Background: Biomarkers are needed to refine short-term breast cancer risk estimates from epidemiologic models and to measure response to prevention interventions. The purpose of our study was to ...determine whether the cytologic appearance of epithelial cells obtained from breast random periareolar fine-needle aspirates or molecular marker expression in these cells was associated with later breast cancer development. Methods: Four hundred eighty women who were eligible on the basis of a family history of breast cancer, prior precancerous biopsy, and/or prior invasive cancer were enrolled in a single-institution, prospective trial. Their risk of breast cancer according to the Gail model was calculated, and random periareolar fine-needle aspiration was performed at study entry. Cells were characterized morphologically and analyzed for DNA aneuploidy by image analysis and for the expression of epidermal growth factor receptor, estrogen receptor, p53 protein, and HER2/NEU protein by immunocytochemistry. All statistical tests are two-sided. Results: At a median follow-up time of 45 months after initial aspiration, 20 women have developed breast cancer (invasive disease in 13 and ductal carcinoma in situ in seven). With the use of multiple logistic regression and Cox proportional hazards analysis, subsequent cancer was predicted by evidence of hyperplasia with atypia in the initial fine-needle aspirate and a 10-year Gail projected probability of developing breast cancer. Although expression of epidermal growth factor receptor, estrogen receptor, p53, and HER2/NEU was statistically significantly associated with hyperplasia with atypia, it did not predict the development of breast cancer in multivariable analysis. Conclusion: Cytomorphology from breast random periareolar fine-needle aspirates can be used with the Gail risk model to identify a cohort of women at very high short-term risk for developing breast cancer. We recommend that cytomorphology be studied for use as a potential surrogate end point in prevention trials.
Breast tissue and duct fluid provide a rich source of biomarkers to both aid in the assessment of short-term risk of developing breast cancer and predict and assess responses to prevention ...interventions. There are three methods currently being utilized to sample breast tissue in asymptomatic women for risk assessment: nipple-aspirate fluid (NAF), random periareolar fine-needle aspiration (RPFNA) and ductal lavage. Prospective single-institution trials have shown that the presence of atypical cells in NAF fluid or RPFNA specimens is associated with an increased risk of breast cancer. Furthermore, RPFNA-detected atypia has been observed to further stratify risk based on the commonly used Gail risk-assessment model. A prospective trial evaluating risk prediction on the basis of atypical cells in ductal-lavage fluid is ongoing. The ability of other established non-genetic biomarkers (mammographic breast density; serum levels of bioavailable estradiol, testosterone, insulin-like growth factor-1 and its insulin like growth factor binding protein-3) to stratify risk based on the Gail model is as yet incompletely defined. Modulation of breast intra-epithelial neoplasia (i.e. hyperplasia with or without atypia) with or without associated breast-tissue molecular markers, such as proliferation, is currently being used to evaluate response in Phase II chemoprevention trials. RPFNA has been the method most frequently used for Phase II studies of 6–12 months duration. However, ductal lavage, RPFNA and random and directed core needle biopsies are all being utilized in ongoing multi-institutional Phase II studies. The strengths and weaknesses of each method are reviewed.
Aims : Immunohistochemistry (IHC) and fluorescence in‐situ hybridization (FISH) are both commonly used assays for evaluation of HER‐2/neu status in breast cancer. However, there is still no consensus ...on which method is most predictive of patient response to HerceptinTM. Recently, the automated cellular imaging system (ACIS)TM has been shown to improve the accuracy and reproducibility in scoring IHC. Our aim was to compare the results of HER‐2/neu expression and gene amplification in the same patients by IHC using the ACISTM system and by FISH.
Methods and results : Two hundred and forty‐seven breast cancer cases were studied. The concordance rate between IHC‐ACIS (≥ 2.2) and FISH (≥ 2.0) was 94%. Fifteen patients were discordant; three had borderline FISH values and three had borderline IHC values. The other nine discordant cases consisted of five IHC‐ACIS+, FISH– and six IHC‐ACIS–, FISH+. HER‐2/neu overexpression was more common in tumours that were high‐grade, aneuploid, progesterone receptor and bcl‐2 negative, with MIB‐1 > 10%.
Conclusion : HER‐2/neu assessment by the ACIS is reliable, rapid and inexpensive, and correlates highly with results obtained by FISH.
