-up needs in some groups.

Effects of a 1-Year Physical Activity Intervention on Markers of Hemostasis among Breast Cancer Survivors: A Randomized Controlled Trial.

Introduction Physical activity may reduce the development of breast cancer. Whereas hypercoagulability has been linked to adverse outcomes in breast cancer patients, the effects of physical activity on their hemostatic factors are unknown. The study aimed to assess whether long-term (1 year) physical activity can affect hemostatic factors in breast cancer patients. Methods Fifty-five women (35-75 years) with invasive breast cancer stage I/II were randomized to a physical activity intervention ( n = 29) lasting 1 year or to a control group ( n = 26), and analyzed as intention to treat. Fibrinogen, factor VII antigen, tissue factor pathway inhibitor, and von Willebrand factor (VWF) antigen as well as prothrombin fragment 1 + 2, the endogenous thrombin potential and D-dimer, were measured in plasma before intervention (baseline), and then after 6 and 12 months. Results Maximal oxygen uptake (measure of cardiorespiratory fitness) decreased the first 6 months among the controls, but remained stable in the intervention group. We found no significant differences between the two study groups regarding any of the hemostatic factors, except a significantly higher increase in factor VII antigen in the intervention group. The effect of the intervention on VWF was, however, significantly affected by menopausal stage, and a significant effect of the intervention was found on VWF among postmenopausal women, even after adjustment for dietary intake. Conclusion Long-term physical activity had no effect on the majority of the hemostatic factors measured, but led to increased plasma concentrations of factor VII antigen and prevented an increase in VWF concentration after breast cancer treatment in postmenopausal women. The clinical impact of these findings for risk of vascular thrombosis warrants further studies.

Dietary changes in early-stage breast cancer patients from pre-surgery and over the 12 months post-surgery.

The time after a breast cancer diagnosis is a potential period for making positive dietary changes, but previous results are conflicting. The main aim of the present study was to study breast cancer patients' dietary changes during the 12 months post-surgery and from 12 months pre-surgery to 12 months post-surgery with repeated administration of a 7-d pre-coded food diary and an FFQ, respectively. Women (n 506), mean age 55·3 years diagnosed with invasive breast cancer (stages I and II), were included. The dietary intake was quite stable over time, but the intake was lower for energy (0·3 and 0·4 MJ/d), alcohol (1·9 and 1·5 g/d) and vegetables (17 and 22 g/d) at 6 months than 3 weeks post-surgery (food diary) and at 12 months post-surgery than pre-surgery (FFQ), respectively. Furthermore, energy percentage (E%) from carbohydrates increased between 0·8 and 1·2 E% and E% from fat decreased between 0·6 and 0·8 E% over time, measured by both dietary assessment methods. We observed a higher intake of dairy products (11 g/d) at 6 months post-surgery (food diary), and a lower intake of dairy products (34 g/d) and red and processed meat (7·2 g/d) at 12 months post-surgery (FFQ). Moreover, 24 % of the patients claimed they made dietary changes, but mostly they did not change their diet differently compared with those patients who claimed no changes. In conclusion, breast cancer patients reported only minor dietary changes from 12 months pre-surgery and during the 12 months post-surgery.

Exploring the effects of lifestyle on breast cancer risk, age at diagnosis, and survival: the EBBA-Life study.

PURPOSE: Whether an unfavorable lifestyle not only affects breast cancer risk, but also influences age at onset of breast cancer and survival, is under debate. METHODS: In a population-based cohort, the Energy Balance and Breast Cancer Aspects throughout life (EBBA-Life) study, a total of 17,145 women were included. During follow-up, 574 women developed invasive breast cancer. Breast cancer cases were followed for an additional 9.1 years. Detailed medical records were obtained. Cox's proportional hazard regression models were used to study the association between pre-diagnostic lifestyle factors (weight, physical activity, alcohol use, smoking, and hypertension), breast cancer risk, age at diagnosis, and survival. RESULTS: At study entry, 34.3% of the participating women were overweight and 30.7% were physically inactive. Mean age at breast cancer diagnosis was 58.0 years, and 78.9% of the tumors were estrogen receptor positive. Among menopausal women who did not use hormone therapy and had an unfavorable lifestyle (3-5 unfavorable factors), compared with women who had a favorable lifestyle, we observed a twofold higher risk for postmenopausal breast cancer (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.23-3.69), and they were 3.4 years younger at diagnosis (64.8 versus 68.2 years, P = 0.032). Breast cancer patients with an unfavorable lifestyle, compared with patients with a favorable lifestyle, had almost a two times higher overall mortality risk (HR 1.96, 95% CI 1.01-3.80). CONCLUSIONS: Our study supports a healthy lifestyle improving breast cancer prevention, postponing onset of disease, and extending life expectancy among breast cancer patients.

Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment.

BACKGROUND: Breast cancer treatment has metabolic side effects, potentially affecting risk of cardiovascular disease (CVD) and recurrence. We aimed to compare alterations in serum metabolites and lipoproteins during treatment between recipients and non-recipients of chemotherapy, and describe metabolite profiles associated with treatment-related weight gain. METHODS: This pilot study includes 60 stage I/II breast cancer patients who underwent surgery and were treated according to national guidelines. Serum sampled pre-surgery and after 6 and 12 months was analysed by MR spectroscopy and mass spectrometry. In all, 170 metabolites and 105 lipoprotein subfractions were quantified. RESULTS: The metabolite and lipoprotein profiles of chemotherapy recipients and non-recipients changed significantly 6 months after surgery (p < 0.001). Kynurenine, the lipid signal at 1.55-1.60 ppm, ADMA, 2 phosphatidylcholines (PC aa C38:3, PC ae C42:1), alpha-aminoadipic acid, hexoses and sphingolipids were increased in chemotherapy recipients after 6 months. VLDL and small dense LDL increased after 6 months, while HDL decreased, with triglyceride enrichment in HDL and LDL. At baseline, weight gainers had less acylcarnitines, phosphatidylcholines, lyso-phosphatidylcholines and sphingolipids, and showed an inflammatory lipid profile. CONCLUSION: Chemotherapy recipients exhibit metabolic changes associated with inflammation, altered immune response and increased risk of CVD. Altered lipid metabolism may predispose for treatment-related weight gain.

Validation of repeated self-reported n-3 PUFA intake using serum phospholipid fatty acids as a biomarker in breast cancer patients during treatment.

BACKGROUND: The role of n-3 polyunsaturated fatty acids (PUFAs) in breast cancer is not clear and under debate. To explore this relationship it is important to have proper validated dietary assessment methods for measuring the intake of n-3 PUFAs. The aim of the current study is to validate two different methods used to assess the intake of selected n-3 PUFAs as well as food sources of long-chained n-3 PUFAs. Also, we aim to study how stable the intake of fatty acids is during breast cancer treatment. METHODS: The study-population was patients with breast cancer (Stages I-II) or ductal carcinoma in situ (DCIS-grade III) undergoing treatment (n = 49) in Norway. Dietary intake was assessed by two self-administered methods, a 256 food item food frequency questionnaire (FFQ) and a 7-day pre-coded food diary (PFD). The FFQ was administered presurgery and twelve months postsurgery, and the PFD was administered shortly after surgery (10 +/- 2 days), six and twelve months postsurgery. Fasting blood samples (presurgery, six and twelve months postsurgery) were analysed for serum phospholipid fatty acids, a biomarker for intake of n-3 PUFAs. RESULTS: Mean (SD) age was 54.2 (7.8) years at diagnosis, and the mean (SD) body mass index (BMI) was 24.8 (3.4) kg/m2. Correlation coefficients between dietary intakes of n-3 PUFAs measured with the FFQ and the PFD ranged from 0.35 to 0.66. The correlation coefficients between the PFD and the biomarker (serum phospholipid n-3 PUFAs) as well as between the FFQ and the biomarker demonstrated stronger correlations twelve months after surgery (ρ 0.40-0.56 and 0.36-0.53, respectively) compared to around surgery (ρ 0.08-0.20 and 0.28-0.38, respectively). The same pattern was observed for intake of fatty fish. The intake of n-3 PUFAs did not change during treatment assessed by the FFQ, PFD or biomarker. CONCLUSION: These results indicate that the FFQ and the PFD can be used to assess dietary intake of fish and n-3 PUFAs in breast cancer patients during breast cancer treatment. Still, the PFD shortly after surgery should be used with caution. The diet of patients undergoing breast cancer treatment was quite stable, and the intake of n-3 PUFAs did not change.