Irradiation of the mammalian foetus produces a broad spectrum of congenital abnormalities, growth retardations, developmental delays, and functional deficits, depending upon the dose and the specific ...gestational phase of irradiation. The developing brain is particularly susceptible to production of deleterious effects, with decreased brain size, behavioural alterations, and mental retardation having been documented. Supplementing the limited human data, rodent models have been extensively used to investigate the specific processes by which relatively low doses, with correspondingly minor cellular damage to the developing neocortex, can produce dramatic postnatal consequences in brain structure and function. The effects of a variety of physical (dose, linear energy transfer, dose rate, fractionation) and biological (species, strain, gestational age, time course post-irradiation) parameters have been examined in an attempt to provide much needed information on such critical aspects as dose response, threshold doses for effect, and extrapolation to human risk estimates. Various acute cellular responses (e.g. appearance of pyknotic cells and macrophages) observed in the developing neocortex 0-24 h after in utero irradiation can be associated with postnatal effects. Moreover, it is possible to correlate thinning of specific layers of the cerebral cortex with specific behavioural aberrations, allowing prediction of brain structural changes from functional alterations, and vice versa. Thus, it is possible to speculate as to the mechanisms and targets for extremely sensitive, radiation-induced cellular damage in the developing foetal brain, that will interfere with the orderly and precisely programmed development of the mammalian brain, leading finally to postnatal expression as delays in growth and development, perturbations in behaviour, and alterations in brain structure.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Women at increased risk for breast cancer are often also at increased risk for ovarian cancer, reflecting common risk factors and intertwined etiologies for both diseases. Unlike breast cancer ...prevention, primary ovarian cancer prevention has been impractical due to the low incidence, lack of risk and response biomarkers and difficulties in sampling ovarian tissue. Challenges in the development of ovarian cancer prevention drugs, however, may be circumvented through the development of breast cancer prevention strategies that simultaneously decrease ovarian cancer. In the present study, three commonly used mammary cancer carcinogen models 7,12-dimethylbenzαanthracene (DMBA), N-methyl-N-nitrosourea (MNU) and estradiol (E2) were combined with local ovarian DMBA administration to induce progression to mammary and ovarian cancer concurrently in the rat. Animals were treated for 3 or 6 months, and tissue histology as well as proliferation, hormonal and inflammation biomarkers were assessed. Mammary and ovarian morphologies (measured as descriptive histology and dysplasia scores) were normal in vehicle controls. Mammary hyperplasia was observed in DMBA/DMBA (mammary carcinogen/ovarian carcinogen) and MNU/DMBA-treated rats; however, ovarian preneoplastic changes were seldom observed after these treatments. All E2/DMBA-treated rats had mammary hyperplasia, atypia, ductal carcinoma in situ and/or invasive adenocarcinoma, while 50% also developed preneoplastic changes in the ovary (ovarian epithelial and stromal hyperplasia and inclusion cyst formation). In both the mammary gland and ovary, decreased estrogen receptor alpha expression was detected, and in the mammary gland elevated Ki-67 and cyclooxygenase-2 expressions were observed. This combined breast and ovarian cancer rat model (systemic E2 treatment and local ovarian DMBA) may be useful for future dual target breast and ovarian cancer prevention studies.
Abstract
Background: High dose marine omega-3 fatty acid supplementation is currently undergoing assessment in early phase primary prevention trials. A potential mechanism of action is thought to be ...inflammation resolution. Since post-menopausal women may have higher systemic levels of pro-inflammatory cytokines, and hormones may affect response to fatty acids, we conducted two parallel pilot trials of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as Lovaza® supplementation in women at high risk for development of breast cancer. This post-hoc analysis examines whether five cytokines involved in inflammatory processes (HGF, MCP-1, NGF, PAI-1, TNF-alpha) are impacted by menopausal status.
Methods: Separate trials were conducted in pre-menopausal (N=36) or post-menopausal (N=35) women. Blood (fasting) and benign breast tissue (non-fasting, sampled by random periareolar fine needle aspiration) was acquired before and after intervention with 4 g Lovaza® daily for 6 months. In addition to standard risk and response biomarkers, panels of cytokines associated with inflammatory processes were assayed by Luminex® technology: HGF, insulin, MCP-1, NGF, PAI-1, resistin, TNF-alpha. For breast tissue, values were normalized to protein content.
Results: Thirty-four women in each trial completed the intervention and provided pre-study and post-study specimens. At baseline, higher values for post-menopausal compared to pre-menopausal women were observed for serum levels of MCP-1 (p=0.002, non-parametric Mann-Whitney test), PAI-1 (p=0.001), and TNF-alpha (p=0.019). The same was observed for off-study specimens. There was no statistically significant (non-parametric Wilcoxon signed rank test) effect of the intervention in either cohort for MCP-1 or PAI-1. However, for TNF-alpha, while there was no modulation observed in pre-menopausal women, there was a modest decrease (medians of 3.7 to 3.4 pg/ml; p=0.016) for post-menopausal women. An effect on TNF-alpha would not have been detected if the two cohorts had been combined.