Circulating microRNAs associated with prolonged overall survival in lung cancer patients treated with nivolumab.

BACKGROUND: The introduction of immune check-point inhibition in non-small cell lung cancer (NSCLC) therapy represents improved prospects for the patients. The response rates to check-point inhibitors are approximately 20% in unselected NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with higher response rates. However, patients with low PD-L1 levels may also have durable responses, and improved strategies for patient stratification are needed. MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming to identify circulating predictive biomarkers associated with increased overall survival after immune check-point treatment. Using next generation sequencing, we performed microRNA profiling in serum from NSCLC patients (n = 20) treated with nivolumab. Serum samples from 31 patients were used for validation using qPCR assays. Serum samples were collected prior to immune therapy initiation. RESULTS: Based on multivariate regression analysis, we identified a signature of seven microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p, miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) > 6 months in discovery cohort (p = .0003). We further validated this in another similar set of samples (n = 31) and the model was significantly associated with overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of 71% and 90%, respectively. CONCLUSIONS: In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.

Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer.

BACKGROUND: High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear. METHODS: Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35-75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics. RESULTS: The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m(2); total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5%. Most (93%) of the patients had estrogen receptor (ER) positive tumors (≥ 1% ER+), and 82% had progesterone receptor (PgR) positive tumors (≥ 10% PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (ß 0.46, CI 0.22-0.69, p < 0.001), HDL cholesterol (ß 0.95, CI 0.51-1.39, p < 0.001), HDL free cholesterol (ß 2.88, CI 1.28-4.48, p = 0.001), HDL phospholipids (ß 0.70, CI 0.36-1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (ß -0.25, p = 0.008), and in particular between HDL1's contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression. CONCLUSION: Our findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies.

Cyclic endogenous estrogen and progesterone vary by mammographic density phenotypes in premenopausal women.

Estrogen and progesterone are key factors in the development of breast cancer, but it remains unclear whether these hormones are associated with mammographic density phenotypes in premenopausal women. We measured percent mammographic density, nondense area, and absolute mammographic density using computer-assisted breast density readings (Madena) from digitized mammograms taken on a scheduled day of the menstrual cycle (day 7-12) among 202 healthy, premenopausal women (Energy Balance and Breast cancer Aspects Study-I). Daily salivary concentrations of 17ß-estradiol and progesterone throughout an entire menstrual cycle and fasting morning serum concentrations of hormones on 3 specific days of the menstrual cycle were assessed. Salivary and serum 17ß-estradiol and progesterone were positively associated with percent mammographic density, we observed by 1 SD increase in overall salivary estradiol (ß-value equal to 2.07, P=0.044), luteal salivary progesterone (ß-value equal to 2.40, P=0.020). Women with above-median percent mammographic density had a 20% higher mean salivary 17ß-estradiol level throughout the menstrual cycle. The odds ratio for having above-median percent mammographic density (>28.5%) per 1 SD increase in overall salivary 17ß-estradiol was 1.66 (95% confidence interval 1.13-2.45). Women in the top tertile of the overall average daily 17ß-estradiol concentrations had an odds ratio of 2.54 (confidence interval 1.05-6.16) of above-median percent mammographic density compared with women in the bottom tertile. Our finding of a relationship between estrogen, progesterone, and percent mammographic density and not with other mammographic density phenotypes in premenopausal women is biologically plausible, but needs to be replicated in larger studies.

Alcohol consumption, endogenous estrogen and mammographic density among premenopausal women.

INTRODUCTION: Alcohol consumption may promote aromatization of androgens to estrogens, which may partly explain the observations linking alcohol consumption to higher breast cancer risk. Whether alcohol consumption is associated with endogenous estrogen levels, and mammographic density phenotypes in premenopausal women remains unclear. METHODS: Alcohol consumption was collected by self-report and interview, using semi quantitative food frequency questionnaires, and a food diary during seven days of a menstrual cycle among 202 premenopausal women, participating in the Energy Balance and Breast Cancer Aspects (EBBA) study I. Estrogen was assessed in serum and daily in saliva across an entire menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken between days 7-12 of the menstrual cycle. Multivariable regression models were used to investigate the associations between alcohol consumption, endogenous estrogen and mammographic density phenotypes. RESULTS: Current alcohol consumption was positively associated with endogenous estrogen, and absolute mammographic density. We observed 18 % higher mean salivary 17ß-estradiol levels throughout the menstrual cycle, among women who consumed more than 10 g of alcohol per day compared to women who consumed less than 10 g of alcohol per day (p = 0.034). Long-term and past-year alcohol consumption was positively associated with mammographic density. We observed a positive association between alcohol consumption (past year) and absolute mammographic density; high alcohol consumers (≥7 drinks/week) had a mean absolute mammographic density of 46.17 cm(2) (95 % confidence interval (CI) 39.39, 52.95), while low alcohol consumers (<1 drink/week) had a mean absolute mammographic density of 31.26 cm(2) (95 % CI 25.89, 36.64) (p-trend 0.001). After adjustments, high consumers of alcohol (≥7 drinks/week), had 5.08 (95 % CI 1.82, 14.20) times higher odds of having absolute mammographic density above median (>32.4 cm(2)), compared to low (<1 drink/week) alcohol consumers. CONCLUSION: Alcohol consumption was positively associated with daily endogenous estrogen levels and mammographic density in premenopausal women. These associations could point to an important area of breast cancer prevention.

High-density lipoprotein-cholesterol, daily estradiol and progesterone, and mammographic density phenotypes in premenopausal women.

High-density lipoprotein-cholesterol (HDL-C) may influence the proliferation of breast tumor cells, but it is unclear whether low HDL-C levels, alone or in combination with cyclic estrogen and progesterone, are associated with mammographic density, a strong predictor of breast cancer development. Fasting morning serum concentrations of HDL-C were assessed in 202 premenopausal women, 25 to 35 years of age, participating in the Norwegian Energy Balance and Breast Cancer Aspects (EBBA) I study. Estrogen and progesterone were measured both in serum, and daily in saliva, throughout an entire menstrual cycle. Absolute and percent mammographic density was assessed by a computer-assisted method (Madena), from digitized mammograms (days 7-12). Multivariable models were used to study the associations between HDL-C, estrogen and progesterone, and mammographic density phenotypes. We observed a positive association between HDL-C and percent mammographic density after adjustments (P = 0.030). When combining HDL-C, estradiol, and progesterone, we observed among women with low HDL-C (<1.39 mmol/L), a linear association between salivary 17ß-estradiol, progesterone, and percent and absolute mammographic density. Furthermore, in women with low HDL-C, each one SD increase of salivary mid-menstrual 17ß-estradiol was associated with an OR of 4.12 (95% confidence intervals; CI, 1.30-13.0) of having above-median percent (28.5%), and an OR of 2.5 (95% CI, 1.13-5.50) of having above-median absolute mammographic density (32.4 cm(2)). On the basis of plausible biologic mechanisms linking HDL-C to breast cancer development, our findings suggest a role of HDL-C, alone or in combination with estrogen, in breast cancer development. However, our small hypothesis generating study requires confirmation in larger studies.

Gene variations in oestrogen pathways, CYP19A1, daily 17ß-estradiol and mammographic density phenotypes in premenopausal women.