For breast tissue, higher values for post-menopausal women at baseline were observed for HGF (p=0.029), MCP-1 (p=0.013), NGF (p=0.001), and TNF-alpha (p=0.001), but not PAI-1 (p=0.79). Off-study values were also typically higher in post-menopausal women. As with serum levels, there was a significant decrease in TNF-alpha values over the course of the study (p=0.042) in post-menopausal women but not pre-menopausal women. A decrease was also observed for HGF (p=0.002) and MCP-1 (p=0.001) for post-menopausal women but not pre-menopausal women.
Conclusion: This post-analysis suggests caution when admixing pre-menopausal and post-menopausal women in small clinical trials of omega-3 fatty acid supplementation, especially when assessing biomarkers of inflammatory processes. For trials with both, sufficient subjects should be enrolled that stratification prior to randomization is possible.
Citation Format: Kimler BF, Fabian CJ. Differential response of inflammatory cytokines to omega-3 fatty acid supplementation based on menopausal status. abstract. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-10-02.
Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs primarily in women of reproductive age. The disease is characterized by exaggerated T-cell activity and abnormal T-cell ...signalling. The mitogen-activated protein kinase (MAPK) pathway is involved in the maintenance of T-cell tolerance that fails in patients with SLE. Oestrogen is a female sex hormone that binds to nuclear receptors and alters the rate of gene transcription. Oestrogen can also act through the plasma membrane and rapidly stimulate second messengers including calcium flux and kinase activation. In this study, we investigated whether oestrogen influences the activation of MAPK signalling through the phosphorylation of extracellular signal–regulated kinase 1/2 (ERK1/2) in activated SLE T cells. SLE and control T cells were cultured in serum-free medium without and with oestradiol (10−7 M) for 18 h. The T cells were activated with phorbol 12 myristate 13-acetate and ionomycin for various time points (0–60 min), and the amount of phosphorylated ERK1/2 was measured by immunoblotting. There were no differences in ERK1/2 phosphorylation between SLE and control T cells at 5 and 15 min after the activation stimulus. However, comparison between the amount of phosphorylated ERK1/2 in SLE T cells from the same patients cultured without and with oestradiol showed a significant oestrogen-dependent suppression (P = 0.48) of ERK1/2 in patients with inactive/mild systemic lupus erythematosus disease activity index (SLEDAI) (0–2) compared with patients with moderate (4–6) or active (8–12) SLEDAI scores. These results suggest that the suppression of MAPK through ERK1/2 phosphorylation is sensitive to oestradiol in patients with inactive or mild disease, but the sensitivity is not maintained when disease activity increases. Furthermore, studies are now necessary to understand the mechanisms by which oestrogen influences MAPK activation in SLE T cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background: 15-20% of patients with triple negative breast cancer (TNBC) harbor deleterious germline (g) BRCA1/2 mutations. Recent data suggests that in metastatic TNBC (mTNBC) gBRCA1/2 ...mutations are associated with response to PARP inhibitors (PARPi) and platinum chemotherapy. However, diagnosis of mTNBC is associated with short overall survival (OS) with no available biomarkers that can identify mTNBC patients with better prognosis.
Aim: Utilizing data from a prospective registry, the objective of this study was to investigate whether presence of gBRCA1/2 mutation impacts overall survival for patients with mTNBC treated prior to clinical availability of PARPi.
Methods: 643 patients with stage I-IV TNBC were enrolled in an IRB approved multisite prospective registry between 2011 to 2018. Clinical, demographic, and treatment information was collected and patients were followed for recurrence and survival. 100/643 patients had metastatic breast cancer (de novo stage IV disease or metastatic recurrence). OS (from the time of diagnosis of metastatic disease to death from any cause) was estimated according to the Kaplan-Meier method and compared among groups by log-rank test.
Results: For the 100 mTNBC patients, the median age at diagnosis of metastatic disease was 55 years, 17% were African American, 20% had novo stage IV and 80% had relapsed disease. 84% had visceral disease, 12% had bone-only disease, and 4% had lymph node only disease. Metastatic treatment: 87% received chemotherapy, 7% received radiation only without chemotherapy and 6% did not receive any treatment. No patients received treatment with PARP inhibitor. Among de-novo stage IV patients, 35% (7/20) had breast surgery for removal of primary tumor during their course of metastatic treatment. For all 100 patients, 12% (n=12) had gBRCA mutation; 72% (n=72) had no gBRCA mutation; and 16% (n=16) had unknown BRCA mutation status. When compared with non-carriers, gBRCA carriers were younger at time of metastatic diagnosis (median age 49 vs. 57 years, p=0.02). There was no difference in prevalence of visceral disease, de-novo stage IV disease or median lines of metastatic chemotherapy among gBRCA carriers and non-carriers. At a median follow up of 31 months, median OS for all patients is 21 months (95% CI 13-23 months). Median OS is 18 months (95% CI 15-27 months) for non-carriers and has not yet been reached for gBRCA mutation carriers (p=0.023). 3-year estimated OS is 63% in gBRCA carriers compared to 28% in non-carriers (p=0.02). On multivariate Cox regression analysis, gBRCA carrier status was associated with reduced risk of death (HR=0.33; 95%CI 0.23-0.91, p=0.033)
Conclusions: gBRCA mutation associated mTNBC patients have a clinically significant improved OS at 3 years compared to mTNBC patients without BRCA mutations (3-year OS of 63% vs 28%). Further research is needed to understand tumor and host biological reasons for this observation. Outcomes of gBRCA mutation associated mTNBC are likely to be further improved with availability of PARPi. Given that patients with gBRCA mutation are at risk for second breast/ovarian cancers, these findings also underscore need for further research regarding the role of prophylactic surgeries mTNBC with gBRCA mutation.