INTRODUCTION: High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women. METHODS: Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17ß-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17ß-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models. RESULTS: The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17ß-estradiol. We observed an 87% lower level of daily 17ß-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m(2)) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm(2)); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)). CONCLUSION: Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.

Insulin-like growth factor-1, growth hormone, and daily cycling estrogen are associated with mammographic density in premenopausal women.

BACKGROUND: Mammographic density represents epithelial and stromal proliferation, while insulin-like growth factor (IGF)-1, insulin-like growth factor-binding protein-3, growth hormone (GH), and estrogen may influence cellular proliferation. However, whether these growth factors independently, or in combination with estrogen, influence mammographic density in premenopausal women remains unclear. MATERIALS AND METHODS: Growth factors were assessed in 202 ovulating premenopausal women participating in the Energy Balance and Breast Cancer Aspects-I study. Estrogen was assessed in serum, and daily in saliva, throughout a menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms (days 7-12 of the menstrual cycle). Associations between growth factors, estrogen, and mammographic density were studied in regression models. RESULTS: Women with a mean age of 30.7 years had a mean percent mammographic density of 29.8%. Among women in the strata (above median split) of IGF-1 (>25 nmol/l) or GH (>0.80 mlU/l), we observed that an increase in salivary 17ß-estradiol was associated with a higher odds for having higher percent mammographic density (>28.5%). The odds ratios (ORs) per standard deviation increase in 17ß-estradiol were 1.81 [95% confidence interval (CI) 1.08-3.03] in the high IGF-1 stratum and 2.08 (95% CI 1.10-3.94) in the high GH stratum. Furthermore, women in these strata of growth factors (above median) who had an overall average 17ß-estradiol above median (>16.8 pmol/l) had higher ORs for having higher percent mammographic density (>28.5%): IGF-1 4.13 (95 % CI 1.33-12.83) and GH 4.17 (95 % CI 1.41-12.28). CONCLUSION: Growth factors, in combination with cycling estrogen, were associated with percent mammographic density, and may be of potential clinical relevance.

Genetic polymorphism CYP17 rs2486758 and metabolic risk factors predict daily salivary 17ß-estradiol concentration in healthy premenopausal Norwegian women. The EBBA-I study.

CONTEXT: The relationship between low-penetrance genes, metabolic risk factors, and levels of endogenous 17ß-estradiol and progesterone, which play a role in breast cancer risk, remains unclear. OBJECTIVE: The aim of this study was to determine whether common polymorphisms in CYP17, in combination with metabolic risk factors (individually or clustered), alter salivary concentrations of free biologically active 17ß-estradiol and progesterone among healthy premenopausal Norwegian women. DESIGN: Eight single nucleotide polymorphisms in CYP17 were genotyped in 203 healthy premenopausal women aged 25-35 yr in the Norwegian EBBA-I Study, conducted in 2000-2002. Daily salivary concentrations of 17ß-estradiol and progesterone were measured throughout one menstrual cycle. A clustered metabolic score was calculated, including waist circumference, mean arterial pressure, insulin resistance, fasting triglycerides, and total cholesterol/high-density lipoprotein cholesterol ratio. The study hypothesis was tested in multivariable linear regression and generalized estimating equation models. RESULTS: Women in the upper tertile of clustered metabolic score with the CYP17 rs2486758 minor allele had daily salivary 17ß-estradiol concentrations that were 53% higher than other study women throughout the menstrual cycle (P < 0.001). Similarly, women in the upper tertile of total cholesterol/high-density lipoprotein cholesterol ratio, fasting triglycerides, and insulin resistance had 44, 32, and 24% higher daily salivary 17ß-estradiol concentrations, respectively (all P < 0.05). CONCLUSION: The CYP17 rs2486758 minor allele may predispose to higher 17ß-estradiol levels, particularly in premenopausal women with a high clustered metabolic score. Thus, modification of metabolic risk factors may have significant implications for the prevention of breast cancer in women with the minor allele of CYP17 rs2486758.