Citation Format: Larson K, Wang YY, Finke K, O'Dea AP, Khan Q, Nye L, Heldstab J, Godwin AK, Kimler BF, Sharma P. Impact of germline BRCA mutation status on survival in women with metastatic triple negative breast cancer abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-16.
Abstract
Neo-adjuvant endocrine therapy (NAET) provides opportunity for on-treatment assessment of endocrine responsiveness and need for adjuvant chemotherapy (C) in ER+/HER2 negative breast cancer ...(BC). We investigated Ki67-IHC response to NAET, the 21-gene Recurrence Score (RS; Oncotype DX), and Postoperative Endocrine Prognostic Index (PEPI) as predictors of response and recurrence in a neoadjuvant trial of fulvestrant (F) + anastrozole (A). The combination had been shown to improve survival compared to A alone in ER+ metastatic breast cancer.
Design: Single arm phase II trial of postmenopausal women with clinical stage II/III ER+/HER2 negative BC and RS <25. Following initial biopsy (CNB) women received NAET for 4 months: A 1mg (PO) daily continuously from day 1 until surgery + F 500mg IM on day 1, 14 and 28 of cycle 1, and on the last day of 3 subsequent 28 day cycles (total 6 doses of F) followed by surgery. Ki67-IHC and RS (weighted heavily by gene expression of ESR1, HER-2, Ki67, and PR) were assessed at baseline and at surgical resection (3-4 weeks after last F). Chemotherapy was allowed at physician discretion and recommended for PEPI>0. All patients received adjuvant A.
Results: 51 patients were screened and RS was performed on initial CNB with a success rate of 96%. 7 were not eligible due to RS>25. 42 patients were enrolled. 18 (49%) had PEPI score of 0 at surgery. Median RS was 12 at baseline and 17 at surgery for the 36 patients with evaluable tissue at both time points. 28/36 (78%) patients had numeric increase in RS at surgery and 5/36 had RS > 25 at surgery. Increase in RS is likely driven by decrease in ESR1 gene expression (p=0.063). Median RS at surgery but not at baseline was associated with PEPI score of 0 (p=0.02). Ki67 gene expression at surgery was lower in patients with PEPI 0 (p=.003) whereas ESR1 expression was higher (p=.024). Median Ki67-IHC was 5% (mean 7.6%) at baseline and 1% (mean 2.8%) at surgery for the 37 patients with evaluable tissue at both time points. 35 of these 37 (94%) had decrease in Ki67-IHC from baseline to surgery; only 2/37 had an increase in Ki67-IHC at surgery. 22% of women received adjuvant chemotherapy. At median follow up of 61 months, only 3/42 patients have had a recurrence: the two patients with an increase in Ki67-IHC from baseline to surgery had a recurrence; plus a third who was taken off trial during therapy due to clinical progression and received C prior to surgery.
Conclusions: 4 months of neo-adjuvant anastrozole + fulvestrant results in decrease in Ki67-IHC in 94% of women with stage II/III ER+ HER2 negative breast cancer. No patients with decrease in Ki67-IHC at surgery have had a breast cancer recurrence. The majority of patients treated with this regimen do not need chemotherapy. A small number of patients with on-therapy increase in Ki67-IHC are at high risk of recurrence. Oncotype DX RS and expression of some of the component genes (ESR1 and Ki67) change with NAET. Expression of ESR1 and Ki67 genes at surgery after NAET is associated with PEPI score of 0 and should be explored as potential response biomarkers in NAET trials.
Citation Format: Khan QJ, Fabian CJ, Kimler BF, O'Dea AP, Mamen J, Amin A, Wagner J, Springer M, Baccaray S, Sharma P. Change in oncotype DX variables and Ki67 response and outcome in women with ER positive early breast cancer treated with neo-adjuvant anastrozole and fulvestrant abstract. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-13-04.
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